Novartis perseveres with pelabresib

Novartis hasn’t given up on its MorphoSys-originated BET inhibitor pelabresib, but it needs to carry out another phase 3 study before filing in the US – and details of that trial have just been listed on clinicaltrials.gov.

Pelabresib remains high profile, given that Novartis paid €2.7bn for MorphoSys in early 2024 but still hasn’t managed to file it with regulators, something that was supposed to happen that year. Manifest-3, set to start in April, looks similar to the earlier Manifest-2 pivotal study in enrolling JAK inhibitor-naive myelofibrosis patients, and testing pelabresib plus Novartis/Incyte’s JAK inhibitor Jakafi, versus Jakafi.

More severe

But with Manifest-3 Novartis appears to be targeting more severe patients, based on baseline total symptom score (TSS). Patients are required to have an average TSS of ≥15 within seven days before randomisation, versus ≥10 in Manifest-2.

And the new trial will have co-primary endpoints of ≥35% spleen volume reduction (SVR35) and absolute change in TSS, both at week 24, and both cut by baseline TSS.

Manifest-2 primarily evaluated SVR35 at 24 weeks in all comers, but although it met this endpoint it disappointed on the key secondary endpoint of ≥50% TSS reduction. Novartis might hope for a better result here by homing in on the more serious end of the myelofibrosis spectrum.

More worryingly, Manifest-2 also found an imbalance in “leukaemia transformation” events – progression from myelofibrosis to acute myeloid leukaemia – with the combo versus Jakafi monotherapy. Novartis’s chief executive, Vas Narasimhan, noted in October 2024 that this issue had to be “fully resolved” before filing could take place, as the company abandoned plans to seek approval based on 48-week data, itself a delay from original plans. 

At the time Narasimhan mooted the possibility of further trials – something that’s now come to pass.

EU vs US

In the EU, however, Novartis believes that 96-week data from Manifest-2 will be enough to support a submission, according to the company's JP Morgan presentation, which disclosed the need for a new phase 3 trial in the US, as well as in China and Japan.

The company reported long-term results at ASH, showing that in the intent-to-treat population 45% of patients receiving pelabresib/Jakafi achieved SVR35 at 96 weeks, versus 30% of the control group.

On the key issue of leukaemic transformation the presenter, Memorial Sloan Kettering’s Dr Raajit Rampal, noted that the rates between the two arms were “essentially similar”, at 5.1% with the combo and 3.7% with Jakafi.

He added that cases of leukaemic transformation in the pelabresib/Jakafi arm had “remained stable” since week 48, but had increased in the Jakafi cohort.

When asked whether the data would be enough for regulatory filings, he replied that this was above his pay grade, but concluded: “I’d hope this would be sufficient to allow regulators to see this is benefiting patients.”

It seems that the FDA isn’t yet convinced, and is notably taking a stricter stance than the EMA.

Pelabresib phase 3 trials in myelofibrosis

Notes: *over 7-day period prior to randomisation; SVR35=≥35% spleen volume reduction; TSS=total symptom score. Source: OncologyPipeline & clinicaltrials.gov.