John Mascarenhas, MD: The emerging agents in myelofibrosis I think can be broken down into other JAK [Janus kinase] inhibitors like fedratinib, momelotinib, pacritinib, and then non-JAK inhibitors such as imetelstat, which is an infusional drug that has likely direct stem cell activity. PRM-151, which is a pentraxin-2 analog, is a drug that affects the microenvironment and is an antifibrotic agent. And then there are a number of early stage or early phase tested drugs like LCL161, which is a SMAC [second mitrochondrial-derived activator of caspases] mimetic. It induces and upregulates apoptosis, or program cell death, in the myelofibrosis cells. So there are a number of different drugs that are being evaluated at early phases, and I would say probably in late phase development that is most pertinent to the clinician in practice, it’s probably the JAK2 inhibitors, fedratinib and pacritinib.
The JAKARTA-2 trial was a study evaluating fedratinib, which is a very potent JAK2 selective inhibitor. It also has anti-FLT3 [anti—fms-like tyrosine kinase 3] activity and is a BRD4 [bromodomain-containing protein 4] inhibitor in patients who have been previously treated with ruxolitinib, and these patients had enlarged spleens and a significant symptom burden. And this drug was given as an oral drug and was very successful in reducing spleens particularly in this patient population. To a lesser degree symptom burden. But the spleen response probably was the most impressive part about the JAKARTA-2 study. I think the overall spleen response was something like 55%, and it was still successful whether you looked at patients who were ruxolitinib failure in the sense of loss of response, or resistance to the drug, or even progression of disease or intolerance. So across the board it was an effective drug in reducing splenomegaly in patients who’ve previously seen ruxolitinib.
In the absence of a comparative study, what we know is fedratinib is a myelosuppressive agent. It is associated with a certain degree of myelosuppression, anemia, and thrombocytopenia, much like ruxolitinib is. There’s a certain degree of gastrointestinal complications that can be seen with fedratinib because it’s a FLT3 inhibitor. But those are easy to manage and they’re usually low grade and early on in the treatment…. And it’s a drug that’s garnered some concern because of reports of Wernicke encephalopathy. In fact led to a full clinical study hold that was eventually lifted by the FDA upon further review of a handful of cases that occurred out of many patients that were treated.
I think if you look at the analysis very carefully, it’s not quite clear the exact relationship between Wernicke encephalopathy, which is typically from thiamine deficiency, and fedratinib. And it may be something that going forward will require a black box warning, or even supplementation with thiamine if the drug eventually enters the clinic again.
In theory a selective JAK2 inhibitor could potentially be more clone-directed. In actuality, the irony in it is for a long time ruxolitinib was considered a JAK2 inhibitor. But when it really was thought out more, and more investigation was performed, there was a realization that inhibiting JAK1 actually probably has an ameliorating benefit in terms of symptom response too. In fact, there’s a selective JAK1 inhibitor called itacitinib that’s been tested in a phase II study that shows excellent symptom response, modest spleen response, and overall lack of myelosuppression that you see with a JAK2 inhibitor. So you know it’s not quite clear to me that a selected JAK2 inhibitor is necessarily better than a JAK1/2 inhibitor. It’s simply a different compound and has pros and cons.
Right now there’s a general unmet need in the treatment of myelofibrosis. So, for example, patients with low platelets are not amenable, and this is 50,000 or less, to ruxolitinib therapy due to the FDA label. I think that would be an excellent position for a drug like pacritinib, which in the PERSIST-2 study was shown to be an effective drug in this low platelet population, which is an unmet need. In patients with significant splenomegaly upfront, or even second line after ruxolitinib, I think fedratinib would be a reasonable option to give, because it’s demonstrated such significant spleen reduction.
And then there’s a third drug, momelotinib, which is also a selective JAK1/2 inhibitor, which has been shown to be less likely to induce anemia and more likely to improve anemia, which is not what we typically see with ruxolitinib. I think in patients with significant red blood cell transfusion dependence, either upfront or second-line to ruxolitinib, that would be an option to consider. So I do think that there’s a niche for multiple agents that could be filled here.