FDA Grants Priority Review to Ruxolitinib for GVHD

Steven Stein, MD

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for ruxolitinib (Jakafi) for the treatment of patients with acute graft-versus-host disease (GVHD) who have had an inadequate response to corticosteroids, according to Incyte, the manufacturer of the JAK1/JAK2 inhibitor.

Incyte reported in a press release that the full data from REACH1 will be presented at an upcoming medical conference. The FDA previously granted ruxolitinib a breakthrough therapy designation in this setting. Under the priority review, the FDA acts within 6 months of receiving a supplemental application, rather than the standard 10 months.

“Patients with acute GVHD face significant morbidity and mortality risk, underscoring the urgent need for new treatment options,” Steven Stein, MD, chief medical officer, Incyte, said in a statement. “If approved, ruxolitinib will be the first and only treatment available in the United States for patients with acute GVHD who have not responded adequately to corticosteroid therapy. The acceptance of our sNDA is a critical milestone for Incyte and the GVHD community, and we look forward to working with the FDA to bring this innovative therapy to patients who currently have limited treatment options as soon as we are able.”

In the single-arm phase II REACH1 study (NCT02953678), patients with steroid-refractory acute GVHD received ruxolitinib in combination with investigator’s choice of oral prednisone or IV methylprednisolone. The study is part of the REACH clinical trial program.

The REACH program also includes the phase III REACH2 trial (NCT02913261), comparing ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute GVHD after ASCT, as well as the phase III REACH3 trial (NCT03112603) examining ruxolitinib versus best available therapy in patients with corticosteroid-refractory chronic GVHD after bone marrow transplantation. Data from REACH2 and REACH3 are anticipated in 2019.

In June 2016, the FDA granted a breakthrough therapy designation to ruxolitinib for the treatment of patients with acute GVHD. The designation was based on 2 small studies demonstrating high response rates with ruxolitinib in patients with GVHD. Both studies were presented at the 2015 ASH Annual Meeting.^2,3

One of the studies the FDA reviewed was a retrospective analysis of 95 patients who developed corticosteroid-refractory (SR) acute (a) or chronic (c) GVHD following allogeneic hematopoietic cell transplantation for a hematologic malignancy. Fifty-four patients had SR-aGVHD (grade III or IV) and 41 patients had SR-cGVHD (moderate or severe).

The patients, who were from 19 stem cell transplant centers in the United States and Europe, all received ruxolitinib as salvage-therapy. The median number of prior GVHD treatments was 3 for both the SR-aGVHD (range, 1-7) and SR-cGVHD (range, 1-10) patient groups. Median follow-up was 26.5 weeks (range, 3-106) and 22.4 weeks (range, 3-135), respectively.

The overall response rate was 81.5% (n = 44) in the SR-aGVHD group and 85.4% (n = 35) in patients with SR-cGVHD. The median time to response was 1.5 weeks (range, 1-11) and 3 weeks (range, 1-25), respectively. Patients with SR-aGVHD had a 6-month overall survival (OS) rate of 79% (95% CI, 67.3-90.7) and the 6-month OS was 97.4% (95% CI, 92.3-100) in the SR-cGVHD arm.

Among patients who responded to ruxolitinib, GVHD relapse occurred in 3 (6.8%) patients in the SR-aGVHD group and 2 (5.7%) patients in the SR-cGVHD arm. In the overall population, relapse of the primary malignancy was experienced by 5 (9.3%) and 1 (2.4%) of patients with SR-aGVHD or SR-cGVHD, respectively.

During ruxolitinib therapy, cytopenia occurred in 55.6% (n = 30) of the SR-aGVHD arm and 17.1% (n = 7) of the SR-cGVHD arm. Rates of CMV reactivation were 33.3% (n = 18) and 14.6% (n = 6), respectively.

The second study the FDA considered for the breakthrough designation involved 16 patients with hematologic malignancies who received transplants and developed quiescent (n = 12) or de novo (n = 4) severe (NIH criteria) steroid-dependent cGVHD. The transplants included unrelated donor (n =14), matched sibling (n = 2), blood (n = 15), and marrow (n = 1).

Areas affected by the cGVHD included the skin (n = 16), eyes (n = 12), mouth (n = 10), GI tract (n = 8), lungs (n = 4), liver (n = 3), and musculoskeletal system (n = 3). The cGVHD was steroid dependent, with a 24-month (range, 6-53) median duration of continuous exposure to steroids for cGVHD.

Patients received ruxolitinib at 5 mg twice daily as second- (n = 4), third- (n = 7), fourth- (n = 4), or fifth-line (n = 1) salvage therapy. The ruxolitinib dose was raised to 15 mg/daily for 4 patients and 20 mg/daily for 3 patients due to patient weight, physician preference, flare of cGVHD following initial response related to halting immunosuppression, or temporary perioperative hold of ruxolitinib. Patients had a 6-month (range, 1-14) median duration of ruxolitinib treatment.

Patient responses to ruxolitinib were observed at median of 14 days following the start of treatment. The researchers observed complete resolution of clinical manifestations of cGVHD in patients’ lungs, mouth, skin, liver, musculoskeletal system, and GI tract.

Ten patients were able to discontinue prednisone at a median of 72 days (range, 31-120) after starting ruxolitinib. Two patients reduced prednisone to physiologic doses and the other 4 patients were tapering prednisone at the time of the data analysis.

Ruxolitinib is currently approved by the FDA as a treatment for patients with polycythemia vera who are intolerant of or have an inadequate response to hydroxyurea. The JAK1/JAK2 inhibitor also has an FDA-approved indication for the treatment of patients with intermediate or high-risk myelofibrosis.

References

1. FDA Grants Priority Review for Ruxolitinib (Jakafi^®) as a Treatment for Patients with Acute Graft-Versus-Host Disease. Incyte. Published October 26, 2018. Published October 26, 2018. https://bit.ly/2qe9Sdc.
2. Zeiser R, Burchert A, Lengerke C, et al. Treatment of corticosteroid-refractory graft-versus-host disease with ruxolitinib in 95 patients. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015. Orlando, Florida; Abstract 858.
3. Khoury HJ, Kota V, Arellano M et al. Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease (cGVHD). Presented at: 2015 ASH Annual Meeting; December 5-8, 2015. Orlando, Florida; Abstract 1938.

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The sNDA is based on results from the pivotal phase II REACH1 trial, in which ruxolitinib combined with corticosteroids induced an overall response rate of 55% at day 28 in patients with steroid-refractory acute GVHD, meeting the primary endpoint of the study.¹ Thirty-nine of 71 patients achieved an objective response at day 28. Additionally, 52 patients had a response at any time point in the study, translating to a best overall response rate of 73%. The most frequently reported treatment-related adverse events across all grades included anemia (61%), thrombocytopenia (61%), and neutropenia (56%).