on June 2015
OncoSynergy is focused on addressing grave unmet medical needs, particularly orphan (rare) cancers. We approach disease with a “systems-level biology” perspective for maximal effectiveness and to mitigate drug resistance. Current drugs, particularly in oncology, are targeted to attack select single pathways in cancerous tumors and other diseases. We’ve created novel platform drugs that target many disease driving mechanisms at the same and can be applied to a variety of diseases like Cancer, Inflammation and Ebola.
Current targeted drugs in oncology don’t produce durable outcomes because the disease adapts rapidly. Cancer has several mechanisms driving its function. So when a cancer drug blocks only one driver, the remaining mechanisms can quickly compensate. After a few months the drug stops working and the cancer can be even more vicious because only the most aggressive cancer cells have survived and reproduced.
For example, anti-angiogenesis drugs which target the molecule VEGF are very potent at inhibiting the new blood vessel growth (“angiogenesis”) that drives tumor progression. However, our experience of anti-angiogenesis agents in brain cancer has shown that within several weeks the tumor adapts and regrows using a new strategy. By blocking new vessel growth, we’ve starved the tumor cells. This forces them into survival mode. The smartest clones adapt and become migratory and invade even deeper into normal areas of brain in search of nutrients to survive. There, they happily coopt the pre-existing vessels of the brain where they once again thrive due to the new blood supply access and grow faster than ever. Patients who have failed anti-angiogenesis treatment succumb to their disease very rapidly. No treatment has previously been shown to be effective in this resistant setting.
Our lead drug candidate, OS2966, is a humanized monoclonal antibody targeting the CD29 molecule. Targeting CD29 is like combination therapy in a single drug. We have demonstrated multiple mechanisms of action for OS2966 in cancer: 1) anti-invasion, 2) anti-metastasis, 3), anti-angiogenesis, 4) pro-apoptotic (cell death), 5) anti-drug resistance, 6) anti-growth signaling, and 7) anti-proliferation.
In fact, we have published studies demonstrating OS2966 can overcome resistance to anti-angiogenesis drugs in preclinical models of brain cancer.
CD29, also known as beta1 integrin, is a member of the integrin family of adhesion receptors. Integrins function as pairs of alpha and beta subunits. These pairs orchestrate cell signaling and function through several critical cell adhesion molecules like fibronectin and laminins. CD29 is the master beta integrin subunit which pairs with at least a dozen different alpha subunits. The alpha determines specificity for binding such as alpha5 for fibronectin, alpha6 for laminins, and alpha2 for collagens. Thus, instead of targeting 12 different alpha subunits, we get the same effect by inhibiting CD29 alone! This is how we achieve multiple mechanisms of action in a single drug. We call this “S.M.A.R.T. Targeting” (Synergistic Mechanisms to Attenuate Resistance to Therapy).
Platform drugs are treatments that can be used for many different diseases or symptoms. Aspirin is the classic platform drug used, for example, to treat pain, fever, and inflammation, but also to reduce the risk of blood clots and heart attacks.
OS2966 is a platform drug because CD29 function is fundamental to virtually any disease process where the body’s cells are proliferating, migrating, growing, creating new adhesions, and secreting. Thus, it is a drug that can be used for cancer and inflammation. It is also promising for serious viral diseases like Ebola because these are often driven by an overreactive immune response.
We started at UCSF with animal trials and initial proof of concept. We’ve since spun out of the university and can now move much quicker towards commercialization. We have already produced enough clinical grade (cGMP) drug material to complete initial clinical trials early next year.
The FDA drug approval process consists of several stages. Phase 1 of clinical trials is focused on safety and dosing. We’ll start patients on low doses and escalate to determine the optimal dose balanced against any potential adverse effects for followon studies. Phase 1 should finish about this time next year, which is very exciting. The completion of a successful Phase 1 trial is a major value inflection point and may facilitate a potential exit opportunity or lucrative partnership deal.
CD29 has long been predicted to play a critical role for several diseases, particularly aggressive and metastatic cancers.
However, scientists have long assumed that targeting CD29 would be prohibitively toxic because of its essential role in normal cellular signaling processes. However, we took a “Goldilocks Approach” when developing OS2966. It modulates CD29 function without completely shutting it down. The result is we have empirically developed a very effective antibody that doesn’t promote rapid drug resistance. We have also performed pilot toxicity studies in primates and demonstrated preliminary safety even with doses up to 10x the expected clinical dose (100 mg/kg).
The pharmaceutical industry has established targeted therapy approaches as a blockbuster business model. While we intend on OS2966 creating superior returns for our partners and investors, as physicians, we also keep our patients in mind and will always make durable outcomes our critical priority.
A patient with a cold virus may have fever, inflamed mucous membranes, and a cough. These are all symptoms that result from the body fighting the virus. If you take a cold medicine with an NSAID and an antihistamine you usually feel better and can potentially get out of bed and function even though the virus is still in you replicating. You keep taking the cold medicine to feel better until your body’s own defenses eliminate the virus.
Ebola, Dengue, MERS and other emerging viral diseases all operate in a similar way - a lot of the bad health effects are the body overreacting to the virus. However, in the case of MERS and SARS, you get a massive and life-threatening inflammation of the lungs. With Ebola, it’s like your entire body, including multiple vital organs, are involved which is why it is so deadly.
We’re already very well capitalized before this small funding increase. This funding round on Wefunder will be used alongside another $6M intended for cancer drugs. And while this money will be technically earmarked for antiviral research, the development path is the same regardless of clinical indication. For instance, when we do our initial Phase 1 trial, the data can be used for both the Ebola and cancer programs.
We have already significantly derisked our program at every stage of development. We have already humanized and deimmunized the antibody for maximal safety and effectiveness. We have already validated the lead candidate in additional cancer models including aggressive and metastatic forms of breast cancer, ovarian cancer, and pancreatic cancer. We have developed and validated a manufacturing process and have just successfully harvested a clinical scale manufacturing run. We have developed a highly stable formulation that can withstand prolonged storage at up to 40ºC without losing function. Importantly, as above, we have already demonstrated preliminary safety in primates with administration through 3 different routes. Finally, the FDA has already awarded 2 coveted Orphan Drug Designations to OS2966 in the treatment of glioblastoma (brain cancer) and ovarian cancer.
We are leading with oncology because, there is a well-established path for oncology drug approval. Further, there are several enhanced FDA programs to further expedite development to marketing approval. We are now preparing materials in order to meet directly with the FDA this summer (pre-IND meeting). The only steps we have left are formal toxicity studies, IND filing (Investigational New Drug application) and then completing Phase 1.
The biotech sector is thankfully on a major upswing at the moment in terms of public markets, institutional investments, co-development, and M&A. Acquisition appears to be a growing strategy for filling waning big pharma R&D pipelines. There have been many high-profile acquisitions of small biotech companies that haven’t even gone to the clinic yet as well as IPOs of the same. Indeed, several large biopharma companies have approached us already and we have begun early discussions under CDA. But we won’t necessarily sell on the first good offer, the drug has so many applications that we would prefer to carve up the platform - the Ebola portion for instance - and continue to develop the other indications. We don’t just have one asset. We see platform drug assets as a combination of multiple verticals.
Finally, OS2966 is not our only play. We have another platform drug called OS47720 which is a small molecule inhibitor with multiple mechanisms of action and has also shown dramatic effectiveness in preclinical models, particularly in oncology.
My PhD advisor was actually the first to discover the CD29 molecule and we didn’t realize that it might apply to Ebola until we found a Japanese paper written on the subject. The paper showed that blocking CD29 could actually inhibit a model of Ebola infection in vitro. Judy White, a leading Ebola scientist and collaborator recently verified the Japanese findings, and the Ebola outbreak last year prompted us to look into our antibody as a possible solution that could be rapidly deployed to address the crisis in real-time.
We raised a small crowdfunding round through Experiment.com for the initial pilot studies and verified OS2966 is a potent inhibitor of viral entry in laboratory models of Ebola. But in order to demonstrate the full potential of our drug we need to take the antibodies to an animal model and potentially to patients in the field.
Scientists have recently recognized that Ebola Virus Disease is deadly because of the body’s overreaction to the virus. You get a massive inflammatory response and widespread clotting in blood vessels. So, this suggests that one should target the infected host rather than the virus. If you can temper the inflammatory response and prevent the clotting, the patient may have a better chance at survival. OS2966 is predicted to do just this. In addition, as we described above, it also works by interrupting the infectious cycle. So, again, we have potentially multiple mechanisms of action for greater effectiveness.
Other Ebola drugs like ZMapp target proteins on the virus itself. The virus rapidly mutates which can render these drugs completely ineffective. In addition, the Ebola virus is smart (for having no brain): it releases dummy decoy receptors that can bind up ZMapp and decrease its effectiveness.
Again, our antibody actually targets the body’s negative reaction to Ebola, rather than attacking the virus itself.
As above, most serious disease-causing viruses elicit this overreactive response from the body. Further, in the literature we found over two dozen viruses and bacteria that exploit CD29 specifically, including HIV, SARS, Chikungunya, and Dengue fever. We have started collaborating with academic scientists all over the world to explore these avenues further. The number applications for this platform drug are potentially enormous. It is still early days, but OS2966 has the potential for becoming a broad-spectrum antiviral/antibiotic, thus establishing a new exciting class of anti-infectives.
For Ebola, there's one other company that's targeting the host but they're targeting a specific carbohydrate that doesn’t have the same mechanisms of action as our approach. We are first-in-class.
Biotechnology infrastructure is expensive so in order to stay lean, we operate primarily as a virtual company and outsource a large portion of our work (although we do run a small R&D lab in San Francisco). Thus, we've assembled a world class core team of 5 full-time employees. In addition, my Co-Founder is the eminent Dr. Catherine Park, MD, the Interim Chair and Professor of Radiation Oncology at UCSF who has studied the role of CD29 in breast cancer for over a decade.
Our core team is complemented by world-class and industry veteran consultants and advisors who all come together on our several Development Teams. We are very excited to have just recruited Klaus Damm, PhD, previously the Licensing Director of AMGEN(!!!) to lead our Business and Strategy Team. We also just recruited William Slichenmyer, MD who was the VP of Clinical Development at Pfizer and Global Head of Oncology to help lead our Regulatory/Clinical Team. We also have Pamela Munster, MD on board as a clinical advisor; she happens to be in charge of all Phase I trials at UCSF. Our CMC/Manufacturing Team is lead by Steven Chamow, PhD, one of the earliest employees at Genentech with over 20 years of biomanufacturing experience. Finally, we are working closely with three high-level former FDA Directors: 1) Joy Cavagnaro, PhD (Former FDA Senior Pharmacologist and Director of Quality Assurance, CBER), 2) Tim Coté, MD (Former FDA Director of the Office of Orphan Drug Products), and 3) Richard Lewis, MD (Former FDA Deputy Director of the Office of Blood Research and Review (OBRR), CBER).
On the basic science side, we are fortunate to be advised by Rick Horwitz, PhD, co-discoverer of CD29 and the integrin family of receptors. Rick is now the Executive Director of the Paul Allen Institute for Cell Science in Seattle, WA. In addition, we are working with Professor Mina Bissell, PhD, one of the earliest pioneers to study the tumor microenvironment and specifically the role of CD29. See Mina’s compelling TED talk here: https://www.ted.com/talks/mina_bissell_experiments_that_point_to_a_new_understanding_of_cancer?language=en
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