Serendipity and science: Building a multibillion-dollar breakthrough in oncology

Some of the most innovative pharmaceutical and biotech companies in history have played a role in their founding and discovery processes through serendipity, tenacity, and rigor. Founded in 2017, SpringWorks Therapeutics (NDAQ: SWTX) takes a precision medicine approach to acquiring, developing and commercializing life-changing medicines for underserved patient populations suffering from rare diseases and cancer. We are hiring. But SpringWorks’ story goes back much further than 2017 and is one of purposeful research, healthcare provider (HCP) and patient advocacy, and unexpected discoveries.

During an Alzheimer’s disease clinical trial led by Pfizer (NYSE:PSE), nirogacestat, an oral selective small molecule gamma secretase inhibitor, was shown to be effective against desmoid tumors, locally invasive and invasive soft tissue tumors that arise from fibroblasts. showed potential activity. Muscles and nerves grow, become compressed and tangled, causing pain and other complications. Although it had no effect on Alzheimer’s disease, the findings ultimately convinced Pfizer to conduct a Phase 1 solid tumor trial in 2009 in 64 patients with solid tumors. Among the 64 patients, there were a small number of patients with desmoid tumors who had an unexpectedly high response. When data from the phase 1 trial were presented at a joint meeting of the European Agency for Research and Treatment of Cancer, the National Cancer Institute (NCI), and the American Association for Cancer Research, the results caught the attention of his NCI researchers. I did. Dr. Shivani Kumar. “Desmoid tumors can have a significant impact on a patient’s function and quality of life. The response and clinical benefit reported by researchers in a Phase I trial is encouraging for patients with this rare tumor. We felt strongly that this new drug needed to be further evaluated for its potential benefits,” says Dr. Kumar. This led Dr. Kumar to conduct a follow-up phase 2 trial at his NCI, with promising results.

Jean Whiting and Marlene Portnoy, founders of the Desmoid Tumor Research Foundation (DTRF), a nonprofit patient advocacy organization, are enrolling patients in a Phase 2 clinical trial overseen by Dr. Shivani Kumar. played an important role. “Jeanne and I told Dr. Kumar that not only could we join the trial, but we could do it right away. The goal was to find enough patients for her to take two years, but in less than six months. We filled our patients,” Portnoy said.

Although Pfizer decided not to advance nirogacestat in 2015, patients, physicians, and researchers were able to work with NCI researchers and DTRF to bring nirogacestat back into development. The trinity of scientific leadership, healthcare worker advocacy, and patient advocacy, when leveraged against big pharma research, proved to be a key element in the birth of SpringWorks Therapeutics. In September 2017, SpringWorks Therapeutics in-licensed several molecules from Pfizer, starting with desmoid tumors and neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN).

$103 million Series A funding round led by Bain Capital Life Sciences, OrbiMed, Pfizer, and LifeArc, Saqib Islam initially hired to join the company as Founding CEO and Chief Financial Officer He eventually became CEO in 2018. With Islamic leadership, SpringWorks made rapid progress with Ogsiveo (nirogacestat) becoming the first and only FDA-approved product for adult desmoid tumors.

Islam believes that success in the complex world of drug development relies on the coexistence of unexpected serendipity alongside logical and systematic analysis. As a first-principles thinker, he recognizes the role that serendipity and tenacity play in a company’s formation and continued success.

According to the NCI, approximately 1,650 people are diagnosed with desmoid tumors each year. What are the chances that a few of the 64 patients with desmoid tumors happen to be enrolled in a solid tumor study? What would have happened if Dr. Kumar had not wondered how and why this group reacted so dramatically? What would happen if we didn’t push for Phase 2 trials? What would happen if we didn’t have patient advocacy groups pushing to support Phase 2 trials?

“A lot of this business is based on a combination of serendipity and persistence,” says Islam. “Biology is not scalable, and drug development is not linear. Whether we use AI, human ingenuity, or luck to get to the drug discovery part of biotechnology, in some cases all three are truly Sometimes it’s necessary, but ultimately we need to figure out the right tool for the right problem.Inevitably, we have to ask ourselves what molecular features we have, and how this works. This will address the question of whether this works in humans as well.”

“Pain is an important treatment goal for both patients and physicians, as pain remains unmanageable despite undergoing surgery after surgery, chemotherapy, tyrosine kinase inhibitors, and opioids for pain. “This is often the most debilitating symptom that patients with desmoid tumors report when their tumor returns,” says Islam. This further emphasizes the importance of significant pain relief for Ogshiveo patients, and pain relief is listed on the drug’s label. Like many patients, Dana Lawson, a patient advocate for this rare tumor, knows all too well the pain this unfortunate disease brings.

Lawson, who has spent as much time as possible outdoors hiking and running, said the trip to Ogshiveo was hopeless. And after Lawson’s leg was amputated, after years of battling her disease, she thought her fight was over. “Since I had my leg amputated, I had tried everything, so when the tumor recurred in my lower back and pelvis, I felt a renewed sense of hopelessness. As the tumor grew in size, it caused so much pain that I was no longer able to wear a prosthesis. ” Lawson says. As one of her 17 patients in a Phase 2 clinical trial, Ms. Lawson’s own persistence paid off, with her tumor shrinking by 28% in the first year of treatment and surrounding tumors shrinking. When some of the pressure was relieved, she achieved what she describes as a hopeful recovery. Her sciatic nerve. The Phase 2 trial required four patients’ tumors to shrink by at least 30%, and the final scan in Lawson’s trial showed a 43% reduction in tumor size. “I have never seen such an amazing and relentless support community come together to solve a disease. Clinicians, patients, advocacy groups, and researchers are working together to bring this success to the desmoid patient community. biotech companies all sat around the table together,” says Lawson.

“In the case of nirogacestat, we have seen phase 1 data and phase 2 data. What is very clear is that this product is having a significant effect on patients with desmoid tumors.” What was not was (1) Can we design a study that, if successful, would lead to approval? (2) Were there enough patients to conduct the study? (3) Were there enough patients who could benefit from a successful treatment to create a commercial opportunity?

On March 9, 2023, some 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 effects on primary and secondary endpoints: (1) 71% reduction in risk of disease progression compared to placebo, hazard ratio 0.29; It will be converted to . (2) significantly shrink the patient’s tumor in a short period of time; Response (3) Achieved 7 of 7 key secondary endpoints with statistical and clinical significance.

Ogsiveo’s FDA approval is just the first commercial step in SpringWorks Therapeutics’ larger effort. After all, even with effective treatments, questions about commercial opportunities remain.

Although no actual evidence yet exists to determine the average length of time that patients remain in treatment, SpringWorks has determined in clinical studies that patients may require multiple years of treatment. SpringWorks and Islam are confident of commercial success, assuming Ogsiveo’s continued proven therapeutic success and continued collaboration in partnership with healthcare professionals and the desmoid tumor patient community.

SpringWorks also has a number of additional therapeutics in its pipeline in Phase 2, Phase 1, and preclinical trials. Mr. Islam’s previous experience in the pharmaceutical industry makes him the ideal CEO for the company’s pipeline expansion plans across numerous rare disease and oncology disease indications, including mirdametinib, a MEK inhibitor for NF1-PN. Springworks recently announced promising data showing that more than 40,000 people in the United States have been diagnosed with NF1-PN (associated with NF1-PN), multiple myeloma, and more. Prior to joining SpringWorks, he served as chief business officer at Moderna Therapeutics (NADQ: MRNA), executive vice president and chief strategy and portfolio officer at rare disease giant Alexion Pharmaceuticals (NADQ: AZN), and with numerous U.S. He has held the position of Managing Director. He worked in the investment banking divisions of Morgan Stanley (NYSE: MS) and Credit Suisse (NYSE: UBS), where he took some of the most successful pharmaceutical and biotech companies public.

At Islam, we believe that being a successful rare disease company requires the right culture and operational rigor, starting with clinical trials and research and development, all the way to commercial launch and optimization of our products.

“Biology is not scalable, but culture is,” Islam says. “If we have a drug that works, we need to make sure that all patients know about it. We also need to conduct studies that actually produce meaningful results, not just demonstrate marginal benefit.” There is also. In the case of rare diseases, we measure thousands of patients, so we have a sacred obligation to ensure that every patient and their family is taken care of. Sure, we need a little serendipity. But… You also need a rigorous process to get the work done, and that’s where culture comes in.”

Islam’s desire, passion and enthusiasm to drive rigorous business operations within the company is rooted in his personal experience as a patient. Islam, a cancer survivor, takes his role as a member of the founding team and his CEO very seriously. “Our value at our company is not just to care, but to care passionately,” he says. “The best thing we can do as a company is to evaluate the opportunity for patients the most rigorously and most passionately,” Islam says.

Looking to the future, SpringWorks Therapeutics Chief Operating Officer Dr. Badreddin Edris describes Ogsiveo as the company’s first chapter. Simply put, our goal is to do it over and over again. Our next opportunity to do so is with mirdametinib in NF1-PN, which we are working to bring to market by next year and then again for other patient groups desperately seeking therapeutic advances. We plan to introduce it to This is what drives us at SpringWorks, and we will continue to measure ourselves by the impact we have on the patients and families who depend on companies like ours. ”

With this kind of persistence, and perhaps a little more serendipity, there’s a good chance that SpringWorks still has many important chapters left to write.

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