FDA grants fast track designation to PRM-151 for myelofibrosis

Harry S. Jacob, MD, FRCPath(Hon)

About 30 years ago, a fellow in our division, Phil McGlave — who rose to be head of the division of hematology/oncology/transplantation at the University of Minnesota — published an intriguing case report that continues to beguile (McGlave PB. Br J Haematol. 1982;52:189-194). A myeloproliferative patient with severe myelofibrosis and osteosclerosis received an allogeneic marrow transplant that, with time, was associated with complete obliteration of the original dense reticulin fibrosis in the recipient’s subsequent marrow biopsies.
The accompanying article provides insights into this and other similar reports. That a macrophage-differentiating protein, Pentraxin-2 (also known as serum amyloid P) clears fibrosis in marrow — and evidently in pulmonary fibrotic syndromes, as well — suggests that transplanted macrophages may be responsible for the “McGlave phenomenon,” especially if they are appropriately stimulated by endogenous pentraxins.
Moreover, one might postulate that idiopathic myelofibrosis — at least in some cases — results from incompetent, mutated macrophages or from inefficient pentraxin-induced differentiation of normal macrophages. This suggestion can be examined and hopefully will be in the future.

Michael J. Mauro, MD

The FDA provided fast-track designation for Promedior’s compound PRM-151, in development for myelofibrosis (primary and post-essential thrombocythemia/post-polycythemia vera) and other diseases such as pulmonary fibrosis. Acting as an agonist and differentiating factor in monocytes/macrophages, PRM-151 has demonstrated preclinical antifibrotic activity in a variety of disease models and is in clinical trials for myelofibrosis. This unique mechanism of action may be particularly suited for this disease and, building on the success of initial targeted therapy (JAK inhibition), a high interest level and optimism are in order.
Early data from a phase 2 trial with PRM-151 in myelofibrosis — either with or without the JAK inhibitor ruxolitinib (Jakafi, Incyte) — revealed tolerability and safety, as well as broad activity, including regression of marrow fibrosis, improvement in cytopenias, reduction in spleen size and improvement in symptom scores (Verstovsek S. J Clin Oncol. 2014;32:5s.). Results are early and longer follow-up data are needed to answer important questions regarding the depth, duration and consequence of an anti-fibrotic effect in treated patients, including the potential to more definitively improve altered hematopoiesis and blood counts, which is somewhat lacking with the use of JAK inhibitor therapy, as well as complementing the symptom improvement, reduction in organomegaly and apparent survival improvements noted with JAK inhibitor therapy. Of interest, as well, would be potential correlation with reduction in clonal burden in the case of JAK2 (V617F) and other observed molecular drivers in myeloproliferative neoplasms.
Given the broad effects myeloproliferative diseases have on patients, we continue our quest for more comprehensive and more definitive therapy or combinations of therapy. PRM-151 may prove worthy in this venture and bears close watch.