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Over the past decade, combination therapies, which pair two or more therapies simultaneously, have become increasingly prevalent for the treatment of cancer. This approach has been shown to improve efficacy and potentially reduce drug resistance over monotherapy alone. As a result of its promise, in 2020 researchers were conducting approximately 5,000 clinical trials of novel combination therapies for cancer worldwide.

Combination therapy presents an exciting opportunity to advance the standard of care for myelofibrosis, a debilitating blood cancer, as the only approved treatments are monotherapies. This has left patients with significant needs, as none of the available monotherapies address all four hallmarks of the disease: enlarged spleen, anemia, bone marrow fibrosis, and disease-associated symptoms. Physicians, eager to reduce the disease burden for patients, have hailed combination therapy as “the way of the future” in myelofibrosis treatment.

“Many myelofibrosis patients experience a compromised quality of life and share with us symptoms such as severe fatigue, night sweats, bone pain, and fever – symptoms that can leave them bedridden for days and unable to participate in daily activities or stay employed. Promising efforts to develop new therapies that may address symptoms and allow patients to engage in their everyday lives bring hope to the myelofibrosis community. For patients, options matter.”

Kapila Viges, Chief Executive Officer, MPN (Myeloproliferative Neoplasms) Research Foundation

In late 2023, results from the Phase 3 MANIFEST-2 study of our investigational bromodomain and extra-terminal (BET) inhibitor in combination with the current standard of myelofibrosis care, a Janus kinase (JAK) inhibitor, brought us one step closer to making this future a potential reality.

Addressing All Four Hallmarks of Myelofibrosis with BET/JAK Inhibitor Combination Therapy

JAK inhibitor monotherapy has been the standard of care for myelofibrosis since the first drug of this class was approved in 2011. However, JAK activity is not the sole contributor to myelofibrosis, and JAK inhibition is only effective for roughly half of patients.

Further, increased levels of pro-inflammatory cytokines have been associated with all four hallmarks of myelofibrosis. Our BET inhibitor may reduce the expression of these cytokines.

Comprehensive results from our Phase 3 MANIFEST-2 study, investigating the targeted combination of BET inhibition and JAK inhibition as a potential first-line myelofibrosis therapy, were presented at the 2023 ASH Annual Meeting in December. The findings were met with great enthusiasm by the myelofibrosis community. Compared to JAK inhibitor monotherapy, the combination therapy:

• Significantly reduced spleen size, with nearly double the number of patients achieving a ≥35 % reduction
• Showed a strong positive trend in reducing symptom burden
• Improved measures of anemia, including higher hemoglobin response rates, fewer patients requiring transfusions, and fewer anemia adverse events
• Improved bone marrow fibrosis grade and reduced average plasma levels of pro-inflammatory cytokines (IL-8, IL-6, TNF-α, and NF-κB-regulated cytokines)

The combination therapy demonstrated safety results in line with assessments from prior clinical trials. Additionally, pelabresib plus ruxolitinib was associated with fewer grade ≥3 adverse events compared with placebo plus ruxolitinib.

“The MANIFEST-2 results are very exciting and well received by our field, showing a clear difference over this past 12-year period with the combination therapy.”

Ruben A. Mesa, M.D., FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center

The MANIFEST-2 results point towards a potential paradigm shift for the treatment of myelofibrosis – from monotherapy to combination therapy – and we are thrilled about the potential to offer more hope for patients with this debilitating disease.