MANIFEST-2 met primary endpoint,
nearly doubling SVR35 response rate (66% versus 35%)
The key secondary endpoints assessing symptom reduction, TSS50 and absolute change in TSS, showed significant improvements for intermediate-risk patients (p<0.05, p<0.02, respectively) and strong numerical improvements for overall population
Pelabresib plus ruxolitinib showed clinically meaningful anemia improvement versus placebo and ruxolitinib
Safety results were consistent with prior clinical trials, with no new safety signals
MorphoSys intends to submit for approval in the U.S. and Europe in mid-2024
MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announces strong topline results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib compared with placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis.
MANIFEST-2 met its primary endpoint, as the combination therapy demonstrated a statistically significant and clinically meaningful improvement in the proportion of patients achieving at least a 35% reduction in spleen volume (SVR35) at week 24. The key secondary endpoints assessing symptom improvement – proportion of patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at week 24 – showed a strong positive trend favoring the pelabresib and ruxolitinib combination. In an analysis of patients classified as intermediate risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2) – constituting more than 90% of patients in MANIFEST-2 – the combination therapy demonstrated significant improvements in both key secondary endpoints. DIPSS was a pre-defined stratification factor in the MANIFEST-2 study protocol.
MANIFEST-2 Topline Results Overview
MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study that randomized 430 JAK inhibitor-naïve adult myelofibrosis patients, making it one of the largest myelofibrosis studies conducted to date.
Significant Improvement in Spleen Volume Reduction
In MANIFEST-2, 66% of patients receiving pelabresib in combination with ruxolitinib achieved SVR35 at week 24, the primary endpoint, versus 35% of those receiving placebo and ruxolitinib, nearly doubling SVR35 response rates (95% CI [21.6; 39.3], p<0.001).
Meaningful Improvements to Myelofibrosis Symptoms
In a key secondary endpoint, TSS was reduced by 15.99 points at week 24, from 28.26 at baseline, in the pelabresib and ruxolitinib treatment arm and by 14.05 points at week 24, from 27.36 from baseline, in the placebo plus ruxolitinib arm (Δ -1.94, 95% CI [-3.92; 0.04], p=0.0545), using least square mean estimate.
In intermediate-risk patients (DIPSS Int-1 and Int-2), TSS was reduced by 15.18 points at week 24, from 28.20 at baseline, in the pelabresib and ruxolitinib treatment arm versus 12.74 points at week 24, from 27.53 at baseline, in the placebo plus ruxolitinib arm, which was significant (Δ -2.44, 95% CI [-4.48; -0.40], p<0.02). DIPSS is an established prognostic system used to predict patient survival, classifying myelofibrosis patients into the following risk categories: low, intermediate-1, intermediate-2 or high.
Absolute change in TSS was included as a key secondary endpoint to directly measure change in the average TSS from baseline to week 24. It is a continuous endpoint that provides a meaningful, detailed assessment of symptom score reductions, thereby enhancing precision in estimating the magnitude of symptom burden reduction in patients with myelofibrosis. This endpoint was added to the MANIFEST-2 clinical trial protocol following a Type C meeting with the U.S. Food and Drug Administration (FDA) in September 2023.
TSS50, another key secondary endpoint, was achieved by 52% of patients in the pelabresib and ruxolitinib treatment arm at week 24 compared with 46% in the placebo plus ruxolitinib arm (95% CI [-3.5; 15.5], p=0.216). In intermediate-risk patients, TSS50 was achieved by 55% of patients in the pelabresib and ruxolitinib treatment arm at week 24 compared with 45% in the placebo plus ruxolitinib arm (95% CI [0.35; 19.76], p<0.05).
Improvements in Anemia
The MANIFEST-2 results show a greater proportion of patients achieved hemoglobin response (≥ 1.5 g/dL from baseline) with the pelabresib and ruxolitinib combination than with placebo and ruxolitinib.
Pelabresib and Ruxolitinib Combination Was Well-Tolerated
At the time of this analysis, the safety of pelabresib and ruxolitinib was consistent with the previously observed safety profile of this combination therapy; no new safety signals were observed. Importantly, adverse events of anemia were reported less frequently with pelabresib and ruxolitinib than with placebo and ruxolitinib.
Planned Regulatory Next Steps
Based on the strong and comprehensive data generated from the MANIFEST-2 study, MorphoSys will continue conversations with regulatory agencies, with intention to submit a New Drug Application for pelabresib in combination with ruxolitinib in myelofibrosis to the FDA and a Marketing Authorization Application to the European Medicines Agency in the middle of 2024. The combination therapy received Fast Track designation for this disease from the FDA in 2018.
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