Advertisements
Feeds:
Posts
Comments

Archive for the ‘Pharmaceutical Discovery’ Category


Novartis’ Kymriah (tisagenlecleucel), FDA approved genetically engineered immune cells, would charge $475,000 per patient, will use Programs that Payers will pay only for Responding Patients

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2017:

This Pioneering $475,000 Cancer Drug Comes With A Money-Back Guarantee

Novartis defends the eye-popping price of its pioneering gene therapy with arguments about its $1 billion expenditure—and novel “value-based” pricing.

https://www.fastcompany.com/40461214/how-novartis-is-defending-the-record-475000-price-of-its-pioneering-gene-therapy-cancer-drug-car-t-kymriah

 

On 8/30/2017 we wrote:

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of KitePharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/30/fda-has-approved-the-worlds-first-car-t-therapy-novartis-for-kymriah-tisagenlecleucel-and-gileads-12-billion-buy-of-kite-pharma-no-approved-drug-and-canakinumab-for-lung-cancer-may-be/

 

The Price for the Treatment was published on 8/31/2017, a Value-based Pricing Payment Model of a $475,000 per patient charge for the responding patients after ONE month of treatment. Novartis says it takes an average of 22 days to create the therapy, from the time a patient’s cells are removed to when they are infused back into the patient. Kymriah will initially be available at 20 U.S. hospitals within a month, Novartis says. Eventually, 32 total sites will offer the therapy. 

CAR-T gained national attention three years ago when Carl June, a researcher at the University of Pennsylvania, used to put a young girl’s acute lymphoblastic leukemia. Genetically altering the girl’s immune cells had made her deathly ill, but June had used a Roche drug, Actemra, to treat the side effects. She lived, and the results were published in The New England Journal of Medicine. Novartis bought the rights to the Penn treatment for just $20 million up front.

Pharma Buying the right to use from an Academic Institution is a known route to leap frog the R&D lengthy process of Drug discovery.

“I’ve told the team that resources are not an issue. Speed is the issue,” says Novartis’ Chief Executive Joseph Jimenez, told Forbes in a cover story about the work then.

The FDA calls this CAR-T therapy treatment, made by Novartis, the “first gene therapy” in the U.S. The therapy is designed to treat an often-lethal type of blood and bone marrow cancer that affects children and young adults. The FDA defines gene therapy as a medicine that “introduces genetic material into a person’s DNA to replace faulty or missing genetic material” to treat a disease or medical condition. This is the first such therapy to be available in the U.S., according to the FDA.

Two gene therapies for rare, inherited diseases have already been approved in Europe.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

FDA commissioner Scott Gottlieb in a statement.

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” 

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm

The Protocol

A patient’s T cells are extracted and cryogenically frozen so that they can be transported to Novartis’s manufacturing center in New Jersey. There, the cells are genetically altered to have a new gene that codes for a protein—called a chimeric antigen receptor, or CAR. This protein directs the T cells to target and kill leukemia cells with a specific antigen on their surface. The genetically modified cells are then infused back into the patient.

In a clinical trial of 63 children and young adults with a type of acute lymphoblastic leukemia, 83 percent of patients that received the CAR-T therapy had their cancers go into remission within three months. At six months, 89 percent of patients who received the therapy were still living, and at 12 months, 79 percent had survived.

https://www.technologyreview.com/s/608771/the-fda-has-approved-the-first-gene-therapy-for-cancer/?utm_campaign=add_this&utm_source=email&utm_medium=post

CAR-T Therapies: Product/Molecules/MOA under Development:

  • Similar CAR-T treatments were being developed at other institutions including
  • Memorial Sloan-Kettering Cancer Center,
  • Seattle Children’s Hospital, and
  • The National Cancer Institute.
  • The Memorial and Seattle work was spun off into a startup called Juno Therapeutics, which has fallen behind. Juno Therapeutics ended a CAR-T study earlier this year after patients died from cerebral edema, or swelling in the brain.
  • The NCI work became the basis for the product being developed by Kite Pharma. Kite Pharma, which is awaiting FDA approval for its CAR-T therapy to treat a form of blood cancer in adults, was this week bought out by Gilead in a deal worth $11.9 billion.

On Cambridge Healthtech Institute’s 4th Annual Adoptive T Cell Therapy, Delivering CAR, TCR, and TIL from Research to Reality, August 29 – 30, 2017 | Sheraton Boston | Boston, MA

TUESDAY, AUGUST 29 – I covered in Real Time the talk on Juno Therapeutics: Building Better T Cell Therapies: The Power of Molecular Profiling by Mark Bonyhadi, Ph.D., Head, Research and Academic Affairs, Juno Therapeutics

https://pharmaceuticalintelligence.com/2017/08/29/live-829-chis-oncolytic-virus-immunotherapy-and-adoptive-cell-therapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

Precision Medicine is Costly and not a Rapid manufacturing process

All of the CAR-T products are expensive to make, and must be manufactured on an individual basis for each new patient from the patient’s own T-cells, a type of white blood cells, a process that takes weeks.

  • How quickly companies can speed up manufacturing.
  • Kymriah will be manufactured at a facility in Morris Plains, N.J.
  • CAR-T technology, which has so far been used only in patients with blood cancers that have not been cured by other treatments, can be used earlier in the disease or for solid tumors: Breast, Prostate, Melanomas.

https://www.forbes.com/sites/matthewherper/2017/08/30/fda-approves-novartis-treatment-that-alters-patients-cells-to-fight-cancer/#2aecb25b4400

Prediction How Patients will Far Well – Researchers use a big-data approach to find links between different genes and patient survival.

https://www.technologyreview.com/s/608666/a-cancer-atlas-to-predict-how-patients-will-fare/?set=

A pathology atlas of the human cancer transcriptome

+ See all authors and affiliations

Science  18 Aug 2017:
Vol. 357, Issue 6352, eaan2507
DOI: 10.1126/science.aan2507

Modeling the cancer transcriptome

Recent initiatives such as The Cancer Genome Atlas have mapped the genome-wide effect of individual genes on tumor growth. By unraveling genomic alterations in tumors, molecular subtypes of cancers have been identified, which is improving patient diagnostics and treatment. Uhlen et al. developed a computer-based modeling approach to examine different cancer types in nearly 8000 patients. They provide an open-access resource for exploring how the expression of specific genes influences patient survival in 17 different types of cancer. More than 900,000 patient survival profiles are available, including for tumors of colon, prostate, lung, and breast origin. This interactive data set can also be used to generate personalized patient models to predict how metabolic changes can influence tumor growth.

Advertisements

Read Full Post »


FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 9/7/2017

Here’s the inside account of Gilead’s 11-week sprint to its $12B Kite buyout – ENDPOINTS NEWS

UPDATED on 8/31/2017

Gilead-Kite: A New Transformative Deal For Biotech, AUG 30, 2017

Gilead has made a big bet on new technology in Kite’s immunotherapy platforms and has reduced the number of credible large players in the space.

With a reputation for intense diligence and dynamism in its business development efforts, Gilead’s management team will only bolster the immunotherapy field as it prepares to face off with Novartis, its immediate competitor, and enters squarely in the province of Merck and Bristol Myers Squibb, two of the leaders in immuno-oncology.

Gilead has reinvented the transformative transaction for the sector.

https://www.forbes.com/sites/stephenbrozak/2017/08/30/gilead-kite-a-new-transformative-deal-and-maybe-the-new-future-of-healthcare-deals/#fc64fca65d49

 

I attended this week the Cambridge Healthtech Institute’s 4th Annual

Adoptive T Cell Therapy

Delivering CAR, TCR, and TIL from Research to Reality
August 29 – 30, 2017 | Sheraton Boston | Boston, MA

 

The following talks on 8/29/2017 presented the frontier of CAR-T Therapies and Technologies from lab to bed side:

  • Building Better T Cell Therapies: The Power of Molecular Profiling

Mark Bonyhadi, Ph.D., Head, Research and Academic Affairs, Juno Therapeutics

  • Tricked-Out Cars, the Next Generation of CAR T Cells

Richard Morgan, Ph.D., Vice President, Immunotherapy, Bluebird Bio

  • The Generation of Lentiviral Vector-Modified CAR-T Cells Using an Automated Process

Boro Dropulic, Ph.D., General Manager and CSO, Lentigen Technology, Inc.

I covered this event in Real Time for the Press

LIVE – 8/29 – CHI’s Oncolytic Virus Immunotherapy and ADOPTIVE CELL THERAPY, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

https://pharmaceuticalintelligence.com/2017/08/29/live-829-chis-oncolytic-virus-immunotherapy-and-adoptive-cell-therapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

One year ago we published the following:

What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial

https://pharmaceuticalintelligence.com/2016/07/09/what-does-this-mean-for-immunotherapy-fda-put-a-temporary-hold-on-jcar015-three-death-of-celebral-edema-in-car-t-clinical-trial-and-kite-pharma-announced-phase-ii-portion-of-its-car-t-zuma-1-trial/

 

SOURCE

Is Canakinumab the Next Viagra?

In this Revolution and Revelation, Milton Packer explains how safety data can sometimes trump a primary endpoint

by Milton PackerAugust 30, 2017

https://www.medpagetoday.com/Blogs/RevolutionandRevelation/67605

Read Full Post »


Postmarketing Safety or Effectiveness Data Needed: The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, a surge in its shares seen after the approval. Eteplirsen will cost patients around $300,000 a year.

 

Curator: Aviva Lev-Ari, PhD, RN

 

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

Factors at play for FDA Approval of eteplirsen

  1. the help of the families of young boys with Duchenne muscular dystrophy, emotional scenes from these families who have campaigned for so long
  2. an executive team from Sarepta who wouldn’t give up,

Ed Kaye, Sarepta, CEO – EK: It’s all about resilience. One of the things we’ve had is a group of people of like minds and anytime one of us gets down, somebody else is there to pick you up. One of the things we’ve always done is: Every time we’ve felt sorry for ourselves, we just need to think about those patients and what they go through. Our struggles in comparison very quickly become meaningless. You end up saying to yourself: What am I complaining about? Quit whining; get up and do your job.

and

3. an emerging new philosophy from some within the FDA, eteplirsen, now Exondys 51, was approved in patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

9/19/2016

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designationPriority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

SOURCE

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm

The viability of this drug approval depends  on “to be gathered” Postmarketing safety or effectiveness data, aka follow-up confirmatory trials.

Sarepta CEO Ed Kaye on FDA courage, NICE and resilience

BA: When it comes to flexibility, however, the FDA will likely not be flexible if your drug doesn’t prove the desired efficacy in your longer term postmarketing studies. If at the end of this period your drug doesn’t come through, how easy will it be for you to take this off the market? I don’t think anyone, including the FDA, wants a repeat of what happened in 2011 when Roche saw its breast cancer license for Avastin, which had been approved under an accelerated review, pulled after not being safe or effective enough in the follow-up confirmatory trials. But you face this as a possible scenario.

EK: That’s true, but one of the things we’re trying to do to mitigate that is to obviously, with our ongoing studies, prove the efficacy that the FDA wants to see. And you know, if there is a problem with one study then we’d hope to have other data that are supportive. The other thing we’re doing of course is developing that next-generation chemistry in DMD that could prove more effective, so we could certainly consider using that next-gen chemistry to take our work forward and try and make it better.

We have a lot of shots on goal to make sure we can continue to supply a product for these boys, but there is always a risk. If we can’t show efficacy in the way the FDA wants, then yes they have the option to take it off the market.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

Need for follow-up confirmatory trials remains outstanding

FDA’s Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090385.htm

FDA’s Regulations and Policies and Procedures for Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090394.htm

 

Positions on Sarepta’s eteplirsen Scientific Approach

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/23/gene-editing-for-exon-51-why-crispr-snipping-might-be-better-than-exon-skipping-for-dmd/

 

QUOTE START

Retraction Watch

Tracking retractions as a window into the scientific process

Amid controversial Sarepta approval decision, FDA head calls for key study retraction

with one comment

FDAThe head of the U.S. Food and Drug Administration (FDA) has called for the retraction of a study about a drug that the agency itself approved earlier this week, despite senior staff opposing the approval.

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

In a lengthy report Commissioner Robert Califf sent to senior FDA officials on September 16 — that was made public on September 19 — he called for the retraction of a 2013 study published in Annals of Neurologyfunded by the seller of eteplirsen, which showed beneficial effects of the drug in DMD patients. Califf writes inthe report:

The publication, now known to be misleading, should probably be retracted by its authors.

In a footnote in the report, Califf adds:

In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report.

The study was not the key factor in the agency’s decision to approve the drug, according to Steve Usdin, Washington editor of the publication BioCentury; still, Usdin told Retraction Watch he is “really surprised” at the call for retraction from top FDA staff, the first he has come across in the last two decades.

The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, which has seen a surge in its shares after the approval. Eteplirsen will cost patients around $300,000 a year.

DMD affects around 1 in 3,600 boys due to a mutation in the gene that codes for the protein dystrophin, which is important for structural stability of muscles. Eteplirsen is the first drug to treat DMD, and was initially given a green light by Janet Woodcock, director of Center for Drug Evaluation and Research, after a split vote from the FDA’s advisory committee. Despite Califf’s issues with the literature supporting the drug’s use in DMD, he did not overturn Woodcock’s decision, and the agency approved the drug this week.

In 2014, an inspection team visited the Nationwide Children’s Hospital in Columbus, Ohio, where the research was conducted, according to the report. In the report, Ellis Unger, director of the Office of Drug Evaluation I in FDA’s Center for Drug Evaluation, notes:

We found the analytical procedures to be typical of an academic research center, seemingly appropriate for what was simply an exploratory phase 1/2 study, but not suitable for an adequate and well controlled study aimed to serve as the basis for a regulatory action. The procedures and controls that one would expect to see in support of a phase 3 registrational trial were not in evidence.

Specifically, Unger describes concerns about blinding during the experiments, and notes:

The immunohistochemistry images were only faintly stained, and had been read by a single technician using an older liquid crystal display (LCD) computer monitor in a windowed room where lighting was not controlled. (The technician had to suspend reading around mid-day, when brighter light began to fill the room and reading became impossible.)

Unger adds:

Having uncovered numerous technical and operational shortcomings in Columbus, our team worked collaboratively with the applicant to develop improved methods for a reassessment of the stored images…This re-analysis, along with the study published in 2013, provides an instructive example of an investigation with extraordinary results that could not be verified.

Luciana Borio, acting chief scientist at the FDA, is cited in the report saying:

I would be remiss if I did not note that the sponsor has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study–which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings…As determined by the review team, and as acknowledged by Dr. Woodcock, the article’s scientific findings—with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints—do not withstand proper and objective analyses of the data. Sarepta’s misleading communications led to unrealistic expectations and hope for DMD patients and their families.

Here’s how Sarepta describes the study’s findings in the press release Borio refers to:

Published study results showed that once-weekly treatment with eteplirsen resulted in a statistically significant increase from baseline in novel dystrophin, the protein that is lacking in patients with DMD. In addition, eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT) demonstrated stabilization in walking ability compared to a placebo/delayed-treatment cohort. Eteplirsen was well tolerated in the study with no clinically significant treatment-related adverse events. These data will form the basis of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for eteplirsen planned for the first half of 2014.

However, Usdin noted that the drug’s approval and the study are two independent events, adding that the 2013 study just “got the ball rolling” for eteplirsen, and the FDA conducted many of its own experiments analyses, as detailed in the newly released report.

Jerry Mendell, the corresponding author of the study (which has so far been cited 118 times, according to Thomson Reuters Web of Science) from Ohio State University in Columbus, told us the allegations were “unfounded” and said the data are “valid.” Therefore, he added, he will not be approaching the journal for a retraction, noting that the FDA asked him hundreds of questions about the paper and audited the trials.

Clifford Saper, the editor-in-chief of Annals of Neurology from the Beth Israel Deaconess Medical Center (which is part of Harvard Medical School), said in an email:

It takes more than a call by a politician for retraction of a paper. It takes actual evidence.

He added:

If the FDA commissioner has, or knows of someone who has, evidence for an error in a paper published in Annals of Neurology, I encourage him to send that evidence to me and a copy to the authors of the article, for their reply. At that point we will engage in a scientific review of the evidence and make appropriate responses.

Linda Lowes, sixth author of the present study, is the last author of a 2016 study in Physical Therapy that was retracted months after publication. Its notice reads:

This article has been retracted by the author due to unintentional deviations in the use of the described modified technique to assess plagiocephaly in the study participants, such that the use of the modified technique cannot be defended for the stated purpose in this population at this time.

Califf was a cardiologist at Duke University during the high-profile scandal of researcher Anil Potti at Duke, which led to more than 10 retractions, settled lawsuits, and medical board reprimands. In 2015, he told TheTriangle Business Journal:

I wish I had gotten myself more involved earlier…There were systems that were not adequate, as we stated. … That was a tough one, I think, for the whole institution.

We’ve contacted the FDA for comment, and will update the post with anything else we learn.

END QUOTE

Correction 9/21/16 10:44 p.m. eastern: When originally published, this post incorrectly reported that Califf was part of an inspection team that visited the Nationwide Children’s Hospital in Ohio, and attributed quotes from Ellis Unger to Califf. We have made appropriate corrections, and apologize for the error.

Like Retraction Watch? Consider making a tax-deductible contribution to support our growth. You can also follow us on Twitter, like us on Facebook, add us to your RSS reader, sign up on our homepage for an email every time there’s a new post, or subscribe to our daily digest. Click here to review our Comments Policy. For a sneak peek at what we’re working on, click here.

SOURCE

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

Related Resources on FDA’s Policies on Drugs:

Read Full Post »

Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com


physiology-cover-seriese-vol-3individualsaddlebrown-page2

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

http://www.amazon.com/dp/B019VH97LU 

2015

 

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction 

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1  Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

 

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2  The  evolution of myoglobin and hemoglobin
2.3  More complexity in proteins evolution
2.4  Life on earth is traced to oxygen binding
2.5  The colors of life function
2.6  The colors of respiration and electron transport
2.7  Highlights of a green evolution

 

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

Chapter 4.  Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

 

Chapter  7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Chapter 7.  Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

 

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

9.9 Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

Read Full Post »


Agenda @Biotech Week Boston: WHERE THE HEART, TECHNOLOGY AND BUSINESS OF SCIENCE CONVERGE, Conference: October 4 – 7, 2016 | Exhibition: October 5-7, 2016 Boston Convention and Exhibition Center

Reporter: Aviva Lev-Ari, PhD, RN

Conference: October 4 – 7, 2016 | Exhibition: October 5-7, 2016

Boston Convention and Exhibition Center,
Boston, MA

WHERE THE HEART, TECHNOLOGY AND BUSINESS OF SCIENCE CONVERGE

#BIOTECHWEEKBOSTON

https://lifesciences.knect365.com/biotech-week-boston

October 6, 2016 – Key Sessions

Toni Hoover, Ph.D.

Harnessing Science, Technology and Innovation to Improve Global Health

Bill & Melinda Gates Foundation

Rick Berke

STAT Panel Discussion – President Clinton or President Trump: What Our Next President Will Mean for Biotech and Pharma

STAT (STATnews.com)

October 6, 2016

7:30 am 30 mins

Single-use XCell™ ATF Systems for Continuous Processing: 100% Cell Retention, 8x Faster Set-up, No autoclave

12:35 pm 30 mins

cGMP Biologics Production Using Corynex ® : A Highly-Productive Gram-Positive Microbial Protein Secretion System

12:35 pm 30 mins

Advanced Materials for Single Use Systems

12:35 pm 30 mins

Fast Trak Your Molecule to Market: When, Why and How to Outsource Biomanufacturing

12:35 pm 30 mins

An Integrated BalanCD ® CHO Media Solution for Early Therapeutic Antibody Development, Scale-Up and Commercial Supply

12:35 pm 30 mins

Reveal Information that Gives Insights – New Approaches to Sub-Visible Particle Characterization

9:15 am 525 mins

BWB Exhibit Hall Open

9:30 am 45 mins

Harnessing Science, Technology and Innovation to Improve Global Health

  • Toni Hoover, Ph.D., Bill & Melinda Gates Foundation

10:30 am 10 mins

Asahi Kasei Product Presentation

10:40 am 10 mins

How to Reduce Costs, Make Informed Decisions and Gain Insight for Innovation Through BioSolve

10:50 am 10 mins

Increasing Protein Production with Novel Cell-Ess Supplement without Affecting Metabolic Profile

12 pm 60 mins

Oral Poster Presentations

 1:10 pm
10 mins

Lonza Presentation

1:20 pm 15 mins

Distek Presentation

1:35 pm 10 mins

PendoTECH Presentation

2:15 pm 90 mins

Town Hall Forum: An Update on Single-Use Standardization and Alignment

4 pm 10 mins

Sartorius Presentation

4:10 pm 20 mins

Catalent Presentation

4:30 pm 10 mins

Asahi Kasei Presentation

4:40 pm 10 mins

Meissner Filtration Products Presentation

5 pm 60 mins

STAT Panel Discussion – President Clinton or President Trump: What Our Next President Will Mean for Biotech and Pharma

  • Rick Berke, STAT (STATnews.com)
  • Mason Tenaglia, IMS Institute for Healthcare Informatics, Payer & Managed Care Insights
  • Damien Garde, STAT (STATnews.com)
  • Dylan Scott, STAT (STATnews.com)

October 7, 2016

Key Sessions

Steve Wozniak

Innovation & Customer Centricity – Sponsored by Pall Life Sciences

Apple Computer Inc

7:15 am 30 mins

Accelerating Mammalian and Microbial Culture with Single-Use Technology

12:35 pm 30 mins

Unlocking Downstream Efficiency

9:10 am 330 mins

BWB Exhibit Hall Open

9:15 am 60 mins

Innovation & Customer Centricity – Sponsored by Pall Life Sciences

Pall Life Sciences
  • Steve Wozniak, Apple Computer Inc

10:15 am 10 mins

Steve Wozniak Meet & Greet at Pall Lounge

12:30 pm
60 mins

Panel Discussion: Immuno-oncology: What’s Next?

1:30 pm 30 mins

Passport Prize Drawing

10:50 am 20 mins

Innovations in Live Banking of Bio-Specimens: Prospective Advantages to the Retrospective Clinical Failures

11:10 am 20 mins

Innovations in Cell & Gene Therapy

11:30 am 60 mins

PANEL DISCUSSION: Innovations and Technology to Drive Improvements in Healthcare Delivery

SOURCE

https://lifesciences.knect365.com/biotech-week-boston

Read Full Post »


Value for Patients – Turning Advances in Science: A Case Study of a Leading Global Pharmaceutical Company – Astellas Pharma Inc.

Astellas Pharma Inc. (https://www.astellas.com/en/) and Astellas Pharma U.S., Inc. (https://www.astellas.us/)

UPDATED on 4/3/2017

Astellas Pharma Inc. and Ogeda SA announced today that Astellas and Ogeda shareholders have entered into a definitive agreement under which Astellas has agreed to acquire Ogeda a privately owned drug discovery company. Ogeda is a clinical-stage drug discovery company that discovers and develops small molecule drugs targeting G-protein coupled receptors (GPCRs). The lead investigational candidate, fezolinetant, is a selective NK3 receptor antagonist, and the positive data from a Phase 2a study result for the non-hormonal treatment of menopause-related vasomotor symptoms (“MR-VMS”) was announced in January 2017. This transaction expands Astellas’ late stage pipeline and is expected to contribute to its mid-to-long term growth.

SOURCE

http://www.prnewswire.com/news-releases/astellas-to-acquire-ogeda-sa-300433141.html

https://endpts.com/astellas-swoops-in-on-a-mid-stage-drug-for-hot-flashes-in-860m-biotech-buyout-deal/?utm_medium=email&utm_campaign=Monday%20%20April%203%202017&utm_content=Monday%20%20April%203%202017+CID_4adac18d4a997566831a3ca0829b655e&utm_source=ENDPOINTS%20emails&utm_term=Astellas%20swoops%20in%20on%20a%20mid-stage%20drug%20for%20hot%20flashes%20in%20860M%20biotech%20buyout%20deal

UPDATED on 8/24/2016

Some analysts suggested Pfizer paid too much, particularly since it will split profits from Xtandi with Japan-based Astellas Pharma, which helps market the drug. Pfizer defended the deal, saying it would add 5 cents to its earnings per share in the first full year.

“The proposed acquisition of Medivation is expected to immediately accelerate revenue growth and drive overall earnings growth potential for Pfizer,” Ian Read, chairman and chief executive of Pfizer, said in the statement on Monday.

SOURCE

http://www.nytimes.com/2016/08/23/business/dealbook/medivation-pfizer-14-billion-deal.html?_r=0

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures  https://pharmaceuticalintelligence.com/biomed-e-books/series-e-titles-in-the-strategic-plan-for-2014-1015/2014-the-patients-voice-personal-experience-with-invasive-medical-procedures/

 

Tokyo-based Astellas Pharma Inc., a top 20 global pharmaceutical research company, has a strong, global company legacy, precision focus and patient-centric vision in creating innovative pharmaceuticals in areas of unmet medical need.

2012-05-10 003_Astellas building

Image SOURCE: Photograph of the Astellas Pharma U.S. building. Courtesy of Astellas Pharma U.S., 5/10/2012.   

The company’s commitment to science is based on development of medicines that address high unmet medical needs in therapeutic areas that include:

  • oncology,
  • urology,
  • immunology,
  • nephrology, and
  • neuroscience.

The company is also exploring advancements in new therapeutic areas and related diseases such as,

  • ophthalmology—retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic macular edema (DME) and Stargardt’s macular degeneration (SMD) and
  • muscle diseases.

And they are investing in new technologies and modalities, such as,

  • regenerative medicine and cell therapy, and
  • next-generation vaccines.

The company is committed to improving the lives of patients through innovative science and with the highest sense of ethics and integrity. This commitment is reflected in the Astellas Group Code of Conduct, which applies to all employees across the globe and can be accessed through the link below.

Astellas Group Code of Conduct

Boosting research and development productivity remains an important issue for Astellas Pharma Inc., because innovation is vital for the company’s success in developing new therapeutic areas, technologies and modalities of treatment.

Dr. Bernhardt Zeiher, President, Development, is responsible for the more than 800-person development organization that is involved in developing these innovative therapies through cutting-edge clinical research. Dr. Zeiher’s team conducts clinical investigations of novel biological targets and new chemical entities with unique mechanisms of action and looks to determine whether the findings in preclinical testing will translate to benefit for patients.  Clinical studies are conducted globally with operational hubs in the United States, Netherlands and Japan. Astellas relocated their Development headquarters from Japan to the United States in 2008.

Building on its 120-year heritage, Astellas uses creativity and innovation to bring patients new medicines through the more than 17,000 global employees who work to improve the lives of patients and their families. Astellas was formed through the merger of Japan’s third and fifth largest pharmaceutical companies, Yamanouchi, founded in 1923, and Fujisawa, founded in 1894. Yamanouchi brought a record of developing blockbuster drugs, a pipeline full of promising new compounds and a sales and marketing culture of deeply grounded, data-driven expertise. Fujisawa brought dominance in transplantation, a soaring reputation for in-depth understanding of the disease states and treatments within its market niches, and a track record for developing high-profile, market-leading products that become new standards of care.

The company has made steady progress; they reported annual global sales of 1,372,706 million yen (approx. $13.2 billion) through the end of fiscal year 2015, with an annual research and development investment of 225,665 million yen (approx. $2.2 billion) through the end of fiscal year 2015.

Below is my interview with Astellas Dr. Bernhardt Zeiher, President, Development, which occurred in June, 2016.

What is your overall Research & Development (R&D) strategy?

Dr. Zeiher: We are focused on turning innovative science into value for patients in areas of high unmet need where we have, or can quickly acquire, expertise and where Astellas believes new scientific understanding is poised to drive significant innovation. Our commitment to R&D is based on the development of medicines that address high unmet medical needs in our main therapeutic areas of focus: oncology, urology and immunology.  We also have increased efforts to explore advancements in new therapeutic areas such as ophthalmology, nephrology, neuroscience and muscle diseases where there is a high level of unmet medical need. Building on our patient-centric vision, Astellas has been actively investing in new technologies and modalities, such as regenerative medicine and next-generation vaccines.

What are your R&D strengths?

Dr. Zeiher: Astellas is building on its legacy of bringing transformative medications to patients by investing in some of today’s most dynamic areas of scientific exploration. Innovations delivered by Astellas have helped to address and largely solve some of the most significant scientific challenges in urology and transplant. We also have built a strong presence in oncology with treatments for difficult-to-treat cancers, such as prostate and non-small cell lung cancer.

Moving forward in oncology, Astellas has made a deliberate effort to build leadership through organic efforts with a pipeline exemplifying the “follow the biology” approach that includes treatments for prostate, non-small cell lung and pancreatic cancer, and continued research in therapies for breast cancer and acute myeloid leukemia, among others. We also have forged strategic acquisitions and collaborated with industry and academic leaders to further build our portfolio.

In addition, we are leveraging what we know across conditions with similar biologies or mechanisms, building on our expertise to expand into adjacent diseases and proactively seek new opportunities. For example, leveraging our expertise in transplantation and infectious diseases, Astellas is developing the world’s first DNA vaccine for cytomegalovirus (CMV) infections. Currently in clinical trials, ASP0113 is a potential first-in-class agent for immunocompromised individuals undergoing solid organ or hematopoietic stem cell transplant who are at high risk of viral reactivation.

Describe your near-term R&D projects and pipeline activities?

Dr. Zeiher: Currently, the company is working on 35 investigational programs in Phase II and Phase III/registration development, of which half involve new molecular entities. We have a diverse pipeline with a balance of early- and later-stage assets. Later-stage programs include novel therapies/vaccines for cancer, anemia and infectious diseases.

  • Our two most advanced novel oncology agents, ASP2215 and ASP8273, continue to progress through the pipeline. ASP2215 shows promise in the treatment of relapsed or refractory acute myeloid leukemia, and ASP8273 is being evaluated as a treatment for a type of non-small cell lung cancer.
  • Leveraging our expertise in kidney disease, we are developing a first-in-class oral treatment for anemia associated with chronic kidney disease through our licensing agreement with FibroGen.
  • Astellas is developing the world’s first DNA vaccine for cytomegalovirus (CMV) infections. Currently in clinical trials, ASP0113 is a potential first-in-class agent for immunocompromised individuals undergoing solid organ or hematopoietic stem cell transplant who are at risk of viral reactivation. We are also working on a therapeutic vaccine, ASP4070, for Japanese red cedar pollen allergy.

We are building expertise in two new therapeutic areas—ophthalmology and muscle diseases—where there is significant unmet need. Through the Astellas Institute for Regenerative Medicine (AIRM) and external collaborations, we are addressing ophthalmologic diseases with a higher risk of blindness, including age-related and Stargardt’s macular degeneration, retinitis pigmentosa (RP), and diabetic macular edema (DME). In the muscle disease area, we are collaborating with our partner, Cytokinetics, on a skeletal muscle troponin activator which is being investigated in Spinal Muscular Atrophy (SMA). In addition, Astellas and Cytokinetics have agreed to amend their collaboration agreement to enable the development of CK-2127107 for the potential treatment of ALS and to extend their joint research focused on the discovery of additional next-generation skeletal muscle activators through 2017.

The pharmaceutical industry is intensely competitive and it requires an extensive search for technological innovations. How are you positioned to be a leader in developing new medicines that address unmet medical needs in critical therapeutic areas?

Dr. Zeiher: Astellas is focused on accelerating scientific discovery with an open innovation model. The Astellas open innovation model combines in-house R&D with strategic merger and acquisition approaches to advance research in untouched and complex disease states, allowing the company to maintain steady productivity and maximize its return on R&D investment.

With open innovation, Astellas undertakes research activities in the best possible environment. In some cases, the best environment is within the Astellas research laboratories. In many other cases, we look to collaborate with top biotech and academic leaders.  By building partnerships with top researchers and companies that complement our existing expertise, Astellas is able to quickly advance into new technologies and therapeutic areas of research where there is significant unmet medical need.

This approach has helped Astellas credibly enter into, compete and lead in some segments of the most competitive therapeutic areas in the pharmaceutical industry – oncology – and is accelerating the company’s efforts to develop treatments for important emerging therapeutic categories, such as ophthalmology and musculoskeletal disease, as well as leading technologies, such as regenerative medicine and vaccines.

For example, LAMP-vax is a next-generation DNA vaccine that utilizes the body’s natural cellular processing of Lysosomal Associated Membrane Protein (LAMP) to develop a more complete immune response to a target antigen.  The ability to activate a more complete immune response gives the LAMP-vax technology potential across a number of diseases, including allergic disease and cancer immunotherapy.  In 2015, Astellas established a licensing agreement with Immunomic Therapeutics, Inc. for the LAMP-vax products for the treatment or prevention of any and all allergic diseases in humans, including ARA-LAMP-vax for peanut allergy and other research-stage programs for food or environmental allergies.

Earlier this year, Astellas acquired Ocata Therapeutics, Inc., and established the Astellas Institute for Regenerative Medicine (AIRM) to serve as the global hub for Astellas regenerative medicine and cell therapy research. Our most advanced cellular therapy programs are in ophthalmology, but we are exploring other therapeutic areas. We are working on treatments for ophthalmologic diseases that leave patients at risk for blindness, which include retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt’s macular degeneration (SMD).

Zeiher_Bernie

Image SOURCE: Photograph of Dr. Bernhardt Zeiher, President of Development, at Astellas. Courtesy of Todd Rosenberg, 11/17/2014. 

Dr. Bernhardt Zeiher serves as President, Development, at Astellas. In this role, he is responsible for all phases of drug development.

Prior to his current role, Dr. Zeiher was executive vice president and Therapeutic Area head, Immunology, Infectious Diseases and Transplantation at Astellas. Of note, he led the development of CRESEMBA® (isavuconazonium sulfate), which received Qualified Infectious Disease Product (QIDP) designation from the U.S. Food and Drug Administration and was approved in 2015 for the treatment of two rare invasive fungal infections. Prior to joining Astellas, he served as vice president of the Inflammation/Immunology therapeutic area at Pfizer.

Dr. Zeiher earned his Doctor of Medicine at the Case Western Reserve University School of Medicine, and completed an internal medicine residency at University Hospitals of Cleveland as well as a fellowship in Pulmonary and Critical Care Medicine at University of Iowa Hospitals and Clinics. Dr. Zeiher has received several awards, including being named a Fellow by American College of Physicians in 2004, awarded to those who demonstrate excellence and contributions to both medicine and the broader community of internists.

Editor’s note:

We would like to thank Jeff Winton, Andrew Lewis and Julie Monzo from the Astellas communications team for the tremendous help and support they provided during this interview.

 

REFERENCE/SOURCE

Astellas Pharma Inc. (https://www.astellas.com/en/) and Astellas Pharma U.S., Inc. (https://www.astellas.us/)

Other related articles:

Retrieved from http://3blmedia.com/News/Astellas-USA-Foundation-Giving-Back-Means-Living-Smarttm-Together-Our-Communities

Retrieved from http://3blmedia.com/News/Astellas-and-World-Transplant-Games-Federation-Announce-Launch-Fit-Life-Promote-Physical

Retrieved from http://www.fiercepharma.com/pharma-asia/japan-s-astellas-shows-nearly-50-gain-q1-even-as-sales-drag-price-revisions

Retrieved from http://3blmedia.com/News/Astellas-Farma-Brasil-Ranked-Among-20-Greatest-Workplaces-Brazil

 

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

LIVE 4:50 pm – 5:55 pm 4/25/2016 Early Detection and Prevention of Cancer & Innovation Break: Announcing the C³ Prize from Astellas Oncology and the World Medical Innovation Forum @2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

https://pharmaceuticalintelligence.com/2016/04/25/live-450-pm-555-pm-4252016-early-detection-and-prevention-of-cancer-innovation-break-announcing-the-c%C2%B3-prize-from-astellas-oncology-and-the-world-medical-innovation-forum-2016-world/

Top Seven Big Pharma in Thomson Reuters 2015 Top 100 Global Innovators

https://pharmaceuticalintelligence.com/2016/01/04/top-seven-big-pharma-in-thomson-reuters-2015-top-100-global-innovators/

Eye Lens Regenerated

https://pharmaceuticalintelligence.com/2016/03/19/eye-lens-regenerated/

 

2012

Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

https://pharmaceuticalintelligence.com/2012/06/27/picturing-us-trained-phds-paths-pharmaceutical-industrys-crisis-of-productivity-partnerships-between-industry-and-academia/

Medicines in Development for Cancer in 2012: An Excellent Response from America’s Biopharmaceutical Research Companies

https://pharmaceuticalintelligence.com/2012/07/31/medicines-in-development-for-cancer-in-2012-an-excellent-response-from-americas-biopharmaceutical-research-companies/

Read Full Post »


Targeting amyloidopathy

Larry H. Bernstein, MD, FCAP

LPBI

 

Targeting a rare amyloidotic disease through rationally designed polymer conjugates

Inmaculada Conejos–Sánchez, Isabel Cardoso, Maria J. Saraiva, María J.Vicent
Journal of Controlled Release 178 (2014), 95–100
Saraiva et al. discovered in 2006 a RAGE-based peptide sequence capable of preventing transthyretin (TTR) aggregate-induced cytotoxicity, hallmark of initial stages of an inherited rare amyloidosis known as Familial Amyloidotic Polyneuropathy (FAP). To allow clinical progression of this peptidic sequence as FAP treatment, a family of polymer conjugates has been designed, synthesised and fully characterised. This approach fulfills the strategies defined in the Polymer Therapeutics area as an exhaustive physico-chemical characterisation fitting activity output towards a novel molecular target that is described here. RAGE peptide acts extracellularly, therefore, nointracellular drug delivery was necessary. PEG was selected as carrier and polymer–drug linker optimisation was then carried out by means of biodegradable (disulphide) and non-biodegradable (amide) covalent bonds. Conjugate size in solution, stability under invitro and in vivo scenarios and TTR binding affinity through surface plasmon resonance (SPR) was also performed with all synthesised conjugates. In their in vitro evaluation by monitoring the activation of caspase-3 in Schwann cells, peptide derivatives demonstrated retention of peptide activity reducing TTR aggregates (TTRagg) cytotoxicity upon conjugation and a greater plasma stability than the parent free peptide. The results also confirmed that a more stable polymer–peptide linker (amide) is required to secure therapeutic efficiency.

Polymer therapeutics are well established as successful first generation nanomedicines for treatment of infectious diseases and cancer[1]. Polymer–protein, drug and aptamer conjugates are innovative chemical entities capable of improving bioactive compound properties and thus increasing efficacy and decreasing toxicity[2,3]. Design of second generation of conjugates is now focussing on improved polymer structures, polymer–based combination therapy and novel molecular targets with great potential to further progress the clinical importance of these unique technologies [4]. Novel conjugates for the treatment of neuropathological disorders are proposed in this study. Amyloidosis is well known in the form of Alzheimer’s and Parkinson’s disease, but the target disease here is a rarer pathological disorder named familial amyloid polyneuropathy (FAP). FAPs constitute an important group of inherited amyloidosis diseases, and one of the most commonFAPs is caused by a mutated protein called transthyretin (TTR), which forms amyloid deposits, mainly in the peripheral nervous system [5]. The aggregation cascade of this mutated protein, produces a TTR aggregate (TTRagg) able to trigger neurodegeneration through engagement with the receptor-for-advanced-glycation-end-products (RAGE) which is present on peripheral neurons. RAGE signalling has been defined to be involved in many human pathologies such as Alzhehimer’s disease, diabetes and ageing, among others. This receptor is also up-regulated in tissues fromFAP patients [6]. The secreted RAGE form, named soluble RAGE (sRAGE), acts as a decoy to trap ligands and prevent interaction with cell surface receptors. sRAGE was shown to have important inhibitory effects in several cell cultures and transgenic mouse models, in which it prevented or reversed full-length RAGE signalling.

Saraiva et al. [7] discovered a specific peptidic sequence (named RAGE peptide) that is able to suppress TTRagg-induced cytotoxicity in cell culture. A reduced version of that peptide was proved to maintain the activity and the affinity of the initial peptide. The final peptide (compound A) contains 6 amino acids and responds to the sequence (from N to C terminus): YVRVRY. Although this provides an opportunity to design novel therapeutics for FAP treatment, peptide therapeutics themselves display well known challenges for in vivo use, e.g. low stability, poor pharmacokinetics and potential immunogenicity. Moreover the RAGE peptide demonstrates low solubility in plasma limiting its potential for i.v.administration.

……

Herein, novel specific nanoconjugates for the treatment of amyloidosis, and in particular familial amyloidotic polyneuropathy are reported. Apart from the research reported by Prof Arima et al. [22] using a hepatocyte-targeted FAP siRNA complex with lactosylated dendrimer (G3)/α-cyclodextrin(Lac-α-CDE(G3)), no other type of polymer therapeutic has been reported up to now for the treatment of this chronic degenerative family of diseases. Our rational design started from an active biomolecule of peptidic nature (RAGE peptide) that recognises the TTR prefibrillar aggregates responsible to promote cell death in FAPpatients [7]. The clinical progress of this promising inhibitor was masked by the well-known limitations of peptides, such as low solubility, low stability and possible immunogenicity. PEGylation through various linking strategies was successfully accomplished here as a solution for the named drawbacks, using a systematic approach to maintain peptide activity and receptor binding specificity. The data relating toTTR binding affinity, conjugate linker stability and the conjugate size distribution in solution of PEG– RAGE peptide conjugates indicate that the conjugates containing amide linkers have the greatest potential for further development as FAP inhibitors. Moreover, this novel conjugate has promising possibilities as a FAP therapeutic to be used alone in the early stages of the disease or as part of rationally designed combination therapy [23,24]. Preliminary in vivo studies (biodistribution) are shown in the supporting information demonstrating the enhanced plasma stability of the peptide upon conjugation (Fig.5S) , showing nospecific accumulation in any organ and renal excretion. More exhaustive in vivo experiments are currently ongoing with selected conjugates.

 

Read Full Post »

Older Posts »