FDA Pushes Back Approval Decision on Ruxolitinib for Steroid-Refractory cGVHD


The FDA has extended the review period of the supplemental new drug application for ruxolitinib as treatment of patients aged 12 years or older with steroid-refractory chronic graft-versus-host disease.

The FDA has extended the review period of the supplemental new drug application (sNDA) for ruxolitinib (Jakafi) as treatment of patients aged 12 years or older with steroid-refractory chronic graft-versus-host disease (GVHD), according to a press release by Incyte.

The Prescription Drug User Fee Act (PDUFA) target action date was moved back 3 months to September 22, 2021, in order to review updated data from the REACH3 (NCT03112603) trial, which supports the application for FDA approval.

The randomized, parallel assignment, multi-center trial has an actual enrollment of 330 patients and an estimated completion date of May 14, 2022. REACH3 was split into 2 arms. During arm 1, patients received ruxolitinib. In arm 2, BAT.

The primary end point of the study is the efficacy of ruxolitinib versus investigator’s choice of best available therapy (BAT). Secondary outcomes include rate of failure-free survival (FFS), change in the modified Lee cGVHD symptom scale score, best overall response rate, overall response rate at the end of cycle 3, duration of response (DOR), overall survival (OS), cumulative incidence of non-relapse mortality, percentage of participants with a 50% or more reduce in daily corticosteroid dose at cycle 7, the percentage of patients successfully tapered off all corticosteroids at cycle 7, the cumulative incidence of malignancy relapse/recurrence, changes in functional assessment of cancer therapy, incidence and severity of adverse events (AEs), pharmacokinetics, and utilization of medical resources. 

In order to participate, patients must have undergone allogeneic stem cell transplantation from any donor source, using bone marrow, peripheral blood stem cells, or cord blood, have evidence of myeloid and platelet engraftment, and have clinically diagnosed moderate to severe cGVHD. Patients who have received 2 or more systemic treatments for cGVHD in addition to corticosteroids, have previously exposure to JAK inhibitors for active GVHD, failed prior allogenic stem cell transplantation within the past 6 months from cycle 1 day 1, or a relapsed primary malignancy, are not eligible to participate.

In a prior analysis of the study, the ORR for ruxolitinib was 49.7% versus 25.6% for BAT (odds ratio [OR], 2.99; 95% CI, 0.86-4.80; P < .0001). In the ruxolitinib arm, 43% had a partial response and 6.7% had a complete response. In the BAT ARM, 22.6% of patients had a partial response and 3% had a complete response. Additionally, 37.2% of patients in the BAT arm crossed over to ruxolitinib.

Median FFS was not reached while it was reached at 5.7 months in the BAT arm. In the ruxolitinib arm, 24.2% of patients achieved a clinically meaningful decrease in symptoms compared to 11% in the BAT arm. The best overall response was also higher in the ruxolitinib arm, 76.4%, versus 60.4% in the BAT arm.

In terms of AEs, both arms experienced similar rates. In the ruxolitinib arm, 97.6% experienced any grade AE and 91.8% of patients in the BAT arm experienced any grade AE. Additionally, grade 3 or higher AEs and serious AEs were both more common in the BAT arm. Grade 3 or higher AEs occurred in 57% of patients in the ruxolitinib arm and 57.6% in the BAT arm. Serious AEs occurred at a rate of 36.7% in the BAT arm versus 33.3% in the ruxolitinib arm. The risk of death in the ruxolitinib arm was 18.8% versus 16.5% in the BAT arm. 

Any grade anemia occurred in 29.1% in the ruxolitinib arm and 12.7% in the BAT arm. In the ruxolitinib arm, 21.2% had any grade thrombocytopenia versus 14.6% in the BAT arm. Viral infections occurred in 33.9% of patients in the ruxolitinib arm and 29.1% in the BAT arm.

“We remain confident in the data from the REACH3 trial supporting our sNDA submission for ruxolitinib and look forward to continued dialogue with the FDA throughout the remainder of the review process,” said Steven Stein MD, chief medical officer, Incyte in a press release. “We will work closely with the agency and are dedicated to bringing this innovative treatment to patients with steroid-refractory chronic GVHD who urgently need new treatment options.”

Ruxolitinib is a first-in-class JAK1/JAK2 inhibitor. It currently holds an indication for the treatment of polycythemia vera in adults who are intolerant to or have had an inadequate response to hydroxyurea. Other indications for this agent include intermediate or high-risk myelofibrosis (MF), post-polycythemia vera MF and post-essential thrombocythemia MF in adults, and for the treatment of steroid refractory acute GVHD in adults and patients 12 years of age and older.

Incyte announces U.S. FDA has extended the sNDA review period for ruxolitinib (Jakafi®) in chronic graft-versus-host disease (GVHD). News release. Incyte. June 8, 2021. Accessed June 9, 2021. https://bit.ly/3iBiKpk.
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