No pharma company wants to see half of its late-stage cancer pipeline wiped out in one morning, but that’s the situation Sanofi has found itself in.
The French pharma has halted development of its oral selective estrogen receptor degrader (SERD) amcenestrant after getting a look at a phase 3 interim analysis.
Sanofi’s press release was light on detail behind dropping the SERD, but in an interview with Fierce Biotech hours after the news broke, the company’s global head of R&D John Reed gave greater insight.
“The futility threshold was crossed, and made it unlikely that we were going to have a positive outcome on the progression free survival for the Ameera-5 study,” he says.
This leaves Sanofi with just one new oncology asset in the phase 3 pipeline: the antibody-drug conjugate tusamitamab ravtansine, which is being studied in non-small cell lung cancer. Combined with a recent partial clinical hold placed on Sanofi’s potential multiple sclerosis drug tolebrutinib, discontinuing amcenestrant “is negative for sentiment for the company’s R&D productivity and topline growth prospects,” SVB Securities analysts said in a note Wednesday.
That this fail was more important than your average pipeline cull was perhaps reflected by the almost 6% fall in Sanofi’s shares at market open on Wednesday—a hefty drop for such a Big Pharma. The shares were trading at $41.72 compared to a previous close of $44.81.
It may be some consolation to Sanofi that they’re far from the first pharma to see their SERD dreams go up in smoke. Roche suffered its own setback in April, when giredestrant failed a midphase breast cancer clinical trial, although the Swiss pharma is continuing to enroll patients in its pivotal program.
“I’ll leave others to decide how excited or not to be about the class. But I would say so far, the activity that’s been seen by virtually everyone in this space has been a bit underwhelming.” — John Reed, Sanofi’s global head of R&D
So was the problem with amcenestrant, or are SERDs another dead end for cancer drug development?
“It’s a good question,” says Reed. “I would say that the preponderance of data so far with the oral SERD has not been overwhelming.”
Preclinical work on SERDs backed up the theory that degrading the estrogen receptor can generate substantially more robust clinical activity than some of the conventional ways of trying to reduce signaling by hormone receptors, such as the aromatase inhibitors, Reed says. But the results from various human trials have not lived up to the hype.
“I’ll leave others to decide how excited or not to be about the class,” he adds. “But I would say so far, the activity that’s been seen by virtually everyone in this space has been a bit underwhelming.”
Sanofi may be out of the SERD game for good, but AstraZeneca, Eli Lilly and Roche are still keeping the faith. Another is Menarini, with a SERD called elacestrant in the late-stage Emerald trial, which has so far suggested that the therapy may be most effective on patients with an ESR1 mutation.
Reed wasn’t tempted to see whether amcenestrant could also redeem itself with this patient group, however.
“That would have really been limited to the later lines of therapy and more of a niche play,” he says. “We theoretically could have done that. But again, we weren’t convinced that was the best place to place our investments.”
What’s next for the oncology franchise?
Losing half of your investigational phase 3 cancer candidates is a bad day for any pharma, but Reed insists that dropping amcenestrant doesn’t knock Sanofi’s oncology strategy too far off course. The company is in the process of rebuilding its offering in this space anyway, he says.
“It’s been a long time since Sanofi really had a presence in oncology of substantial size,” Reed says. “Five years ago, we had only six molecules in development. Today, we have more than a dozen.”
Of these, amcenestrant was “the most advanced opportunity,” says Reed, who admits that much of Sanofi’s cancer pipeline is “clearly very young.” When it comes to tusamitamab, readouts for the ADC are coming in the first quarter of 2023, which gives the pharma an opportunity to “put some wind back into our sails.”
The relatively immature state of Sanofi’s cancer pipeline is the result of a conscious strategy to take a “fresh look at oncology and to do some things that are novel,” Reed says. “We’ve not been following the checkpoint bandwagon that everyone else jumped on. In fact, we even gave Libtayo back to Regeneron.”
Reed points to natural killer (NK) cell biology as an example of the innovation Sanofi is trying to foster, with three different approaches including an “off-shelf” NK platform from the acquisition of Kiadis in 2020. Other deals in recent years have also fed into this strategy, including using Synthorx’s synthetic biology platform to develop “highly engineered lymphokines that stimulate the proliferation of NK cells.”
Meanwhile, Reed says Sanofi’s ambition with its next generation T-cell engagers is to “convert cold tumors into hot tumors”—meaning they can be infiltrated by T-cells. “We hope that will … open the doors to doing something meaningful with immuno-oncology and a variety of solid tumours that currently don’t yield to checkpoint inhibitor approaches.”
The final pillar of Sanofi’s remaining cancer strategy is ADCs. Sanofi signed a collaboration with Seagen spanning three ADCs in March, and Reed hints that “we’re going to be doing more” in this space.
So the loss of amcenestrant hardly spells the end of Sanofi’s oncology aspirations, but it’s certainly set back any hopes of getting multiple new candidates approved in the short term.
In the meantime, Sanofi seems to be focused on quicker wins. The company has secured its reputation as a leader in the immunology space with the blockbuster dermatitis drug Dupixent, and Reed says the company has up to 17 other candidates in this space at various stages in the clinic. “We’ve now built a very robust portfolio around that of immunology medicines for autoimmune and inflammatory diseases,” he explains.
“So there’s plenty of opportunities there to expand the indications and double down in some of the investments on exciting molecules in the immunology portfolio,” Reed adds. “While allowing some of this young oncology portfolio to mature.”