The FDA is not only approving a lot more drugs these days, it seems to have also developed a sense of dramatic timing. Late last Friday, the agency approved its seventh checkpoint inhibitor, a type of cancer drug that blocks a tumor’s ability to hide from the immune system. Less than 72 hours later, two scientists who discovered checkpoint inhibition won the Nobel Prize for Physiology or Medicine.
The approval brings to the U.S. market the drug cemiplimab (Libtayo) for a type of skin cancer called cutaneous squamous cell carcinoma. The FDA’s nod, its seventh in eight years, underscores the impact of James Allison of MD Anderson Cancer Center in Houston and Tasuku Honjo of Kyoto University in Japan. Allison was senior author of a 1996 paper that described how blocking an immune-system protein called CTLA-4 could unmask a tumor and let the immune system go after it. Allison did this research while at the University of California, Berkeley. That discovery led to the first approved checkpoint inhibitor, ipilimumab (Yervoy), in 2011.
Seven years later, partners Regeneron Pharmaceuticals (NASDAQ: REGN) and Sanofi (NYSE: SNY), got the regulatory green light for cemiplimab, in a type of cancer that according to the FDA has no other drug approved to treat it: cutaneous squamous cell carcinoma that has grown worse or spread to other parts of the body, with no option of surgical removal or radiation treatment. The companies estimate between 4,000 and 8,000 people die from the disease each year in the U.S.
In a key study that led to the drug’s approval, 47 percent of patients showed at least some improvement after treatment. Of those patients, 60 percent had improvement, or “response” in clinical speak, that lasted at least a year, with no relapse of tumor growth. “Regeneron and Sanofi are likely to have this indication to themselves for several years at least,” wrote Leerink Research analyst Geoffrey Porges in a note to investors this morning. Merck is testing its blockbuster immunotherapy pembrolizumab (Keytruda) in the same indication in a Phase 2 study that isn’t expected to produce data until 2020.
Regeneron and Sanofi have announced a list price that adds up to $12,130 a month. If a course of treatment lasts 6 to 8 months, Porges estimates cemiplimab could hit global sales of $1.4 billion in 2021.
The companies, however, are years behind Merck (NYSE: MRK), Bristol-Myers Squibb (NYSE: BMY), Roche, and AstraZeneca (NYSE: AZN) in developing checkpoint inhibitors for many other cancers, including some of the most prevalent like lung and colon. So the partners are looking not to compete head-on with these other companies, but instead want to use cemiplimab in combination with other therapies including drugs in their respective pipelines.
“We’re confident cemiplimab is just as good” as the other checkpoint inhibitors on the market, said Regeneron’s head of translational science and oncology Israel Lowy in a recent interview. “But predominantly the long-term plan is to bring forward all sorts of combinations.”
Joanne Lager, Sanofi’s head of oncology global development, said that among several in-house candidates to combine with cemiplimab is a better version of ipilimumab, the drug that came directly from Allison’s mid-1990s discovery and is owned by Bristol-Myers. Ipilimumab is approved on its own for melanoma (a type of skin cancer), and also for kidney and colon cancer when combined with Bristol’s leading checkpoint inhibitor, nivolumab (Opdivo). Ipilimumab blocks the protein CTLA-4 but has not gained as much traction as subsequent checkpoint inhibitors because of side effects such as terrible skin rashes.
Sanofi and Regeneron recently began early studies of their CTLA-4 inhibitor in people with a range of solid tumors, a step toward determining a more focused plan of attack with cemiplimab and anti-CTLA-4 combinations. (LAG-3 and CD38 are other protein targets that the partners, and others in the field, are also looking to attack with combination strategies.)
The race to develop combinations has been fierce ever since the field began to realize that checkpoint inhibitors alone, while providing stunning results in some patients, had no effect on a solid majority. Response rates—any sign that a drug is fighting a tumor, no matter how short-lived—are often in the 20 to 40 percent range. In some cancers, combinations have improved patient outcomes further, at least in clinical studies.
But other potential combination partners, such as the class of experimental drugs known as IDO inhibitors, have failed and cost companies billions of dollars, prompting calls for a more deliberate approach in combination development.
Regeneron and Sanofi say that, despite being late to the dance with cemiplimab, they have tools and skills in-house that will help winnow down the sprawling matrix of potential combinations. One is Regeneron’s technology to genetically alter mice to produce human traits such as antibody proteins. “We can humanize mice for various targets we’re testing,” said Lowy. Further on, Regeneron wants to apply its antibody expertise to PET imaging so that it can get a more precise read on the location and density of checkpoint proteins, and more important, a better gauge of the potential of a combination to advance into human trials. “It’s a new way of giving us a glimpse into what’s happening at a tumor site,” said Lowy, “but it’s not yet ready for widespread use.”
Cemiplimab blocks a different checkpoint protein, PD-1. Today’s other Nobel medicine prize recipient, Honjo, discovered PD-1 in 1992, and found that it acts like a brake on immune activity. Like Allison did with CTLA-4, Honjo and others showed they could treat cancer in mice when they blocked PD-1 with antibodies.
The first PD-1 inhibitors, nivolumab (Opdivo) from Bristol and pembrolizumab (Keytruda) from Merck, were approved by the FDA in 2014, and are used to treat skin, lung and several other cancers. Opdivo, Bristol’s top-selling drug in 2017, earned the company $5 billion in global revenue that year, and Keytruda brought in $3.8 billion for Merck the same year. The other approved PD-1 blockers are atezolizumab (Tecentriq) from Roche and durvalumab (Imfinzi) from AstraZeneca.
[The story has been updated with the correct number of checkpoint inhibitors approved by the FDA. It is seven, not six.]
Image from the Nobel Prize press conference, Oct. 1, 2018.