The Speed of Science

By Sacha Zimmerman

William Pao ’86 has devoted his life and career to treating illness and creating new medicines and therapeutics for patients worldwide. As the chief development officer and executive vice president for Pfizer, Pao is responsible for the company’s pipeline of innovative medicines. Below he talks to Sidwell Friends Magazine about his work.

ON FINDING SOLUTIONS TO CANCER: When I was 13, my father died of colon cancer. I vowed to make a difference in the lives of cancer patients, but I wasn’t sure how I would do that. Later, I obtained both an MD and PhD degree. As an MD, I specialized in oncology. In the clinic, I saw mostly patients with lung cancer and ran clinical trials of new molecules in development. As a PhD, I worked in the laboratory to identify new approaches to treating cancer patients and to understand better—at the molecular level—why some therapies worked better in some patients but not others. I started treating patients with lung cancer in the early 2000s, the standard of care for all patients with metastatic disease was “modern chemotherapy doublets.” Untreated patients had an overall median survival of six to eight months, and those who got chemotherapy lived for about 10 to 12 months. The one-size-fits-all paradigm and dismal survival rates—often with devastating side effects—were extremely frustrating. Ultimately, with the advent of new “targeted therapies,” which work more precisely than chemotherapies and with fewer side effects, I helped develop a more “precision medicine” approach for patients, where we could tailor therapy according to the genetic makeup of patients’ tumors. I also helped several pharmaceutical companies develop medicines, including Tagrisso for patients with a specific type of lung cancer. Today, the subset of patients treated with Tagrisso have a median overall survival of more than three years. By 2013, I was running a lab, seeing patients, running trials, and heading up a Division of Hematology/Oncology at Vanderbilt University. One day, a headhunter asked if I was interested in leading an oncology drug-discovery unit in pharma. Although I loved what I was doing in academia, after long consideration I decided to take the plunge and develop drugs fulltime and at-scale. In this manner, I thought I could impact not only tens to hundreds of patients but maybe thousands to hundreds of thousands or even millions of patients. Now, I’ve contributed to the development of many medicines and, in my new role at Pfizer, even vaccines.

ON WHY RESEARCH IS COMPELLING: Cutting-edge research is incredibly exciting, because you are doing things that no one in history has ever done before. You need to forge new paths and even challenge dogma. Of course, there will be setbacks and failures. But with resiliency and persistence, and by learning from every experience, you push fields of knowledge forward. And hopefully, for me at least, such research will eventually lead to new ways to treat patients with huge unmet medical needs.

ON THE THRILL-OF-DISCOVERY: The first time I worked in a molecular immunology lab was in the early 1990s. I was sequencing genes using what today is an old-fashioned method, where one step involved going into a darkroom and developing film to see the results. I still remember my heart pounding with excitement in the darkroom as I couldn’t wait to see the results of my multi-day experiments. I wanted to know first if the experiment had technically worked. And second, I was thrilled by the fact that I was seeing results for the first time that no one else had ever seen before. The excitement of seeing new results has stayed with me until today.

ON WORKING IN TRANSLATIONAL MEDICINE: Back in the early 2000s, there were new oral therapies being developed called epidermal growth factor receptor (EGFR) inhibitors. Based on laboratory experiments, the field knew that EGFR was a good target in cancer but didn’t know which patients would benefit the most from them. The initial studies were done in what we call “all-comer” populations— i.e., many different cancer types without any selection criteria. After several years, the field learned that EGFR inhibitors worked best in only a subtype of lung cancer patients, and the question was why. We figured it out: These patients had a genetic defect in their tumors involving the gene encoding EGFR. This discovery meant that we could select patients ahead of time for treatment with EGFR inhibitors by analyzing the genetic makeup of their tumors prior to treatment. We could then also spare those who wouldn’t benefit from the drug and give them other therapies. We also figured out why such drugs eventually stopped working in the patients who originally benefited. After about a year, more than half of patients’ tumors acquired a new mutation in EGFR, which blocked the drug from binding appropriately to its target. This led to the development of Tagrisso. This is an example of translational medicine. That is, we try to translate what happens in the clinic back to the lab and from the lab to the clinic. In this case, we used cancer genomics (the genetic makeup of tumors) and personalized medicine (the tailoring of therapy to the right patients at the right time).

ON WHAT HE WANTS TO ACCOMPLISH AT PFIZER: Like many, I watched Pfizer defy conventions established in the industry, bringing a safe and effective vaccine and an oral antiviral at record speed when the world needed them most. That ability to move at the speed of science is one of the reasons I joined this company with the hopes of applying that same agile mind-set, scientific prowess, and innovative approach to other therapeutic areas. Within the walls of Pfizer, we refer to this streamlined approach as “lightspeed.” And while we recognize that we cannot deliver all future breakthroughs at such a pace, there are certainly durable lessons from COVID-19 trials that we are carrying through to all our programs. We are fully embracing digital throughout the development process. During COVID- 19, with everyone in lockdown, we had to rely on technology and remote monitoring to continue our trials, and we did so with great success. Incorporating technology into clinical trials is critical for speeding up many aspects of development and also improving participants’ experiences. We are enhancing scientific dialogue between regulators and sponsors. The COVID-19 pandemic has pressure-tested how we interact with regulatory systems like never before. Regulators took a pragmatic approach to regulatory requirements to expedite development without compromising patient safety. These process enhancements and real-time reviews should be made permanent, at least for seriously debilitating and life-threatening conditions where every minute counts, to routinely facilitate faster scientific exchanges, and accelerate the safe development of medicines and vaccines. We are improving access to and awareness of clinical trials. One of the key factors that contributed to the speed of clinical development for COVID-19 vaccines and treatments was quick patient enrollment. Many courageous volunteers around the world raised their hands and believed that science could win. We need to seize this moment to continue to engage the public in medical research and make it easier for potential participants from all backgrounds to find, learn more about, and ultimately participate in medical research. Pfizer is committed to doing its part to make trials more accessible and equitable.

ON SIDWELL FRIENDS: I was a lifer at Sidwell Friends. For me, it was a special place, with a strong and close community, outstanding teachers, and amazing friends. I appreciate that at Sidwell, we were encouraged to pursue excellence, and the environment fostered curiosity and creativity. Importantly, the School set a foundation for life-long learning. At the same time, the Quaker values of respect for individuals and equality, and service to others shaped me to honor and hear all voices in my daily life, and to do work in the hopes of benefiting others.

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Sidwell Friends Alumni Magazine is published three times a year for the community. It features School news, stories, profiles, and alumni Class Notes.

Email magazine@sidwell.edu with story ideas or letters to the editor.