Study summary

Adding pelabresib to ruxolitinib nearly doubled the share of people whose spleen shrank substantially

MANIFEST-2 trial · 430 people, phase 3 · Published March 2025, Nature Medicine

What was tested

Pelabresib, a pill that blocks BET proteins driving inflammation and scarring in the marrow, added to ruxolitinib, against ruxolitinib plus placebo, as first JAK-inhibitor treatment for myelofibrosis.

What they found

• 65.9% had their spleen shrink by at least 35% at 24 weeks vs 35.2%.
• Symptom improvement was slightly better but not statistically significant (52.3% vs 46.3%).
• Anemia was less common and less severe with the combination.

What it means

The first add-on to a JAK inhibitor to show a large spleen benefit, with signs it may affect the marrow disease itself. Novartis is now running a second phase 3.