About The Trial
Trial Name: Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2)
ClinicalTrials.gov ID: NCT04603495
Sponsor: Constellation Pharmaceuticals
Completion Date (Estimated): December 2027
Spotlight
Clinical Role
Clinical
Supplement Spotlight
CE
Subscribe
News
Article
Pelabresib and Ruxolitinib Achieve Primary End Point in Phase 3 MANIFEST-2 Trial
Author(s):
Key Takeaways
- Pelabresib combined with ruxolitinib showed significant improvements in spleen volume, symptom score, anemia, and bone marrow fibrosis in JAK inhibitor-naïve myelofibrosis patients.
- At 24 weeks, 65.9% of patients achieved a ≥35% reduction in spleen volume, with sustained benefits observed at 48 weeks.
Pelabresib is an investigational, oral, small molecule that inhibits bromodomain and extraterminal (BET) proteins.
The MANIFEST-2 trial (NCT04603495) evaluating pelabresib (CPI-0610; Novartis) in combination with ruxolitinib (Jakafi; Incyte Corp) met its primary end point, demonstrating meaningful improvements in spleen volume, total symptom score (TSS), anemia, and bone marrow fibrosis (BMF) compared with ruxolitinib and placebo in patients with Janus kinase inhibitor (JAKi)-naïve myelofibrosis (MF). The data will be presented at the 66th ASH Annual Meeting and Exposition on December 8, 2024.1
Bone marrow producing blood cells | Image Credit: © chopoo - stock.adobe.com
MF is a fatal disease characterized by splenomegaly, anemia, and fibrosis of the bone marrow. JAKis are first-line treatment for MF, but many patients become JAK inhibitor naïve and fail to respond to the therapy. Ruxolitinib is a JAKi therapy with demonstrated success in MF symptom relief and decreased fibrosis; however, it is highly associated with worsening anemia. As a result, multiple clinical trials are investigating use of ruxolitinib with other agents.2,3
Pelabresib is an oral, small moleculem, bromodomain and extraterminal domain (BET) inhibitor that decreases expression of BET proteins that has demonstrated meaningful success in treating patients with JAKi-naïve MF. In the global, randomized, double-blind, phase 3 MANIFEST-2 trial, patients receiving pelabresib in combination with ruxolitinib achieved more profound and sustained responses compared with ruxolitinib as a monotherapy.2-4
"This study importantly is following patients longer term from the primary analysis at 24 weeks to understand the durability of the outcome measures of spleen and symptom reduction as well as anemia response and better characterize the rates of progression of disease and evolution to AML," said John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute.
In the trial, patients were randomized 1:1 to receive either pelabresib or placebo once daily for 14 consecutive days of 21-day cycles in combination with ruxolitinib, which was administered twice daily for 21-day cycles. The primary end point was a ≥35% reduction in spleen volume (SVR35), with key secondary end points of absolute change in TSS and ≥50% reduction in TSS from baseline (TSS50) at week 24 and week 48.2
At week 24, 65.9% of patients in the pelabresib and ruxolitinib arm achieved SVR35, as well as TSS50 response of 52.3%. Anemia occurred in less than half of patients receiving the treatment and 10.7% had a hemoglobin response.2,3
Preliminary data from patient outcomes at week 48 show that SVR35 response was achieved by 56.5% of patients receiving pelabresib and ruxolitinib compared with 37.5% of patients on placebo and ruxolitinib, demonstrating sustained benefits beyond week 24. TSS50 responses were 45.3% and 39.4% in the pelabresib and ruxolitinib and placebo arms, respectively. Additionally, there were dual SVR35 and TSS50 responses in 36% of patients on pelabresib and ruxolitinib compared with 19% on placebo and ruxolitinib.2
"We see continued benefit and superiority in spleen volume response at 48 weeks and durable symptom improvement without any new concerning treatment emergent toxicities," said Mascarenhas. "The imbalance of patient developing accelerated and blast phase disease initially noted in the first 24 weeks has not expanded and remains static now. The overall benefit of the addition of pelabresib in terms of clinical benefit and toxicity remains favorable and the longer outcome measure of OS will continue to be followed."
The researchers observed small improvements in hemoglobin from 24 to week 48, reporting an increase from 10.7% to 12.6% in the combination group compared with 6% to 6.9% in the placebo group. Higher rates of BMF improvement of ≥1 grade continued to week 48 in patients receiving pelabresib and ruxolitinib.2,3
The findings highlight the promising potential of pelabresib in addressing the various complications associated with MF, expanding therapeutic options for patients. With deeper, more sustained responses, there is renewed hope for mitigating disease progression in patients with JAKi-naïve MF.
REFERENCES
1. Phase 3 study of pelabresib (cpi-0610) in myelofibrosis (mf) (manifest-2) (manifest-2). ClinicalTrials.gov Identifier: NCT04603495. Updated May 8, 2024. Accessed October 4, 2024. https://clinicaltrials.gov/study/NCT04603495?a=37
2. Mascarenhas J, Grosicki S, Chraniuk D, et al. 3178 updated results from the phase 3 manifest-2 study of pelabresib in combination with ruxolitinib for janus kinase inhibitor–naïve patients with myelofibrosis. Presented at: 66th ASH Annual Meeting and Exposition. December 8, 2024. San Diego, CA. Abstract 3178.
3. Patients with anemia and myelofibrosis have worse survival outcomes when treated with ruxolitinib. Pharmacy Times. December 2, 2024. Accessed December 4, 2024. https://www.pharmacytimes.com/view/real-world-analysis-shows-anemia-worsens-survival-in-myelofibrosis
4. Pelabresib and ruxolitinib show benefit in treating patients with jak inhibitor-naïve myelofibrosis. Pharmacy Times. October 5, 2024. Accessed December 4, 2024. https://www.pharmacytimes.com/view/pelabresib-and-ruxolitinib-show-benefit-in-treating-patients-with-jak-inhibitor-na-ve-myelofibrosis
Related Videos
Related Content
