From ‘Bench to Bin or to Bedside'?
How to improve the success rate of drug candidates
On their way to the clinic, many promising drug candidates bite the dust. On March 21, Medical Delta held an Medical Delta Café on the subject, hosted by Batavia Biosciences at the Leiden Bio Science Park. Representatives from various links in the value chain shared their views on improving the success rate. Unvaluable advice: take the entire value chain into account - right from the start. Many speakers mention GMP production of test batches as a key success factor.
“One year of research into ZIKA brought us closer to a vaccine on the market than ten years of HIV research”, says keynote speaker Dan Barouch from Harvard University. “We have a quite promising vaccine candidate for HIV, but for ZIKA we developed an even more effective candidate within ten months.” The main reason for that? Everything is different between the two. Whereas the ZIKA virus is homogeneous, the variability of the HIV virus between individuals is larger than the global variation in the influenza virus. Apart from the differing challenges posed by diseases, Barouch sees GMP product manufacturing as a key hurdle to translational research: “The cost and necessary experience are beyond the reach of most academic groups. In many cases the publicly-funded NIH supports such initial activities.”
Frank Staal and his group at the LUMC make stem cell-based gene therapy a clinical reality. They are very close to treating Severe Combined Immuno Deficiency (SCID) caused by a dysfunctional RAG protein. “Gene therapy is about transferring the correct versions of a mutated gene into the patient, using crippled virus as a vehicle. We had a good mouse model in place that works with SCID patient specific stem cells.”
A three million grant by ZonMW further enabled the researchers to launch the first stem cell gene therapy in Holland and the first gene therapy for RAG-SCID in the world. Staal also points at GMP produced clinical batches as a road block. “Only six parties worldwide were able to produce what we needed - and only Batavia Biosciences could deliver in time.” A last hurdle lies ahead now: to pass the complex regulatory track involving COGEM, CCMO, the GMO Office and the Ministries of I&M and VWS.
To promote the knowledge on that kind of subjects, several parties initiated a Clinical Development Module in Leiden for post graduate biomedical researchers. “It teaches about the challenges researchers face during development of their own clinical trial”, says director Marcel Kenter of this initiative, the Paul Janssen Future Lab.
Technology Transfer Officers (TTOs) such as Thijs Spigt at Erasmus MC try to link promising early stage developments like Staal's to interested companies. “Please contact us, we have many initiatives to support you”, Spigt invites his audience. He also explains the TTOs limitations: “We are entrepreneurial, not entrepreneurs.” In the Q&A Batavia Biosciences CEO Menzo Havenga mentions the gap between a 200,000 euros costing Proof of Principle and the 3,000,000 required for Proof of Concept to convince big pharma. Spigt: “When massive public funding is lacking, there is always the option of a publicly funded start-up to bring a promise closer to realisation.”
Peter Bertens from the Association Innovative Medicine (formerly Nefarma) will not necessarily make potential start-up candidates happy with his statistics: “Currently there are 7,000 medicines under development in the world. The chance of success is less than ten percent. Only one in three candidates survives costly phase II research.”Failure is not only a consequence of obvious factors such as lack of funding, poor test results or clinical trial complexity. Bertens also mentions, among other factors: “portfolio priorities, lack of fundamental biology knowledge, poor preclinical models and insufficient oral availability of the drug.” For a higher success rate he regards improved target selection by early Proof of Concept assessment as pivotal. The use of biomarkers and improved animal models can facilitate this. Also important according to Bertens: improved communication throughout the supply chain.
Ineke Slaper is Programme Manager Translational Research & International Programmes at ZonMW, (co)financer of Staal's research and the Paul Janssen Future Lab. While monitoring research programmes she often notices compliance with regulations and GMP production as hurdles. Her advice: “Define various steps towards implementation in a clinical development programme. That knowledge is often lacking in the academic world.” On moderator Colja Laane's question if concentration of funds towards a limited number of projects could improve success rate, she answered that he could be right.
After Slaper - representative from a public fund - it was Edward van Wezel's turn as representative from BioGeneration Ventures, co-investor of 'hits' such as Dezima and Acerta Pharma. He indicates that venture capitalists are more interested in early stage research than big pharma: “There is no ideal phase to step in, as long as there are proper preclinical data and a good animal model. Notwithstanding, the art of our trade is to recognise potential as early as possible as this promises the largest value increase. At present, we for instance notice very early stage private involvement in immuno-oncology.”
Amazingly, Van Wezel indicates that IP-awareness within the academia has been an issue until recently: “There was a lot of naivety, but luckily the TTOs have improved that a lot.” Among other issues he mentions reproduceability of science data and sourcing of management. “Furthermore, scientists tend to underrate what is already around. You have to have a product candicate that really stands out.”
From the back end
From venture capital we now move to private biopharmaceutical services with Ruud Santing, CEO of Eurofins Sinensis. He emphasises the importance of well-specified and thoroughly considered outsourcing: “The vital question that needs answering: what exactly do you need to prove? You have to know your product and the reason for each analysis. This defines the selection of analytic techniques. Equally important: to consider the trade-offs between quality and timeliness as well as sensitivity versus robustness.” Of course, Santing prefers a partnership model over 'throwing over the wall' outsourcing. “FTE-reservation for a certain period is worth considering, as this offers maximum flexibility.”
Batavia Biosciences is also a biopharmaceutical CRO service provider, among other things involved in process development and GMP manufacturing. Just like Santing, CEO Menzo Havenga sees a lot going wrong, such as the use of unallowed cell lines or drug candidates that require elaborate purification with too low yield. He therefore recommends: “Think from the back end of the supply chain. An experienced manufacturing organisation can help a lot with that. Take things such as manufacturability, reimbursement, patient population, raw material costs and release costs into account. Thinking back from the end of the chain will rise awareness for using only pharmaceutical grade components and for staying within the allotted regulatory boundaries.”
It is great to witness so many links from the pharmaceutical supply chain assembled in one gathering. If anything, this MD Café promoted awareness for everything that comes after early stage discovery. It would help tremendously if public resources in the Netherlands could be used to cover at least part of those expenses in a similar fashion as the NIH does. Funding always is an issue. The speakers underlined that other factors also deserve attention. More so: if vital issues such as proper data, a good animal model, GMP manufacturing and regulatory requirements are well thought-over beforehand, the change of funding will increase dramatically.
Tekst by: Leendert van der Ent