Myelofibrosis is a blood cancer – belonging to a group of diseases called myeloproliferative neoplasms – caused by genetic abnormalities in bone marrow stem cells. As per DelveInsight’s estimate, there were around 19,400 prevalent cases of myelofibrosis in the US. 

Pelabresib is an investigational oral small-molecule drug designed to inhibit BET-mediated gene transcription involved in the pathogenesis of myelofibrosis. Preclinical data suggest that combining pelabresib with therapies targeting overlapping pathways, such as JAK/STAT, may enhance responses by inhibiting the molecular drivers of myelofibrosis. The Phase III MANIFEST-2 trial was initiated based on compelling data from Arm 3 of the ongoing Phase II MANIFEST study (NCT02158858), which evaluates the combination of pelabresib and ruxolitinib in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis.

MANIFEST-2 (NCT04603495) is a global, double-blind, Phase III clinical trial that randomized JAK inhibitor-naïve adult patients with myelofibrosis in a 1:1 ratio to receive either pelabresib in combination with ruxolitinib or placebo plus ruxolitinib. The primary endpoint of the study is a 35% or greater reduction in spleen volume (SVR35) from baseline at 24 weeks. Key secondary endpoints include the absolute change in total symptom score (TSS) from baseline at 24 weeks and the proportion of patients achieving a 50% or greater improvement in total symptom score (TSS50) from baseline at 24 weeks.

At the ASH 2023 conference, MorphoSys shared the top-line data from MANIFEST-2. Although the study met its primary endpoint, with the pelabresib/ruxolitinib combination nearly doubling the spleen volume reduction (SVR35) response rate at 24 weeks (66% versus 35% for the ruxolitinib plus placebo arm), it failed to meet the secondary endpoint of reducing symptoms of myelofibrosis, undermining MorphoSys's claims.

The updated data from the Phase III MANIFEST-2 study (NCT04603495) presented at the 2024 ASCO Annual Meeting demonstrated that combining pelabresib (CPI-0610) with JAKAFI led to a significant and lasting reduction in splenomegaly. There was also a trend toward reduced tumor symptom score (TSS) from baseline, as well as improvements in anemia and bone marrow fibrosis at week 24 compared to treatment with ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis.

Among all responders who achieved SVR35 response, the proportion who lost response at any point was lower in the pelabresib/ruxolitinib arm (13.4%) compared to the ruxolitinib-alone arm (27.8%). When considering the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Importantly, the SVR35 response was consistently higher with the combination therapy across all predefined subgroups and hematologic subgroups.

There was a strong trend for a numerical decrease in absolute change in TSS from baseline at week 24 with the doublet compared to the monotherapy, with a mean difference of -1.94 points. A higher proportion of patients who received the combination achieved a 50% reduction in TSS (TSS50) compared to those on ruxolitinib alone (52.3% vs. 46.3%), although this difference was not statistically significant. The doublet also resulted in a two-fold increase in patients achieving both SVR35 and TSS50 responses compared to ruxolitinib alone (40.2% vs. 18.5%).

Additional updated data showed a numerically higher proportion of patients experiencing a hemoglobin response with the combination therapy compared to the monotherapy. Regarding hallmarks of the disease, bone marrow fibrosis improved in 38.3% of patients in the pelabresib/ruxolitinib arm versus 25.3% in the ruxolitinib-alone arm, while it worsened in 17.0% and 27.7% of patients, respectively. Furthermore, there was a significantly greater reduction in proinflammatory cytokine levels at week 24 from baseline with the doublet compared to the monotherapy.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 96.7% of patients in the doublet arm and 96.7% in the monotherapy arm, with grade 3 or higher effects observed in 49.1% and 57.0% of patients, respectively. Serious adverse events (AEs) were reported in 29.7% and 29.4% of patients, respectively.

On February 5, 2024, MorphoSys announced Novartis's intention to submit a voluntary public takeover offer for all outstanding MorphoSys shares, valuing the company at EUR 2.7 billion. This acquisition will grant Novartis access to MorphoSys's extensive oncology pipeline, including pelabresib. The proposed acquisition is expected to close in the first half of 2024, with plans to submit a New Drug Application for pelabresib in combination with ruxolitinib to the US FDA and a Marketing Authorization Application to the EMA in the second half of 2024.

KOL insights

“The combination of pelabresib and ruxolitinib showed significantly reduced splenomegaly, a trend toward improved symptom score, and improvements in multiple measures of anemia and the bone marrow microenvironment compared with placebo plus ruxolitinib, impacting the four hallmarks of myelofibrosis” – Expert Opinion.

“As such, these results support a potential paradigm shift in the treatment of patients with MF”–Expert Opinion.

Conclusion

Pelabresib, a first-in-class oral inhibitor of BET proteins, is a potentially game-changing treatment option for myelofibrosis; it was well-tolerated when combined with ruxolitinib and in the Phase III MANIFEST-2 study in patients who had not yet taken a JAK inhibitor. 

It's worth noting that Novartis owns JAKAFI. The success of pelabresib in the MANIFEST-2 study could strengthen Novartis' position in the field of cancer treatment and provide new momentum to its research efforts. This suggests that the partnership between Novartis and MorphoSys, the developer of pelabresib, is likely to be mutually beneficial and could lead to further advancements in cancer therapy.