Platform drugs for orphan diseases like Cancer and Ebola
What they do: OncoSynergy develops platform drugs to treat orphan diseases. Their lead antibody drug candidate, OS2966, is effective in treating therapy resistant and metastatic cancers in animals. OS2966 also shows an ability to inhibit Ebola in the lab and will soon be tested on primates.Why it's a big deal: They’re taking a completely new approach to drug development. Most drugs interfere with specific molecules that help a disease's cells grow and survive, which ultimately fails because diseases are driven by more than one molecule. The disease just adapts and becomes more aggressive. Just like Aspirin acts as an anti-fever, anti-pain, anti-inflammation, and anti-clotting drug, OS2966 blocks multiple molecules that drive the disease simultaneously. Scientists have been looking for a way to deploy this kind of treatment for decades, and OncoSynergy is one of the first to develop platform drug candidates that have been tested safely in large mammals and primates. OS2966 has enormous potential for improving the standard of care for patients with deadly diseases.
Platform drug for the treatment of very serious diseases.
Dramatic efficacy in clinically relevant cancer models.
Awarded Orphan Drug Designation by the FDA in oncology.
Only multi-mechanism experimental Ebola drug in development.
Founder is a MD, PhD, and Oxford Junior Fellow.
Why investors us
$13,178,475 since our founding
Because they’ve developed a brand new approach to treating aggressive cancers that may also be effective against Ebola. Every pharmaceutical company targets these diseases in the same way, and the disease always wins. OS2966 has dramatic effectiveness in preclinical models, they can manufacture it at clinical scale, have run safe trials in primates, and will be starting Phase I clinical trials soon.But it's the founder that really gets us really excited. After a combined MD, PhD program at UVA and 3 years studying cancer at Oxford, Dr. Carbonell ran his own research lab at the same time that he was a Neurosurgery resident at Cedars Sinai Medical Center (a leading neuro-oncology institution). But he wanted to cure cancer, so he left the cocoon of academia, maxed out all his credit cards and became an entrepreneur. He has since developed a drug from a theory, through animal testing to the FDA. He’s raised nearly $6 Million and has already begun talks with big pharma about partnership and acquisition opportunities. If anyone can provide new hope for Ebola and Cancer patients it’s this guy.
Shawn is a brain surgery dropout. He left clinical neurosurgery training in order to start OncoSynergy so that he could focus all of his efforts to advance medicine and improve outcomes for cancer patients. Shawn had spent 18 years prepping for a career as an academic neurosurgeon until one day his obsession with a new strategy for fighting cancer took over and he left his dream to be an entrepreneur.
Shawn was laser focused on neurosurgery from the beginning of his career as an undergrad at the University of Washington. Shockingly, neuroscience was not an available major at the University of Washington in the early 90s so he received his BS in Psychology instead. He then pursued the dual MD/PhD at the University of Virginia through the Medical Scientist Training Program (MSTP) where he was a Dean's Merit Scholar.
After he received his PhD in Neuroscience, still hungry for more, Shawn deferred neurosurgery residency for 3 years to study brain metastasis at Oxford University as a Nicolas Kurti Junior Fellow at Brasenose College. Oxford eventually tried to recruit Shawn as a young faculty member, but he left to continue his surgical training at Cedars-Sinai in Beverly Hills and build an academic powerhouse and lab with one of the most respected brain cancer experts in the world.
Oxford is where Shawn first had a hunch about the potential for targeting a molecule called CD29 and its ability to block very fundamental critical path drivers of serious disease. However, during residency at Cedars-Sinai, 15 hour days turned to 20 hour days and Shawn dove headfirst into determining how to most rapidly bring his ideas into the clinic. After a two-week vacation developing his master plan, Shawn was so energized by the potential that he immediately decided to resign from his training program. His Chairman tried to retain him as a full-time tenure-track scientist but Shawn had already decided he needed to develop this outside of academia and bootstrap OncoSynergy.
For Shawn it was all about speed. He knew targeting CD29 could be a blockbuster approach and his patients typically only had a year to live from time of diagnosis. The academic credentials was worth nothing at this point, he wanted to get the drug out the door as soon as possible and that meant leaving the ivory tower . Shawn lost more than a paycheck when leaving clinical medicine , he lost his lab, he burnt bridges, and started maxing out his credit cards. But luckily he was able to demonstrate initial proof of concept at UCSF during his second postdoc and in six months spun out OncoSynergy. Four years and nearly $6 million in funding later OS2966 has FDA Orphan Drug Status and is ready for testing in patients.
What does OncoSynergy do?
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.
How do most other drugs work? Specifically for cancer?
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.
How is your drug different?
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.
How does your drug work specifically?
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).
This is a platform drug, what does that mean?
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.
How fast are your progressing? When will the drug be ready?
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.
Why haven’t other pharma companies discovered this approach?
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.
Can you provide an analogy for your approach?
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.
What are the risks for investors? What are the hurdles to completion?
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.
What are your opportunities for potential exits?
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.
Where/how does Ebola fit in here with OS2966?
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.
How would OS2966 work to treat Ebola Virus Disease?
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.
What other infectious diseases may benefit from a host-directed treatment approach like this?
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.
Has anyone else adopted this platform strategy for antiviral drugs?
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.
Who is the rest of your team?
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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