Serendipity And Science: Forging Billion-Dollar Oncology Breakthroughs

Serendipity, persistence, and rigor have played a role in the foundation and discovery processes of some of the most innovative pharmaceutical and biotechnology companies in history. SpringWorks Therapeutics (NDAQ: SWTX), founded in 2017, takes a precision medicine approach to acquiring, developing, and commercializing life-changing medicines for underserved patient populations suffering from rare diseases and cancer. But the story of SpringWorks stretches back long before 2017, and is one of purposeful research, healthcare provider (HCP) and patient advocacy, and unexpected findings.

During clinical trials led by Pfizer (NYSE: PSE), Nirogacestat, an oral, selective, small molecule gamma secretase inhibitor, showed potential activity against Desmoid Tumors, a locally aggressive and invasive soft-tissue tumor arising from fibroblasts, which can grow, press against, and intertwine with muscles and nerves, causing pain and other complications. While prior gamma secretase inhibitors were shown to be ineffective for Alzheimer’s, the emerging link between this drug class and cancer ultimately convinced Pfizer to run a Phase 1 solid tumor trial in 2009, which included 64 patients with solid tumors. Of the 64 patients, there were a small number of Desmoid Tumor patients who unexpectedly had a high response. When data from the Phase 1 trial was presented at the joint meeting of the European Organization for Research and Treatment of Cancer, National Cancer Institute (NCI), and American Association for Cancer Research, the results caught the attention of an investigator from the NCI, Shivaani Kummar, MD. “Desmoid tumors can result in significant impact on functioning and quality of life of patients. Seeing the responses and clinical benefit reported by the investigators in the Phase I trial, I felt strongly that we should further evaluate this new drug for its likelihood to benefit patients with this rare tumor,” says Dr. Kummar. This prompted Dr. Kummar to conduct a follow-up Phase 2 trial at the NCI, which showed promising results.

Jeanne Whiting and Marlene Portnoy, the founders of Desmoid Tumor Research Foundation (DTRF), a nonprofit patient advocacy organization, played a critical role in enrolling patients for the Phase 2 clinical trial overseen by Shivaani Kummar, MD. “Jeanne and I told Dr. Kummar not only can we fill the trial, but we can fill it fast! While the goal was to find enough patients in 2 years, we filled it in less than 6 months” says Portnoy.

Even as Pfizer decided in 2015 not to take Nirogacestat forward, patients, physicians, and researchers were able to team up with NCI investigators, and the DTRF to bring Nirogacestat back into development. The triumvirate of scientific leadership, HCP advocacy, and patient advocacy, when leveraged against big pharma research, proved to be the key ingredients for SpringWorks Therapeutics’ genesis. In September 2017, SpringWorks Therapeutics in-licensed several molecules from Pfizer, initially starting with Desmoid Tumors and Neurofibromatosis Type 1-Associated Plexiform Neurofibromas (NF1-PN).

With a $103 million Series A financing round led by Bain Capital Life Sciences, OrbiMed, Pfizer and LifeArc, Saqib Islam was initially recruited to join the company as founding Chief Business Officer and Chief Financial Officer, but ultimately took over as CEO in 2018. Through Islam’s leadership, SpringWorks has progressed rapidly to Ogsiveo (Nirogacestat) becoming the first and only FDA-approved product for adult Desmoid Tumors.

Islam believes in the complex world of drug development, to be successful, unexpected and fortuitous events coexist alongside logical and systemic analyses. As a first principles thinker, he acknowledges the role serendipity and persistence play in the formation and continued success of the company.

According to NCI, approximately 1,650 people are diagnosed each year with Desmoid tumor. What was the likelihood that out of 64 patients, several with Desmoid tumor would happen to be enrolled in the solid tumor study? What would have happened if Dr. Kumaar from the NCI did not walk by the poster and wonder how and why the small group of Desmoid tumor patients were responding so dramatically? What if Dr. Kumaar had not pushed to run a Phase 2 trial, while Pfizer was in discussions to shut down the program? What would have happened if there was not a patient advocacy group pushing to support the Phase 2 trial?

“So much of this business is based on the combination of both serendipity and persistence,” says Islam. “Biology is not scalable and drug development is not linear. Whether you’re using AI, human ingenuity, or good luck to get to the drug discovery piece of biotech – and sometimes you really do need all three – in the end you need to figure out the right tool for the right problem. Inevitably, we are problem solving for what are the characteristics of the molecule we have and will this work in a human.”

“Pain is a key treatment goal for both patients and physicians, since it is often the most debilitating symptom reported by patients with Desmoid tumors who often go through surgery after surgery, chemotherapy, tyrosine kinase inhibitors, and opioids for pain, while still dealing with tumor recurrence,” says Islam. This further highlights the importance of the significant reduction in pain for Ogsiveo patients, with pain reduction making its way into the drug’s label. Like many patients, Dana Lawson, a patient advocate for this rare tumor, is intimately familiar with the pain this unfortunate disease brings.

Maximizing her time hiking and running in the outdoors, Lawson describes her journey before Ogsiveo as hopeless. And after Lawson’s leg was amputated, years into her journey with the disease, she thought she had reached the end of her fight. “Because I amputated my leg, I left no stone unturned, so when the tumor came back on my hip and pelvis, it brought back a sense of hopelessness. As my tumor expanded in size, it caused so much pain that I could no longer wear my prosthesis,” says Lawson. As one of the 17 patients in the Phase 2 Clinical Trial, Lawson’s own persistence was rewarded with what she describes as a restoration of hope when her tumor reduced in size by 28% in the first year of treatment, relieving some of the tumor’s compression around her sciatic nerve. With the Phase 2 trial requiring 4 patients to have their tumor reduced by at least 30%, Lawson’s final scan in the trial showed a reduction of 43% reduction in tumor size. “I’ve never seen such an amazing and relentless community of support come together to bring a resolution to a disease. We had the clinicians, patients, advocacy groups, researchers, and biotechnology company all sitting around the table together to bring this success to the Desmoid patient community,” says Lawson.

“With Nirogacestat,” Islam reflects, “we had seen Phase 1 data and Phase 2 data. What was abundantly clear is that this product was having a significant benefit in patients with Desmoid Tumors.” But what wasn’t clear at that time was: (1) Could you design a study that if successful would lead to an approval? (2) Were there enough patients to run the study? (3) Were there enough patients who would benefit from a successful treatment to create a commercial opportunity?

On March 9, 2023, several of Islam’s questions were answered with Phase 3 trial data published in the New England Journal of Medicine (NEJM). Ogsiveo demonstrated highly significant and clinically meaningful impact on primary and secondary endpoints: (1) 71% reduction in the risk of diseases progression compared to placebo, translating to a hazard ratio of 0.29, (2) significantly shrinking patients tumors with a rapid time to response (3) hitting 7 out of 7 key secondary endpoints with statistical and clinical significance.

Ogsiveo’s FDA approval is only the first commercial step in SpringWorks Therapeutics’ larger journey. After all, even for therapies that work, there’s still the question about commercial opportunity.

While no real world evidence yet exists to determine the average time patients will remain on treatment, SpringWorks determined in its clinical studies that patients can require multiple years on treatment. SpringWorks and Islam are confident of commercial success, assuming that Ogsiveo’s therapeutic success continues to be borne out, and they can continue to work cooperatively to engage HCPs and the Desmoid Tumor patient community.

SpringWorks also has a number of additional therapeutics in the pipeline undergoing Phase 2, Phase 1, and Pre-Clinical studies. Islam’s previous experience in pharma makes him an ideal CEO for a planned pipeline expansion across numerous rare disease and oncology indications such as Mirdametinib, a MEK Inhibitor for NF1-PN (SpringWorks recently released promising data, indicating over 40,000 people in the US have been diagnosed with NF1-PN), Multiple Myeloma, and more. Prior to joining SpringWorks, Islam served as the Chief Business Officer at Moderna Therapeutics (NADQ: MRNA), Executive Vice President, Chief Strategy and Portfolio Officer at rare disease giant Alexion Pharmaceuticals (NADQ: AZN), and held numerous Managing Director positions in the investment banking divisions of Morgan Stanley (NYSE: MS) and Credit Suisse (NYSE: UBS) where he took some of the most successful pharma and biotech companies public.

Islam believes in order to build a successful rare disease company, you have to have the right culture and operational rigor, starting with the clinical trials and R&D and stretching all the way through the commercial launch and optimization of a product.

“While biology is not scalable, culture is,” says Islam. “When you have a drug that works, you have to make sure every patient knows it exists. You also have to make sure you run a study that’s going to actually yield an outcome that’s meaningful, not just demonstrate some marginal utility. In rare disease, because you’re measuring patients in thousands, there is a sacred obligation to make sure that every patient and family is cared for. You need a bit of serendipity, sure. But you also need a rigorous process to see the work through. And that’s where culture comes in.”

Islam’s desire, passion, and intensity to drive operational rigor within his company, extends from his personal experience as a patient. As a cancer survivor, Islam takes his role as a founding team member and CEO very seriously. “Our value at the company is not just caring, but caring hard,” he says. “The best thing we can do as a company is to be the hardest, most intense evaluators of opportunities for patients,” says Islam.

Looking ahead, SpringWorks Therapeutics’ Chief Operating Officer, Badreddin Edris, Ph.D describes Ogsiveo as the company’s first chapter, “With Ogsiveo, we brought a much-needed treatment to patients with desmoid tumors. Simply put, our goal is to repeat that again and again. The next opportunity for us to do so is with mirdametinib in NF1-PN, which we are working to bring to market by next year, and then to do so again for other groups of patients who desperately are seeking treatment advances. This is what drives us at SpringWorks, and we will continue to measure ourselves by the impact that we provide to patients and their families, who are depending on companies like ours.”

With that sort of persistence, and perhaps a bit more serendipity, there’s a high likelihood that SpringWorks has many important chapters left to author.

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