If you ask Pfizer’s chief scientist Mikael Dolsten, M.D., Ph.D., what the next pandemic will be, you may be surprised at the answer. It’s not viral or respiratory, and, in fact, it’s here now.
It’s obesity, and, luckily, the drugs are finally here to treat it.
Pfizer missed out on the first wave of the global obesity drug market. Peers Eli Lilly and Novo Nordisk are much further ahead with the injectable drugs Zepbound and Wegovy, respectively. But Dolsten and co. expect to make up ground, thanks to Pfizer’s background in developing oral small-molecule drugs.
“We were intrigued. We came from one pandemic, the COVID pandemic, and noted how obesity and diabetes were rapidly turning into a global metabolic pandemic,” Dolsten said in an interview with Fierce Biotech.
Pfizer had developed a few GLP candidates internally, but he tips his hat to the companies that developed the first GLP-1 drugs for finally cracking into a market that had seemed impenetrable. Regulating human body weight had been done incrementally before, with many safety issues. But Novo and then Lilly managed to turn their peptide meds into weekly injections that could fit into a person’s normal lifestyle.
“It was clear that they were the first mechanism to unlock weight reduction in a more meaningful, impressive way —you know, 10% or even more,” Dolsten said. “We felt that this was a really good start of maturing scientific and medical insights on what these patients needed.”
But Pfizer saw a problem. The injectables were expensive to make, meaning capacity would be limited. Instead of the hundreds of billions of patients who could be addressed, the first wave of meds would likely be available for tens of millions instead.
“We felt that our skills in making small oral molecules, tablets, would play to the advantage for us and for patients. And we started to use that pretty unique skill set to internally design oral GLPs,” Dolsten said.
That led to three different oral GLP drugs, which could someday become a major part of Pfizer’s portfolio. The furthest along is danuglipron, which is in phase 2b. But even with the weight of the Pfizer organization, the obesity program has faced some issues.
One of the candidates, lotiglipron, was cut last year after liver safety concerns were raised. Pfizer then centered around danuglipron, even though more than half of the people taking the med twice a day in a midphase test dropped out due to intolerability. About 40% dropped out of the placebo cohort, too.
Up to 73% of people taking danuglipron reported nausea. Rates of vomiting and diarrhea hit 47% and 25%, respectively.
Dolsten said that lotiglipron had chemical differences from danuglipron, and the elevated liver function tests were spotted in patients experiencing very rapid weight loss. Only a few hundred patients ever received the drug, whereas danuglipron has gone on to be tested in more than 1,500 people at this point.
“It's very well tolerated when it comes to all vital organs and is a safe drug,” Dolsten said. Twice daily dosing of danuglipron showed mean weight reductions ranging from -6.9% to -11.7%, compared to +1.4% for placebo at 32 weeks, or -8% to -13% when adjusted for placebo. Pfizer has since dropped the twice-daily program and is now trying to fine-tune the dosing to once daily. Dolsten said the goal is to provide an option for patients who want to have control over their life, and "not be dependent on an injectable in the refrigerator.”
He wouldn’t divulge more details on the current status of the danuglipron program—he’s been similarly tight-lipped with investors on recent earnings calls, too. He was also noncommittal on phase 3 plans when Pfizer reported fourth-quarter results in late January.
Open to change
Dolsten, who has been at the helm of Pfizer’s shifting R&D organization as the New York pharma faces its future after the heyday of the COVID years, also just reworked his team. He took on new duties as chief scientific officer and elevated Chris Boshoff, M.D., Ph.D., to serve as chief oncology research and development officer, leading the integration of Seagen’s medicines into the Pfizer stable.
The time had come to shake up the creative force that brought multiple COVID-19 products to the world, but, also, Pfizer had to integrate Seagen, which was acquired for $43 billion. Pfizer previously was separated into early and late R&D. The company cut R&D expenses by 24% in the fourth quarter of 2023, riven by lower spending across vaccine programs and certain acquired assets.
“Having had the privilege to work over many years in a successful R&D organization, I think there isn't one way to organize for 30 years. But in different time periods, you want to emphasize continuity of a project from end to end,” Dolsten said.
The change has been, at times, painful, with layoffs hitting hundreds of employees. At the beginning of January, about 285 people were cut at an R&D site in New York, followed by 52 more at a facility in South San Francisco. Dolsten doesn’t think there will be any more at this time, and the bulk of the reorganization is complete.
“When you work in a business environment, you can never be absolutely certain because you try to adjust expense towards growth trajectory, but in general, we have concluded our plans and set up R&D for success,” Dolsten said. “We think we have a setup that should be very fit for purpose. But I think creative organizations need always to be agile and open to change.”
One of the bigger changes is separating out the oncology unit into one enterprise, overseen by Boshoff, with the remaining non-oncology portfolio sitting under Dolsten. It’s a change for Dolsten, who has long had a hand in the cancer work directly. But he still has a pulse on the unit, as the entire organization pitches in services such as design of products, safety analysis, toxicology and pharmaceutical sciences.
“After having ran oncology science for many, many years, it keeps me involved and allows me and my colleague Chris Boshoff to be very close together—not just [because] we happen to sit next to each other,” Dolsten said. “We also have a scientific awareness that allows us to talk and get advice from each other.”
The non-oncology science includes vaccines, inflammation and immunology, internal medicine and infectious diseases as well as non-malignant hematology and rare neuromuscular diseases. All of that is now under Dolsten’s purview, with experts in each particular area reporting up to him.
“We have like a small internal biotech in each of those areas of the research unit. And then I have a late-stage clinical operation that basically helps all of them,” he explained. “And then we get a nice mix between scale and operational excellence and the ability to still preserve that science.”
Dolsten said the change was an effort to boost clinical success rates. The industry average for clinical success from phase 1 to approval is about 10%, but Pfizer’s is 20%. The company is particularly good from phase 2 on, where you “pick the winners,” he said. There, Pfizer boasts about 60% success, compared to the industry standard of 30%.
The focus has mainly been on late-stage internal research. But that doesn’t mean there isn’t room for deals. CEO Albert Bourla, Ph.D., told investors not to expect a huge deal in terms of dollar signs from Pfizer this year, then gave the old “never say never” line during fourth-quarter earnings.
Dolsten pointed to Global Blood Therapeutics, a 2022 acquisition, as a sign that Pfizer will pounce when it sees something good.
“They had a very admirable skill set in sickle cell disease,” Dolsten said. The biotech’s programs are now nearing phase 3 under Pfizer’s leadership.
But Pfizer has also been on the other side of the deal dance. The company partnered with Roivant in December 2022 to form Telavant around the TL1A-directed antibody RVT-3101. Then, barely a year later, the joint venture was flipped to Roche for $7.1 billion.
The asset seemed promising, showing in a phase 2b trial that it induced remission in 32% of patients with inflammatory bowel disease, compared to 12% in the placebo arm. Dolsten said the original Roivant deal was all about prioritizing and sticking to what Pfizer is good at. They recognized that Roivant could lead the charge while retaining the right to commercialization later.
Even after selling to Roche, Pfizer will benefit with billions in milestones written into the deal for later.
Cerevel Therapeutics was a similar example. The neuroscience biotech took on a few internal Pfizer assets, ran for a few years and then was bought out by AbbVie for $8.7 billion in December 2023. Pfizer was later revealed to be one of the possible suitors in that deal, given the prior relationship, but ultimately let it go to AbbVie. Dolsten said they will take the cash from that deal and invest it back into internal R&D.
“We get more assets than every year [we] can take care of,” Dolsten said. “I think [Telavant] was a nice example of things we produce that are good quality, because if we don't decide to move it on, others [are] willing to pay higher up—even billions.”