Posts Tagged ‘new drug development’

Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

On Monday, 7th June 2021, a controversial new Alzheimer’s Disease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.


The Controversies

The route to FDA clearance for Aducanumab has been bumpy – and contentious.

Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.

When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.

Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”

Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.

The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.

Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.

The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.

The findings of another trial for some patients backed up those conclusions.

Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.

The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.

Support for approval of the drug

Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.

The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”

The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”

Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.

Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.

Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.

Case studies connected to the Drug Approval

Case 1

Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,

It really offers us so much hope for a long, healthy life.

Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.

She said,

I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.

Case 2

Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.

Knap said,

I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.

When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.

Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.

Joe added,

We were aware that things were starting to fall between the cracks as these instances got more often

Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.

It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.

They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.

Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).

The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.

This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.

Jenny claims that the medicine has had no significant negative effects on her.

There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.

According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.

Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.

There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”

The drug’s final commercialization announcement

Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.

The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.

The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.

Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.

Other Relevant Articles

Gene Therapy could be a Boon to Alzheimer’s disease (AD): A first-in-human clinical trial proposed

Reporter: Dr. Premalata Pati, Ph.D., Postdoc


Alzheimer’s Disease – tau art thou, or amyloid

Curator: Larry H. Bernstein, MD, FCAP


Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

Reporter : Irina Robu, PhD


Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Curator: Aviva Lev-Ari, PhD, RN


Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN


Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP


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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

Reporter: Stephen J. Williams, Ph.D.

From Biospace.com


JP Morgan Healthcare Conference Update: Sage, Mersana, Shutdown Woes and Babies

Speaker presenting to audience at a conference

With the J.P. Morgan Healthcare Conference winding down, companies remain busy striking deals and informing investors about pipeline advances. BioSpace snagged some of the interesting news bits to come out of the conference from Wednesday.

SAGE Therapeutics – Following a positive Phase III report that its postpartum depression treatment candidate SAGE-217 hit the mark in its late-stage clinical trial, Sage Therapeutics is eying the potential to have multiple treatment options available for patients. At the start of J.P. Morgan, Sage said that patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression, compared to 13.6 for placebo. The company plans to seek approval for SAGE-2017, but before that, the FDA is expected to make a decision on Zulresso in March. Zulresso already passed muster from advisory committees in November, and if approved, would be the first drug specifically for postpartum depression. In an interview with the Business Journal, Chief Business Officer Mike Cloonan said the company believes there is room in the market for both medications, particularly since the medications address different patient populations.


Mersana Therapeutics – After a breakup with Takeda Pharmaceutical and the shelving of its lead product, Cambridge, Mass.-based Mersana is making a new path. Even though a partial clinical hold was lifted following the death of a patient the company opted to shelve development of XMT-1522. During a presentation at JPM, CEO Anna Protopapas noted that many other companies are developing therapies that target the HER2 protein, which led to the decision, according to the Boston Business Journal. Protopapas said the HER2 space is highly competitive and now the company will focus on its other asset, XMT-1536, an ADC targeting NaPi2b, an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is currently in Phase 1 clinical trials for NaPi2b-expressing cancers, including ovarian cancer, non-small cell lung cancer and other cancers. Data on XMT-1536 is expected in the first half of 2019.

Novavax – During a JPM presentation, Stan Erck, CEO of Novavax, pointed to the company’s RSV vaccine, which is in late-stage development. The vaccine is being developed for the mother, in order to protect an infant. The mother transfers the antibodies to the infant, which will provide the baby with protection from RSV in its first six months. Erck called the program historic. He said the Phase III program is in its fourth year and the company has vaccinated 4,636 women. He said they are tracking the women and the babies. Researchers call the mothers every week through the first six months of the baby’s life to acquire data. Erck said the company anticipates announcing trial data this quarter. If approved, Erck said the market for the vaccine could be a significant revenue driver.

“You have 3.9 million birth cohorts and we expect 80 percent to 90 percent of those mothers to be vaccinated as a pediatric vaccine and in the U.S. the market rate is somewhere between $750 million and a $1 billion and then double that for worldwide market. So it’s a large market and we will be first to market in this,” Erck said, according to a transcript of the presentation.

Denali Therapeutics – Denali forged a collaboration with Germany-based SIRION Biotech to develop gene therapies for central nervous disorders. The two companies plan to develop adeno-associated virus (AAV) vectors to enable therapeutics to cross the blood-brain barrier for clinical applications in neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, ALS and certain other diseases of the CNS.

AstraZeneca – Pharma giant AstraZeneca reported that in 2019 net prices on average across the portfolio will decrease versus 2018. With a backdrop of intense public and government scrutiny over pricing, Market Access head Rick Suarez said the company is increasing its pricing transparency. Additionally, he said the company is looking at new ways to price drugs, such as value-based reimbursement agreements with payers, Pink Sheet reported.

Amarin Corporation – As the company eyes a potential label expansion approval for its cardiovascular disease treatment Vascepa, Amarin Corporation has been proactively hiring hundreds of sales reps. In the fourth quarter, the company hired 265 new sales reps, giving the company a sales team of more than 400, CEO John Thero said. Thero noted that is a label expansion is granted by the FDA, “revenues will increase at least 50 percent over what we did in the prior year, which would give us revenues of approximate $350 million in 2019.”

Government Woes – As the partial government shutdown in the United States continues into its third week, biotech leaders at JPM raised concern as the FDA’s carryover funds are dwindling. With no new funding coming in, reviews of New Drug Applications won’t be able to continue past February, Pink Sheet said. While reviews are currently ongoing, no New Drug Applications are being accepted by the FDA at this time. With the halt of NDA applications, that has also caused some companies to delay plans for an initial public offering. It’s hard to raise potential investor excitement without the regulatory support of a potential drug approval. During a panel discussion, Jonathan Leff, a partner at Deerfield Management, noted that the ongoing government shutdown is a reminder of how “overwhelmingly dependent the whole industry of biotech and drug development is on government,” Pink Sheet said.

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

36th Annual J.P. Morgan HEALTHCARE CONFERENCE January 8 – 11, 2018

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements


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Antibody alternatives in specific aptamer 3-D scaffold binding

Curator: Larry H. Bernstein, MD, FCAP



New Proteomics Tools to Open Up Drug Discovery

Dr. Paul Ko Ferrigno, Chief Scientific Officer, and Dr. Jane McLeod, of Avacta Life Sciences



Size matters: Smaller molecules allow a tighter packing density on solid surfaces for improved signal-to-noise in assays, such as SPR or ELISA.


Size matters: Smaller molecules allow a tighter packing density on solid surfaces for improved signal-to-noise in assays, such as SPR or ELISA.


In the current genomic era of very accurate DNA analyses by in situ hybridization, DNA chip analyses, and deep sequencing, it is often assumed that antibodies have an analogous ability to identify molecular targets accurately. Nothing could be further from the truth. Proteomics as a field is still lagging behind its genomic counterpart in the level of detail we can achieve, the level of data we can collect and the overall levels of accuracy and reliability that the collected data represent.

From the estimated 20,000 human genes 100,000 different possible proteins have been predicted. What is more, the variation achieved via the post-translational modification of these proteins brings another layer of complexity to cellular signalling. All this means that while studying the genetic blueprint can offer insights into the cell, it is only through examining the functional protein units that we can comprehensively map the dynamic interactions that occur within the cell to drive an organism or disease process.


Why not use antibodies?

Antibodies form the basis of molecular recognition in proteomics, whether this is to identify a protein within a complex mixture or label a specific protein within a cell. Both their target specificity and high binding capacity have made these molecules fantastically useful tools within diagnostics. However, the large majority of commercially available antibodies are for use as reagents in research and development, where they are simply not as well validated and issues with their manufacture have created problems that have hindered drug development.

It has proven next to impossible to develop antibodies to certain targets. This may be because of their high homology to the host protein, so the immune system fails to recognise them as different, or due to antigen processing resulting in the loss of post-translational modifications or discontinuous epitopes. However, without the necessary antibodies to investigate these targets the corresponding research avenues have remained closed and key drug targets may have been missed.

Almost worse than lacking the necessary research tools is the problem of antibody reproducibility. Matthias Uhlen revealed that of the 5,436 antibodies tested as part of the Protein Atlas project over 50 percent failed to recognize their target in at least one of two commonly used assays. Antibodies that are not specific to their target or do not recognize their target at all are responsible for increasing the cost of biological research, with an estimated $800 million spent globally every year on bad antibodies. Many published studies have had to be retracted due to antibody-derived error and those that remain unidentified in the literature will continue to lead researchers down blind alleys. This level of misinformation in the published literature is not just hindering the progression of the field, but possibly even sending it backwards and costing more than is needed — an issue not to be taken lightly when so many research budgets are coming under the knife.

More recently there has been a call from a number of leading scientists for the use of polyclonal antibodies, considered to be the worst offenders in terms of batch-to-batch irreproducibility, to be abandoned. They suggest a move towards recombinant systems of production, which would remove the restrictions of the immune system on antibody production. Yet, they state that $1 billion dollars investment would be required to re-route antibody production down this path and suggest that a period of five to ten years may be required to bring about these changes.

Simply producing recombinant antibodies rather than animal-derived affinity reagents will still leave us with a number of problems regarding their use. Antibodies are simply too large to target many smaller, hidden epitopes and the presence of key disulphide bonds within their structure makes them all too susceptible to reduction within the cell, rendering them useless for applications such as live cell imaging of molecules within the cytoplasm. Moreover, can we afford to wait another decade for a solution to this problem before we pursue protein targets for basic understanding and drug development?





Antibody alternatives for new targets and techniques

Antibody alternatives are already available to researchers in the life sciences field. They are produced either from nucleic acid or protein molecules. Aptamers are short, single-stranded RNA or DNA molecules that fold to form 3D scaffolds, which can present a specific interaction surface to allow specific binding to its target molecule. Protein scaffolds are formed from parts of or whole proteins modified to present a peptide sequence. This peptide sequence works in a similar manner to present a specific interaction surface for specific binding to a desired target.

These antibody alternatives are produced in recombinant systems, minimizing batch-to-batch variation and allowing them to be produced to theoretically any target. Additionally, as they do not use animals in their production they are generally less expensive to produce than traditional antibodies.





While companies such as Affibody and Avacta Life Sciences are aiming to open up the drug pipeline, by offering these alternative affinity reagents to previously inaccessible targets for use in research and development, many have moved into exploiting their therapeutic potential. Noxxon produce an RNA-based scaffold, Spiegelmers, which are currently in phase 2 clinical trials for diabetic nephropathy, and Molecular Partners have reached phase 3 clinical trials with their protein scaffold DARPins, for wet age-related macular degeneration.

These new antibody alternatives are smaller than traditional antibodies. This opens up the use of new technologies, such as super resolution microscopy. While the diffraction limit remained at about 250 nmm the length of the antibody at 15 nm was of little importance, tagging your molecule as accurately as necessary. Removing this limit in super resolution microscopy has meant that antibodies are now too large to provide the required level of accuracy. Instead, using an antibody alternative of only 2nm to tag your protein of interest opens up this new technique offering greater precision to intracellular localization.




As these scaffolds have been engineered to be fit-for-purpose many contain no intramolecular disulphide bonds and so are not sensitive to the reducing environment of the cell. This function enables their use as intracellular reporters of molecular conformation, as well as in standard assays like IHC or western blotting, so allowing scientists to use the same reagent across both intracellular and biochemical assays, thus bridging the gap between cell biology and biochemical studies.

Offering increased reproducibility, access to an increased range of applications, and the opportunity to hit previously inaccessible targets, antibody alternatives are opening up potential new avenues of drug discovery.



About the Authors

Dr. Paul Ko Ferrigno is Chief Scientific Officer at Avacta Life Sciences and a Visiting Professor at the University of Leeds. He has been working on peptide aptamers since 2001 in Leeds and at the MRC Cancer Cell Unit in Cambridge, UK where his team developed the Affimer scaffold technology.

Dr. Jane McLeod is a Scientific Writer at Avacta Life Sciences.





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Supporting Open Innovation in Pharmaceuticals

Curator: Larry H. Bernstein, MD, FCAP



Compound Passport Service: supporting corporate collection owners in open innovation
David M. Andrews1 ,Sebastien L. Degorce1 , David J. Drake2 , Magnus Gustafsson3 , Kevin M. Higgins2 and Jon J. Winter1
   1 Oncology iMed Chemistry, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TF, UK 2 R&D Information, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TF, UK 3 R&D Information, AstraZeneca, Pepparedsleden 1, 431 83 Molndal, Sweden
A growing number of early discovery collaborative agreements are being put in place between large pharma companies and partners in which the rights for assets can reside with a partner, exclusively or jointly. Our corporate screening collection, like many others, was built on the premise that compounds generated in-house and not the subject of paper or patent disclosure were proprietary to the company. Collaborative screening arrangements and medicinal chemistry now make the origin, ownership rights and usage of compounds difficult to determine and manage. The Compound Passport Service is a dynamic database, managed and accessed through a set of reusable services that borrows from social media concepts to allow sample owners to take control of their samples in a much more active way.
The challenges of discovering and developing novel therapeutics have been well documented [1]; and the combination of the ‘low hanging fruit’ of drug targets having been picked off [2] along with the challenge to maintain the pace of new discovery has led to an increase in the complexity of targets and disease pathways in discovery portfolios. Additionally, the pharmaceutical industry has realigned resources away from early R&D [3], making industry more reliant on collaboration with academic groups to share the risks (and rewards) of conducting discovery and early validation efforts [4].  
These efforts are frequently captured under the generic term ‘open innovation’, first coined by Henry Chesbrough in 2003 [5]. Since then, a huge variety of definitions for open innovation have been suggested; the authors prefer the definition adopted by the Wellcome Trust: ‘The process of innovating with others for shared risk and reward to produce mutual benefits for each organisation, creating new products, processes or ideas that could not otherwise have been achieved alone, or enabling them to be achieved more quickly, cheaply or efficiently’ [6].  
We found that in AstraZeneca (AZ), as is the case across the pharmaceutical industry [7], many more collaborative agreements were being put in place in which the rights for assets could reside with a partner, exclusively or jointly. With more opportunities being investigated to take advantage of our in-house assets, we needed to improve our ability to ensure that compounds subject to a contractual agreement with third parties are managed and used in accordance with AZ’s obligations. Such agreements could mean compounds should be restricted to agreed tests and/or prevented from being shared with other parties.
The problem: compound rights tracking   Many corporate screening collections have been built on the premise that collection members that had been generated in house and were not the subject of paper or patent disclosure were proprietary to the company. Collaborative screening arrangements [8] and medicinal chemistry [9,10] now make the origin, ownership rights and contractually governed usage of compounds difficult to determine and complex to manage. When we looked at the compound management tools available within our own organization (or those available from vendors) we found that, in general, solutions were monolithic one-size-fits-all packages and lacked the information granularity necessary to answer key questions around compound-asset rights: compound and sample restrictions were either single sample or all examples from a project; delegation of approval was difficult and all approval was manual; approval tracking and compliance monitoring was difficult and error-prone; in consequence it was difficult to provide partners with a record of requests for ‘their’ samples.  
The root cause was that the design of the compound asset infrastructure predated the emergence of shared risk, collaborative, open innovation projects and the infrastructure had been designed against a background where there was a presumption that a company could solely own the rights to the portion of its compound library that was not in the public domain. Together, this created the risk that AZ scientists could unwittingly release the structures of early-stage hits to collaborators that were already the subject of an agreement with another collaborator. Put simply, the infrastructure of material transfer agreements and confidential disclosure agreements was very good at tracking the supply of single compounds but could not cope with the tens to thousands of compounds that needed to be correctly tracked as a result of open innovation collaborations. We aimed to design a dynamic database, managed and accessed through a set of reusable services that borrowed from social media concepts to allow sample owners to take control of their samples in a much more active way. Our design is driven by the vision that a greater number of collaborative agreements are being put in place and that, within those agreements, compound rights can be shared or reside with AZ or the collaboration partner. In turn this drove the need to improve our ability to keep our contractual agreements and progress compounds through approval flows in a timely and efficient manner. In addition to making it easy to record and update details of collaborations, we wanted simply and quickly to add, edit and remove compound assets, as well as to provide fast, reliable and automated approval where possible or to alert approvers where a manual approval is required. Finally, we wanted scientists to be able to determine compound status easily; able to request approval to take specific actions (e.g. testing) within the context of a system that maintained a permanent record.  
For the service to function correctly, for each open innovation compound, three pieces of information (metadata) need to be captured and kept up-to-date: (i) who owns any rights to the compound – AZ, the partner or are the rights shared? (ii) Can the compound be tested freely within AZ or does the collaboration agreement indicate that a collaboration coordinator needs to approve test requests? (iii) Has the compound been provided to the partner structure-blinded or has the compound structure been shared with the partner? The service can control ‘trafficking’ as well as maintain a permanent compound ‘life history’. It can be interrogated and receive updates via calls from other systems. Hence, we refer to it as the Compound Passport Service (CPS). Our shared vision and understanding of the underlying metadata allowed us to formulate the main concepts of the system and associated ‘use cases’.  
System concepts and use cases   CPS centres on assets, which are entities reflecting agreed constraints of compound usage by third parties and are grouped together in asset rights groups (ARG). Additionally, an ARG is a group of rights and rules applied to a number of assets. For each ARG a number of roles can be defined: coordinator – sets up and manages the ARG; delegate – a deputy for the coordinator who can add or remove approvers and add or update assets; approver – a person able to approve or reject requests manually, when the system is unable to make an automatic decision. For each ARG it is also possible to delineate request rules that define which requests can be automatically approved or rejected (e.g. that all compounds within an ARG can be tested in a specific test without any manual approval needed). A user in another system that is fully integrated with CPS becomes a requester when asking for approval to perform a specific action, for example to run a test on a specific compound and CPS responds with the following: ‘approved’, ‘rejected’ or ‘manual approval needed’ (Fig. 1).   This structure provides a framework that allows users to take control of their compounds in real-time and in a very granular way. It also has the potential to speed up the flow of compounds through the design-make-test-analyse (DMTA) cycle [11] by giving users the option to set up rules for automatic approval or rejection of tests. To enable these goals, we considered seven critical scenarios (use cases) that the system needed to service (Table 1).  
FIGURE 1   Compound Passport Service (CPS) concepts and definitions. The CPS is based upon assets, which are entities reflecting agreed constraints of compound usage by third parties, and are grouped (together with the rights and rules applying to the assets) in asset rights groups (ARG). For each ARG a number of roles are defined: coordinator – sets up and manages the ARG; delegate – a deputy for the coordinator who can add or remove approvers and add or update assets; approver – a person able to approve or reject requests manually. Within each ARG it is also possible to delineate request rules that define which requests can be automatically approved or rejected. A user in another system that is fully integrated with the CPS becomes a requester when asking for approval to perform a specific action; the CPS responds with the following: ‘approved, ‘rejected’ or ‘manual approval needed.
More-efficient approval flows and search  
The CPS was designed to manage complex compound sharing rules and requirements over the entire lifecycle of a collaboration project. The following is a case history of a recent project that was used to help design a system with the flexibility required. A collaboration project had two chemical series: A and B. Series A originated from screening of the AZ compound collection, and samples were tested by the partner organization in a structure blind format. Synthetic optimisation was performed by AZ but the compounds were never judged to be of sufficient selectivity to merit sharing with the partner. Owing to their origin in a collaboration project, however, series A compounds were not permitted to be tested outside the originating project. Later, the compounds were of no further interest to the project and permitted to be used by AZ projects for any purpose.  
Series B originated from the partner organization, and samples were initially shared for testing by AZ in a structure-blind format. After some months of optimization, the chemical structures were shared with AZ but the ownership of the compounds was retained by the partner. Later still, the series was judged of sufficient quality for the intellectual property to be shared jointly between the two organizations. Finally, after the biological target hypothesis was invalidated, notional ownership of the compounds was returned to the partner organization and no further testing was permitted by AZ (Fig. 2).  
FIGURE 2   The Compound Passport Service (CPS) can be used to manage an asset throughout its lifecycle. In this case study, at the start of the collaboration, compounds were tested at AstraZeneca (AZ) and the collaborator structure-blinded. Over the course of research, SAR failed to develop in series A which became of no further interest and was retained by AZ. Series B provided very productive SAR and, through the course of the collaboration, compound properties were updated in the CPS to note initially that the structures had been shared with AZ, then ownership became shared and therefore the series B compounds were unlocked and freely available for test across both organisations (the figure shows the initial collaboration status).
All of the compound status changes in this scenario are mapped on to three key properties that are captured by the CPS (Table 2). The owner of the ARG is able to change the properties of individual or groups of compounds as required, independently, as the project evolves. Such changes are recorded with time stamps as ‘transitions’, and can be tracked over the lifetime of an ARG. The ability to track all such transitions increases the transparency of compound ownership to AZ and partner organizations, prevents un-authorised testing of samples by other project teams within AZ and enables questions of the provenance of compounds to be easily resolved.    When placing test requests in a dedicated in-house requesting tool, the CPS is called and the sample status is displayed. Users might be presented with a warning that corresponding samples are subject to approval. Depending on the permission status, the requester can either decide to seek approval or cancel their tentative requests. Extreme cases such as auto-rejection (strictly no testing) or auto-approval (green list) are dealt with instantaneously, whereas manual approvals are immediately sought with daily reminders being sent to the approver until a response is obtained. A feature much appreciated by users is that the system sends an approval email to authorisers giving them the full context of the requests to ensure efficient decision making rather than having to access the CPS to gain the wider context.  
Green lists (leading to auto-approvals) are crucial to ensure no impact of sample restrictions on the DMTA cycle. In the case of required manual approvals, the impact of delay is minimised by the creation of project delegates. Green list assays refer to tests agreed with the partner and typically include project assays [primary target, selectivity, in vitro drug metabolism pharmacokinetics (DMPK), among others]. Similarly, a green list of requesters typically includes project members who are fully aware of the collaboration. Delegates have the same approval rights as primary authorisers and requests come to all independently, so that the first person to approve them releases the samples for testing.
Interface with other services   The envisioned central role and future extensibility of asset rights management led to the rapid conclusion that the compound passport solution needed to be delivered as a service [12]. The adoption of a service-orientated architecture has provided a flexible and reusable set of business services that provide access to and management of the compound passport database. Additional commodity services provide master data for projects, people and compounds (Fig. 3).
FIGURE 3   Service-orientated architecture provides a flexible and reusable set of business services that provide access to and management of the Compound Passport Database. Additional commodity services provide master data for projects, people and compounds. In this way, the Compound Passport Service (CPS) sits at the centre of a web of independent services controlling compound registration, distribution and test approval. Utilisation of reusable services allows integration with new systems as they become available in the future.
Impact on open innovation   Since the CPS was launched in 2014, it has been uploaded with metadata relating to 15,000–20,000 assets, and compounds are being added almost daily. The ability to track ownership rights along with more-efficient test approval has already enabled faster and more-efficient approval flows. Additionally, in considering whether to unblind the structure of a HTS hit series, we have also been able to identify that more than one external party had an interest in the chemical equity. Based upon an understanding that SAR would probably diverge as potency against the different targets was optimised, we have been able to adopt a risk-management approach to allow both partners to proceed with the investigation and possible optimization of the shared chemical start point.

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