Bristol Myers Squibb’s JAK2 Inhibitor Inrebic Becomes First New Myelofibrosis Therapy in a Decade with Full EU Approval

February 10, 2021 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) recently announced that the European Commission (EC) has granted full marketing authorization for Inrebic (fedratinib), a highly selective JAK2 inhibitor, for the treatment of disease-related splenomegaly (enlarged spleen) or symptoms in adult patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, including patients who have not previously received JAK inhibitors (JAK inhibitor-naïve) and those who have previously been treated with ruxolitinib (Jakavi/Jakafi).Novartis/Patients treated with Incyte’s oral JAK1/JAK2 inhibitor (patients previously treated with a JAK inhibitor).

It is worth mentioning that,Inrebic is the first new therapy for myelofibrosis approved in Europe in nearly a decade., and it will also be the first once-daily oral therapy to significantly reduce spleen volume and symptom burden in patients with myelofibrosis who have failed ruxolitinib treatment, are intolerant to ruxolitinib, or are JAK inhibitor-naïve. For nearly a decade, there has been no treatment option for patients with myelofibrosis whose disease progressed on ruxolitinib; this rare bone marrow disorder is characterized by debilitating symptoms and splenomegaly.

Inrebic was acquired by Bristol-Myers Squibb through its $74 billion acquisition of Celgene. In August 2019, Inrebic received approval from the U.S. FDA for the treatment of adult patients with intermediate-2 and high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Inrebic works byFDAapproved through the Priority Review program and previously granted Orphan Drug designation. In addition, Inrebic has also received approval in Canada.

Myelofibrosis is a serious bone marrow disorder that disrupts the body’s normal production of blood cells. This approval,making Inrebic the first in the United States in nearly a decadeFDAThe First Approved Novel Drug for Myelofibrosis, will provide patients with a new once-daily oral treatment option. In 2011,Novartis/Incyte's JAK1/JAK2 inhibitor Jakafi (ruxolitinib) receivedFDAApproved as the first drug for the treatment of myelofibrosis, this medication is taken orally twice daily.

It is important to note that the prescribing information for Inrebic includes a Boxed Warning regarding the risk of serious and fatal encephalopathy (brain injury or dysfunction), including Wernicke’s encephalopathy. In clinical studies, serious encephalopathy occurred in 1.3% (n=8/608) of patients treated with Inrebic, with a mortality rate of 0.16% (n=1/608). Wernicke’s encephalopathy is a neurological emergency caused by thiamine (vitamin B1) deficiency. Thiamine levels should be assessed in all patients prior to initiating Inrebic therapy and periodically during treatment. Treatment should not be initiated in patients with thiamine deficiency; thiamine supplementation must be administered before starting therapy. If encephalopathy is suspected, Inrebic should be discontinued immediately and parenteral thiamine therapy initiated. Monitoring should continue until symptoms resolve or improve and thiamine levels normalize.

This approval is based on the results of the JAKARTA and JAKARTA2 studies. Dr. Claire Harrison, Professor of Hematology at Guy’s and St Thomas’ NHS Foundation Trust in London, UK, and investigator for both studies, stated: “Myelofibrosis is a serious bone marrow disorder that is often debilitating, and for nearly a decade, only one approved treatment option has been available. Clinical data demonstrate that Inrebic leads to clinically meaningful reductions in spleen volume and symptoms in patients whose disease has progressed on ruxolitinib or who are JAK inhibitor–naïve. In the European Union, approximately one in every 100,000 people isDiagnosis“Today’s approval provides an important new option for patients with myelofibrosis who still urgently need new therapies.”

Myelofibrosis-Splenomegaly (Image source: oncohemakey.com)

The development program for Inrebic comprised multiple studies, including the Phase III clinical study JAKARTA and the Phase II clinical study JAKARTA2. A total of 608 patients received at least one dose of treatment (dose range: 30 mg to 800 mg), including 459 patients with myelofibrosis, of whom 97 had previously been treated with Jakafi.

This EU approval is based on the results of the JAKARTA and JAKARTA2 studies. JAKARTA was a randomized, placebo-controlled study conducted in 289 patients with primary or secondary myelofibrosis who had not previously been treated with JAK inhibitors, evaluating the efficacy and safety of two doses (400 mg and 500 mg) of Inrebic versus placebo. The results showed that at the end of treatment cycle 6, 37% (n=35/96) of patients in the Inrebic 400 mg dose group achieved a ≥35% reduction in spleen volume from baseline, and 40% (n=36/89) of patients achieved a ≥50% improvement in the total symptom score for myelofibrosis from baseline, compared to 1% (n=1/96) and 9% (n=7/81), respectively, in the placebo group, with statistically significant differences (both p<0.0001).

JAKARTA2 was a single-arm, open-label study conducted in 97 patients with primary or secondary myelofibrosis who had previously received Jakafi treatment, to evaluate the efficacy and safety of Inrebic (starting dose 400 mg). The results showed that Inrebic treatment demonstrated clinically meaningful response rates. Among the intent-to-treat (ITT) population (n=97), 31% of patients achieved a ≥35% reduction in spleen volume at the end of cycle 6. Of these 97 patients, 79 (81%) met the narrower criteria for Jakafi resistance or intolerance. In this cohort, the proportion of patients achieving a ≥35% reduction in spleen volume at the end of cycle 6 was 30% (95% CI: 21, 42), consistent with the response rate observed in the ITT population. Furthermore, the proportion of patients achieving a ≥50% symptom improvement rate was 27% in both the ITT population (95% CI: 18, 37) and among those included in the analysis using the narrower criteria (95% CI: 17, 39).

Molecular structure of fedratinib (Image source: Wikipedia)

The active pharmaceutical ingredient of Inrebic is fedratinib, an oral kinase inhibitor that is active against both wild-type and mutationally activated Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor, exhibiting greater inhibitory activity against JAK2 compared to its family members JAK1, JAK3, and TYK2. Aberrant activation of JAK2 is associated with myeloproliferativeTumor(MPN), including myelofibrosis and polycythemia vera.

In cellular models expressing mutant-activated JAK2 or FLT3, fedratinib reduces the phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibits cell proliferation, and induces apoptotic cell death. In a mouse model of myeloproliferative neoplasms driven by JAK2V617F, fedratinib blocked STAT3/5 phosphorylation, improved survival rates, and alleviated disease-related symptoms, including leukocytosis, hematocrit levels, splenomegaly, and fibrosis. (Bioon.com)

Original Source: Bristol-Myers Squibb Receives European Commissionapproval for Inrebic® (fedratinib) for Adult Patients with Newly Diagnosed and Previously Treated Myelofibrosis