Incyte and Novartis Announce Positive Phase 3 REACH3 Data for Jakafi/Jakavi in Glucocorticoid-Refractory Chronic Graft-versus-Host Disease

REACH3 Clinical Trial Primary Endpoint Data

July 15, 2021 /BioonBIOON/ --Novartis(Novartis) and its partner Incyte recently jointly announced that the positive results from the pivotal Phase 3 REACH3 study (NCT03112603), which evaluated the oral JAK1/2 inhibitor Jakavi/Jakafi (ruxolitinib) for the treatment of steroid-refractory chronic graft-versus-host disease (GVHD), have been published in the prestigious international medical journal *The New England Journal of Medicine* (NEJM), with the article titled:Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease。

REACH3 byNovartisCo-sponsored with Incyte, this is a randomized, open-label, multicenter Phase 3 study in patients receiving allogeneicStem cellsconducted in pediatric patients (aged ≥12 years) and adult patients with steroid-refractory or steroid-dependent chronic graft-versus-host disease (GvHD) following transplantation. Data show:Compared with best available therapy (BAT), ruxolitinib significantly improved the prognosis of patients with steroid-refractory/dependent chronic GvHD., including improved failure-free survival (FFS) and patient-reported symptoms. New subgroup analyses showed that at week 24 of treatment, compared with BAT,Ruxolitinib demonstrated a higher overall response rate (ORR) across all major subgroups (including baseline organ involvement).

Chronic GvHD is a life-threatening disease that isStem cellsLong-term complications of transplantation can affect multiple organs; approximately half of patients receiving first-line steroid therapy will develop steroid-refractory/steroid-dependent disease. Notably,Ruxolitinib was in a large-scale randomizedClinical TrialThe first drug to demonstrate efficacy in the treatment of steroid-refractory/dependent chronic GvHD.

Ruxolitinib is a first-in-class JAK1/JAK2 inhibitor marketed by Incyte in the United States (brand name: Jakafi), while Novartis is licensed to market it outside the United States (brand name: Jakavi). Based on the results of the REACH3 study, Incyte has submitted a supplemental New Drug Application (sNDA) to the US FDA for Jakafi for the treatment of pediatric (≥12 years) and adult patients with steroid-refractory chronic graft-versus-host disease (cGVHD). Currently, this sNDA is under reviewFDAReview, target action date: September 22, 2021.NovartisSeparately, regulatory submissions for Jakavi for the treatment of acute and chronic GvHD outside the United States are ongoing.

Hematology, University Medical Center Freiburg, Germany,TumorStudy andStem CellsDr. Robert Zeiser of the Department of Transplantation stated: "Patients with chronic GVHD experience severe and life-threatening symptoms across multiple organs, which makes the disease more difficult to treat and increases the risk of poor prognosis. With these new results from the REACH3 study, we can more clearly see the therapeutic benefits of ruxolitinib as a potential new standard of care for patients with chronic GVHD who have an inadequate response to first-line corticosteroids."

The REACH3 study met its primary endpoint: at Week 24 of treatment, the overall response rate (ORR) was significantly higher in the ruxolitinib group compared with the BAT group (49.7% vs 25.6%, p < 0.0001). Additionally, at any time point through Week 24, 76.4% of patients in the ruxolitinib group achieved a best overall response (BOR) compared with 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 with 6.24 months in the BAT group.

In addition, ruxolitinib also demonstrated statistically and clinically significant improvements in key secondary endpoints: (1) Compared with the BAT group, the ruxolitinib group showed a significant improvement in failure-free survival (FFS; defined as early disease relapse, initiation of new systemic therapy for chronic GvHD, or death) (median FFS: not reached vs. 5.7 months; HR=0.370; 95% CI: 0.268–0.510; p<0.0001). (2) Evaluated using the modified Lee Symptom Scale (mLSS) based on the proportion of responders achieving a reduction in Total Symptom Score (TSS) of ≥7 points from baseline, the ruxolitinib group demonstrated greater improvement in patient-reported symptoms compared with the BAT group (24.2% vs. 11.0%; p=0.0011). (3) New subgroup analyses revealed that patients treated with ruxolitinib achieved better outcomes regardless of the specific organs involved at baseline.

In this study, no new safety signals were observed, and adverse events (AEs) attributed to treatment were consistent with the known safety profile of ruxolitinib. The most common Grade ≥3 adverse events in the ruxolitinib and BAT groups were thrombocytopenia (15.2% vs. 10.1%),`Anemia`(12.7% vs 7.6%), neutropenia (8.5% vs 3.8%), and pneumonia (8.5% vs 9.5%). Although dose adjustments due to adverse events were required in 37.6% and 16.5% of patients in the ruxolitinib and BAT groups, respectively, the proportions of patients discontinuing treatment due to adverse events were low in both groups (16.4% for the ruxolitinib group vs 7% for the BAT group). Mortality rates were similar between the treatment groups (18.8% in the ruxolitinib group vs 16.5% in the BAT group). Mortality primarily attributable to complications of chronic GvHD and/or its treatment was slightly higher in the ruxolitinib group than in the BAT group (13.3% vs 7.9%).

Detailed Data from the REACH3 Clinical Study (Click image to enlarge)

Graft-versus-host disease (GvHD) is a common and potentially life-threatening complication following allogeneic stem cell transplantation. It is a reaction in which donor cells attack the recipient's normal cells, as the donor cells recognize the recipient's cells as foreign. The two main types of GvHD are acute GvHD (occurring within 100 days post-transplantation) and chronic GvHD (occurring within 100 days post-transplantation). In allogeneic`Stem Cells`Following 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. Additional treatment options are urgently needed for patients who are unresponsive to initial corticosteroid therapy or are considered steroid-refractory.

The results of the REACH3 study complement the positive findings previously reported 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. 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, the US FDA approved ruxolitinib (marketed by Incyte in the United States under the brand name Jakafi), based on the results of the single-arm Phase II REACH1 study, for the treatment of steroid-refractory acute graft-versus-host disease (aGVHD) in pediatric and adult patients aged 12 years and older. Notably, ruxolitinib is the first to be approvedFDAApproved 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 2020, the results of the REACH2 study were published in *The New England Journal of Medicine* (NEJM): compared with the best available therapy (BAT) group, the Jakavi group demonstrated a significantly higher overall response rate (ORR) at Day 28 (62% vs 39%, p < 0.001), meeting the primary endpoint of the study. Regarding key secondary endpoints, compared with the BAT group, a significantly higher proportion of patients in the Jakavi group maintained a durable ORR through Week 8 (40% vs 22%, p < 0.001). Furthermore, failure-free survival (FFS) was prolonged in the Jakavi group compared with the BAT group (5.0 months vs 1.0 months; HR=0.46, 95% CI: 0.35–0.60). Other secondary endpoints also exhibited favorable trends, including duration of response (DOR).

Vitiligo model Amy Deanna (Image source: AsiaOne)

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 US market, it is marketed under the brand name Jakafi and sold by Incyte; outside the US, it is marketed under the brand name Jakavi and byNovartisSales.

Currently, Incyte Corporation is also developing a ruxolitinib cream formulation, 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 adolescents and adults.`Vitiligo`(TRuE-V project). Incyte holds the global rights to develop and commercialize ruxolitinib cream.

In the treatment of atopic dermatitis, the TRuE-AD program was successfully completed in the first half of 2020. Currently, the United StatesFDAThe New Drug Application (NDA) for ruxolitinib cream for the treatment of atopic dermatitis in adolescents and adults (≥12 years of age) is under review.

Regarding the treatment of vitiligo, the TRuE-V program achieved success this May, with both Phase 3 studies meeting their primary and key secondary endpoints: compared with vehicle cream, rRuxolitinib Cream Demonstrates Significant Efficacy in the Treatment of Vitiligo—Significantly Improves Facial Vitiligo and Whole-Body Lesion Repigmentation, with a Favorable Safety Profile. Based on data from the TRuE-V program, Incyte plans to submit applications for market approval of ruxolitinib cream for the treatment of vitiligo in the United States and the European Union in the second half of 2021. If approved,Ruxolitinib cream will become the first and only for the treatment ofVitiligoDrugs for the repigmentation of skin lesions.(Bioon.com)

Source:Incyte Announces Positive Phase 3 REACH3 Study Data Published in NEJM for Ruxolitinib (Jakafi®) in Chronic Graft-Versus-Host Disease