Regeneron Pharmaceuticals Inc. and Sanofi may have entered the immuno-oncology race late, but they are confident they can gain ground following positive phase 2 data for targeted cancer drug cemiplimab.
Regeneron, which sells the cholesterol-cutting Praluent and new eczema drug Dupixent with Sanofi, is not known for being an oncology company. It is moving into a field crowded with new therapies and dozens of phase 3 trials, specifically for the checkpoint inhibitors that target a link between cancer cells' PD-L1 protein and healthy cells' PD-1 receptor.
These include other PD-1 inhibitors such as Merck & Co. Inc.'s Keytruda and Bristol-Myers Squibb Co.'s Opdivo, but also PD-L1 blockers including AstraZeneca PLC's Imfinzi, Roche Holding AG's Tecentriq and Bavencio from Merck KGaA and Pfizer Inc.
Israel Lowy, Regeneron VP of Global Clinical Development and Head of Translational Science and Clinical Oncology
Source: Regeneron Pharmaceuticals Inc.
Though Regeneron knew it would not be first to market, having its own PD-1 is essential, Israel Lowy, Regeneron vice president of global clinical development, said in an interview.
"A credible immunotherapy program really needs to have PD-1 in it. If we have our own, then we are flexible to figure out how we make combinations, which way we do it, and obviously from an economic standpoint, when we want to manufacture and commercialize," said Lowy, who also serves as head of translational science and clinical oncology.
"While PD-1 is remarkably effective, it's not the answer to cancer," he said. "From the outset, we've explored combinations."
These have included some typical treatments such as chemotherapy, radiation and various cytokine-targeting drugs. But it also includes other pipeline assets, such as REGN1979, for which Regeneron presented data at the American Society of Hematology, or ASH, conference in Atlanta earlier this month.
The company also announced a partnership with ISA Pharmaceuticals BV to combine cemiplimab with its targeted cervical cancer treatment.
Breaking out in skin cancer
Regeneron's foot in the immuno-oncology door is with cutaneous squamous cell carcinoma, or CSCC, a form of skin cancer that had a 46.3% response rate to cemiplimab in the latest trial.
"It's kind of an underappreciated opportunity," Lowy said, adding that they are looking to wrap trials in the first quarter of 2018 and file soon after.
"There are about between 4,000 and 8,000 deaths a year from this, which actually is close to what you see from melanoma. So at the end of the day, it's not such a small indication," Lowy said.
Yet some are cautious on cemiplimab's first move; Barclays analyst Geoff Meacham highlighted the crowded PD-1 space and the "limited potential market" for CSCC in a June 5 note following initial data presented at the American Society of Clinical Oncology meeting. Regeneron is also aiming for an indication in non-small cell lung cancer, another crowded space for PD-1/PD-L1 treatments.
Taking on CAR-T in blood cancer
While CSCC could be a small patient pool, compelling data for the most common blood cancers would be a big notch in Regeneron's oncology belt — one that it is now pursuing with cemiplimab and another in-house experimental therapy, bispecific antibody REGN1979.
The drug's bispecific nature means its two arms do different, targeted jobs: one links up to T-cells, the body's natural defense against cancers, while the other arm latches onto cancer cells and serves them up to the T-cells. The result can be effective but unstable, and sometimes toxic.
In two phase 1 studies presented at ASH, 29.3% of patients responded to treatment with just REGN1979. Alone, cemiplimab had a complete response rate, or no detectable signs of cancer, in 8.3% of non-Hodgkin lymphoma, or NHL, patients and 26.9% in Hodgkin lymphoma patients. Overall, half of Hodgkin patients responded to treatment while 11.1% with NHL did.
Together with REGN1979 in only NHL — which includes diffuse large B-cell lymphoma, the target of a cluster of recent CAR-T cell therapy trials — cemiplimab has had no complete responses yet and one patient, or 8.3% of the combo study, has responded to therapy.
As PD-1 is a crowded field, the checkpoint inhibitor's results had some disappointed. REGN1979 looked promising in NHL but cemiplimab looked "questionable" compared to the competition, RBC Capital Markets analyst Kennen MacKay said in a Dec. 10 note, adding that cemiplimab's response rates appeared below those for existing options such as Keytruda and Opdivo.
Yet it is too early in the trial to make that call, according to the researchers.
"The expectation is that the checkpoint inhibitors are a way that the tumor tries to escape the onslaught of the immune system," Max Topp, the presenting researcher on the combination study and head of hematology at the University Hospital of Wuerzburg, Germany, said in an interview on the sidelines of ASH. "So by capping that, we may still have the punch delivered by the bispecific to get rid of the lymphoma. That obviously is the hypothesis, and now we are getting close to actually asking that question."
The cemiplimab study is still in early days compared to the one focusing just on REGN1979, researchers said. In the latter, led by Rajat Bannerji, chief of hematologic malignancies at the Rutgers Cancer Institute of New Jersey, 50% of high-dose patients and 18.5% of the lower-dose patients responded to therapy.
"We're seeing activity in these very refractory patients that don't have any other choices in terms of potential therapy," Bannerji said in an interview.
Those are lower rates than in CAR-T therapy, which is also targeting this space, but the safety profile on REGN1979 looks stronger and could be promising, RBC's MacKay said.
"While we're not the first with the PD-1, I think we are now among the first combining a T-cell activator bispecific with a PD-1. We wasted no time in coming from behind, so to speak, to now being leading with combinations," Lowy said.