FDA Grants Priority Review to sNDA for Ruxolitinib to Treat Steroid-Refractory cGVHD

The sNDA submission for ruxolitinib to treat steroid-refractory chronic graft-versus-host disease in adult and pediatric patients 12 years and older was based on the phase 3 REACH3 study, which is assessing the safety and efficacy of ruxolitinib compared with best available therapy.

The FDA has accepted and granted priority review to a supplemental new drug application (sNDA) for the first-in-class JAK1/JAK2 inhibitor ruxolitinib (Jakafi) for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD) in adult and pediatric patients 12 years and older, according to the drug’s developer, Incyte.1

A prescription drug user fee act (PDUFA) target action date has been set by the FDA for June 22, 2021.

The submission is being reviewed as part of the Project Orbis program, an initiative of the United States FDA Oncology Center of Excellence that “provides a framework for concurrent submission and review of oncology drugs among international regulatory agencies.” Countries participating for this particular application include Canada, Australia, Switzerland, Brazil, and the United Kingdom.

“Chronic GVHD is a life-threatening complication following stem cell transplant that burdens a vulnerable patient population, which today has limited treatment options,” Peter Langmuir, MD, group vice president of Oncology Targeted Therapies at Incyte, said in a press release. “The acceptance of this sNDA represents an important milestone for Incyte as we continue our work towards helping more people living with GVHD, particularly for those who do not respond to steroids. We look forward to working closely with the FDA to bring this innovative therapy to patients and to providing continued support to the GVHD community in the United States.”

The sNDA submission was based on results from the randomized, open-label, multicenter phase 3 REACH3 study (NCT03112603), which is assessing the safety and efficacy of ruxolitinib compared with best available therapy (BAT) in patients with steroid-refractory cGVHD. Results from this study were presented at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition.2

The study’s primary end point is overall response rate (ORR) at week 24, defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR). Key secondary end points include failure-free survival (FFS), change in the modified Lee Symptom Scale (mLSS) score at week 24, best overall response (BOR), duration of response (DoR), overall survival (OS), and safety.

A total of 329 patients were randomized 1:1 to receive either ruxolitinib (n = 165) or BAT (n = 164) and were treated for 6 28-day cycles. Notably, crossover from BAT to ruxolitinib was allowed on or after day 1 of cycle 7 in patients who did not achieve or maintain CR or PR, developed toxicity to BAT, or had a cGVHD flare.

At the data cutoff of May 8, 2020, 125 patients (38%) were on randomized treatment (ruxolitinib, 50%; BAT, 26%). However, 82 (50%) and 122 (74%) patients discontinued ruxolitinib and BAT, respectively, and 61 (37%) had crossed over to ruxolitinib. Reasons for discontinuation included lack of efficacy (15% ruxolitinib vs 43% BAT), adverse events (AEs; 17% vs 5%), and relapse (5% vs 4%).

The study met its primary end point with the efficacy boundary crossed at interim analysis (ORR, P =.0003). On day 1 of cycle 7, the ORR was found to be significantly higher in the ruxolitinib arm at 50% versus 26% with BAT (OR, 2.99; P <.0001). Moreover, the CR rate was also higher with ruxolitinib (7% vs 3%).

FFS was significantly longer for patients treated with ruxolitinib (median FFS, not reached vs 5.7 months; HR, 0.370; 95% CI, 0.268-0.510; <.0001), and the mLSS responder rate was higher as well (24% vs 11%; OR, 2.62; =.0011).

Regarding safety, the rates of AEs up to day 1 of cycle 7 were comparable in the 2 arms. The most common AEs observed in at least 15% of patients in the ruxolitinib versus BAT arms were anemia (29% vs 13%), hypertension (16% vs 13%), pyrexia (16% vs 9%), and alanine aminotransferase (ALT) increase (15% vs 4%). Infections of any type occurred in 64% of patients who received ruxolitinib and 56% who received BAT (19% vs 18% grade 3), and included fungal (12% vs 6%), viral (34% vs 29%), and bacterial (28% vs 26%) infections. Overall, 31 patients treated with ruxolitinib (19%) and 27 with BAT (16%) died, with the main cause of death being cGVHD (13% vs 8%, respectively).

Ruxolitinib was approved by the FDA in 2019 for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older. The JAK1/JAK2 inhibitor is also approved by the FDA for the treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea and intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post-essential thrombocythemia MF in adults.


1. Incyte Announces Acceptance and Priority Review of sNDA for Jakafi® (ruxolitinib) as a Treatment for Patients with Chronic Graft-Versus-Host Disease. News release. Incyte. Published February 22, 2021. Accessed February 22, 2021. https://www.businesswire.com/news/home/20210222005224/en/Incyte-Announces-Acceptance-and-Priority-Review-of-sNDA-for-Jakafi%C2%AE-ruxolitinib-as-a-Treatment-for-Patients-with-Chronic-Graft-Versus-Host-Disease

2. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study. Presented at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020. Abstract 77. https://ash.confex.com/ash/2020/webprogram/Paper137694.html