On November 20, 2023 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported 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 (Press release, MorphoSys, NOV 20, 2023, View Source [SID1234637880]).

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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.

"We are very pleased with this positive outcome. Pelabresib in combination with ruxolitinib demonstrated strong reductions in spleen volume and symptoms over ruxolitinib monotherapy – the most impressive benefits seen in clinical studies of patients with myelofibrosis," said Jean-Paul Kress, M.D., Chief Executive Officer of MorphoSys. "Importantly, we saw significant symptom improvements for the vast majority of patients in the study. We look forward to our continued conversations with regulatory agencies and intend to file for approval in the U.S. and Europe."

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).

"I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis," said John Mascarenhas, M.D., Director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai, New York. "The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume – the best prognostic indicator we have at our disposal for long-term myelofibrosis patient outcomes. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation."

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).

"Myelofibrosis patients experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever – symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment," said Ruben A. Mesa, M.D., FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center. "Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis."

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.

ASH 2023 Annual Meeting Oral Presentation

Detailed findings of the Phase 3 MANIFEST-2 study will be presented during an oral presentation, held on Sunday, December 10, at 5:15 p.m. PST, at the 65th American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California. MorphoSys will host an investor event with the company’s management team and medical experts to review these data on Monday, December 11.

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.

Conference Call Details

MorphoSys management will host a conference call on Tuesday, November 21, at 2:00 p.m. CET (1:00 p.m. GMT; 8:00 a.m. EST) to review the Phase 3 MANIFEST-2 topline results.

Participants for the conference call and webcast may pre-register and will receive dedicated dial-in details to easily and quickly access the call: View Source;linkSecurityString=11493ccf0c. Please dial in 10 minutes before the beginning of the conference.

The live webcast (audio and presentation) can be directly accessed via View Source or via the Investors section under "Events & Conferences" on MorphoSys’ website, www.morphosys.com and after the call, a slide-synchronized audio replay of the conference call will be available at the same location.