Expanding the Target Universe and the Therapeutic Opportunities of Small Molecules Through Covalency – Previously Thought Impossible

Innovation That Matters

By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx).

The current repertoire of tools suitable to interrogate biology and to translate this into therapeutic opportunities has been confined generally to small molecules and biologicals – although new approaches including gene editing and RNA-based technologies are only recently emerging. Biologics have found multiple important therapeutic applications, but their large size generally restricts their targets to extracellular space and limits their therapeutic utility to non-oral applications. As a result, there are broad range of intracellular and extracellular target classes that have today been termed “undruggable”, such as transcription factors, E3 ligases and adapter proteins.  Indeed, it has been estimated that 90% of the proteome contains proteins with biological and therapeutic relevance, but they are beyond the reach of current technologies.

Vividion is addressing the limitations of small molecules using a chemical proteomics approach, pioneered by Benjamin Cravatt of Scripps Research, that is centered around a collection of small molecule fragments featuring covalent modifying motifs. These fragments are deployed on a proteome-wide scale using screens in native biological systems to unveil targets unprecedented in terms of scope, breadth, and potential, while eliminating the artifacts and limitations of traditional screening methods.  Vividion’s approach has uncovered new druggable pockets on highly desirable target proteins and sets up a range of therapeutic strategies, including direct functional and allosteric modulation and targeted degradation, thus widening the potential of small molecules against previously termed “undruggable” targets.

Vividion, a 2017 Fierce 15 company, launched in 2017 with $50M Series A round by ARCH Venture Partners and Versant Partners. In March 2018, Vividion announced a strategic, multi-year collaboration with Celgene for the identification and development of unique small molecules against a limited set of pre-defined, high-valued, and difficult-to-drug targets across a range of oncology, inflammatory and neurodegenerative indications. This Celgene deal featured $101M upfront including small equity investment, with a focus to advance new small molecules against this set of targets.

In April 2019, Vividion announced an oversubscribed $82M round Series B round led by Nextech Invest, additional new investors BVF Partners, Casdin Capital, Mubadala Ventures, Trinitas Capital, Mirae Asset Capital, Altitude Life Science Ventures, and Alexandria Venture Investments. Existing investors ARCH Venture Partners, Versant Ventures, Cardinal Partners and Celgene Corporation also participated in the round.

Spearheading the Cravatt spinout is Diego Miralles, M.D., a 25+ year industry-seasoned veteran, whose distinguished career included President of Adaptive Therapeutics, Head of Innovation at Johnson & Johnson, Head of Janssen Research and Early Development in La Jolla, CA, and VP of Clinical Development at Tibotec – where he was involved with  the development and approval of Prezista® and Intelence® amongst other drugs.

Rich Soll (Senior Advisor, Strategic Initiatives and Head, Boston Office, WuXi AppTec) and WuXi AppTec Content Team recently discussed Vividion with Miralles

Shaped by his experiences as a HIV physician treating this once deadly disease, Miralles declared “how many people are alive today because of small molecule therapies? Antibodies, cell therapy and gene therapy are very exciting, but are not global treatments. Even though antibody therapeutics have been around for over 30 years, only a small percentage of the population of the world has access to antibodies as a therapeutic modality. Small molecules and vaccines are the only global treatments and that is why, from my experience as a HIV physician, I am very excited to help expand the therapeutic reach of small molecules. For the foreseeable future, they are the only means by which we can ultimately treat all eight billion people in our planet!”

“Vividion’s technology platform addresses three key points,” stated Miralles, “ (1) the need to screen and identify targets in their native systems in whole cells, where proteins are screened in a more natural environment, (2) the ability to expand the chemical space, where molecules of high sp­3 character (or topology)  have higher 3 dimensional complexity while remaining small and being infinitely more progressable, and (3) demonstration of covalency (bond formation) between protein target and molecule with high selectivity.”

The molecules arising from the Vividion platform, bind to pockets housing a cysteine across the whole proteome, both at direct functional or allosteric site(s) and help to elucidate the effects of covalent ligand binding on protein function. Vividion is specifically interested only in well-validated, compelling, high value targets that have been traditionally undruggable. The list of targets it is pursuing is somewhere between 150 to 300, all of which address important unmet medical needs, and therefore would result in highly differentiated drugs.

Vividion’s initial focus was in immune pathways, as noted by Miralles, “there’s a lot of highly validated targets in this space and, of course, this folds in immunological diseases as well as oncology; in addition, PBMCs gives us easy access to screen in primary tissues.”

“We have made a lot of progress in starting to cure cancer with molecular drugs.” Miralles continued, “an example is the most recent study published in the New England Journal of Medicine on the combination of the BTK inhibitor, ibrutinib and the Bcl2 inhibitor, venetoclax in high-risk, previously untreated older patients with chronic lymphocytic leukemia.  In this Phase II study, this non-chemotherapy, oral combination study, 88% of patients had complete remission with normal or incomplete blood count recovery after 12 cycles of treatment[i]. I do believe Vividion’s approach to small molecules will significantly expand our therapeutic armamentarium and bring even more benefits for patients.”

“Protein degradation as a therapeutic approach could theoretically have an additional impact on drug resistance,” Miralles suggested, “but it remains to be seen.”

To maximize the value of the platform, Miralles noted that the right targets need to be selected in order to yield highly differentiated products with high impact.

Central to accomplishing its goal has been the partnership established between Vividion and WuXi AppTec. “WuXi has been instrumental in our progress. The company has provided very high-quality services to us,” commented Miralles, “it allowed us to move a very large number of programs forward simultaneously.”

“The key is in the execution,” remarked Miralles, “we are currently prosecuting four programs, and that requires a lot of chemistry capabilities – particularly since some of the programs involve bispecific degraders. Therefore, in order to execute on all those programs, you need to be able to have access to a very competent and reliable external workforce, and for that, WuXi has been integral. We have extensively used WuXi’s chemistry and pharmacokinetics platforms.”

To ensure its leadership position, Vividion is continuously investing in both technology and pipeline.  “Vividion is not going to be a binary company,” asserted Miralles, “in contrast to many small companies who do not have access to technology platforms to generate multiple lead program(s). We feel that investment in expanding our technology will give us a lot of options.”

Projecting forward over the next 4-5 years, Miralles hopes to have 4-5 programs in the clinic and a range of partnerships with biotech and pharma. What other tools or technologies might Miralles like to see that Vividion may not have yet? Miralles commented: “(1) a deeper understanding of virtual chemistry and its implementation and (2) more predictive, computational approaches of protein structure and small molecule interactions with targets.”

Miralles also reflected on personal choices and paths not taken, i.e. doing things differently from the actual course of action. “I learned from my experiences, both good and bad. So I would not have taken a different path since it has all added to the person I am today. All of those collective experiences have made me a better person and a leader.”

In closing, Miralles offered some thoughts on the landscape by 2030. “I hope that the number of biological problems that remain challenging would be significantly smaller, as we are closing in on many of the causes of human disease and suffering. I also believe that with the scientific understanding of the past 10 years, particularly when it comes to genomics, coupled to a new era of technology developments – which includes the Vividion platform – the number of diseases that remain intractable will be much smaller than it is today. That will translate into more drugs approved per year, and by then, we should be approving  >100 drugs/year.

[i] https://www.nejm.org/doi/full/10.1056/NEJMoa1900574

Subscribe to WXPress

Receive our newsletter and information on upcoming events.