Novartis Announces Positive Phase 3 REACH3 Trial Results for Jakavi (Ruxolitinib) in Steroid-Refractory Chronic Graft-versus-Host Disease

December 06, 2020 /Bio ValleyBIOON/ --Novartis(Novartis) recently announced the detailed results of the pivotal Phase III REACH3 study (NCT03112603) at the 62nd Annual Meeting of the American Society of Hematology (ASH). This is a randomized, open-label, multicenter study in patients receiving allogeneicStem CellsConducted in pediatric (≥12 years) and adult patients who developed steroid-refractory or steroid-dependent chronic graft-versus-host disease (GvHD) after transplantation. The data showed that, compared with best available therapy (BAT), the oral JAK1/2 inhibitor Jakavi (ruxolitinib) significantly improved a range of efficacy endpoints in patients with steroid-refractory/dependent chronic GvHD, including failure-free survival (FFS) and patient-reported symptoms.

Chronic GvHD isStem CellsA life-threatening complication of transplantation, with approximately half of patients progressing to steroid-refractory/dependent disease. Notably, Jakavi is in a large-scale randomizedClinical TrialThe first drug to demonstrate efficacy in the treatment of steroid-refractory/dependent chronic GvHD. Based on the results of the REACH3 study,NovartisPlan to submit regulatory application documents for Jakavi in the treatment of steroid-refractory/dependent GvHD patients in European countries outside the United States in the first half of 2021.

University Medical Center Freiburg, Department of Hematology,TumorandStem CellsDr. Robert Zeiser from the Department of Transplantation stated: “Stem Cells"The destructive and potentially life-threatening impact of chronic GvHD after transplantation poses a significant challenge to treatment, especially for nearly half of patients who do not respond adequately to steroid therapy. Based on the compelling results from the REACH3 study, we now have a potential new standard of care for these patients."

In the REACH3 study, at Week 24 of treatment, the primary endpoint was met: the overall response rate (ORR) was significantly higher in the Jakavi group compared to the best available therapy (BAT) group (49.7% vs. 25.6%; p < 0.0001). Furthermore, Jakavi demonstrated statistically and clinically significant improvements in key secondary endpoints: (1) Failure-free survival (FFS; defined as early disease recurrence, initiation of new systemic therapy for chronic GvHD, or death) was significantly improved in the Jakavi group compared to the BAT group (median FFS: not reached vs. 5.7 months; HR = 0.370; 95% CI: 0.268–0.510; p < 0.0001). (2) Based on the modified Lee Symptom Scale (mLSS), evaluated by the proportion of responders achieving a ≥7-point reduction from baseline in the Total Symptom Score (TSS), patient-reported symptoms showed greater improvement in the Jakavi group than in the BAT group (24.2% vs. 11.0%; p = 0.0011). (3) The best overall response (BOR) was achieved in 76.4% of patients in the Jakavi group versus 60.4% in the BAT group (OR = 2.17; 95% CI: 1.34–3.52). The median duration of response (DOR) was not reached in the Jakavi group, compared to 6.24 months in the BAT group.

In this study, no new safety signals were observed, and treatment-emergent adverse events (AEs) were consistent with the known safety profile of Jakavi. The most commonAdverse ReactionsYesAnemia(29.1% vs 12.7%), thrombocytopenia (21.2% vs 14.6%),Hypertension(15.8% vs 12.7%) and fever (15.8% vs 9.5%). Although dose adjustments were required in 37.6% of patients receiving Jakavi and 16.5% of those receiving BAT, the number of patients who discontinued treatment due to adverse events (AEs) was low (16.4% and 7%, respectively). Mortality rates were similar between the treatment groups (19% vs 16% for BAT). Deaths in the Jakavi group were slightly more frequent and primarily caused by chronic graft-versus-host disease (GvHD).

Graft-versus-host disease (GvHD) is a common and potentially life-threatening complication following allogeneic stem cell transplantation, characterized by donor cells attacking the recipient's normal cells because they recognize them as foreign. The two main types of GvHD are acute GvHD (occurring within 100 days post-transplantation) and chronic GvHD (occurring after 100 days post-transplantation). In allogeneicStem CellsFollowing transplantation, approximately 50% of patients experience acute or chronic graft-versus-host disease (GvHD), or both. Symptoms of chronic GvHD can affect the skin, gastrointestinal tract, liver, oral cavity, lungs, and joints. There is an urgent need for additional therapeutic options for patients who do not respond to initial steroid therapy or are considered steroid-refractory.

The results of the REACH3 study complement the previously reported positive findings from the pivotal Phase III REACH2 study of Jakavi for acute GvHD, which was the first Phase III trial to successfully meet its primary endpoint in the treatment of acute GvHD. The data demonstrated that, compared with best available therapy (BAT), Jakafi significantly improved a range of efficacy endpoints in patients with steroid-refractory acute GvHD.

In May 2019, based on the results of the single-arm Phase II REACH1 study, the U.S. FDA approved ruxolitinib (marketed in the United States by Incyte under the brand name Jakafi) for the treatment of steroid-refractory acute graft-versus-host disease (GvHD) in adult and pediatric patients aged 12 years and older. Notably, ruxolitinib is the firstFDADrugs approved for the treatment of steroid-refractory GvHD. In the REACH1 study, the overall response rate (ORR) at Day 28 of ruxolitinib treatment was 57%, and the complete response rate (CR) was 31%.

In April this year, the results of the REACH2 study were published in The New England Journal of Medicine (NEJM): Compared with the BAT treatment group, the Jakavi treatment group showed a significantly higher overall response rate (ORR) on Day 28 (62% vs. 39%, p < 0.001), meeting the primary endpoint of the study. Regarding key secondary endpoints, the proportion of patients maintaining a durable ORR within 8 weeks was significantly higher in the Jakavi treatment group compared to the BAT treatment group (40% vs. 22%, p < 0.001). Furthermore, failure-free survival (FFS) was prolonged in the Jakavi treatment group compared to the BAT treatment group (5.0 months vs. 1.0 months; HR = 0.46, 95% CI: 0.35–0.60). Other secondary endpoints also demonstrated positive trends, including duration of response (DOR).

Ruxolitinib is a first-in-class oral Janus kinase 1 and Janus kinase 2 (JAK1/JAK2) inhibitor. Its current indications include myelofibrosis, polycythemia vera (PV), and corticosteroid-refractory acute graft-versus-host disease (GvHD). In the U.S. market, the drug is marketed under the brand name Jakafi by Incyte; outside the United States, it is marketed under the brand name Jakavi by Novartis AGNovartisSales.

Currently, Incyte is also developing ruxolitinib cream, which is in Phase III clinical development: (1) for the treatment of patients with mild-to-moderate atopic dermatitis (TRuE-AD program), and (2) for the treatment of vitiligo in adolescents and adults (TRuE-V program). Incyte holds global rights to develop and commercialize ruxolitinib cream. Previously reported Phase II study data showed that, compared with the vehicle control group (drug-free cream), patients treated with ruxolitinib cream demonstrated significant improvement in the Facial Vitiligo Area Scoring Index (F-VASI) score, systemicVitiligoSignificant improvement in skin lesion repigmentation was observed. In February this year, the Phase III program of ruxolitinib cream for the treatment of atopic dermatitis achieved success. (Bioon.com)

Original Source: Novartis announces first data from REACH3 trial showing Jakavi? (ruxolitinib) significantly improved outcomes in patients with steroid-resistant/dependent chronic GvHD