Category Archives: myelofibrosis

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.

Targeted kinase inhibition in inflammation & oncology: lots of gambling, and some winners

We’ve had a lot of news in the last 6 weeks from ACR, ASH and the release of clinical trial results. Here’s what we’ve learned in, and some thoughts on what might come next:
1) Rigel and partner AstraZeneca threw craps in the RA game. Syk inhibition is less effective than Jak inhibition in Rheumatoid arthritis (RA), per ACR presentations on Jak inhibitor tofacintinib and clinical trial data released on Syk inhibitor fostamatinib. Whether the difference in efficacy is due to suboptimal dosing of the Syk inhibitor fosta’nib, or reflects distinct biological readouts is a critical question, particularly as fosta’nib has off-target activity on Jak1 and other relevant kinases. It is interesting that Pfizer’s tofacitinib, widely viewed as a pan-Jak inhibitor with potential toxicity issues, has scored approval in DMARD-IR patients, and can therefore be prescribed before biologic therapy.  I’ll admit I did not see this coming and felt tofa’nib would get approval, to start, in TNF-IR patients only. AZN is clearly running the clinical trials needed to show a clean safety profile for fosta’nib, but may now lose out in the marketplace on the basis of efficacy. It remains to be seen how this will play out as Rheumatologists weigh the safety/efficacy profiles of these drugs, but clearly in a “treat to target” regimen, where the target is no clinical sign of disease and no advance in joint degradation, fosta’nib has a tough road ahead. They may yet persevere but it will take a combination of squeaky-clean safety data and a clear demonstration of protection from joint damage. The compound is also moving forward in B cell malignancies (see below).

            We will not learn anytime soon if better Syk inhibitors would be better RA drugs, as Biogen Idec may have lost its bet on Portola’s Syk inhibitor. Biogen has quietly withdrawn its phase 2 clinical trial for PRT062607, aka BIIB057 (clintrials.gov). The withdrawal occurred prior to the recent data coming out on fosta’nib and seems more likely to be related to the specific compound than to the pathway. Looking more widely at drug development in this space, the only other clinical stage compound is the inhaled Syk inhibitor R343, for asthma and other lung diseases, currently in phase 2 and unlikely to provide any insight into the systemic inhibition of the pathway in RA. We may have to wait for clinical readouts in RA following inhibition of Btk – this is the next kinase downstream of Syk – before we understand the utility of targeting this pathway. More on Btk to follow.
2) Jak inhibitors: does three of a kind equal two pair? There are actually four Jak kinases: Jaks 1,2,3 and Tyk2. People used to spend a lot of time discussing the specificity of different Jak inhibitors and the toxicity/efficacy expectations of targeting Jak3 vs Jak2 vs Jak1. The reality is that all Jaks are obligate hybridizers: distinct Jaks hybridize to transduce signals from cell surface receptors. It is very likely that different Jak specificities matter less than we think and that the current crop of Jak inhibitors are more alike than they are different, off target specificity aside. That being said, the Jak inhibitors appear to be poised to reap hefty winnings, in wildly distinct diseases. Novartis’ and Incyte’s ruxolitinib (Jakafitm),first-in-class “Jak2-selective” inhibitor, was approved for use in myelofibrosis in early 2011 and in 2012 is already poised to take in $100MM in sales as patients move onto this drug earlier in the treatment paradigm. The therapeutic rationale of Jak inhibitor use was well understood from genetic analysis of myelofibrosis, and the commercial and clinical validation is now clear, prompting Gilead to recently pay ~$400MM to buy the phase 1 Jak1/2 inhibitor CYT387 along with the rest of YM Biosciences. Other Jak2-selective inhibitors in development include the Sanofi Aventis compound SAR302503, currently in phase 2, and the Cell Therapeutics compound pacritinib. While myelofibrosis is the clear POC arena for these compounds, look for companies to begin moving these into new therapeutic areas as the compounds advance.

 3) Jaks are wild in RA. I’ve already mentioned the success of Pfizer’s pan-Jak inhibitor tofacitinib (brand name Xeljanztm), recently approved for use in RA patients who have an inadequate response to DMARDs such as methotrexate. Other Jak inhibitors being developed to compete in the inflammation area include the Jak1-specific inhibitor GLPG0634 from Galapagos, licensed in early 2012 by Abbott (now AbbVie), who paid $150MM upfront for rights to the Phase 1 compound. It should be noted that GLPG0634 does appear to have a different side effect profile than the other Jak inhibitors, in that no impact on lipid levels were seen, nor signs of anemia and neutropenia. These side effects have been seen in clinical trials of ruxolitinib and with tofa’nib and are generally ascribed to Jak2 inhibition. Given the promiscuous nature of Jak heterodimerization this differentiation remains somewhat surprising. Indeed, Cell Therapeutics, who is developing S*BIO’s Jak2-inhibitor pacritinib in myelofibrosis, claims not to see anemia or thrombocytopenia (another class side effect) in the clinic. Finally, Vertex has moved its Jak3-selective inhibitor VX-509 into phase 2b following decent results in a phase 2a RA trial. No matter how you look at it, the data suggest that hitting any combination of Jaks, or just one if we believe the Galapagos selectivity data, is sufficient for efficacy in RA. This is almost certainly due to the prevalence of heterodimerization, as mentioned, but also due to the sheer number of pathogenic pathways impacted by Jak inhibition, including numerous cytokine and growth factor pathways. Despite the risk of side effects from such broad blunting of the immune system, this approach so far appears to be more efficacious, and at least as safe, as inhibition of Syk. On the basis of efficacy in RA, one might be tempted to move Jak inhibitors into stubborn and complex diseases like systemic lupus erythematosis. That’s another bet altogether but I’ll be looking for those investigator trials!

4) PCI’s Btk inhibitor shows its hand. The recent American Society of Hematology (ASH) meeting was a showcase for Pharmacyclics’ (PCI) and JNJ’s Btk inhibitor ibrutinib, aka ib’nib. This Btk inhibitor produced remarkable efficacy in several B cell lymphomas, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and Mantle Cell Lymphoma, the latter being generally viewed as a very intractable disease. The data have been reviewed in detail elsewhere (e.g. fiercebiotech story), but clearly ib’nib has validated Btk inhibition as a therapy with broad application in B lymphoma oncology. The field is still young, with the next closest drug in development Avila’s AVL-292, who reported phase 1b data at ASH. AVL-292 demonstrated efficacy in Non-Hodgkin’s Lymphoma (NHL), CLL, multiple myeloma (MM) and other indications. Avila was acquired by Celgene earlier this year, further highlighting the interest in Btk inhibition in oncology. Ib’nib and AVL-292 covalently bind to the kinase domain of Btk, forming an irreversible bond that prevents substrate from accessing the active site of the enzyme. Historically, covalent inhibition has been associated with off-target toxicity, as it is possible for the drug to link irreversibly to unwanted targets. Happily, this does not appear to be an issue with this new class of covalent inhibitors, and toxicity is generally considered mild. Regardless, non-covalent inhibitors are being developed by several companies, perhaps with the goal of differentiating from the leading compounds. The CGI compound GDC-0834, now held by Genentech, in a non-covalent active site inhibitor under development for inflammatory disease, as is the Roche compound RN486.  Given the current status of the Syk inhibitor fosta’nib in RA, it will be interesting to see if these companies stay the course, or move their inhibitors onto new disease targets. It was the success of Syk inhibition in early RA and B cell lymphoma trials that stirred interest in Btk, and the field will respond accordingly to any new Syk inhibitor data.

This is a lot of information to absorb, but it stimulates the obvious question: What’s next? Here are just a couple of thoughts:

- What is considered safe and efficacious today will change tomorrow. As combination therapy takes hold in B cell oncology, additive toxicity may become problematic. If we consider the obvious combination of a Btk inhibitor with other kinase inhibition, or with biologic therapy, the safety/efficacy profile of these compounds will evolve. This is even more true in RA, where toxicity will drive physicians away from drugs.

- Escape is possible (or inevitable). As has already been described in myelofibrosis, patients needing chronic therapy may select for drug resistance. In myelofibrosis, such resistance is associated with the recruitment of other Jaks to take over for Jak2. Having a well-stocked armory may allow continued control over the disease, even as signaling pathways shift – in the context of B cell lymphomas this may mean Syk inhibitors, Btk inhibitors, PI3K inhibitors, mTOR inhibitors, in succession or in tolerable combination therapies.

- In RA the success of tofa’nib heralds a new wave of oral medications that can challenge biologic therapies, in particular the anti-TNF biologics. This is no surprise, and it will be of considerable interest to watch how clinical practice evolves. I’m hoping that diligence is being applied to the collection of samples for analysis of response and non-response in patients receiving the new, targeted orals as it will be fascinating to understand why some patients fail while some succeed – something not yet adequately understood in RA.

- Finally its important to remember that “success” in RA still means that most patients fail to reach ACR 50 and ACR 70 scores, suggesting that they are continuing to experience disease despite treatment. Until these numbers come up, perhaps in the context of personalized medicine, we cannot declare that the work in RA is done. We note in passing that there are a plethora of diseases that could benefit from these new kinase inhibitors, and expect to see their use tested more widely.