Rashes and lesions caused by cutaneous sarcoidosis can cover much of the body, sometimes becoming disfiguring. There are no FDA-approved treatments for this rare disease, which has been overlooked by much of the biopharmaceutical industry. According to Roivant Sciences, no industry-sponsored clinical trial in this inflammatory skin disorder has succeeded — until now.
Priovant Therapeutics, a Roivant subsidiary, has preliminary results from a proof-of-concept Phase 2 study showing not only that many patients responded to treatment with its drug, brepocitinib, but also that many of them achieved clear or almost clear skin. Based on these results, the company is looking ahead to a Phase 3 study. The pill could reach the market sooner as a treatment for two other rare diseases. Each of these indications offers blockbuster sales potential.
The cause of cutaneous sarcoidosis is unknown, but it develops as an inflammatory response that attacks bodily tissues. Durham, North Carolina-based Priovant estimates 40,000 Americans are affected by this disease. Without any FDA-approved drugs for the disorder, patients turn to off-label use of corticosteroids, immunosuppressants, and biologic medicines. These drugs bring limited efficacy and significant safety risks.
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The results reported Friday are from a placebo-controlled Phase 2 clinical trial that enrolled 31 adults. Two doses of brepocitinib, taken as a once-daily pill, were tested over 16 weeks. The drug was evaluated according to a rating scale used to score disease activity in cutaneous sarcoidosis — the higher the score, the worse the disease. Preliminary results show the high dose group achieved an average 22.3 point improvement at week 16 compared to a 0.7 point improvement for the placebo arm. Statistically significant separation was observed as early as week 4 and maintained through the rest of the study.
All patients who received the high dose achieved at least a 10-point improvement on the rating scale compared to 14% of those who received a placebo; 62% of patients in the high-dose group achieved functional remission compared to none in the placebo group. In Priovant’s announcement of the results, Dr. Misha Rosenbach, director of the Cutaneous Sarcoidosis Program at the Hospital of the University of Pennsylvania and principal investigator in the study, described the trial outcomes as “the sort of data you dream of seeing when you look at trial results — and I would call this a transformational moment for sarcoidosis.”
Brepocitinib is a small molecule designed to inhibit TYK2 and JAK1, proteins that play key roles in inflammatory pathways. The rationale for blocking both with a single drug is providing potentially better efficacy than inhibiting either target alone. JAK inhibitors are already established in immunology through products such as AbbVie’s Rinvoq and Incyte’s Jakafi. But after a post-marketing study for Pfizer’s JAK-blocking drug Xeljanz showed a higher risk of cardiovascular complications and cancer, the FDA in 2021 called for black box warnings for the entire drug class.
Roivant’s business model is to identify and license promising assets that have been shelved or do not fit the priorities of a pharma company. Roivant then forms subsidiaries to develop these assets. Brepocitinib came from the labs of Pfizer. Roivant subsidiary Priovant licensed rights to the drug in 2021. In an interview during the J.P. Morgan Healthcare Conference in San Francisco last month, Roivant CEO Matt Gline said industry sentiment at the time was that the safety warning on JAK inhibitors could spell the end of this drug class.
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“It was in that moment that we came in and we said, no way, that at least is an overblown idea,” he said. “These are some of the best anti-inflammatory drugs ever discovered. We’re going to work on them for severe orphan disease, where there aren’t other options.”
In rare disease, the unwanted effects of JAK inhibitors pose less of a barrier to developing a drug. Put another way, the tolerance for safety risks is higher simply because patients don’t have many, if any, treatment options. As an example, Gline pointed to the Phase 3 results for brepocitinib in dermatomyositis. The only FDA-approved treatment for this rare inflammatory skin disease is intravenous immunoglobulin; steroids and immunosuppressants offer off-label treatment options. Gline said that while blocking JAK proteins can increase cardiovascular and cancer risks to patients, untreated dermatomyositis can also increase these risks, as can high doses of steroids.
“If you look at the safety data for our drug in dermatomyositis, the patients on drug look less sick on these axes than the patients on placebo,” he said. “Even though the JAK inhibitor is probably marginally contributing some risk in those areas, simply by treating the patient, you are also reducing risk in those areas from the disease itself. So that trade-off just works in our favor on the safety data for this drug.”
In the cutaneous sarcoidosis trial, Priovant said brepocitinib was well tolerated during the study treatment period and no serious adverse events were reported. The adverse events that did occur were graded as mild or moderate. To date, brepocitinib has been evaluated in more than 1,500 patients across several indications. The company said the drug’s safety profile is consistent with that of approved JAK1 and TYK2 inhibitors.
Pfizer owns 25% of Priovant. Under the licensing agreement, Priovant holds brepocitinib’s rights for the U.S. and Japan while Pfizer has rights to the molecule for the rest of the world. When Pfizer and Roivant unveiled Priovant in 2022, brepocitinib was in Phase 3 testing in dermatomyositis. Last September, Priovant announced statistically significant results from the study. On Friday, Roivant said an FDA new drug application for brepocitinib has been submitted in this indication, which affects an estimated 70,000 patients. A Phase 3 test of this drug in the rare eye disease non-infectious uveitis is expected to yield preliminary data in the second half of the year. Priovant is continuing to explore brepocitinib’s potential in other indications.
The investment community already had blockbuster expectations for brepocitinib in dermatomyositis and non-infectious uveitis. Leerink Partners analyst David Risinger said in a research note that the cutaneous sarcoidosis results give the drug blockbuster potential in yet another disease. While the bank had expected clinical trial success in this indication, he said the drug is “substantially exceeding expectations.”
Priovant plans to meet with the FDA to discuss the design of a Phase 3 clinical trial for brepocitinib in cutaneous sarcoidosis with a goal of starting that study by the end of this year.
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