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FDA Contemplates Changes in Trial Design, Drug Development and Use of AI in Clinical Trials

Curator: Stephen J. Williams, Ph.D.

Several pharma companies just told the FDA what AI in clinical trials should look like.

It is not what most people expect.
I went back through the RTCT comment letters from Novartis, Lilly, Bayer, Daiichi and others. Read together, they are the clearest signal yet on how AI will get adopted in drug development over the next few years.
Three things they make clear.
Adoption starts at the data layer, not the decision layer. Every letter drew the same line: AI supports qualified clinical judgment, it does not replace it. Daiichi was explicit that AI should not autonomously make dose escalation or safety decisions. But underneath that line, they want automation everywhere. Reconciliation, coding consistency, discrepancy detection, safety surveillance. That is where AI enters trials first, and it is where the near-term value is.
The bar is oversight, not sophistication. Lilly put it best: the FDA should select for the most mature oversight of AI, not the most mature AI. Across the letters, the requirements are validation, audit trails, data lineage, change control, human review that is evidenced rather than assumed. A brilliant model with weak governance does not clear this bar. A well governed one doing unglamorous work does.
The industry is already building the plumbing. Lilly and Bayer, independently, both proposed a DMF-style pathway letting AI vendors disclose model documentation directly to the FDA with sponsors referencing it.
Put those together and the future looks less like AI making trial decisions and more like AI making trial data trustworthy fast enough for humans to decide sooner.
The sponsors who lead this will not be the ones with the most sophisticated models. They will be the ones whose data operations were modernized and able to clean enough to move in real time.

 

FDA News Release

FDA Announces Major Steps to Implement Real-Time Clinical Trials

Agency unveils real-time trial proofs-of-concept and upcoming pilot program

For Immediate Release:

April 28, 2026

On May 27, 2026, the FDA posted a notice in the Federal Register extending the comment period for the Request for Information until June 29, 2026. 

The U.S. Food and Drug Administration today announced two major steps as part of an initiative to advance the implementation of real-time clinical trials (RTCT). First, the agency unveiled the successful initiation of two proof-of-concept clinical trials that will report endpoints and data signals to the agency in real time. Second, the agency released a Request for Information (RFI) regarding a proposed pilot program for RTCT that will launch this summer.  

Early-phase clinical trials are a bottleneck in drug development, often characterized by high uncertainty, limited patient populations, and inefficient decision-making processes. Data is typically reported from sites to sponsors, who analyze and subsequently submit data to the FDA. With improvements in AI and data science, sponsors and trial sites have the opportunity to conduct real-time trials in a way that enhances safety monitoring and radically increases efficiency.  

“For 60 years, we’ve been conducting clinical trials in the same way, where key data signals can take years to reach the FDA. The lag time can delay regulatory decisions unnecessarily and slow down the drug development timeline,” said FDA Commissioner Marty Makary, M.D., M.P.H. “We are boldly advancing a modern approach whereby FDA scientists can view safety signals and endpoints in real time as a trial progresses. This will help us accelerate promising therapies, and build toward our ultimate goal of running real-time, continuous trials across all phases of drug development.”  

The FDA is announcing the successful initiation of proof-of-concept RTCTs by AstraZeneca and Amgen. AstraZeneca is conducting a Phase 2 multi-site trial, TRAVERSE, in patients with treatment-naïve mantle cell lymphoma, with participation from The University of Texas MD Anderson Cancer Center and University of Pennsylvania. Amgen is conducting a Phase 1b trial, STREAM-SCLC, in patients with limited-stage small cell lung carcinoma and final site selection is in process. For each trial, the FDA met with the sponsor on the establishment of criteria for reporting signals in real time. The agency has since received and validated signals for AstraZeneca’s trial through Paradigm Health, thereby establishing the feasibility of the technical framework required for real-time signal sharing.

The FDA seeks to build on these proofs-of-concept with a broader pilot program. Today’s RFI seeks input on potential pilot program design and implementation, as well as evaluation metrics and success criteria.

“Real-time trials have been talked about for years. We demonstrated that it is not only possible, but also potentially transformative for the clinical trials ecosystem,” said Chief AI Officer Jeremy Walsh. “We have to consider our processes from the standpoint of a patient awaiting a potentially powerful treatment.”

Real-time clinical trials are an important step towards the agency’s goal of facilitating continuous trials. At present, most clinical development occurs in discrete phases. Because each defined phase of clinical development is run according to a protocol and typically as a separate study, there is generally a hiatus in the development program after one phase ends and the next begins. This slows the pace of product development. Because real-time trials allow the FDA to view key insights in real time, this hiatus could be eliminated or reduced to a minimum, enabling “continuous” trials.

The agency will accept comments on the RFI until May 29, 2026. The agency intends to disseminate final selection criteria in July and complete pilot selections in August. 

https://www.youtube.com/live/hPT6X4SKOjw?si=ZfLrn3NmYvyqFILm

 

https://www.ajmc.com/view/fda-will-require-only-1-study-to-approve-new-drugs-speeding-up-process

 

News|Articles|February 19, 2026

FDA Will Require Only 1 Study to Approve New Drugs, Speeding Up Process

Author(s)Julia Bonavitacola

Fact checked by: Christina Mattina

A commentary by FDA officials Vinay Prasad, MD, MPH, and Martin Makary, MD, MPH, details the new system for drug approvals in the US.

FDA Commissioner Martin Makary, MD, MPH, and his top deputy Vinay Prasad, MD, MPH, announced in a commentary published in The New England Journal of Medicine that the FDA will revamp its method of approving drugs for use in the US.1 The commentary announced that the agency’s historic reliance on 2 clinical trials will end, with only 1 pivotal trial needed for a drug to be approved for use nationwide.

“Going forward, the FDA’s default position is that 1 adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorization of novel products,” the FDA officials wrote in their commentary.

The FDA had previously worked under guidelines stating that “adequate and well-controlled investigations” were needed before a drug could be approved for widespread use, which were interpreted as generally requiring 2 clinical investigations.2 These guidelines had been in place since 1998, with only supplementary guidance published in 2019 and 2023. The newly announced shift marks the first substantial change in the methods of FDA approvals since the FDA obtained the authority to grant marketing authorizations.1

Makary and Prasad noted that these guidelines had been flexible in the past—specifically in oncology, where 1 study was often enough for a drug approval—but were confusing to drug manufacturers seeking to understand when only 1 trial would be acceptable. Moving forward, the default of using only 1 trial to grant a drug approval should clear up questions surrounding the necessary number of trials.

“The FDA’s historical reliance on 2 clinical trials rather than 1 was intended to provide credible causal evidence that a therapy could improve clinical outcomes with acceptable safety in a world where biologic understanding was more limited than it is today,” the FDA officials wrote. “Two trials should be seen as just 1 of many interlocking facets of clinical credibility, and in 2026 there are powerful alternative ways to feel assured that our products help people live longer or better than requiring manufacturers to test them yet again.”

This move is another step in Makary’s attempts to shorten FDA reviews, which started when he began his tenure last year.3 These include mandating the use of artificial intelligence for staffers and offering new medications a 1-month drug assessment if the FDA believes that the drug serves a national interest.

About 60% of first-of-a-kind drugs have been approved based on a single study in the past 5 years due to legislative initiatives that encouraged flexibility in reviewing drugs for conditions that were hard to treat. The drugs more likely to be affected by this new standard are for common diseases rather than those for rare diseases or cancers, which were already more often receiving approval based on a single trial.

This announcement comes a day after the FDA announced that it will now review Moderna’s seasonal mRNA flu vaccine application, which it had previously refused to look at due to perceived safety and efficacy concerns.4 The increased scrutiny of vaccines presents a contrast to the newly streamlined default standard for FDA approvals.

References

  1. Prasad V, Makary MA. One pivotal trial, the new default option for FDA approval—ending the two-trial dogma. N Engl J Med. 2026;394(8):815-817. doi:10.1056/NEJMsb2517623
  2. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence. FDA. Updated November 30, 2023. Accessed February 19, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical
  3. Perrone M. FDA will drop two-study requirement for new drug approvals, aiming to speed access. AP News. Updated February 18, 2026. Accessed February 19, 2026. https://apnews.com/article/fda-drug-approval-studies-makary-prasad-a5aaa5501ae15f264bbd20d0dffa4dc4
  4. Steinzor P. FDA reverses course, will review Moderna’s mRNA flu vaccine. AJMC®. February 18, 2026. Accessed February 19, 2026. https://www.ajmc.com/view/fda-reverses-course-will-review-moderna-s-mrna-flu-vaccine

 

Pharm Stat. 2022 Aug 26;22(1):96–111. doi: 10.1002/pst.2262

Should the two‐trial paradigm still be the gold standard in drug assessment?

Stella Jinran Zhan 

1

, Cornelia Ursula Kunz 

2

, Nigel Stallard 

1,

✉

  • Author information
  • Article notes
  • Copyright and License information

PMCID: PMC10087480  PMID: 36054079

Abstract

Two significant pivotal trials are usually required for a new drug approval by a regulatory agency. This standard requirement is known as the two‐trial paradigm. However, several authors have questioned why we need exactly two pivotal trials, what statistical error the regulators are trying to protect against, and potential alternative approaches. Therefore, it is important to investigate these questions to better understand the regulatory decision‐making in the assessment of drugs’ effectiveness. It is common that two identically designed trials are run solely to adhere to the two‐trial rule. Previous work showed that combining the data from the two trials into a single trial (one‐trial paradigm) would increase the power while ensuring the same level of type I error protection as the two‐trial paradigm. However, this is true only under a specific scenario and there is little investigation on the type I error protection over the whole null region. In this article, we compare the two paradigms by considering scenarios in which the two trials are conducted in identical or different populations as well as with equal or unequal size. With identical populations, the results show that a single trial provides better type I error protection and higher power. Conversely, with different populations, although the one‐trial rule is more powerful in some cases, it does not always protect against the type I error. Hence, there is the need for appropriate flexibility around the two‐trial paradigm and the appropriate approach should be chosen based on the questions we are interested in.

 

Szczepan Baran

Making preclinical evidence predict the clinic for 2- and 4-Legged Patients |  CSO, Instem | Co-Founder, Digital Preclinical Society | Co-Chair, VQN | President, 3Rs Collaborative

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For fifty years, preclinical safety ran on one rule: do the animal study, then justify the exception. Last week the #FDA‘s #OncologyCenterofExcellence released a draft guidance that quietly turns that rule around. Read the headlines and it is an animal-reduction story. One relevant species instead of two. A single three-month study instead of separate one- and three-month studies. A structured risk assessment in place of a study. And yet the reduction is not the point. The precondition is.


Each of those moves is permitted only when you already understand the product, the #targetbiology, and the #toxicity well enough to defend the omission. The study used to be the default. Now the knowledge is the default, and the study is what you add when the knowledge runs out. That is a higher bar, not a lower one. Dropping a study you cannot defend is easy. Defending the decision is the work.

Here is the part that should focus the mind. Across 7,565 drugs and five species, only one of 26 system organ classes showed strong cross-species concordance for both small molecules and biologics. Running the study was never the same as understanding the risk. I wrote this week’s Digital Record on what the guidance actually asks of sponsors, and why the teams that win the timeline treat their evidence as an asset, not an archive. If you lead nonclinical safety or translational science for an oncology biologic or a conjugate, read it as an evidence standard, then ask the harder question of your own programs: which study are you running out of habit, and could you defend dropping it on Monday. Know more. Run less. Defend both.


Issue #3 is free here: https://lnkd.in/eSYzkh_x

 

FDA Reports Meeting Year One Goals for Reducing Animal Drug Testing

June 8, 2026

On May 29, 2026, the Food and Drug Administration (FDA) released its latest guidance related to FDA’s intent to reduce unnecessary animal testing for nonclinical safety assessments, Oncology Pharmaceuticals: Streamlined Nonclinical Safety Studies for Biologics and Conjugated Products. The guidance is intended to help reduce unnecessary animal testing by incorporating an integrated knowledge-based risk assessment with a focus on three-month toxicology studies for certain oncology pharmaceuticals.

Sponsors may propose alternative approaches for a three-month general toxicology study for product classes not described in the guidance, provided such approaches are sufficient to address product safety. Such approaches for a three-month general toxicology study may include a non-sacrificial toxicology study, an alternative study design to reduce animal numbers, or a weight of evidence (WoE) risk assessment for products with well-understood targets to replace animal studies. These approaches could be supplemented with new approach methodologies (NAMs), as appropriate.

FDA’s recommendations cover general toxicology and WoE Assessment. For general toxicology, FDA stated that animal toxicology studies should use pharmacologically relevant species or WoE risk assessment in its absence. FDA stated that if pharmacological activity is similar to humans in both rodent and non-rodent species, then general toxicology may be conducted in a single rodent species and supplemented with WoE risk assessment as appropriate.

A WoE risk assessment may include multiple factors. The factors include nonclinical and clinical data generated with the investigational product (e.g., pharmacology, safety, and pharmacokinetics), a literature-based assessment of potential toxicities with the molecular target, toxicity findings in animals and humans associated with the same class of pharmaceuticals, and other data. The Center for Drug Evaluation and Research’s (CDER) oncology review divisions will determine when the WoE risk assessment is sufficient to address the safety risks based on the totality of evidence.

This guidance builds upon FDA’s initial Roadmap to Reducing Animal Testing in Preclinical Safety Studies (April 2025) to provide a strategic, stepwise approach using NAMs, such as organ-on-a-chip systems, computational modeling, and advanced in vitro assays (e.g., organoids and microphysiological systems). The principles come from a growing scientific recognition that animals are inadequate models of human health, i.e., over 90% of drugs that appear safe and effective in animals do not go on to receive approval in humans. In addition, the time and cost of long-term animal studies delay therapies reaching patients, e.g., developing a monoclonal antibody costs $600-750 million and may take up to nine years, with typical programs using 144 non-human primates at costs reaching $50,000 per animal.

FDA’s one-year progress report, Reducing Animal Testing in Nonclinical Studies Year One Progress and the Path Forward (April 2026) declared that the necessary foundations or goals had been met or exceeded, resulting in additional guidance. Some of those goals included:

  • On July 31, 2025, FDA made the Innovative Science and Technology Approaches for New Drugs pilot program permanent. The program employs the Drug Development Tool Qualification regulatory framework, providing a clear, predictable pathway for developers to gain formal FDA acceptance of NAMs.
  • In August 2025, FDA and the National Institutes of Health formalized a partnership in a Memorandum of Understanding to accelerate the standardization, qualification, and adoption of human-relevant alternative methods.
  • In October 2025, the CDER / Office of New Drugs Streamlined Nonclinical Studies and Acceptable New Approach Methodologies database went live, providing a searchable, regularly updated inventory of specific drug development contexts where streamlined nonclinical programs are acceptable.
  • In November 2025, FDA researchers from the National Center for Toxicological Research and CDER, collaborating with Emulate Inc. and the University of North Carolina at Chapel Hill, published challenges and solutions in measuring commonly used biomarkers for drug-induced liver injury in a liver-on-a-chip platform.
  • On December 2, 2025, FDA released draft guidance, Monoclonal Antibodies: Streamlined Nonclinical Safety Studies.
  • On December 8, 2025, FDA crossed a technological threshold by qualifying the AI-Based Histologic Measurement of NASH its first AI-based drug development tool for use in metabolic dysfunction-associated steatohepatitis clinical trials.
  • On March 18, 2026, FDA published a draft guidance document: General Considerations for the Use of New Approach Methodologies that established four core validation principles to transform the abstract question of “When is an alternative acceptable?” into concrete, actionable requirements. On the same date, FDA’s Level 2 update to “Pyrogen and Endotoxins Testing: Questions and Answers” guidance provided the flexibility for manufacturers to transition from Limulus Amoebocyte Lysate (LAL) reagents for bacterial endotoxin testing to transition from harvesting horseshoe crabs for production of LAL reagent to recombinant agents.

We will continue to monitor FDA’s continuing implantation of a framework to reduce animal testing in nonclinical studies.

This blog was drafted by Brian Malkin, a Spencer Fane attorney on the FDA Pharmaceutical and Biologics Market Team. For more information, visit spencerfane.com.

 

https://www.the-scientist.com/is-this-the-end-of-animal-testing-fda-announces-plans-to-phase-out-animals-in-drug-safety-studies-73031

 

F

or decades, preclinical testing in mice, rats, and nonhuman primates has been a crucial part of drug development, an important although not infallible way to ensure some measure of safety for human participants in clinical trials. In 2022, Congress passed the FDA Modernization Act 2.0, stating that the agency was no longer compelled by law to require animal testing.1 However, the act did not prohibit the FDA from requiring animal testing, and animal toxicity data remained an essential step in the path towards human trials.

But on April 10, the FDA announced plans to phase out these requirements, stating that they would be “reduced, refined, or potentially replaced” with New Approach Methodologies (NAMs). These methods include human-derived cell models, such as organoids and organ-on-a-chip systems, as well as in silico approaches such as pharmacokinetic modeling and toxicity-predicting machine learning algorithms. Within the year, certain monoclonal antibodies, which are most commonly used in the treatment of cancer and serious autoimmune disease, could be evaluated using a “primarily non-animal-based testing strategy.” According to the roadmap accompanying the FDA announcement, “In the long-term (3–5 years), FDA will aim to make animal studies the exception rather than the norm for pre-clinical safety/toxicity testing.”

This announcement has been met with both hopefulness and concern in the scientific community. On one hand, there is broad support for moving away from animal testing, which is ethically fraught, expensive, and not always predictive of human biological responses. On the other hand, scientists and pharmaceutical industry professionals have expressed that NAMs are not yet advanced enough to fully replace animal models.2,3 Moreover, there are concerns that dramatic reductions in budgets for scientific research and the firing of thousands of workers at the FDA and NIH will stall further development of NAMs and interfere with the functioning of the very systems that would be responsible for validating, standardizing, and monitoring the efficacy of these technologies.

Alex Rubinsteyn, a University of North Carolina at Chapel Hill researcher who uses machine learning approaches to inform the development of personalized cancer vaccines, supports reducing animal testing but is uncertain about how this will play out in practice in the current climate. “I think this could become a disaster,” he said. “But it could also potentially unlock a much faster rate of progress.”

Few would dispute the shortcomings of current animal testing pathways: About 90 percent of drugs that make it through preclinical trials never obtain FDA approval for use in humans, largely due to insufficient efficacy or safety.4 Joseph Wu, who studies patient-specific in vitro models of cardiovascular disease at Stanford University, said that this high failure rate is partly due to the inherent differences between human and rodent biology. Furthermore, he noted, “The heterogeneity that exists among humans cannot be captured by using a traditional mouse model.”

Additionally, despite attempts to streamline evaluations of drugs for currently untreatable diseases, “[Drug development] is still really slow and really expensive,” said Rubinsteyn. “And it’s unmatched to clinical realities for certain kinds of disease: There are sufficiently deadly diseases where you really would want to go much faster than you’re allowed to go.”

How Do In Vitro and In Silico Approaches Stack Up Against In Vivo?

Despite the inherent flaws in animal testing, many researchers say that NAMs are not yet advanced enough to fully replace traditional drug safety studies. For example, in a late 2024 report to the FDA Science Board, members of the NAMs subcommittee—convened in 2023 to provide recommendations on integrating NAMs into regulatory processes—wrote that, “Technical limitations to current NAMs exist…today, no assays fully capture the critical hazard endpoints for assessing all currently existing human or animal organ systems; therefore, NAMs cannot fully eliminate the use of integrated physiological systems such as in animal and human trials.”2

In a published response to the FDA announcement, the president of the National Association for Biomedical Research, Matthew Bailey, echoed these sentiments. “No AI model or simulation has yet demonstrated the ability to fully replicate all the unknowns about many full biological systems.”

Similarly, Rubinsteyn noted that while these models can be useful when the space is sufficiently constrained, in other situations, they are still no match for the complexity of biology. “The thing that I work on the most—personalized cancer vaccines—is totally plagued by machine learning models not capturing the relevant realm.”

“We could improve those models with cell lines, but ultimately, the cell lines will be different if we put them in the context of a living organism,” he continued. “[In vivo], the tumor cells will shift what they express. They have to deal with being in contact with other cells in the tissue. They’ll have to pull in vasculature, and they’ll have to deal with the immune environment. So, they’re going to shift how they behave.”

To address this problem, other research groups are building organ-on-a-chip systems as a closer approximation of how cells behave in living tissues. These models can have layers of cells supported by an extracellular matrix with a simplified vascular system, recapitulating some of the cell-cell interactions and mechanical forces present in a living organism.

Yu Shrike Zhang, a Harvard Medical School researcher who uses bioprinting, microfluidics, and other techniques to create improved organ-on-a-chip platforms, noted that these models are quite advanced for certain tissue types.5 “For the liver, the models are pretty precise in general,” Zhang said. “It’s been [studied] for a very long time, and people know exactly how it works.”

Indeed, a liver-on-a-chip model developed by the biotechnology company Emulate, Inc., was able to correctly identify drugs known to be toxic or nontoxic to the liver with a sensitivity of 87 percent and a specificity of 100 percent.6

Using organ-on-a-chip models, Zhang said, “In three to five years, I think we can probably get to a pretty high level in terms of testing [toxicity or biological responses] for individual organs.” Modeling interactions between different organs, however, is a more challenging task. Crosstalk between organ systems is complex and incompletely understood, and organs can be influenced, or influence each other, via changes in metabolism, blood circulation, immune function, endocrine signalling, or nervous system activity.7

Scaling is also a concern, according to Zhang. As size changes, different physical forces and properties increase or decrease in different ways. So, it is not yet entirely clear how to best model a 200-pound human body using organ-on-a-chip systems, some of which may be only a few cell layers thick.

“Things are quite complicated, both biologically and in terms of how these devices operate,” said Zhang. “Being able to really reproduce that organism-level interaction—I think that’s still something that will be really important to look into. Maybe that’s something that’s going to be mature in the next three to five years? I mean, no one knows. But I think that’s probably one of the major limitations right now.”

Refine, Reduce, Replace and the Promise of NAMS

Even scientists who are extremely enthusiastic about NAMs seem to view them as a tool to reduce, not completely replace animal testing. Wu, for example, has spent decades developing in vitro models using cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) to improve our understanding of cardiovascular disease. He has created an extensive biobank of human iPSCs, capturing genetic diversity in health and disease, and even founded a company, Greenstone Biosciences, which aims to accelerate the drug discovery process by combining in vitro and in silico approaches.

However, Wu said, “I’m a proponent of using all models. I’m not a proponent of saying that, ‘Oh, in the future, we should just get rid of mouse models.’” Instead, he said, applying these strategies prior to animal testing could greatly reduce the number of animals that would be needed for each experiment, enabling researchers to identify promising targets and screen for well-defined types of toxicity.

For example, Wu was part of a project led by fellow Stanford University cardiovascular biologist Mark Mercola, in which the team used iPSC-derived human cardiomyocytes and machine learning to classify existing drugs as low risk or intermediate/high risk for causing dangerous arrhythmias. Using area under the curve as a measure of the model’s accuracy—for which 0.5 indicates a random classifier and one is a perfect classifier—the model correctly identified risk with an area under the curve value of 0.95.8 In the future, a system like this one could help researchers spot potentially cardiotoxic compounds early in the drug development process. This has the potential to prevent the investment of time, money, and animal lives into investigating a drug that might treat one disease very well but be ultimately useless because of severe adverse effects.

Furthermore, unlike studies performed in strains of genetically identical mice, research with human cells can provide not only general safety predictions, but they also help identify which individuals might be most at risk for particular side effects and even suggest mechanisms for mitigating these effects.

For example, the chemotherapy drug doxorubicin can lead to heart failure in a subset of patients, but for many years, the mechanism of this cardiotoxicity was not known, and there was no way to predict which patients were at risk. In a study of eight breast cancer patients, Wu and his team showed that iPSC-derived cardiomyocytes from patients who experienced this side effect were more sensitive to doxorubicin toxicity than cells from patients who did not. 9 In the future, this could serve as a tool for screening patients prior to treatment. In a subsequent study, the researchers used a CRISPR-based approach to screen cardiomyocytes for genes that contributed to this vulnerability. One gene, which coded for the enzyme carbonic anhydrase 12, seemed to play a large role: When expression of this gene was inhibited in the cells, they were protected from doxorubicin toxicity.10 An antagonist of this enzyme, Indisulam, was also protective in heart cells. Only after all these experiments did the researchers test the drug in mice.

Continue reading below…

Since then, Wu and his team have used iPSC-derived cells, patient data, and AI to identify a candidate compound for the treatment of marijuana-induced vasculature inflammation, and two potential therapies for cardiac fibrosis.11–13 “These three papers all have mouse models, but they’re toward the end,” said Wu. “They’re only done for validation—the initial screen, initial validation, initial design, all that stuff is done [using] organoids, stem cells, and AI.”

The first candidate is currently in a Phase 1 clinical trial for the treatment of inflammation associated with heart failure, the second is in an open-label study for treating idiopathic pulmonary fibrosis. In the coming years, studies such as these will provide crucial data to answer the question of whether these newer drug development techniques can increase efficiency and reduce failure rates in clinical trials.

An Uncertain Future for Drug Development

Much work remains to be done, however, if animal testing is to be truly replaced in the next three to five years. In addition to the development of the NAMs technologies themselves, the FDA roadmap also calls for the creation of open-access toxicity information databases, developing strategies to validate NAMs, determining appropriate thresholds for eliminating animal testing, figuring out how to standardize these techniques so that they can be compared across many different laboratories, coordinating with other federal agencies, and monitoring how well all of this is working.

“Transitioning from animal-based testing to NAMs for safety will require careful planning, robust science, and collaboration,” the roadmap states.

But will this be possible in the chaos currently afflicting many government agencies and the dramatic changes to support for scientific research in the United States? The Trump administration has already terminated 1.8 billion dollars in National Institutes of Health (NIH) grants; the administration’s proposal for the upcoming year would slash the budget of the NIH by 40 percent.14,15

Some of these governmental budget cuts and funding freezes adversely impact the laboratories that have been instrumental in developing the very NAMs technologies the FDA is hoping to promote. For example, Harvard University bioengineer Donald Ingber, a pioneer in organ-chip research and scientific founder of Emulate, Inc., received stop-work orders on two major organ-on-a-chip projects in late April 2025.

Beyond the technologies themselves, planning and collaboration efforts may also be impacted by the major changes at these agencies. So far, 2025 has been marked by many cancelled or postponed scientific meetings at the FDA and NIH, as well as firings of thousands of workers, including many top-level officials and a large portion of communications roles, and the resignation of Peter Marks, director of Center for Biologics Evaluation and Research.

Rubinsteyn, for his part, worries about how reductions in animal testing requirements will play out in such an environment, raising concerns that insufficient oversight could create opportunities for unscrupulous companies to bring potentially unsafe drugs to market.

“I do think that this is, in principle, a positive direction for change,” he said. But depending on how these changes are implemented, “it could go quite wrong.”

Disclosure of conflicts of interest: Yu Shrike Zhang sits on the scientific advisory board and holds options with Xellar Biosystems.

Comparative Study 

Toxicol Sci

. 2015 Dec;148(2):355-67. doi: 10.1093/toxsci/kfv189. Epub 2015 Oct 5.

Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study

Lya G Soeteman-Hernández 1, Mick D Fellows 2, George E Johnson 3, Wout Slob 1

Affiliations Expand

Abstract

In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement).

Keywords: TK6 cells, benchmark dose 

https://www.drugdiscoverynews.com/why-toxicology-is-still-the-toughest-test-for-nam-adoption-17194

 

Toxicology remains the most challenging field for adopting new approach methodologies (NAMs) as it requires predicting systemic, long-term human health effects that are inherently complex to replicate outside a living organism. While NAMs offer human-relevant data, the industry faces significant hurdles in validating these methods to the same level of trust as traditional animal models.

DDN spoke with Justin Boyd, Product Manager at Sartorius, to explore how NAMs are being applied in practice across drug discovery and safety assessment, and what ultimately determines whether they transition from scientifically compelling tools into routine components of toxicology workflows.

You’ve spent much of your career building biologically relevant cellular models of disease. How does that emphasis on relevance shape how you think about NAMs in toxicology, compared with more traditional animal-based approaches?

I recently joined the vendor side of NAMs. For nearly two decades before that, as a drug hunter, I was less focused on building models and more on applying them. In that context, I thought of NAMs as fit-for-purpose tools to rapidly explore the effects of experimental drugs on the proximal human biology I care about.

Now, as Product Manager of a NAMs portfolio, I still strongly believe in that utility. The strengths of NAMs lie in: (1) conservation of human biology, (2) speed to data-driven decision-making, and (3) cost to execute study. That said, I don’t see NAMs as replacing the value of a whole organism — whether mouse, rat, or non-human primate. A preclinical toxicity study in animals provides a more comprehensive view of how a compound behaves in the context of an intact organism, including systemic interactions that are still not well captured in vitro.

However, NAMs create an opportunity to rank and/or differentiate compounds with higher molecular resolution while remaining “in human.” That kind of insight can meaningfully inform decisions about which compounds are worth advancing into more expensive and time-consuming animal studies.

Ultimately, I think of NAMs for toxicity as key complementary models for evaluating tissue-specific risk to drive decision to go into the animal models, leading to better stewardship of resources for drug discovery and animal welfare.

NAMs are often discussed as ethical or regulatory advances, but from your perspective, where do they most clearly outperform legacy toxicology methods scientifically?

With respect to performance, there are two clear areas where NAMs excel. First, NAMs can recapitulate aspects of human biology more faithfully than preclinical species. This becomes especially important when studying the proximal biology engaged by an experimental drug, where species differences can significantly limit interpretability.

Second, NAMs substantially reduce the time and cost required to reach a decision. From a project or program management perspective, the ability to make informed and confident stage-gate decisions is where the highest value lies. In this context, NAMs enable a more expedient and cost-effective approach to predicting toxicity in the pre-Investigational New Drug (IND) to IND space.

Although, it’s likely that animals will be used at this point, NAMs can and should be deployed to derisk the Good Laboratory Practice (GLP) toxicity studies in animals and potentially reduce the numbers of cohorts and time for treatments.

Many toxicology assays still rely on relatively reductionist systems. How close are we to NAMs that genuinely capture the complexity of chronic diseases like Alzheimer’s or Parkinson’s when it comes to assessing safety?

I think this is a tricky question, and I would start by noting that the complexity of Alzheimer’s (AD) and Parkinson’s disease (PD) pathobiology is part of what limits our ability to clearly distinguish mechanisms that cause disease from those that simply exacerbate progression. As such, “who, when, and how” these diseases are treated and the potential toxicity from treatment remain controversial.

In some cases, NAMs, particularly complex in vitro models with multiple cell types and structures, can recapitulate complex non-cell autonomous biology, such as the impact of inflammation on neuronal health. Moreover, computation-based NAM tools can help predict the trajectory of biology and stratify at-risk populations for toxicity outcomes.

So, when asking how close we are to NAMs that genuinely capture the complexity of chronic diseases like AD and PD, I would say they are, in many ways, as close to recapitulating that complexity as our current understanding allows us to define it.

Drug-induced nephrotoxicity remains a major clinical challenge. From your experience working with human kidney microtissues, why has traditional animal toxicology struggled to predict renal risk in humans?

It sounds cliché, but animals are not humans. In the case of the kidney, there are two key drivers of translational gaps.

First, the expression of key kidney genes and their protein products — particularly those governing transport and metabolism — differs significantly between preclinical species and humans. Second, baseline renal metabolism itself varies across species, further compounding these differences.

Given that the primary function of the kidney is to clear waste, toxins, and excess fluids from the blood, these species-specific differences directly impact our ability to predict nephrotoxicity using traditional animal models.

You’ve worked extensively with 3D human epithelial tissue models. What does moving from 2D cultures to 3D systems fundamentally change in how we understand toxicity mechanisms?

The difference between traditional 2D cultures and 3D systems, in the context of toxicity, is relatively straightforward. By recapitulating tissue structure, 3D models allow us to move beyond simply asking whether a compound is toxic, to understanding where that toxicity occurs and to what extent.

Understanding the relationship between exposure (where a polarized, functional cell sees a compound) and response is uniquely addressed in our systems compared to 2D. This is particularly important in epithelial tissues, where basolateral versus apical exposure can lead to very different toxicity outcomes. In skin, intestine, and lung, for example, cells may be exposed either from the basolateral side via systemic circulation or from the apical side through local administration or environmental contact. That distinction is fundamentally lost in 2D systems.

Do you see NAMs primarily as screening tools, or are they mature enough to inform dose selection, risk stratification, and IND-enabling decisions?

I believe NAMs have always been able to inform dose selection, risk stratification, and IND-enabling decisions. In fact, screening may not be the best deployment of NAMs due to scalability challenges and cost. The appropriateness of a NAM’s utility is dependent upon the limitations of the human biology you can explore within the NAM and the modality of the therapeutic. If the NAM contains the biology that you are targeting and the therapeutic modality is compatible with the model, then the NAM should be appropriate for dose selection, risk stratification and IND decisions.

One advantage you’ve previously highlighted is integrating human tissue models with live-cell analysis. Why is temporal resolution — seeing toxicity unfold in real time — so important?

There is both a practical and a biologically relevant dimension to the importance of temporal resolution in toxicity responses. From a practical standpoint, when developing any assay, identifying the time point at which the signal is maximal is essential for ensuring robustness and is a key part of assay optimization. In the context of toxicity, being able to observe the behavior and toxicity signals over time will enable you to identify the most appropriate time of incubation for maximal signal response.

Biologically, however, toxicity is not a single event — it manifests in different ways depending on mechanism. If you use tool compounds that induce toxicity through different mechanisms, knowing the kinetics of the toxicity response can help resolve whether your assay can distinguish direct and indirect mechanisms leading to toxicity.

In that sense, time to toxicity signal can be as informative as the signal itself, particularly when evaluating unknown compounds. In the context of advanced cell models for toxicity, often the exposure times can be prolonged (days to weeks) to predict clinical outcome.

NAMs can be scientifically compelling but still fail to gain traction. From a product and commercialization standpoint, what determines whether a NAM actually gets embedded into routine toxicology workflows?

This is the $100+ million question. Adoption of any platform is influenced by a range of factors — cost, fit-for-purpose utility, biological relevance, format, and ease of use among them. In practice, different players in the field tend to emphasize the aspects they value most, often based on their own balance of biological relevance versus scalability.

At the moment, traction tends to emerge organically through a “let’s try it and see if it works” approach. This is not unique to NAMs. However, toxicology is a particularly high-bar area, where established gold standards inherently challenge any new model system more than exploratory or discovery settings do. That makes sense: Toxicology groups are ultimately responsible for generating a weight of evidence that supports progression to the clinic.

In that context, NAMs introduce both opportunity and friction. While they offer potentially better predictive insight, they also require additional effort to validate against established approaches — often more effort than is required to continue using what is already accepted. Because of this, I would argue that regulators are the key gatekeepers of NAM adoption in toxicology. Ultimately, they define what is essential versus optional in the data package required to advance into the clinic. In my view, the biggest lever for accelerating adoption is therefore not customer preference, but regulatory acceptance.

What is the incentive to explore better models of toxicology if existing ones are “good enough” to reach regulatory endpoints? We could discuss the ethics and scientific rationale around choosing better, more predictive models. But if NAMs remain encouraged rather than required, it is difficult to expect meaningful acceleration in their uptake. I really hope that regulators recognize that there’s a big difference between accepting NAMs and requiring them. Making NAMs essential for toxicity studies for IND filing would catalyze their adoption far more effectively than incremental product refinement alone.

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About the Author

  • Bree Foster, PhD

  • Bree Foster is a science writer at Drug Discovery News with over 2 years of experience at Technology Networks, Drug Discovery News, and other scientific marketing agencies. She holds a PhD in comparative and functional genomics from the University of Liverpool and enjoys crafting compelling stories for science.

he 90% myth

Posted: by Chris Magee on 9/06/25

More on these Topics:

ANIMAL RIGHTSANIMAL STATISTICSDRUG DEVELOPMENTFACT CHECKMISINFORMATIONMYTHBUSTING

Why do 90% of new drugs fail?

If you’ve read anything on animal testing, you’ll have read something to the effect that ‘more than 90% of drugs tested in animals fail in humans’. Is that some damning indictment of animal models? Absolutely not. Let’s unpack this a bit.

Note: The 90% statistic refers to regulatory safety testing. Other sorts of animal use, like discovering decapod sentience through ‘curiosity-driven’ basic research, will be discussed in another article since the applications are so broad and the application of the research so complex that percentages are usually meaningless. 

Tl;DR:

The drug attrition rate, which isn’t 90%, isn’t due to the use of animals and there’s no such thing as a drug that’s developed and tested using only animals before heading to human trials.

Let’s start at the beginning.

 

How drugs get licensed

In drug trials, all drugs intended for humans are tested on humans: they are tested and refined through three stages of clinical trial before being licensed for public use. Phase 1 of human testing looks primarily at safety, whereas phases 2 and 3 are for safety and then efficacy. Each stage uses more human volunteers than the last and the later stages might include those with a particular medical condition. There is also a post-licensing stage 4, where new treatments are introduced to the wider population, for instance into the clinic by specialist doctors.  

Image: Sanford Health 

Adverse reactions noted after a drug is licensed are fed back to the medicine’s regulator, the Medicines and Healthcare Devices Regulatory Authority (MHRA), which might do things like update the safety information in the booklet that comes with the medicines. Lots of medicines have their safety advice updated as the medicine is used in a greater number of patients.  

This is because drugs are licensed on the grounds of what they do in general, e.g. shrink a tumour or lower blood sugar. However, to what extent they work in an individual will vary greatly depending on dozens of factors from genetics to weight to hormones – even to the time of day. This is why there are specialist doctors for different diseases, as well as GPs, who take a patient-centric perspective on the medical tools available for that person (or animal). Hence, very few medicines are withdrawn – it’s usually a case of finessing the practice and guidance on using them safely and optimally and adapting their use for specific patients. 

 

Preclinical testing

Before drugs can go to human trials, they must pass a standard battery of safety tests using both animal and non-animal methods. These tests tend to be specified by bodies like the OECD (mainly for chemicals) and the International Conference on Harmonisation (mainly for pharmaceuticals), which can pool knowledge about how to use the best methods of safety testing, whatever these may be. 

Non-animal methods of drug testing can perform well but tend to be limited in scope to one organ system or one effect, whereas animal models tend to give a broader picture of how drugs will act in a whole living body and across a dozen organs at once. 

For some applications, non-animal methods are enough to conclude that drug development shouldn’t proceed, and the compound is therefore eliminated before hitting either the human or animal testing stages.  

With those drugs that do proceed, animals are very good at ‘predicting’ if a drug will be ‘safe’ in the first human trials.  

There are different statistical tools that can be used to determine this safety. Bayesian modelling (figure 1 below) can find ‘true positives’ (PPVs) and ‘true negatives’ (NPV) i.e. a percentage certainty that something will be safe in stage 1 human trials. Likelihood ratios (figure 2) offer a probability of safety. 

Bayesian modelling, NPV safety prediction
Organ category  Dog to human   Mouse to human  
Pulmonary  96%  95% 
Biochemical  95%  93% 
Renal  95%  96% 
Ophthalmology  94%  96% 
Haematology  93%  92% 
Cutaneous  91%  82% 
Musculoskeletal  91%  92% 
Cardiovascular  91%  75% 
Nervous system  90%  93% 
Liver  88%  89% 
Gastrointestinal  76%  69%

Figure 1: IQ Consortium translational database 

Likelihood ratios
Pre-test probability  Pre-test odds  Post-test odds  Post-test probability 
10%  0.11  3.16  76% 
20%  0.25  7.11  88% 
30%  0.43  12.18  92% 
40%  0.67  18.95  95% 
50%  1.00  28.43  97% 
60%  1.50  42.65  98% 
70%  2.33  66.34  99% 
80%  4.00  113.72  99% 
90%  9.00  255.87  100% 

Figure 2: Data from https://pubmed.ncbi.nlm.nih.gov/24329742/  

Different species of animal do more or less well at translating to humans depending on the target organs, the type of thing being tested and the size of its molecules. These species differences are well-known, as is the fact that you can increase your certainty that something will be safe or not if a rodent and a non-rodent species both yield similar results. 

Thus, the normal testing regime uses species like rats, plus a non-rodent species, usually a dog or primate. Around three-quarters of tests involve suffering in the mildest category, such as a blood test, with a quarter in the moderate category and very few in severe. This is because most of the information about the possible dangers of a new drug comes from a post-mortem of the animal that reveals changes to the internal organs and tissues, rather than observing whether a live animal gets sick or not. 

The fact that animals are good predictors of safety in humans is important because 40% of potential new drugs are ultimately removed due to failing these pre-human tests. This means that 40% of possible new drugs would have killed or seriously injured humans in phase 1 trials without the pre-human tests (which would be about 900 people a year in the UK).  

 

Preclinical results shape the human trial

But this is not the whole picture. The preclinical tests of all descriptions, including effects seen in animals, human cells, tissue samples and more, help to inform the design of human clinical trials in the first place. For instance, one or several of the tests might hint at potential issues with the liver, so extra measures can be taken to minimise that risk during the human trial. 

All drugs have potential side effects, and their use is always a balance of risk vs potential benefit for the individual patient. All of this means that a large number of drugs proceed to human trials as ‘safe enough to try’ but with a question mark over whether their risks will be manageable or not.  

An example of this management is paracetamol, which works better as a painkiller if taken regularly every 4-6 hours to allow it to build up in the tissues and bloodstream. However, we all know not to take a day’s dose all at once. 

 

So, what of the 90%? 

Drugs ‘fail’ at every stage of development and for several reasons. For every 100 possible drugs that even get to the animal testing stage, some 5,000 other compounds have already been eliminated. Drugs continue to be removed all the way through human testing too, in ever smaller numbers as we zero in on something that’s going to work. 

Percentages thus become less and less helpful for understanding what is happening. Having eliminated 5,000 candidates, for instance, we can be left with 10. If three of those 10 fails, then that’s 30%, which sounds massive, but it’s only 0.06% of the huge pile of 5,000 possible drugs we started with. 

In the same way, the 90% statistic is easy to misunderstand. 

As we’ve seen, 40% of possible drugs are removed as dangerous by the pre-human safety tests that are mainly in animals. The 90% that ‘fail’, then, is 90% of the 60% that pass preclinical trials. Also, by ‘failure’ it means to have failed for the purpose intended – many drugs can later be repurposed even if they fail in their intended application. 

What all this means is, for every 100 potential new drugs at the start of the process, 6 will become drugs in the pharmacy, 40 will be removed by preclinical tests and 54 will be removed for other reasons. 

Exactly what those reasons are is the critical point. 

Of those 54: 

  • C40-50% (26 drugs) will not be effective at the safe dose (something the animal test isn’t looking for); 
  • C25-30% (15 drugs) suspected or known toxicities cannot be managed; 
  • C10-15% (8 drugs) don’t absorb into the body or get to their target organ properly; and 
  • c10% (5 drugs) fail due to a lack of commercial need or misplaced strategic planning. 

In this way, lots of drugs fail to make it to the chemists’ shelves, but this has very little to do with the efficacy of the animal model as a safety screen for stage 1 clinical trials. Animals do that job very well.

What is exciting about new approaches – whether they use animals or not – is that they may be able to chip away at the other reasons for failure (more on this later).

 

Different targets have different success rates

One other complication is that ‘failure’ rates are not uniform.

Currently, translation from preclinical findings to clinical success varies a lot depending on the disease area. Eye treatments are about 35% successful, vaccines are about 40%. The most complex diseases of the most complex organs have, as you’d expect, a much higher failure rate which skews the averages and gives you this slightly bogus 90% figure by some methods of counting. However, there is no evidence that implicates animal models as the major reason for failure. In fact, researchers who found a c95% drug attrition rate also found that 86% of positive results in animals translated into positive results in humans.

This accords perfectly with the IQ Consortium translation database, of animal to human translation, recreated as a table in figure 1 above, which also averages out at 86%  

 

So, where do NAMs fit in?

The term ‘New Approach Methodologies‘ refers to the subset of non-animal technologies concerned with regulatory testing – i.e. the tests required by governments. Non-animal technologies have been in development and used in drug testing since the early 1970s, being applied alongside animal models to try to design better drugs, better clinical trials and spot potentially dangerous compounds. They have a more limited range of applications than a whole-body system, but can nevertheless be a quick, cheap and useful way of spotting red flags or pointing to a way forward. They are a standard part of the toolkit for drug testing, with their use accelerating exponentially in the past 20 years as technology improves. We have ever-better non-animal tests, which are still limited but can tell us enough in some cases to guide a decision on what compounds to try to turn into medicines. 

 

Organs on chips

Some of these techniques are relatively new approaches like organ-on-a-chip technologies. First conceived in the late 1990s, the first successful chip was developed in 2010. These devices, roughly the size of an AA battery, are made from a flexible, translucent polymer. Inside are tiny tubes, each less than a millimetre in diameter, lined with living cells taken from a particular human or animal organ. 

These can spot toxicities ranging from liver issues with new drugs to the effects on animals of industrial chemicals. They can be used early to avoid animal use and some emerging technologies could prevent up to 10% of drugs that would ultimately fail from entering animal trials in the first place. In a study completed in late 2022, for instance, liver chips identified compounds that were deemed safe enough to try by animal models, but would ultimately harm humans in wider testing, with 87% accuracy.  

That doesn’t mean it can spot 87% of drug toxicities, but 87% of those that would have failed later and specifically for liver-related safety reasons. Given that 40% of compounds are removed prior to human testing, 30% later fail due to unmanageable toxicity and 30% of those do so due to effects on the liver, using this test routinely would help to reduce the number of drugs that later failed human trials for unmanageable toxicity by around a third, or 4-5 drugs for every 100 entering testing. 

However, if also used early in the drug testing process they might also spot toxicities that would previously have needed an animal to detect, and this might be enough to halt testing. Liver toxicity is the reason for 14% of failures during preclinical tests so this would amount to a further 5 compounds per 100 that would not progress to the animal stage. As you can see from liver chip vendor Emulate’s own graphic, their chip reduces animal use, and is applied before animal trials. There would still, by their model, be an 82% failure rate and, of course, most drugs don’t fail for liver-related reasons.

Source: https://emulatebio.com/toxicology/

The UK authorises around 35 new drugs for use each year, yet for every drug approved another 9 fail, which would be around 315 trials, some 10% of which could be halted before hitting the animal or human stage, potentially preventing thousands of research animals from being born. This would undoubtedly save pharma companies money since human trials get more expensive the more they progress – from $ 25 million in Phase 1 to $ 54 million in Phase 3. 

The UK’s national centre for Refining, Reducing or Replacing animal use has a project to replace ‘second species’ animals like dogs and primates with computer models that have passed its proof-of-principle stage and are well into development, albeit with another three years of development left to run.

Even if this doesn’t work, it will tell us what we need to do to get it to work. As Jonas Salk, who used primates to create a polio vaccine, once said “There is no such thing as a failed experiment because learning what doesn’t work is a necessary step to learning what does.”  

 

New targets

Animal numbers will inevitably continue their steady march, with an occasional lurch, downward in terms of numbers, but it’s important to understand how all this fits together. Whilst it’s very easy to predict the future in general terms – clean energy, personalised medicine, healthier food – actually getting there is a bit of a slog. 

The other big reason for drug failure beyond the liver, for instance, is Torsades de Pointes. French for “twisting of the points” it’s a dangerous heart arrhythmia that’s the reason for a very similar proportion of preclinical and clinical failures as liver problems. It makes heart chips the next big target for validation, with sincere hopes that they can be made to work as well as liver chips. 

However, this is the low-hanging fruit on offer in terms of organ chips, with diminishing returns as the targets get harder, and the target systems get more complicated. A test for the heart or a kidney is one thing, a test for the Central Nervous System is quite another. In addition, heart arrhythmia and liver issues are the biggest single areas of failure for safety reasons, but the remaining 40% of reasons affect many other organs, each of which will need its own new animal or non-animal testing strategy. 

 

Where next? 

There is no one approach, then, that will create a revolution. We need new approaches, and we need new improvements to old approaches. My latest laptop, for instance, isn’t conceptually different from the first laptop I owned but it’s a lot lighter and faster due to hundreds of innovations across all of its components. Improvements to clinical outcomes will come from organ chips, big data and AI, but also from higher standards of scientific rigour, new animal models, more powerful technology and the synergies that arise from using it all together. 

Happily, there are very few regulatory barriers to adopting new non-animal technologies, the ethical framework for using new animal models is well-understood and nobody is opposed to using non-animal methods over animals. In addition, whatever the costs of failure during clinical trials, the cost of preclinical R&D and discovery clocks in at $403 million, making it easily the most expensive single stage in the drug development process. Hence, the greatest savings in cost or animal use associated with improvements in technology may have nothing to do with the requirements of the regulator and can be implemented as soon as new technologies mature. 

We do need to accelerate the validation of new animal and non-animal methods now that they’re emerging with rapidly increasing frequency. The OECD, the international association for sharing solutions to common problems, is the curator of scientific guidelines for the testing of chemicals. It makes the point that resources should be made available to test the reproducibility and reliability of new methods developed by single labs so that, if they work, they can be applied more widely, and more quickly. Inherent to their thinking is a bias against animal use. 

We also need to make sure that politicians aren’t distracted by ideological sideshows or lured towards counterproductive policy directions, like deadlines that amount to deregulation of harmful industries. whose products are only harmful when metabolised in a whole body. There are concrete measures that governments, or prospective governments, could be proposing but politicians of all stripes need to understand where to apply funding and focus to have a positive impact on man, animals and the environment. 

https://www.understandinganimalresearch.org.uk/news/the-90-myth

 

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Some Recent Challenging News from Gene Therapy Companies: Sarepta’s Gene Therapy Halted by FDA, Spark Therapeutics Program Gets a Realignment and  Review from Roche

 

Curator: Stephen J.Williams,  Ph.D.

 

Sarepta Therapeutics has received a order from the FDA to halt clinical trials on its Duchenne Muscular Dystrophy gene therapy Elevidys on July 18, 2025 following three deaths.

 

From FDA: https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold 

 

FDA Requests Sarepta Therapeutics Suspend Distribution of Elevidys and Places Clinical Trials on Hold for Multiple Gene Therapy Products Following 3 Deaths

 

For Immediate Release:

July 18, 2025

The U.S. Food and Drug Administration today announced it has placed Sarepta Therapeutics investigational gene therapy clinical trials for limb girdle muscular dystrophy on clinical hold following three deaths potentially related to these products and new safety concerns that the study participants are or would be exposed to an unreasonable and significant risk of illness or injury. The FDA has also revoked Sarepta’s platform technology designation.

The FDA leadership also met with Sarepta Therapeutics and requested it voluntarily stop all shipments of Elevidys today. The company refused to do so.  

“Today, we’ve shown that this FDA takes swift action when patient safety is at risk.” said FDA Commissioner Marty Makary, M.D., M.P.H. “We believe in access to drugs for unmet medical needs but are not afraid to take immediate action when a serious safety signal emerges.”

The three deaths appear to have been a result of acute liver failure in individuals treated with Elevidys or investigational gene therapy using the same AAVrh74 serotype that is used in Elevidys. One of the fatalities occurred during a clinical trial conducted under an investigational new drug application for the treatment of Limb Girdle Muscular Dystrophy.

“Protecting patient safety is our highest priority, and the FDA will not allow products whose harms are greater than benefits. The FDA will halt any clinical trial of an investigational product if clinical trial participants would be exposed to an unreasonable and significant risk of illness or injury,” said Director of the FDA’s Center for Biologics Evaluation and Research Vinay Prasad, M.D., M.P.H.

Elevidys is an adeno-associated virus vector-based gene therapy using Sarepta Therapeutics, Inc.’s AAVrh74 Platform Technology for the treatment of Duchenne muscular dystrophy (DMD). It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin, a shortened protein (138 kDa, compared to the 427 kDa dystrophin protein of normal muscle cells) that contains selected domains of the dystrophin protein present in normal muscle cells. The product is administered as a single intravenous dose.

Duchenne muscular dystrophy is a rare and serious genetic condition which worsens over time, leading to weakness and wasting away of the body’s muscles. The disease occurs due to a defective gene that results in abnormalities in, or absence of, dystrophin, a protein that helps keep the body’s muscle cells intact.

Further, today, the FDA revoked the platform technology designation for Sarepta’s AAVrh74 Platform Technology because, among other things, given the new safety information, the preliminary evidence is insufficient to demonstrate that AAVrh74 Platform Technology has the potential to be incorporated in, or utilized by, more than one drug without an adverse effect on safety.

Elevidys received traditional approval for use in ambulatory DMD patients 4 years of age and older with a confirmed mutation in the DMD gene on June 20, 2024. It was approved for non-ambulatory patients on June 22, 2023 under the accelerated approval pathway. This pathway can allow earlier approval based on an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit, while the company conducts confirmatory studies to verify the predicted clinical benefit. Continued approval for non-ambulatory patients is contingent upon verification and description of clinical benefit in a confirmatory trial. Given the new safety information, The FDA has notified the company that the indication should be restricted to use in ambulatory patients. The FDA is committed to further investigating the safety of the product in ambulatory patients and will take additional steps to protect patients as needed.

 

On July 18 Sarepta appeared to be disregarding the FDA release (according to the New York Times)

 

Source: https://www.nytimes.com/2025/07/18/health/fda-sarepta-elevidys-duchenne.html 

 

Published July 18, 2025 

 

In a remarkable public dispute between drugmaker and regulator, the biotech company Sarepta Therapeutics is defying the Food and Drug Administration’s request that it halt distribution of its treatment for a deadly muscle-wasting disease.

In a news release on Friday evening, the agency said that it requested that the company voluntarily stop all shipments of the therapy, known as Elevidys, citing the deaths of three patients from liver failure who had taken the product or a similar therapy.

In its own news release later on Friday evening, Sarepta, which is based in Cambridge, Mass., said that it would continue to ship the treatment for patients who do not use wheelchairs. The company said its analysis showed no new safety problems in those patients and that it was committed to patient safety.

Dr. Marty Makary, the F.D.A. commissioner, said in the agency’s statement that its request to Sarepta demonstrated that the F.D.A. “takes swift action when patient safety is at risk.”

“We believe in access to drugs for unmet medical needs but are not afraid to take immediate action when a serious safety signal emerges,” he said.

In the past, the F.D.A. has sometimes asked companies to pause distribution of a drug until a new problem is better understood and mitigated. However, it can also press its case, and begin a process to revoke the drug’s license, which would begin with a formal notification and opportunity to respond and participate in a public hearing.

 

On July 21, 2025 Sarepta announces on their website in press release

 

Sarepta Therapeutics Announces Voluntary Pause of ELEVIDYS Shipments in the U.S.

07/21/25 7:40 PM EDT

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Jul. 21, 2025– Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today issued the following statement:

Today, Sarepta Therapeutics notified the U.S. Food and Drug Administration (FDA) of its decision to voluntarily and temporarily pause all shipments of ELEVIDYS (delandistrogene moxeparvovec) for Duchenne muscular dystrophy in the United States, effective close of business Tuesday, July 22, 2025.

This proactive step will allow Sarepta the necessary time to respond to any requests for information and allow Sarepta and FDA to complete the ELEVIDYS safety labeling supplement process. The Company looks forward to a collaborative, science-driven review process and dialogue with the FDA.

“As a patient-centric organization, the decision to voluntarily and temporarily pause shipments of ELEVIDYS was a painful one, as individuals with Duchenne are losing muscle daily and in need of disease-modifying options,” said Doug Ingram, chief executive officer, Sarepta. “It is important for the patients we serve that Sarepta maintains a productive and positive working relationship with FDA, and it became obvious that maintaining that productive working relationship required this temporary suspension while we address any questions that FDA may have and complete the ELEVIDYS label supplement process.”

Sarepta remains committed to transparency and patient safety and will continue to provide timely updates to patients, families, healthcare providers, and the broader Duchenne community as additional information becomes available.

About ELEVIDYS (delandistrogene moxeparvovec-rokl)
ELEVIDYS (delandistrogene moxeparvovec-rokl) is a single-dose, adeno-associated virus (AAV)-based gene transfer therapy for intravenous infusion designed to address the underlying genetic cause of Duchenne muscular dystrophy – mutations or changes in the DMD gene that result in the lack of dystrophin protein – through the delivery of a transgene that codes for the targeted production of ELEVIDYS micro-dystrophin in skeletal muscle.

ELEVIDYS is indicated for the treatment of Duchenne muscular dystrophy (DMD) in individuals at least 4 years of age.

  • For patients who are ambulatory and have a confirmed mutation in the DMD gene
  • For patients who are non-ambulatory and have a confirmed mutation in the DMD gene.

However this is not the first time Sarepta has been in the hot seat… 

 

Read this interesting article from Derrick  Lowe of Science.  I will put it in its entirety as Derick Lowe really writes some great articles in his blog.

 

Source: https://www.science.org/content/blog-post/sarepta-why 

 

Sarepta. Why? 21 Jun 2024

 

I really, really wish that I were not writing about Sarepta again. But here we are. Perhaps a quick review will explain my reluctance.

Back in 2013, the company was trying to get approval for an unusual “exon skipping” molecule (eteplirsen) as a therapy for Duchenne muscular dystropy. Nothing wrong with that – in fact, there’s a lot that’s right with that, since Duchenne is a perfect “unmet medical need” situation, and the exon-skipping idea was an innovative approach ten years ago (and it’s still not exactly a standard-issue therapy). Attacking very hard-to-treat diseases with new mechanisms of action is just what we’re supposed to be doing in this business.

The approval, though, was having trouble for some very good reasons. Sarepta’s trial was very, very small and the FDA later found that their trial design was very, very flawed. But in 2016 eteplirsen was suddenly approved, to the surprise of many observers (including me). A few years later, a follow-up drug (golodirsen) from the company (golodirsen) was also rejected by the FDA (with a Complete Response Letter) but then was later suddenly approved, although no new data had been presented. That was particularly mystifying since the eventually-published CRL detailed a number of real problems with eteplirsen since its approval, problems that looked to be possibly even greater with the follow-up drug. To the best of my knowledge, the confirmatory Phase III trial that was required at the time of golodirsen’s approval is still going on and is expected to read out next year. In 2021, another Sarepta exon-skipping drug (different exon this time) was approved (casimirsen) on the basis of biomarker levels that were expected to show eventual clinical benefit, and I believe that its confirmatory trial is part of the golodirsen one. That one at least did not go through the first-rejected-then-approved pathway.

More recently the company has been working on an outright gene therapy (elevidys) for Duchenne, and the initial results were quite promising. The company got accelerated FDA approval for that one last June for 4- and 5-year-old patients, even though actual clinical benefit had not yet been established. But gene therapy is a winding road, and last October the Phase III results for Elevidys were a complete miss in the primary endpoint. Arguing commenced, with the company saying that the results in the secondary endpoints showed that the drug was “modifying the trajectory” of the disease, and the CEO called the results a “massive win” and said that the company would use them to ask for a much wider label approval from the FDA. Apparently during the conference call, when he was asked about why he was so confident, he said that the FDA’s CBER head Peter Marks was “very supportive”. (It should be noted that since then another Duchenne gene therapy effort, this one from Pfizer, also failed its Phase III, so it’s not like this is a straightforward area).

Boy, was that the truth. The agency has just granted that use expansion, and it turns out that it was all due to Peter Marks, who completely overruled three review teams and two of his highest-level staffers (all of whom said that Sarepta had not proven its case). Honestly, I’m starting to wonder why any of us go to all this trouble. It appears that all you need is a friend high up in the agency and your clinical failures just aren’t an issue any more. Review committees aren’t convinced? Statisticians don’t buy your arguments? Who cares! Peter Marks is here to deliver hot, steaming takeout containers full of Hope.

Back in 2016, when eteplirsen first came up for its advisory committee vote, I wrote that there was a matrix of possible votes and interpretations, which I summed up this way:

(1) A negative vote, which is a rejection of the potential of the drug, the suffering of DMD patients, and their right to try a therapy which apparently does no harm, for a disease that has no other options.

(2) A negative vote, which is the only possible one, considering that the company’s trial data are far too sparse and unconvincing to allow a recommendation to approve the drug. If this gets recommended, what doesn’t? Why do we require new drugs to show efficacy at all?

 

(3) A positive vote, which is a victory for patient advocates everywhere, and in particular for the extremely ill boys who suffer from this disease, or. . .

 

(4) A positive vote, which marks an undeserved and potentially hazardous victory of emotional rhetoric and relentless patient advocacy over the scientific and medical evidence.

As I’ve said many times since, including just a few days ago, I believe that the FDA is tilting very, very noticeably towards #4 while proclaiming the wonderful new world of #3. And while I realize that this may make me sound like a heartless SOB, I think this is a huge mistake that we will be paying for for a long time.

 

Note that there has been reported deaths in 2024.

 

The following was from some data published in Nature in 2025 from Clinical Trial ClinicalTrials.gov: NCT05096221.

Mendell JR, Muntoni F, McDonald CM, Mercuri EM, Ciafaloni E, Komaki H, Leon-Astudillo C, Nascimento A, Proud C, Schara-Schmidt U, Veerapandiyan A, Zaidman CM, Guridi M, Murphy AP, Reid C, Wandel C, Asher DR, Darton E, Mason S, Potter RA, Singh T, Zhang W, Fontoura P, Elkins JS, Rodino-Klapac LR. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med. 2025 Jan;31(1):332-341. doi: 10.1038/s41591-024-03304-z

 

Abstract

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials.

As noted in the adobe abstract everything seemed to fine as reported in  this trial.

However there was a report of an immunoloically related death in 2023:

 

For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), a gene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4-5 years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. Two deaths following DMD gene therapy with high-dose AAV vectors were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal AAV toxicity.

 

Now this may have been dose related as the patient was given a high dose.

 

DMD gene therapy death exposes risks of treating older patients

By Nick Paul Taylor  May 19, 2023 9:35am

Duchenne muscular dystrophy (DMD) Cell & Gene Therapy gene therapy viral vectors

Cure Rare Disease plans to continue its programs with alternative vectors. (iStock / Getty Images Plus)

Cure Rare Disease has shared a deep dive into the death of the only participant in a gene therapy trial. The nonprofit and its collaborators tied the death of a patient with Duchenne muscular dystrophy (DMD) to an immune reaction to the viral vector, raising concerns about dosing older, more advanced people. 

Commercial development of DMD gene therapies has focused on younger patients, with Sarepta Therapeutics limiting enrollment in its phase 3 trial to children aged 4 to 8 years old. The restrictive recruitment criteria have stopped many DMD patients from accessing gene therapies in clinical trials run by Sarepta and its rivals. The patient dosed in the Cure Rare Disease clinical trial was 27 years of age, and the therapy had been designed for him. 

Last year, the nonprofit reported that the patient, who was the brother of its CEO, died after receiving the therapy. The death led to an investigation into what happened after the patient received the therapy, which was designed to use CRISPR transactivation to upregulate an alternate form of a key DMD protein.

Writing in preprint journal medRxiv (PDF), Cure Rare Disease described the findings of the investigation. A post-mortem showed injuries to the patient’s lungs, likely caused by a strong immune reaction to the high dose of the adeno-associated virus (AAV) vector that was given to try to ensure sufficient expression to achieve a therapeutic effect. There was minimal expression of the transgene in the liver. 

At 1×1014 vg/kg, the studied dose was similar to that tested in other clinical trials but resulted in a higher vector genome load, a finding the researchers attributed to the patient’s lower lean muscle mass, 45%. The analysis suggests the patient had “a more severe innate immune reaction than others receiving similar or slightly higher doses of rAAV in microdystrophin gene therapy trials.” 

Based on the finding, the researchers identified a need for more data on the characteristics that may predispose people to severe innate immune reactions and concluded “dose determination will remain a challenge for custom-designed AAV-mediated therapies, as by definition the precise therapeutic dose will not have been established.”

As for the application of CRISPR, the researchers said the toxicity and eventual death of the patient meant that an assessment of the safety and efficacy of the treatment was not possible.  

AAV related clinical trials have been  halted for drug-induced liver injury, predominantly due to severe immune reaction.  In many cases it appears when high dose AAV therapy is used.

 

Duan D. Lethal immunotoxicity in high-dose systemic AAV therapy. Mol Ther. 2023 Nov 1;31(11):3123-3126. Doi: 10.1016/j.ymthe.2023.10.015

.10.015. Epub 2023 Oct 10. PMID: 37822079; PMCID: PMC10638066.

Abstract

High-dose systemic gene therapy with adeno-associated virus (AAV) is in clinical trials to treat various inherited diseases. Despite remarkable success in spinal muscular atrophy and promising results in other diseases, fatality has been observed due to liver, kidney, heart, or lung failure. Innate and adaptive immune responses to the vector play a critical role in the toxicity. Host factors also contribute to patient death. This mini-review summarizes clinical findings and calls for concerted efforts from all stakeholders to better understand the mechanisms underlying lethality in AAV gene therapy and to develop effective strategies to prevent/treat high-dose systemic AAV-gene-therapy-induced immunotoxicity.

Table 1.

Fatality cases following high-dose systemic AAV delivery

Drug name AAV Clinical profile Reference
Serotype Dose (vg/kg) Promoter Transgene Disease Patient age Time of death Cause of death Immunotoxicity Clinical trial ID
Acute death PF-06939926 AAV9 2 × 1014 miniMCK μDys gene DMD 16 years 6 days post-dosing heart failure innate response NCT03362502 Lek et al.,8 Philippidis9, and Lek et al.10
CRD-TMH-001 AAV9 1 × 1014 CK8e dCas9-VP64 and gRNA DMD 27 years 8 days post-dosing lung failure innate response (cytokine-mediated) NCT05514249 Lek et al.10
Subacute death Zolgensma AAV9 1.1 × 1014 CBA SMN gene SMA ≤2 years (4 patients) 5–6 weeks post-dosing liver failure adaptive response post-marketing Philippidis, Whiteley, and Kishimoto and Samulski6,19,20
Zolgensma AAV9 1.1 × 1014 CBA SMN gene SMA 6 months 8 weeks post-dosing kidney failure innate response (complement mediated) post-marketing Guillou et al.7
AT132 AAV8 1.3–3 × 1014 DES MTM1 gene XLMTM ≤5 years (4 patients) 20–40 weeks post-dosing liver fa

 

Table from Duan D. Lethal immunotoxicity in high-dose systemic AAV therapy. Mol Ther. 2023 Nov 1;31(11):3123-3126. source: https://pmc.ncbi.nlm.nih.gov/articles/PMC10638066/ 

 

Roche Decides to Stop backing Sparks Therapeutics Hemophilia A Gene Therapy Program

 

     In 2019, Roche acquired Children’s Hospital of Pennsylvania (CHOP) spinout Spark Therapeutics for $4.8 billion, one of the largest pharma acquisitions up to that time.  It was reported on this site here

 

Spark Therapeutics’ $4.8Billion deal Confirmed as Biggest VC-backed Exit in Philadelphia

 

https://pharmaceuticalintelligence.com/2019/03/01/spark-therapeutics-4-8billion-deal-confirmed-as-biggest-vc-backed-exit-in-philadelphia/ 

However as reported by Fierce Biotech (and updated above link) at https://www.fiercepharma.com/pharma/roche-overhauls-spark-gene-therapy-unit-recording-24b-full-impairment  Roche will reorganize the company and deal, bringing in Spark into the corporate fold.  However this meant massive layoffs and possibly either end of the gene therapy program in order to integrate it with Roche’s current programs.  The Spark gene therapy has met with success so it will be interesting to see how Roche continues this program in the future.

However it has been a rough year for many gene therapies.

Other Articles in this Open Access Scientific Journol of Gene Therapy 

Tailored Hope: Personalized Gene Therapy Makes History

Lessons on the Frontier of Gene & Cell Therapy – The Disruptive Dozen 12 #GCT Breakthroughs that are revolutionizing Healthcare

Novartis uses a ‘dimmer switch’ medication to fine-tune gene therapy candidates

Top Industrialization Challenges of Gene Therapy Manufacturing

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Bridging the Gender Gap in Healthcare: Unlocking Biopharma’s Potential in Women’s Health

Curator: Dr. Sudipta Saha, Ph.D.

Nearly half of the global population—and 80 percent of patients in therapeutic areas such as immunology—are women. Yet, treatments are frequently developed without tailored insights for female patients, often ignoring critical biological differences such as hormonal impacts, genetic factors, and cellular sex. Historically, women’s health has been narrowly defined through the lens of reproductive organs, while for non-reproductive conditions, women were treated as “small men.” This lack of focus on sex-specific biology has contributed to significant gaps in healthcare.

A recent analysis found that women spend 25 percent more of their lives in poor health compared with men due to the absence of sex-based treatments. Addressing this disparity could not only improve women’s quality of life but also unlock over $1 trillion in annual global GDP by 2040.

Four key factors contribute to the women’s health gap: limited understanding of sex-based biological differences, healthcare systems designed around male physiology, incomplete data that underestimates women’s disease burden, and chronic underfunding of female-focused research. For instance, despite women representing 78 percent of U.S. rheumatoid arthritis patients, only 7 percent of related NIH funding in 2019 targeted female-specific studies.

However, change is happening. Companies have demonstrated how targeted R&D can drive better outcomes for women. These therapies achieved expanded FDA approvals after clinical trials revealed their unique benefits for female patients. Similarly, addressing sex-based treatment gaps in asthma, atrial fibrillation, and tuberculosis could prevent millions of disability-adjusted life years.

By closing the women’s health gap, biopharma companies can drive innovation, improve therapeutic outcomes, and build high-growth markets while addressing long-standing inequities. This untapped opportunity holds the potential to transform global health outcomes for women and create a more equitable future.

References

https://www.mckinsey.com/industries/life-sciences/our-insights/closing-the-womens-health-gap-biopharmas-untapped-opportunity?stcr=97136BA6BDD64C2396A57E9487438CC6

https://www.weforum.org

https://www.nih.gov

https://www.fda.gov

https://www.who.int

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Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Curators:

 

THE VOICE of Aviva Lev-Ari, PhD, RN

In this curation we wish to present two breaking through goals:

Goal 1:

Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer

Goal 2:

Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.

According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.

These eight subcellular pathologies can’t be measured at present time.

In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.

Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases

  1. Glycation
  2. Oxidative Stress
  3. Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
  4. Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
  5. Membrane instability
  6. Inflammation in the gut [mucin layer and tight junctions]
  7. Epigenetics/Methylation
  8. Autophagy [AMPKbeta1 improvement in health span]

Diseases that are not Diseases: no drugs for them, only diet modification will help

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

Exercise will not undo Unhealthy Diet

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:

  1. Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
  2. IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL

In the Bioelecronics domain we are inspired by the work of the following three research sources:

  1. Biological and Biomedical Electrical Engineering (B2E2) at Cornell University, School of Engineering https://www.engineering.cornell.edu/bio-electrical-engineering-0
  2. Bioelectronics Group at MIT https://bioelectronics.mit.edu/
  3. The work of Michael Levin @Tufts, The Levin Lab
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
Born: 1969 (age 54 years), Moscow, Russia
Education: Harvard University (1992–1996), Tufts University (1988–1992)
Affiliation: University of Cape Town
Research interests: Allergy, Immunology, Cross Cultural Communication
Awards: Cozzarelli prize (2020)
Doctoral advisor: Clifford Tabin
Most recent 20 Publications by Michael Levin, PhD
SOURCE
SCHOLARLY ARTICLE
The nonlinearity of regulation in biological networks
1 Dec 2023npj Systems Biology and Applications9(1)
Co-authorsManicka S, Johnson K, Levin M…
SCHOLARLY ARTICLE
Toward an ethics of autopoietic technology: Stress, care, and intelligence
1 Sep 2023BioSystems231
Co-authorsWitkowski O, Doctor T, Solomonova E…
SCHOLARLY ARTICLE
Closing the Loop on Morphogenesis: A Mathematical Model of Morphogenesis by Closed-Loop Reaction-Diffusion
14 Aug 2023Frontiers in Cell and Developmental Biology11:1087650
Co-authorsGrodstein J, McMillen P, Levin M
SCHOLARLY ARTICLE
30 Jul 2023Biochim Biophys Acta Gen Subj1867(10):130440
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
Regulative development as a model for origin of life and artificial life studies
1 Jul 2023BioSystems229
Co-authorsFields C, Levin M
SCHOLARLY ARTICLE
The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left–Right Functional Differences
1 Jul 2023International Journal of Molecular Sciences24(13)
Co-authorsMasuelli S, Real S, McMillen P…
SCHOLARLY ARTICLE
Bioelectricidad en agregados multicelulares de células no excitables- modelos biofísicos
Jun 2023Revista Española de Física32(2)
Co-authorsCervera J, Levin M, Mafé S
SCHOLARLY ARTICLE
Bioelectricity: A Multifaceted Discipline, and a Multifaceted Issue!
1 Jun 2023Bioelectricity5(2):75
Co-authorsDjamgoz MBA, Levin M
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part I: Classical and Quantum Formulations of Active Inference
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):235-245
Co-authorsFields C, Fabrocini F, Friston K…
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part II: Tensor Networks as General Models of Control Flow
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):246-256
Co-authorsFields C, Fabrocini F, Friston K…
SCHOLARLY ARTICLE
Darwin’s agential materials: evolutionary implications of multiscale competency in developmental biology
1 Jun 2023Cellular and Molecular Life Sciences80(6)
Co-authorsLevin M
SCHOLARLY ARTICLE
Morphoceuticals: Perspectives for discovery of drugs targeting anatomical control mechanisms in regenerative medicine, cancer and aging
1 Jun 2023Drug Discovery Today28(6)
Co-authorsPio-Lopez L, Levin M
SCHOLARLY ARTICLE
Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine
12 May 2023Patterns4(5)
Co-authorsMathews J, Chang A, Devlin L…
SCHOLARLY ARTICLE
Making and breaking symmetries in mind and life
14 Apr 2023Interface Focus13(3)
Co-authorsSafron A, Sakthivadivel DAR, Sheikhbahaee Z…
SCHOLARLY ARTICLE
The scaling of goals from cellular to anatomical homeostasis: an evolutionary simulation, experiment and analysis
14 Apr 2023Interface Focus13(3)
Co-authorsPio-Lopez L, Bischof J, LaPalme JV…
SCHOLARLY ARTICLE
The collective intelligence of evolution and development
Apr 2023Collective Intelligence2(2):263391372311683SAGE Publications
Co-authorsWatson R, Levin M
SCHOLARLY ARTICLE
Bioelectricity of non-excitable cells and multicellular pattern memories: Biophysical modeling
13 Mar 2023Physics Reports1004:1-31
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
There’s Plenty of Room Right Here: Biological Systems as Evolved, Overloaded, Multi-Scale Machines
1 Mar 2023Biomimetics8(1)
Co-authorsBongard J, Levin M
SCHOLARLY ARTICLE
Transplantation of fragments from different planaria: A bioelectrical model for head regeneration
7 Feb 2023Journal of Theoretical Biology558
Co-authorsCervera J, Manzanares JA, Levin M…
SCHOLARLY ARTICLE
Bioelectric networks: the cognitive glue enabling evolutionary scaling from physiology to mind
1 Jan 2023Animal Cognition
Co-authorsLevin M
SCHOLARLY ARTICLE
Biological Robots: Perspectives on an Emerging Interdisciplinary Field
1 Jan 2023Soft Robotics
Co-authorsBlackiston D, Kriegman S, Bongard J…
SCHOLARLY ARTICLE
Cellular Competency during Development Alters Evolutionary Dynamics in an Artificial Embryogeny Model
1 Jan 2023Entropy25(1)
Co-authorsShreesha L, Levin M
5

5 total citations on Dimensions.

Article has an altmetric score of 16
SCHOLARLY ARTICLE
1 Jan 2023BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY138(1):141
Co-authorsClawson WP, Levin M
SCHOLARLY ARTICLE
Future medicine: from molecular pathways to the collective intelligence of the body
1 Jan 2023Trends in Molecular Medicine
Co-authorsLagasse E, Levin M

THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC

PENDING

THE VOICE of  Stephen J. Williams, PhD

Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes

 

  1. 25% of US children have fatty liver
  2. Type II diabetes can be manifested from fatty live with 151 million  people worldwide affected moving up to 568 million in 7 years
  3. A common myth is diabetes due to overweight condition driving the metabolic disease
  4. There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
  5. Thirty percent of ‘obese’ people just have high subcutaneous fat.  the visceral fat is more problematic
  6. there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects.  Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
  7. At any BMI some patients are insulin sensitive while some resistant
  8. Visceral fat accumulation may be more due to chronic stress condition
  9. Fructose can decrease liver mitochondrial function
  10. A methionine and choline deficient diet can lead to rapid NASH development

 

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A Platform called VirtualFlow: Discovery of Pan-coronavirus Drugs help prepare the US for the Next Coronavirus Pandemic

Reporter: Aviva Lev-Ari, PhD, RN

 

ARTICLE|ONLINE NOW, 102021

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Open AccessPublished:January 04, 2021DOI:https://doi.org/10.1016/j.isci.2020.102021

 

The work was made possible in large part by about $1 million in cloud computing hours awarded by Google through a COVID-19 research grant program.

The work reported, below was sponsored by

  • a Google Cloud COVID-19 research grant. Funding was also provided by the
  • Fondation Aclon,
  • National Institutes of Health (GM136859),
  • Claudia Adams Barr Program for Innovative Basic Cancer Research,
  • Math+ Berlin Mathematics Research Center,
  • Templeton Religion Trust (TRT 0159),
  • U.S. Army Research Office (W911NF1910302), and
  • Chleck Family Foundation

 

Harvard University, AbbVie form research alliance to address emergent viral diseases

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Harvard University and AbbVie today announced a $30 million collaborative research alliance, launching a multi-pronged effort at Harvard Medical School to study and develop therapies against emergent viral infections, with a focus on those caused by coronaviruses and by viruses that lead to hemorrhagic fever.

The collaboration aims to rapidly integrate fundamental biology into the preclinical and clinical development of new therapies for viral diseases that address a variety of therapeutic modalities. HMS has led several large-scale, coordinated research efforts launched at the beginning of the COVID-19 pandemic.

“A key element of having a strong R&D organization is collaboration with top academic institutions, like Harvard Medical School, to develop therapies for patients who need them most,” said Michael Severino, vice chairman and president of AbbVie. “There is much to learn about viral diseases and the best way to treat them. By harnessing the power of collaboration, we can develop new therapeutics sooner to ensure the world is better prepared for future potential outbreaks.”

“The cataclysmic nature of the COVID-19 pandemic reminds us how vital it is to be prepared for the next public health crisis and how critical collaboration is on every level—across disciplines, across institutions and across national boundaries,” said George Q. Daley, dean of Harvard Medical School. “Harvard Medical School, as the nucleus of an ecosystem of fundamental discovery and therapeutic translation, is uniquely positioned to propel this transformative research alongside allies like AbbVie.”

AbbVie will provide $30 million over three years and additional in-kind support leveraging AbbVie’s scientists, expertise and facilities to advance collaborative research and early-stage development efforts across five program areas that address a variety of therapeutic modalities:

  • Immunity and immunopathology—Study of the fundamental processes that impact the body’s critical immune responses to viruses and identification of opportunities for therapeutic intervention.

Led by Ulirich Von Andrian, the Edward Mallinckrodt Jr. Professor of Immunopathology in the Blavatnik Institute at HMS and program leader of basic immunology at the Ragon Institute of MGH, MIT and Harvard, and Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Host targeting for antiviral therapies—Development of approaches that modulate host proteins in an effort to disrupt the life cycle of emergent viral pathogens.

Led by Pamela Silver, the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Antibody therapeutics—Rapid development of therapeutic antibodies or biologics against emergent pathogens, including SARS-CoV-2, to a preclinical or early clinical stage.

Led by Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS, and by Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Small molecules—Discovery and early-stage development of small-molecule drugs that would act to prevent replication of known coronaviruses and emergent pathogens.

Led by Mark Namchuk, executive director of therapeutics translation at HMS and senior lecturer on biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Translational development—Preclinical validation, pharmacological testing, and optimization of leading approaches, in collaboration with Harvard-affiliated hospitals, with program leads to be determined.

SOURCE

https://hms.harvard.edu/news/joining-forces

 

 

A Screen Door Opens

Virtual screen finds compounds that could combat SARS-CoV-2

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Less than a year ago, Harvard Medical School researchers and international colleagues unveiled a platform called VirtualFlow that could swiftly sift through more than 1 billion chemical compounds and identify those with the greatest promise to become disease-specific treatments, providing researchers with invaluable guidance before they embark on expensive and time-consuming lab experiments and clinical trials.

Propelled by the urgent needs of the pandemic, the team has now pushed VirtualFlow even further, conducting 45 screens of more than 1 billion compounds each and ranking the compounds with the greatest potential for fighting COVID-19—including some that are already approved by the FDA for other diseases.

“This was the largest virtual screening effort ever done,” said VirtualFlow co-developer Christoph Gorgulla, research fellow in biological chemistry and molecular pharmacology in the labs of Haribabu Arthanari and Gerhard Wagner in the Blavatnik Institute at HMS.

The results were published in January in the open-access journal iScience.

The team searched for compounds that bind to any of 15 proteins on SARS-CoV-2 or two human proteins, ACE2 and TMPRSS2, known to interact with the virus and enable infection.

Researchers can now explore on an interactive website the 1,000 most promising compounds from each screen and start testing in the lab any ones they choose.

The urgency of the pandemic and the sheer number of candidate compounds inspired the team to release the early results to the scientific community.

“No one group can validate all the compounds as quickly as the pandemic demands,” said Gorgulla, who is also an associate of the Department of Physics at Harvard University. “We hope that our colleagues can collectively use our results to identify potent inhibitors of SARS-CoV-2.”

In most cases, it will take years to find out whether a compound is safe and effective in humans. For some of the compounds, however, researchers have a head start.

Hundreds of the most promising compounds that VirtualFlow flagged are already FDA approved or being studied in clinical or preclinical trials for other diseases. If researchers find that one of those compounds proves effective against SARS-CoV-2 in lab experiments, the data their colleagues have already collected could save time establishing safety in humans.

Other compounds among VirtualFlow’s top hits are currently being assessed in clinical trials for COVID-19, including several drugs in the steroid family. In those cases, researchers could build on the software findings to investigate how those drug candidates work at the molecular level—something that’s not always clear even when a drug works well.

It shows what we’re capable of computationally during a pandemic.

Hari Arthanari

SOURCE

https://hms.harvard.edu/news/screen-door-opens?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews02012021

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Tweet Collection by @pharma_BI and @AVIVA1950 and Re-Tweets for e-Proceedings 14th Annual BioPharma &amp; Healthcare Summit, Friday, September 4, 2020, 8 AM EST to 3-30 PM EST – Virtual Edition

Reporter: Aviva Lev-Ari, PhD, RN

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

 

e-Proceedings 14th Annual BioPharma & Healthcare Summit, Friday, September 4, 2020, 8 AM EST to 3-30 PM EST – Virtual Edition

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

Founder & Director, LPBI Group

https://pharmaceuticalintelligence.com/2020/07/28/14th-annual-biopharma-healthcare-summit-friday-september-4-2020-8-am-est-to-3-30-pm-est-virtual-edition/

 

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Hal Barron, Chief Scientific Officer and President R&D, GlaxoSmithKline GWAS not easy to find which gene drives the association  Functional Genomics gene by gene with phenotypes using machine learning significant help

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Hal Barron, Chief Scientific Officer and President R&D, GSK GWAS not easy to find which gene drives the association  Functional Genomics gene by gene with phenotypes using machine learning significant help

Srihari Gopal
@sgopal2

Enjoyed hearing enthusiasm for Neuroscience R&D by Roy Vagelos at #USAIC20. Wonderful interview by Mathai Mammen

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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Nina Kjellson, General Partner, Canaan Data science is a winner in Healthcare Women – Data Science is an excellent match

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Arpa Garay, President, Global Pharmaceuticals, Commercial Analytics, Merck & Co. Data on Patients and identification who will benefit fro which therapy  cultural bias risk aversion

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Najat Khan, Chief Operating Officer, Janssen R&D Data Sciences, Johnson & Johnson Data Validation  Deployment of algorithms embed data by type early on in the crisis to understand the disease

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Sastry Chilukuri, President, Acorn AI- Medidata Opportunities in Data Science in Paharma COVID-19 and Data Science

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Maya Said, Chief Executive Officer, Outcomes4Me Cancer patients taking change of their care Digital Health – consumerization of Health, patient demand to be part of the decision, part the information FDA launched a Program Project Patient Voice

USAIC
@USAIC

We’re taking a quick break at #USAIC20 before our next panel on rare diseases starts at 12:20pm EDT. USAIC would like to thank our Sponsors and Partners for supporting this year’s digital event.

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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Roy Vagelos, Chairman of the Board, Regeneron HIV-AIDS: reverse transcriptase converted a lethal disease to a chronic disease, tried hard to make vaccine – the science was not there

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Roy Vagelos, Chairman of the Board, Regeneron Pharmaceuticals Congratulates Big Pharma for taking the challenge on COVID-19 Vaccine, Antibody and anti-viral Government funding Merck was independent from Government – to be able to set the price

1

Dr Kapil Khambholja
@kapilmk

Christopher Viehbacher, Gurnet Point Capital touches very sensitive topic at #USAIC20 He claims that we are never going to have real innovation out of big pharma! Well this isn’t new but not entirely true either… any more thoughts?
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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Daphne Zohar, Founder & CEO, PureTech Health Disease focus, best science is the decision factors

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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Christopher Viehbacher, Managing Partner, Gurnet Point Capital Dream of every Biotech – get Big Pharma coming to acquire and pay a lot Morph and adapt

anju ghangurde
@scripanjug

Biogen’s chair Papadopoulos big co mergers is an attempt to solve problems; typically driven by patent expirations.. #usaic20

2

anju ghangurde
@scripanjug

Chris Viehbacher/Gurnet Point Capital on US election: industry will work with whoever wins; we’ll have to ‘morph & adapt’ #usaic20

1

Dr Kapil Khambholja
@kapilmk

of

talks about various philosophies and key reasons why certain projects/molecules are killed early. My counter questions- What are chances of losing hope little early? Do small #biopharma publish negative results to aid to the knowledge pool? #USAIC20

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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Laurie Glimcher, President & CEO, Dana-Farber Cancer Institute DNA repair and epignetics are the future of medicine

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Laurie Glimcher, President & CEO, Dana-Farber Cancer Institute COlonorectal cancer is increasing immuno therapy 5 drugs marketed 30% cancer patients are treated early detection key vs metastatic 10% of cancer are inherited treatment early

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Rehan Verjee, President, EMD Serono Charities funding cancer research – were impacted and resources will come later and in decreased amount New opportunities support access to Medicine improve investment across the board

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Philip Larsen, Global Head of Research, Bayer AG Repurposing drugs as antiviral from drug screening innovating methods Cytokine storm in OCVID-19 – kinase inhibitors may be antiviral data of tested positive allows research of pathway in new ways

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Laurie Glimcher, President & CEO, Dana-Farber 3,000 Telemedicine session in the first week of the Pandemic vs 300 before – patient come back visits patient happy with Telemedicine team virtually need be reimbursed same rate working remotely

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Raju Kucherlapati, Professor of Genetics, Harvard Medical School New normal as a result of the pandemic role of personalized medicine

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Rehan Verjee, President, EMD Serono entire volume of clinical trials at Roche went down same at EMD delay of 6 month, some were to be initiated but was put on hold Charities funding cancer research were impacted and resources will come later smaller

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Laurie Glimcher, President & CEO, Dana-Farber Cancer Institute Dana Farber saw impact of COVID-19 on immunosuppressed patients coming in for Cancer Tx – switch from IV Tx to Oral 96% decrease in screenings due to Pandemic – increase with Cancer

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Kenneth Frazier, Chairman of the Board and Chief Executive Officer, Merck & Co. Pharma’s obligation for next generations requires investment in R&D vs Politicians running for 4 years Patients must come first vs shareholders vs R&D investment in 2011

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Kenneth Frazier, Chairman of the Board and Chief Executive Officer, Merck & Co. Antibiotic research at Merck – no market incentives on pricing for Merck to invest in antibiotics people will die from bacterial resistance next pandemic be bacterial

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Kenneth Frazier, Chairman of the Board and Chief Executive Officer, Merck & Co. Strategies of Merck = “Medicine is for the People not for Profit” – Ketruda in India is not reembureable in India and million are in need it Partnership are encouraged

Dr Kapil Khambholja
@kapilmk

Chairman Stelios Papadopoulos asks #KennethFrazier if wealthy nations will try to secure large proportion of #COVID19 drugs/vaccines. #KennethFrazie rightly mentions: pharma industry’s responsibility to balance the access to diff countries during pandemic. #USAIC20

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Dr Kapil Khambholja
@kapilmk

Almost 60% participants at #USAIC20 feel that MNCs are more likely to run their #clinicalTrials in #INDIA seeing changing environment here, reveals the poll. Exciting time ahead for scientific fraternity as this can substantially increase the speed of #DrugDevelopment globally

Clapping hands sign

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Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Barry Bloom, Professor & former Dean, Harvard School of Public Health Vaccine in clinical trials, public need to return for 2nd shot, hesitancy Who will get the Vaccine first in the US  most vulnerable of those causing transmission Pharma’s risk

4

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr. Barry Bloom, Professor & former Dean, Harvard School of Public Health Testing – PCR expensive does not enable quick testing is expensive result come transmission occurred Antibody testing CRISPR test based Vaccine in clinical trials

1

Aviva Lev-Ari
@AVIVA1950

#USAIC20 Dr Andrew Plump, President of R&D, Takeda Pharmaceuticals COllaboration effort around the Globe in the Pandemic therapy solutions including Vaccines

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Top 15 pharmas, then=2020 and now=2026: How the next five years will shake up Big Pharma’s rankings

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Reporter: Stephen J. Williams, PhD

New Drugs on the Horizon: Part 3
Introduction

Andrew J. Phillips, C4 Therapeutics

  • symposium brought by AACR CICR and had about 30 proposals for talks and chose three talks
  • unfortunately the networking event is not possible but hope to see you soon in good health

ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies

Edward B Reilly
AbbVie Inc. @abbvie

  • T-cell receptors (TCR) can recognize the intracellular targets whereas antibodies only recognize the 25% of potential extracellular targets
  • survivin is expressed in multiple cancers and correlates with poor survival and prognosis
  • CD3 bispecific TCR to survivn (Ab to CD3 on T- cells and TCR to survivin on cancer cells presented in MHC Class A3)
  • ABBV184  effective in vivo in lung cancer models as single agent;
  • in humanized mouse tumor models CD3/survivin bispecific can recruit T cells into solid tumors; multiple immune cells CD4 and CD8 positive T cells were found to infiltrate into tumor
  • therapeutic window as measured by cytokine release assays in tumor vs. normal cells very wide (>25 fold)
  • ABBV184 does not bind platelets and has good in vivo safety profile
  • First- in human dose determination trial: used in vitro cancer cell assays to determine 1st human dose
  • looking at AML and lung cancer indications
  • phase 1 trial is underway for safety and efficacy and determine phase 2 dose
  • survivin has very few mutations so they are not worried about a changing epitope of their target TCR peptide of choice

The discovery of TNO155: A first in class SHP2 inhibitor

Matthew J. LaMarche
Novartis @Novartis

  • SHP2 is an intracellular phosphatase that is upstream of MEK ERK pathway; has an SH2 domain and PTP domain
  • knockdown of SHP2 inhibits tumor growth and colony formation in soft agar
  • 55 TKIs there are very little phosphatase inhibitors; difficult to target the active catalytic site; inhibitors can be oxidized at the active site; so they tried to target the two domains and developed an allosteric inhibitor at binding site where three domains come together and stabilize it
  • they produced a number of chemical scaffolds that would bind and stabilize this allosteric site
  • block the redox reaction by blocking the cysteine in the binding site
  • lead compound had phototoxicity; used SAR analysis to improve affinity and reduce phototox effects
  • was very difficult to balance efficacy, binding properties, and tox by adjusting stuctures
  • TNO155 is their lead into trials
  • SHP2 expressed in T cells and they find good combo with I/O with uptick of CD8 cells
  • TNO155 is very selective no SHP1 inhibition; SHP2 can autoinhibit itself when three domains come together and stabilize; no cross reactivity with other phosphatases
  • they screened 1.5 million compounds and got low hit rate so that is why they needed to chemically engineer and improve on the classes they found as near hits

Closing Remarks

 

Xiaojing Wang
Genentech, Inc. @genentech

Follow on Twitter at:

@pharma_BI

@AACR

@CureCancerNow

@pharmanews

@BiotechWorld

@HopkinsMedicine

#AACR20

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Pfizer buys out Array BioPharma for $11.4 Billion to beef up its oncology offerings

Reporter: Stephen J. Williams, PhD

As reported in FiercePharma.com:

by Angus Liu |

Three years after purchasing Medivation for $14.3 billion, Pfizer is back with another hefty M&A deal. And once again, it’s betting on oncology.

In the first big M&A deal under new CEO Albert Bourla, Pfizer has agreed to buy oncology specialist Array BioPharma for a total value of about $11.4 billion, the two companies unveiled Monday. The $48-per-share offer represents a premium of about 62% to Array stock’s closing price on Friday.

With the acquisition, Pfizer will beef up its oncology offerings with two marketed drugs, MEK inhibitor Mektovi and BRAF inhibitor Braftovi, which are approved as a combo treatment for melanoma and recently turned up positive results in colon cancer.

The buy will enhance the Pfizer innovative drug business’ “long-term growth trajectory,” Bourla said in a Monday statement, dubbing Mektovi-Braftovi “a potentially industry-leading franchise for colorectal cancer.”

RELATED: Array’s ‘extremely compelling’ new colon cancer data spark blockbuster talk

In a recent interim analysis of a trial in BRAF-mutant metastatic colorectal cancer, the pair, used in tandem with Eli Lilly and Merck KGaA’s Erbitux, produced a benefit in 26% of patients, versus the 2% that chemotherapy helped. The combo also showed it could reduce the risk of death by 48%. SVB Leerink analysts at that time called the data “extremely compelling.”

Right now, one in every three new patients with mutated metastatic melanoma is getting the combo, despite its third-to-market behind combos from Roche and Novartis, Andy Schmeltz, Pfizer’s oncology global president, said during an investor briefing on Monday.

It is being studied in more than 30 clinical studies across several solid tumor indications. Moving forward, Pfizer believes the combo could potentially be used in the adjuvant setting to prevent tumor recurrence after surgery, Pfizer’s chief scientific officer, Mikael Dolsten, said on the call. The company is also keen to know how it could be paired up with Pfizer’s own investigational PD-1, he said, as the combo is already in studies with other PD-1/L1s.

But as Pfizer execs have previously said, the company’s current business development strategy no longer centers on adding revenues “now or soon,” but rather on strengthening Pfizer’s pipeline with earlier-stage assets. And Array can help there, too.

“We are very excited by Array’s impressive track record of successfully discovering and developing innovative small-molecules and targeted cancer therapies,” Dolsten said in a statement.

On top of Mektovi and Braftovi, Array has a long list of out-licensed drugs that could generate big royalties over time. For example, Vitrakvi, the first drug to get an initial FDA approval in tumors with a particular molecular feature regardless of their location, was initially licensed to Loxo Oncology—which was itself snapped up by Eli Lilly for $8 billion—but was taken over by pipeline-hungry Bayer. There are other drugs licensed to the likes of AstraZeneca, Roche, Celgene, Ono Pharmaceutical and Seattle Genetics, among others.

Those drugs are also a manifestation of Array’s strong research capabilities. To keep those Array scientists doing what they do best, Pfizer is keeping a 100-person team in Colorado as a standalone research unit alongside Pfizer’s existing hubs, Schmeltz said.

Pfizer is counting on Array to augment its leadership in breast cancer, an area championed by Ibrance, and prostate cancer, the pharma giant markets Astellas-partnered Xtandi. For 2018, revenues from the Pfizer oncology portfolio jumped to $7.20 billion—up from $6.06 billion in 2017—mainly thanks to those two drugs.

Source: https://www.fiercepharma.com/pharma/pfizer-never-say-never-m-a-buys-oncology-innovator-array-for-11-4b

 

About Array BioPharma

Array markets BRAFTOVI® (encorafenib) capsules in combination with MEKTOVI® (binimetinib)  tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K  mutation in the United States and with partners in other major worldwide markets.* Array’s lead clinical programs, encorafenib and binimetinib, are being investigated in over 30 clinical trials across a number of solid tumor indications, including a Phase 3 trial in BRAF-mutant metastatic colorectal cancer. Array’s pipeline includes several additional programs being advanced by Array or current license-holders, including the following programs currently in registration trials: selumetinib (partnered with AstraZeneca), LOXO-292 (partnered with Eli Lilly), ipatasertib (partnered with Genentech), tucatinib (partnered with Seattle Genetics) and ARRY-797. Vitrakvi® (larotrectinib, partnered with Bayer AG) is approved in the United States and Ganovo® (danoprevir, partnered with Roche) is approved in China.

 

Other Articles of Note of Pfizer Merger and Acquisition deals on this Open Access Journal Include:

From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer; A Curation of Deals, Discovery and the State of Pharma

Pfizer Near Allergan Buyout Deal But Will Fed Allow It?

Pfizer offers legal guarantees over AstraZeneca bid

Re-Creation of the Big Pharma Model via Transformational Deals for Accelerating Innovations: Licensing vs In-house inventions

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Real Time Coverage of BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

Please follow LIVE on TWITTER using the following @ handles and # hashtags:

@Handles

@pharma_BI

@AVIVA1950

@BIOConvention

# Hashtags

#BIO2019 (official meeting hashtag)

Please check daily on this OPEN ACCESS JOURNAL for updates on one of the most important BIO Conferences of the year for meeting notes, posts, as well as occasional PODCASTS.

 

The BIO International Convention is the largest global event for the biotechnology industry and attracts the biggest names in biotech, offers key networking and partnering opportunities, and provides insights and inspiration on the major trends affecting the industry. The event features keynotes and sessions from key policymakers, scientists, CEOs, and celebrities.  The Convention also features the BIO Business Forum (One-on-One Partnering), hundreds of sessions covering biotech trends, policy issues and technological innovations, and the world’s largest biotechnology exhibition – the BIO Exhibition.

The BIO International Convention is hosted by the Biotechnology Innovation Organization (BIO). BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products.

 

Keynote Speakers INCLUDE:

Fireside Chat with Margaret (Peggy) Hamburg, MD, Foreign Secretary, National Academy of Medicine; Chairman of the Board, American Association for the Advancement of Science

Tuesday Keynote: Siddhartha Mukherjee (Author of the bestsellers Emperor of All Maladies: A Biography of Cancer and  The Gene: An Intimate History)

Fireside Chat with Jeffrey Solomon, Chief Executive Officer, COWEN

Fireside Chat with Christi Shaw, Senior Vice President and President, Lilly BIO-Medicines, Eli Lilly and Company

Wednesday Keynote: Jamie Dimon (Chairman JP Morgan Chase)

Fireside Chat with Kenneth C. Frazier, Chairman of the Board and Chief Executive Officer, Merck & Co., Inc.

Fireside Chat: Understanding the Voices of Patients: Unique Perspectives on Healthcare

Fireside Chat: FDA Town Hall

 

ALSO SUPERSESSIONS including:

Super Session: What’s Next: The Landscape of Innovation in 2019 and Beyond

Super Session: Falling in Love with Science: Championing Science for Everyone, Everywhere

Super Session: Digital Health in Practice: A Conversation with Ameet Nathawani, Chief Digital Officer, Chief Medical Falling in Love with Science: Championing Science for Everyone, Everywhere

Super Session: Realizing the Promise of Gene Therapies for Patients Around the World

Super Session: Biotech’s Contribution to Innovation: Current and Future Drivers of Success

Super Session: The Art & Science of R&D Innovation and Productivity

Super Session: Dealmaker’s Intentions: 2019 Market Outlook

Super Session: The State of the Vaccine Industry: Stimulating Sustainable Growth

 

See here for full AGENDA

Link for Registration: https://convention.bio.org/register/

The BIO International Convention is literally where hundreds of deals and partnerships have been made over the years.

 

BIO performs many services for members, but none of them are more visible than the BIO International Convention. The BIO International Convention helps BIO fulfill its mission to help grow the global biotech industry. Profits from the BIO International Convention are returned to the biotechnology industry by supporting BIO programs and initiatives. BIO works throughout the year to create a policy environment that enables the industry to continue to fulfill its vision of bettering the world through biotechnology innovation.

The key benefits of attending the BIO International Convention are access to global biotech and pharma leaders via BIO One-on-One Partnering, exposure to industry though-leaders with over 1,500 education sessions at your fingertips, and unparalleled networking opportunities with 16,000+ attendees from 74 countries.

In addition, we produce BIOtechNOW, an online blog chronicling ‘innovations transforming our world’ and the BIO Newsletter, the organization’s bi-weekly email newsletter. Subscribe to the BIO Newsletter.

 

Membership with the Biotechnology Innovation Organization (BIO)

BIO has a diverse membership that is comprised of  companies from all facets of biotechnology. Corporate R&D members range from entrepreneurial companies developing a first product to Fortune 100 multinationals. The majority of our members are small companies – 90 percent have annual revenues of $25 million or less, reflecting the broader biotechnology industry. Learn more about how you can save with BIO Membership.

BIO also represents academic centers, state and regional biotech associations and service providers to the industry, including financial and consulting firms.

  • 66% R&D-Intensive Companies *Of those: 89% have annual revenues under $25 million,  4% have annual revenues between $25 million and $1 billion, 7% have annual revenues over $1 billion.
  • 16% Nonprofit/Academic
  • 11% Service Providers
  • 7% State/International Affiliate Organizations

Other posts on LIVE CONFERENCE COVERAGE using Social Media on this OPEN ACCESS JOURNAL and OTHER Conferences Covered please see the following link at https://pharmaceuticalintelligence.com/press-coverage/

 

Notable Conferences Covered THIS YEAR INCLUDE: (see full list from 2013 at this link)

  • Koch Institute 2019 Immune Engineering Symposium, January 28-29, 2019, Kresge Auditorium, MIT

https://calendar.mit.edu/event/immune_engineering_symposium_2019#.XBrIDc9Kgcg

http://kochinstituteevents.cvent.com/events/koch-institute-2019-immune-engineering-symposium/event-summary-8d2098bb601a4654991060d59e92d7fe.aspx?dvce=1

 

  • 2019 MassBio’s Annual Meeting, State of Possible Conference ​, March 27 – 28, 2019, Royal Sonesta, Cambridge

http://files.massbio.org/file/MassBio-State-Of-Possible-Conference-Agenda-Feb-22-2019.pdf

 

  • World Medical Innovation Forum, Partners Innovations, ARTIFICIAL INTELLIGENCE | APRIL 8–10, 2019 | Westin, BOSTON

https://worldmedicalinnovation.org/agenda-list/

https://worldmedicalinnovation.org/

 

  • 18th Annual 2019 BioIT, Conference & Expo, April 16-18, 2019, Boston, Seaport World Trade Center, Track 5 Next-Gen Sequencing Informatics – Advances in Large-Scale Computing

http://www.giiconference.com/chi653337/

https://pharmaceuticalintelligence.com/2019/04/22/18th-annual-2019-bioit-conference-expo-april-16-18-2019-boston-seaport-world-trade-center-track-5-next-gen-sequencing-informatics-advances-in-large-scale-computing/

 

  • Translating Genetics into Medicine, April 25, 2019, 8:30 AM – 6:00 PM, The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

https://pharmaceuticalintelligence.com/2019/04/25/translating-genetics-into-medicine-april-25-2019-830-am-600-pm-the-new-york-academy-of-sciences-7-world-trade-center-250-greenwich-st-fl-40-new-york/

 

  • 13th Annual US-India BioPharma & Healthcare Summit, May 9, 2019, Marriott, Cambridge

https://pharmaceuticalintelligence.com/2019/04/30/13th-annual-biopharma-healthcare-summit-thursday-may-9-2019/

 

  • 2019 Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies, May 17, 2019, Harvard Law School

http://petrieflom.law.harvard.edu/events/details/2019-petrie-flom-center-annual-conference

https://pharmaceuticalintelligence.com/2019/01/11/2019-petrie-flom-center-annual-conference-consuming-genetics-ethical-and-legal-considerations-of-new-technologies/

 

  • 2019 Koch Institute Symposium – Machine Learning and Cancer, June 14, 2019, 8:00 AM-5:00 PM  ET MIT Kresge Auditorium, 48 Massachusetts Ave, Cambridge, MA

https://pharmaceuticalintelligence.com/2019/03/12/2019-koch-institute-symposium-machine-learning-and-cancer-june-14-2019-800-am-500-pmet-mit-kresge-auditorium-48-massachusetts-ave-cambridge-ma/

 

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