It has been almost six years since I backed Maria Soloveychik and Charly Chahwan, founders of SyntheX, for an idea to invent a new way to find and make cancer drugs. They were two young, outsider scientists in IndieBio’s third class and were massive underdogs. The idea they proposed – to engineer cells to accelerate and improve drug discovery, could prove incredibly valuable if successful. Today, SyntheX and Bristol Myers-Squibb announced a research collaboration totaling up to $550 million dollars to discover and develop protein degrader based therapeutics. The road traveled has been hard. The road ahead will be at least as hard. Charly and Maria welcome the challenge.
As a board director at SyntheX, I have had a unique view into their journey to this milestone and gained a deeper appreciation of what it takes to make a biotech company work. I first met Charly and Maria when they applied to IndieBio with the idea to make new cancer drugs by using synthetic biology to discover novel ways to disrupt protein-protein interactions in signaling pathways crucial in cancer. Many cancers come from the wrong proteins binding and communicating, creating an out-of-control feedback loop that makes cells divide without stopping. This is a tumor. Break the connection, stop the cancerous tumor (is the idea). SyntheX designed their cell-based platform to simultaneously test billions of short peptides to disrupt a crucial cancer-causing protein-protein interaction in a single petri dish. It’s like finding a perfectly shaped needle in a needlestack.
Using this discovery method, the cells began revealing the secrets of these key proteins. The SyntheX team discovered a new mechanism of cell death caused by the catastrophic release of calcium within the cell by disrupting a crucial DNA repair protein. They advanced their lead compound that caused this and confirmed the effect also happens in mouse models. They further determined that this calcium-based cell death is immunogenic and engages the immune system to recognize the cancer cells as they die. In parallel to this program, the team continued to evolve their discovery technology to be ever more powerful.
Charly and Maria, the outsiders, began to attract attention from insiders. Decorated industry veterans like Dr. Leonard Post, the scientist behind the best in class PARP inhibitor, Talazoparib, (among his many other contributions to cancer drug discovery), joined the advisory board. Investors noticed as well. IndieBio, 8VC, OMX and others joined a $6M seed round. Based on conviction in Charly and Maria, SyntheX became the single largest investment made at IndieBio and SOSV at the time.
While working to expand the internal pipeline with insights into mechanisms that modulate long deemed ‘undruggable’ proteins, Maria and Charly’s creativity led to the development of another platform that addressed a key drug discovery bottleneck for an up and coming modality – Targeted Protein Degraders. By modifying the circuitry of the platform they created ToRNeDO, with the focus of discovering molecules that can bring two different proteins together, aptly called “molecular glues”. In this case, these glues allow for a particular protein (known as an E3 ubiquitin ligase) to tag a second target protein for destruction. By getting rid of a protein that is miscommunicating in a cell and causing disease, you can treat that disease with potentially less toxicity in patients and evade downstream resistance mechanisms. Meanwhile, the internal pipeline that SyntheX is developing has gained interest from insiders at several pharma companies after they shared their results at various conferences. These initial relationships were key in building the scientific credibility of the team in the broader pharma community and accelerated the path to partnership.
Platforms aren’t products, products are products. It is so easy to fall in love with how you do something but the world only cares about what you sell. Therapeutics companies are no exception. They develop and ultimately sell drugs that treat disease. Designing the right business models make and break companies, and platforms can seduce founders into a CRO business model (screening deals with no shared downstream revenues), hoping it serves enough validation to attract other investors. In the new world of higher interest rates there is far less interest in this approach (the exception would be if enough revenues could be generated at a high enough operating margin to finance the clinical development of internal assets). Over 25% of public biotechs (128 companies as of last month) are trading at or below their cash balance, many far below. A common phenotype of these companies is a promising platform and assets that are years away from an IND (Investigative New Drug approval) or going into humans. Wall street doesn’t care anymore – deliver amazing drugs or get crushed. The biotech index XBI, which tracks the stock price of all biotech stocks on Nasdaq, is down over 54% since its high almost 2 years ago.
Yet for all the lost wealth and blood on Wall Street, the investments into oncology are creating real value for patients. Checkpoint inhibitors, cell therapies for blood cancers, targeted antibody therapies and newer antibody-drug conjugates are getting approved and into patients in record numbers. 2018 saw the largest drop in cancer deaths in history, and then 2019 beat that record. 1.5% fewer people are dying from cancer every year. This adds up. In 1975 the 5 year survival rate of cancer was 49%. Today it is 69%. This is remarkable progress for such a complex disease. Despite the public market pain, oncology is still a great sector to invest in. Not only are there many huge opportunities for new biotech startups, there is still so much progress to be made before we are able to cure cancer for humanity.
SyntheX has had a long history with BMS. They got to know the BMS (then Celgene) team while at JLabs/MBC biolabs, where after presenting their approach and progress, they were awarded the “Celgene Golden Ticket” for two years in a row. In addition to a free bench space at the incubator, the SyntheX team formed a scientific relationship with key BMS scientists who got to know Charly and Maria. This was critical to build trust between the teams for such a large deal with a relatively small startup. With that trust in place, and SyntheX ready to seek a large partner to move their protein degradation platform further into small molecule development, this partnership was proposed to discover and develop drugs to go into the clinic. These deals take a long time, and it is important to budget runways accordingly. Standing by founders to give them the space and confidence to do what is needed, even in the inevitable times of stress is critical.
I am excited to continue standing by Charly and Maria in their quest to treat cancer. Cancer is personal. For Maria, she watched the devastating impacts of cancer on loved ones growing up and wanted to take action. For Charly, it began as a sixteen year old when he and his family survived the war in Lebanon, yet lost four family members to cancer in the next year. This shocked the young Charly into devoting his life to understand and cure cancer. For me, my mother has been battling cancer for years. Millions of others pray for their loved ones to get better. The road will be hard, but that is why we walk it.