What began a year and a half ago as a takeover of Impact Biomedicines Inc. ended Friday with FDA approval for the wholly owned Celgene Corp. subsidiary's rare bone marrow disorders drug, Inrebic (fedratinib).

Inrebic is now the second FDA-approved treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, a chronic condition caused by scar tissue in bone marrow-producing blood cells that travel relentlessly to the spleen and liver. The result is enlarged organs, bone pain, extreme fatigue, shortness of breath and night sweats.

The newly approved drug targets patients for whom Jakafi (ruxolitinib, Incyte Corp.), the first FDA-approved treatment, no longer works.

The approval comes weeks ahead of the Sept. 3 PDUFA date. The application was granted priority review designation, and Inrebic received orphan drug designation.

Long journey to approval

While Celgene acquired the JAK2 inhibitor via the Impact deal for $7 billion in February 2018, the drug's lineage runs deep. Fedratinib was invented at Targegen Inc., then licensed to Sanofi SA in 2010 for $560 million. At the time, it was called TG-101348 and showed clinical improvement in treatment-naïve patients and in patients resistant or intolerant to ruxolitinib. Development halted in 2013 when the Jakarta-2 trial was stopped after potential cases of Wernicke encephalopathy (WE) were found in eight patients receiving one or more doses, which represented less than 1% of treated patients. (See BioWorld, Jan. 9, 2018.)

Sanofi discontinued development, and fedratinib sat on a shelf until 2016, when the asset was spun out into San Diego-based Impact. Sanofi maintained a minority stake in the new company, which managed to get the FDA to lift the clinical hold in August 2017, attributing WE to thiamine depletion and a high metabolic rate in patients. (See BioWorld, Oct. 27, 2017.)

Clarivate Analytics' analyst, Karen Pihl-Carey, noted that "it just goes to show the potential of shelved products when given the right chance and the right investment."

And the brand journey continues as Bristol-Myers Squib Co.'s $74 billion merger with Celgene approaches. (See BioWorld, Jan. 8, 2019.)

Targeting Jakafi failures

Jakafi was approved in November 2011. Incyte's oral tablet is a kinase inhibitor for treating patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Before Jakafi, there were very few options for that patient population, which includes 1.5 people for every 100,000 in the U.S., according to MPN Advocacy & Education International. In the U.S., according to Celgene stats, between 16,000 and 18,500 people are living with myelofibrosis. Pre-2011, treatment included chemotherapy, stem cell transplantation and splenectomy.

Inrebic is for treating intermediate-2 or high-risk primary or secondary myelofibrosis. The approval was based on a clinical trial that saw 35 of 96 patients experience greater than or equal to a 50% reduction in myelofibrosis-related symptoms when treated with a 400-mg daily dose.

An updated analysis of data from the phase II Jakarta-2 study, presented in June at the American Society of Clinical Oncology annual meeting in Chicago, showed 31% of patients resistant or intolerant to Jakafi, part of the intent-to-treat (ITT) population, exhibited a 35% or greater reduction in spleen volume with Inrebic. A smaller subset of patients with more narrow criteria for Jakafi resistance and intolerance showed a similar 30% reduction. In both the ITT and smaller populations, 27% of patients exhibited a 50% or greater symptom response rate.

There is a black box warning on Inrebic's label about potential serious and fatal encephalopathy, with WE getting a mention. SVB Leerink analysts see the warning as a cause for an uptick in Incyte's stock "as some investors had feared that fedratinib would be approved with a clean, line-agnostic label, potentially enabling more direct competition with Jakafi. We believe fedratinib could still represent a competitive threat, though given the data generated to date, as well as the extensive physician experience with standard-of-care Jakafi, we would expect use to be limited primarily to Jakafi failures."

As the Leerink analysts expected, Incyte's shares (INCY;NASDAQ) rose 3.1% on Friday, removing what they called "a potential worst-case scenario."

Shares of Celgene (NASDAQ:CELG) gained $1.43 to close Friday at $94.74.

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