The Difference Between Pacritinib and Other JAK Inhibitors for Myelofibrosis

John Mascarenhas, MD, professor of medicine at 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, discusses the mechanism of action of pacritinib (Vonjo) and how it differs from ruxolitinib (Jakafi) and fedratinib (Inrebic).

On February 28, 2022, the FDA granted approval to pacritinib for the treatment of patients with myelofibrosis and severe thrombocytopenia, defined as a platelet count less than 50x109/L, based on positive results from 3 clinical trials.

According to Mascarenhas, pacritinib targets the JAK/STAT pathway differently than the 2 other FDA-approved JAK inhibitors.

Transcription:

0:07 | So, ruxolitinib is a JAK1/2 inhibitor and fedratinib is a selective JAK2 inhibitor. Pacritinib is a JAK2 selective inhibitor that also inhibits IRAK1, and it is likely that some of these non-JAK receptor kinase inhibition aspects of these drugs likely provide differences both in tolerability and safety but also in efficacy and have the potential to address niches.

0:41 | So, in this case, as a JAK2/IRAK1 inhibitor that down regulates the IL-1 toll like receptor mitogenome NF-κB axis, it also reduces inflammatory cytokines through a nonJAK2-dependent pathway can complement JAK2 inhibition. And it may be for this reason that one can deliver pacritinib at 2 mg twice daily to patients, particularly with thrombocytopenia, that are the hallmark of the cytopenic myelofibrosis patient, and for the spleen and symptoms which we really can't achieve with drugs like ruxolitinib.