ASH13 SnapShots, part 6, Myelofibrosis: How Many Jak Inhibitors Are There?

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)

Part 6a. Myelofibrosis: Therapeutic agents in Phase 2/3.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

I’m splitting this into 2 parts because, well, lets just say there is always a lot to learn. Myelofibrosis is a proliferative cancer of myeloid lineage cells, characterized by bone marrow infiltration and fibrosis, splenomegaly and heptomegaly caused by extramedullary hematopoiesis, and overall disruption of hematopoiesis leading to cytopenic conditions such as anemia and thrombocytopenia. Patients experience diverse symptoms, which has led to the development of patient symptom scoring systems. They are at risk for transformation to acute myeloid leukemia, and in general have greatly reduced overall survival due to chronic anemia leading to bone marrow failure.

Myelofibrosis (MF) is one of a class of myeloproliferative neoplasms (MPN) that also includes Polycythemia Vera (PV) and Essential Thrombocytopenia (ET). In 2005 it was found that nearly all PV cases and about half of MF and ET cases had a mutation in Jak2 (V617F). This marked the beginning of novel drug development for MPN that culminated with the 2011 approval of ruxolitinib (Jakafi) for the treatment of intermediate risk (intermediate-2) or high risk MF. Ruxolitinib is a Jak1/Jak2-selective inhibitor.

The clinical landscape for MF remains dominated by Jak inhibitors, and to go through them is an exercise in duration. Lets spare you all that, and try to summarize quickly, hitting high and low points when they appear. At the outset its fair to make a few generalizations. First, Jak inhibitors are not curative and do not induce PRs or CRs in the way we have discussed in earlier sections. Second, Jak inhibitors themselves can cause cytopenias, and they are therefore dose or duration limited. So, this becomes a balancing act between efficacy (by inhibition of myeloid-lineage cell proliferation) and toxicity (due to inhibition of hematopoiesis). 

Lets sort these by clinical stage.

Sanofi is presenting results from a phase 3 trial of fedratinib, a Jak2-selective inhibitor (Abstract #393). In this trial of patients with high risk or primary (i.e. active) MF the primary endpoints are splenomegaly and patient reported symptoms. Patients have to present with platelet counts above 50 x 10^9/L. 67% of the patients were positive for the V617F Jak2 mutation. 40% of evaluable patients reached the spleen response rate of > 35% reduction in spleen volume as measured by MRI or CT. About the same percent recorded improvement in platelet counts and about 30% of patients reported improved symptoms. This is very much like the ruxolitinib results, as are the AEs reported, which include diarrhea, anemia, higher risk for infection, among others.

UPDATE: via FierceBiotech “A few days ago the pharma giant had to shutter a program for fedratinib after the FDA ordered a clinical halt when their myelofibrosis patients developed Wernicke’s encephalopathy–a neurological condition spurred by biochemical brain lesions.”

Well, thats the end of that drug (another abstract below, just to be thorough). This tox issue is clearly not a class effect, that is, not a Jak inhibitor issue. Instead this drug either hits another signaling or other protein target (that might be interesting). Alternatively, and perhaps more likely, this is compound specific toxicity. Either way, the fact that this tox issue was missed until now (phase 3) is remarkable.

Sanofi also has results (Abstract #661) from a phase 2 trial of fedratinib in MPN patients who were previously on ruxolitinib (so these are ruxolitinib resistant or intolerant). These patients presented with splenomegaly, as evidence of disease activity, and had to have platelet counts above 50 x 10^9/L. The presentation is of results obtained at the 12 week interim cutoff point. Somewhat remarkably (to me anyway) the spleen response rate (defined above) was about 40%. The patient reported outcome was modest, but measurable. This suggests that moving from one Jak inhibitor to another is not as silly as it might sound (we’ve seen this before: anti-TNFs in RA; IFN betas in MS). The downside was the toxicity: 26% of patients discontinued due to AEs that included some grade 3/4 (severe) diarrhea, and a very high rate of anemia and thrombocytopenia. It will be important to track patient outcomes and AEs going forward in this trial.

Incyte will report on a Jak1-selective inhibitor INCB039110 that is in an open-label MF Phase 2 trial (Abstract #663). The primary endpoint in this trial is patient reported symptom score (TSS). Inclusion/exclusion criteria were similar to what is described above. While there was a dose dependent improvement in TSS, there was only a modest improvement in the more objective endpoint of change in spleen volume. Importantly however, Hb level (a measure of RBC count) and platelet counts were preserved. This suggests that Jak1 inhibition might be useful, assuming that there is reasonable efficacy.

Just to remind us how confusing this all can be, Cell Therapeutics will present results obtained in a Phase 2 trial of its Jak2.Flt3 dual inhibitor, pacritinib (Abstract # 395). This trial enrolled patients with primary or secondary MF and included patients whose platelet counts were below 100,000/microliter. This low number is prognostic for transformation to a leukemic state and further, patients with such low counts were specifically excluded from the ruxolitinib registration trials (COMFORT III). 82% of patients had the Jak2 V617F mutation. So, Cell Therapeutics is trying to differentiate pacritinib here, and they are successful. Approximately 40% of patients achieved > 35% reduction in spleen volume. Most patients maintained stable platelet numbers if Hb levels. Notable also were the modest AEs reported. This is an interesting therapeutic to watch.

Next we’ll look at some earlier therapeutics, including novel (i.e. non-Jak targeting) therapies, coming up in part 6b.

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