Incyte Roars Ahead with a Flurry of Milestones
By Mark Terry
April 11, 2023
Wilmington, Del.-based Incyte had an enormously busy March and April, with several big announcements and reports. Steven Stein, M.D., Incyte’s Chief Medical Officer, spoke with BioBuzz about the company’s efforts and plans moving forward.
Stein called Incyte “a science-based research company, or biotech company, that is extremely passionate about the areas in which it operates. Over the last 20 years, we’ve been principally focused on myeloproliferative neoplasms, myelofibrosis, and polycythemia vera with ruxolitinib. But as that drug expanded into a condition called Graft Versus Host Disease (GVHD), we have a bunch of other small molecules, and now large molecules, approved. It’s become an entity that crosses wide spaces in oncology and hematology, and now in dermatology as well.”
On March 22, the FDA approved Incyte’s Zynyz (retifanlimab-dlwr) for adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). MCC is a rare and aggressive form of skin cancer. Stein notes that there are probably 1,000 patients with that diagnosis in the U.S. annually, and there are already two drugs approved for this indication.
“But we executed a very well-done study in roughly 100 people with a high response rate that was durable. The FDA gave us an accelerated approval in an area where accelerated approvals aren’t easy to get. And the reason is, we replicate it with other checkpoint inhibitors with high response rates that are durable. And in terms of having a confirmatory study, it’s already complete, because the confirmatory study is the study itself that will then be followed for overall survival,” Stein said.
Stein doesn’t think that Zynyz for MCC is a “massive commercial opportunity because it’s an extremely rare skin cancer” that will be divided up between three approved drugs. “But it’s a good start to get the drug on the market. And now we can pursue other indications.”
Those include ongoing studies in squamous cell anal carcinoma, MSI-H endometrial cancer, and non-small cell lung cancer. “So there’s quite a large program behind the initial, somewhat commercially small, but important approval,” Stein said.
Later in the month, Incyte’s Pemazyre (pemigatinib) was approved in Japan for the treatment of myeloid/lymphoid neoplasms (MLNs) with FGFR1 fusion. MLNs are a rare and aggressive group of cancers marked by overproduction of myeloid cells, or bone tissue. It often quickly progresses to acute myeloid leukemia (AML).
Stein noted that Pemazyre has been approved around most of the world for second-line cholangiocarcinoma with FGFR2 fusion or other rearrangements, which accounts for about 10-15% of cholangiocarcinoma cases. “We realized a few years ago that there is another extremely rare condition with a lot of unmet medical need that is sort of a mini-leukemia, if you will, a myeloid lymphoid neoplasm. It is so rare there appears to be only about 100 or so cases a year in the U.S., but there is a lot of unmet medical need. So we executed a study in the U.S. and Japan. So it’s been approved in the U.S. and now in Japan. In keeping with the company philosophy, understand the science, chase the science, and pursue unmet need wherever it exists, regardless, somewhat, of the epidemiology.”
Earlier in the month, March 18, the company announced new data from a Phase IIb trial of povorcitinib, an investigational oral JAK1 inhibitor. The data were in adults with extensive nonsegmental vitiligo and were presented at the American Academy of Dermatology (AAD) Annual Meeting. Vitiligo is a chronic autoimmune disease marked by depigmentation of the skin. It isn’t life-threatening, but Stein noted that there is a “large psychosocial component to the condition — not everybody thinks it’s an illness, and some people are very accepting of their depigmentation — but for those that struggle with it, they can have social anxiety, depression and even a higher suicide rate.”
As a comparison to ruxolitinib, a JAK1 and 2 inhibitor, povorcitinib is more specific for JAK1 by about 50-fold. Ruxolitinib is marketed as a cream under the brand name Opzelura, but povorcitinib is an oral medication. Ruxolitinib is indicated for vitiligo patients with less than 10% depigmentation. Povorcitinib is being evaluated for more extreme forms, with more than 10%, sometimes 20 or 30%. “We used the oral JAK inhibitor in these patients and had very good results, where we saw patients’ regimentation of their face and also, to some extent, their whole body in the duration of that study,” Stein said.
The company has plans to move forward with a registration program with the drug in more severe vitiligo. This would require Phase III trials, which would require significantly larger patient populations. Stein indicates there are internal discussions on whether to trigger these trials.
In addition to the vitiligo study, the company presented data at AAD on povorcitinib in hidradenitis suppurativa (HS). Patients with HS get abscesses, fistulas and nodules in crevices of their body that can be extremely debilitating and painful. AbbVie’s Humira is approved for HS, but Stein notes that it’s “not unbelievably effective in HS, so there is a lot of unmet need.”
Despite all the good news, there was some bad news as well. On March 23, the FDA issued a Complete Response Letter (CRL) for ruxolitinib extended-release (XR) tablets for once-daily use in certain forms of myelofibrosis, polycythemia vera and GVHD. The CRL indicated the agency could not approve the application in its present form.
Because it was so recent, there wasn’t much Stein could discuss about the CRL, which he said was “both surprising and upsetting for us, because even in the CRL, the FDA acknowledged that we had met the area under the curve. So what does that mean? When you compare or try to get a slow-release formulation approved, you have to show that it’s equivalent to the immediate release using what is called bioavailability and bioequivalent studies. So the area under the curve for the XR and the R formulation was within FDA criteria and technically would have met the approval, but they did have some other issues with it and gave us a CRL, which we now have to address should we want to proceed and take it forward.”
In addition to these updates, on April 6, Incyte and Biotheryx inked a Research Collaboration and License agreement to discover and develop targeted protein degraders for novel oncology targets. Biotheryx will use its PRODEGY platform to identify and initially develop molecular glue degraders. Incyte is paying the company a technology access fee of $7 million with an additional $6 million in potential R&D funding for costs tied to the collaboration.
Speaking more broadly, Stein noted that ruxolitinib and myeloproliferative neoplasms and GVHD are very important to the company. “It’s a huge franchise and it’ll be losing exclusivity and going off-patent at the end of 2028, so by early 2029 there will be generics. For us as a company, it’s about addressing that area and trying with other mechanisms to improve on ruxolitinib and get other things approved before we lose exclusivity that addresses patient needs.”
One of their programs in this area is INCA033989, an anti-mutant calreticulin (CALR)-targeted antibody for MF and essential thrombocythemia. Preclinical data was presented in December 2022, and the company is making plans for a Phase I study.
The company also has programs in hematology-oncology, with an oral anti-PDL1 checkpoint inhibitor, and its efforts in autoimmune dermatology and inflammatory conditions.
“We are very passionate about what we do,” Stein said. “And we’re getting now a whole host of new indications and focusing on different unmet medical needs, which is very important to us.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
