Upcoming Therapies for Use in MPN


Rami Komrokji, MD:We do also have a couple of other JAK2 inhibitors in development that hopefully are close or can get approved for our patients: pacritinib and momelotinib. Can you also comment a little on those and where the studies are at with those 2 drugs?

Prithviraj Bose, MD:Sure. Pacritinib is a drug that is a JAK2 selective inhibitor, and you were instrumental in its development. This is a drug that also inhibits FLT-3 and thereby causes some nausea, vomiting, and diarrhea. It does not inhibit JAK1. This was looked at in 2 phase III trials, PERSIST-1 and PERSIST-2. PERSIST-1 compared it with the best available therapy in JAK-naïve patients, and the best available therapy arm did not include a JAK inhibitor such as ruxolitinib. So this trial was a positive trial. The primary end point was spleen volume reduction, and pacritinib beat the best available therapy. It was around 19% versus 5%.

The more relevant trial, you might feel, was the PERSIST-2 trial, another phase III trial looking at 2 dosages of pacritinib. It was either 200 mg twice a day or 400 mg once a day, compared again with the best available therapy. But here the best available therapy could contain or could include ruxolitinib, and it did in 45% of patients. Also, these patients could have had prior ruxolitinib. That percentage again was about 45%. They also had to be thrombocytopenic, so platelets less than 100 mm3. This was a much more, you might say, targeted population in a way. So prior RUX [ruxolitinib] was allowed, RUX [ruxolitinib] could be the comparator, as well as low platelets.

Here the results were interesting. When they pooled all the pacritinib results and compared it with the best available therapy, pacritinib was superior for spleen but not for symptoms. However, when they pulled out the patients who got the 200 mg twice daily, it was superior for both spleen and symptoms. But the drug had some concerns with regard to excessive mortality from bleeding and cardiovascular events, and the company then were asked to do another trial to find out the best dosage. And we’re going to hear about that trial soon. That is called the PAC203 study, in which there were 3 dosing arms—100 mg a day, 100 mg twice a day, and 200 mg twice a day—to see what the best dose is.

Because this is a nonmyelosuppressive drug, the niche in which it has been looked at or will be looked at in the new PACIFICA trial is in patients with platelets less than 50 mm3who have no approved options right now. And there it’s going to be compared with the best available therapy, which can include low-dose ruxolitinib, which is very commendable. This could fill an important unmet need for our patients with very low platelets.

Momelotinib is the other drug you mentioned, and that continues to get very interesting and it’s 1 we hope will get approved. This is a JAK1/JAK2 inhibitor like ruxolitinib, and it was studied in 2 phase III trials, SIMPLIFY-1 and SIMPLIFY-2. SIMPLIFY-1 was a head-to-head versus RUX [ruxolitinib], and this was a noninferiority study in which the momelotinib was noninferior for spleen but not for symptoms. The way the statistics were designed, this would not lead to approval because the 2 were tied together. In SIMPLIFY-2 it was compared with the best available therapy in patients who had received prior ruxolitinib and best available therapy could include ruxolitinib. What happened was that the best available therapy ended up being ruxolitinib in 88% of patients, so it sort of became a momelotinib-versus-ruxolitinib trial.

The primary end point was not met, which was superiority for spleen response. That was not met, which meant that all the other end points could not be statistically analyzed because it had a hierarchical design. The other end point actually favored momelotinib in things like symptoms and anemia end points. But because of the statistical design, that could not get it approved. Now this drug has been resurrected by a different company and will be studied in the MOMENTUM trial, in which it will be compared with danazol. It’s a 2:1 randomization with 180 patients. These are patients who have had prior ruxolitinib, and the primary end point here is symptoms. A key secondary end point is anemia as well as spleen. This is a trial we’re all looking forward to.

Rami Komrokji, MD:Absolutely. Maybe in the future, in a year or 2, would it be fair to say that we will still have ruxolitinib as the main up-front treatment for patients with adequate counts? For those with severe thrombocytopenia, maybe pacritinib will be the choice. Then in second-line failure we’ll have the fedratinib and maybe the momelotinib for patients with anemia. Would that be your vision of how we’re going to use those 4 JAK2 inhibitors?

Prithviraj Bose, MD:I think that’s a very fair assessment, and this is exactly where the companies are going for the most part with these drugs, as far as the pivotal trials. As you mentioned, we have pacritinib for low platelets and momelotinib with the advantage of improving anemia, which it does through inhibiting the activin receptor. So yes, I think that’s a very fair assessment of how things might evolve.

Transcript edited for clarity.

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