ASH MEETING MPN REPORT December 2014 By John Crispino

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1 ASH MEETING MPN REPORT December 2014 By John Crispino Attending the ASH meeting this year was an exercise in multitasking and endurance. MPN research and reporting continued to stand out as one of the major focuses in the hematological science community. We counted at least 45 posters reporting MPN research results in all corners of our world. Additionally oral presentations filled up much of the time in the presentation rooms. Your MPNRF representatives met separately with bio tech and pharma companies to track the progress of new treatments in the pipeline. We left exhausted trying to assimilate everything that was presented. More importantly, the feeling of intense research activity in our area leaves a strong takeaway of significant progress. The most exciting news came just before the meeting with the announcement of FDA approval of Jakafi for polycythemia vera patients. There were promising reports on the anti-fibrotic PRM 151 and the telomerase inhibitor Imetelstat. Generally, there were no major breakthroughs that are likely to affect patient lives in the immediate future. But looking not too far down the road things are likely to change. This report will focus on four areas from the ASH presentations: JAK inhibitor Clinical Updates New Mechanisms of Action, clinical updates Combination studies Notable Basic Science Reports

2 JAK INHIBITOR CLINCAL STUDY UPDATES There were several notable clinical advances presented at the meeting, primary related to myelofibrosis. These included the following: 1- Update on pacritinib (CTI Biopharma/ Baxter) and its mechanism of action Pacritinib is a JAK2 and FLT3 kinase inhibitor that has shown significant clinical activity in phase 2 studies of patients with PMF. What makes this JAK inhibitor unique is that it does not cause myelosuppression. Pacritinib reduced spleen size and symptoms, but did not decrease the platelet count or hemoglobin levels. Thus, it may be suitable for patients with low platelet counts. A poster presented by Dr. Singer reported on the company s efforts to better understand the mechanism of action. The results suggest that the unique activity may be due to the drugs lack of inhibition of JAK1, its inhibition of a different kinase named IRAK1, or both. The drug is now in phase 3 development. 2- Update on momelotinib (Gilead) Momelotinib is a JAK1 and JAK2 inhibitor that demonstrated improvement in anemia and splenomegaly in a phase 1/2 clinical trial. This ability of momelotinib to improve anemia in PMF patients clearly distinguishes it from the other JAK inhibitors. Another distinguishing feature is the observation that drug treatment is associated with the development of neuropathy. In a poster presentation, Dr. Tefferi reported that 44% of patients, in survey of 100 patients at the Mayo Clinic, developed neuropathy and that drug discontinuation did not alleviate this side effect during the time of follow-up. However, the neuropathy was not progressive. Therefore, going forward, it will be important to weigh the good (anemia response) with the bad (potential of neuropathy). The ongoing phase 3 trial will provide important insights into the benefits of this JAK inhibitor in PMF. 3- Update on NS-018 (NS Pharma) Dr. Verstovsek presented a poster that reported data from a Phase 1/2 study of the JAK inhibitor NS-018 in PMF. The majority of patients achieved a reduction in the spleen volume, with 50% of having a decrease in spleen size of 50%. The phase 2 portion of the study, which will help determine whether this drug has any features that will distinguish it from ruxolitinib, is underway. 4- Data from a phase 2 trial of a JAK1 inhibitor (INCB039110; Incyte) in PMF In addition to JAK2 inhibitors, Incyte has developed small molecules that target other JAK family members such as JAK1. Given the role of this kinase in inflammatory processes and a lower dependence on JAK1 in red blood cells and platelets, it has been predicted that JAK1 inhibitors will lead to clinical responses without the myelosuppression seen with ruxolitinib. Dr. Mascarenhas presented data from the Phase 2 study of INCB in primary myelofibrosis. The therapy was relatively well tolerated and led to modest response in spleen size and symptom improvements.

3 NEW MECHANISMS OF ACTION, CLINICAL UPDATES 1- Update on the clinical study of imetelstat (Geron) in PMF Dr. Tefferi provided an update on the pilot study data for imetelstat for patients with primary myelofibrosis. Of 33 patients, 4 reached a complete remission, 3 a partial response, and several others showed clinical improvement in such areas as splenomegaly, and/or peripheral counts. In addition to resolution of blood counts and reduction in spleen size, the complete responders displayed reduced bone marrow fibrosis as well as a molecular response. Of note, data presented by Dr. Baerlocher demonstrated that imetelstat therapy was also associated with substantial decreases in CALR mutant allele burden in patients with essential thrombocythemia. With respect to side effects, the drug is associated with myelosuppression, and the noted hepatic toxicity has been shown to be reversible with cessation or lessening of therapy. Geron plans to open a Phase 2 of imetelstat in primary myelofibrosis in mid Geron recently announced the formation of a strategic partnership with the Janssen to facilitate development of the drug. 2- Update on the phase 1 study of PRM151 (Promedior) in PMF PRM151 (pentraxin 2) is a naturally occurring protein that reduces the formation of scar tissues and prevents or reverses fibrosis. Dr. Verstovsek reported that pentraxin 2 levels are significantly reduced in patients with higher grade fibrosis and hypothesizes that this reduction possibly contributes to the development of this phenotype. Data from the stage 1 of the Phase 2 study revealed that PRM151 is a safe drug with no grade 3 or grade 4 toxicities. In addition, the overall response rate was 35%. Moreover, it was found that several patients showed improved bone marrow histology and reduced fibrosis. There were also modest improvements in spleen size, symptoms and peripheral counts. Given the potential of this compound as an anti-fibrotic agent, Promedior is moving ahead with the stage 2 study in COMBINATION STUDIES In addition to these novel, single agent trials, there were several reports of clinical studies that combined ruxolitinib with an investigational drug targeting a different pathway. Three of these studies, which were presented in an oral session on the MPNs, described combination of a hedgehog inhibitor, a PI3 kinase inhibitor, and an HDAC inhibitor. 1- Hedgehog proteins mediate cell signaling and promote growth, especially of cancer cells. They are also suspected of cooperating with activated JAK/STAT signaling in the MPNs. Pre-clinical studies that combine a hedgehog inhibitor with a JAK inhibitor in a mouse model of the disease have provided strong rationale for a clinical study. Dr. Gupta presented data from a phase 1b

4 trial of the combination of a hedgehog inhibitor (sonidegib) and ruxolitinib in patients with myelofibrosis. Results show that the combination led to a reduction in spleen size and that the drugs were generally well tolerated. 2- In addition to STATs, MPN mutations that enhance JAK signaling activate the PI3 kinase pathway. This observation suggests that targeting the two pathways may lead to a stronger antitumor effect. Dr. Gisslinger presented data from the HARMONY Phase 1b study of the combination of a PI3K inhibitor (buparlisib) with ruxolitinib. A spleen response was seen in over 70% of patients that had not had prior exposure to a JAK inhibitor. In addition, a modest decrease in the allele burden was observed. Side effects included the expected anemia and thrombocytopenia. A future phase 2 trial will shed light on the efficacy of this combination in PMF. 3- HDACs are cellular proteins that modify other proteins to alter their functions. Relevant to the MPNs, HDAC inhibition has been shown to affect the interaction of JAK2 with a stabilizing protein named HSP90, leading to impaired activity. Pre-clinical studies have provided compelling data to support combining a HDAC inhibitor with a JAK inhibitor. In his presentation, Dr. Kiladjian discussed results from a phase 1b trial of the pan HDAC inhibitor panobinostat in combination with ruxolitinib. The drug combination included a spleen response that was similar to that seen in clinical trials of ruxolitinib. Side effects of the combination include GI and hematologic toxicities. NOTABLE BASIC SCIENCE REPORTS 1- Calreticulin (CALR) mouse model Mutations in CALR are seen in the majority of ET and PMF patients who lack mutations in JAK2 or MPL. Although Dr. Robert Kralovics, with the support of the MPN Research Foundation, demonstrated that mutant variants of CALR enhance JAK/STAT signaling, the way that these proteins cause the MPNs remains unclear. At this year s ASH meeting, Dr. Marty, working with colleagues including Dr. Villeval, whose research is supported by the MPN Research Foundation, described the development of a CALR animal model. Mice that express mutant CALR variants developed an ET-like disease with elevated platelet counts. Moreover, mice that express the type 1 CALR mutant showed progression to reduced platelet counts, anemia and splenomegaly suggesting evolution to myelofibrosis. This model will be extremely use in determining how calreticulin mutations contribute to the disease and may also elucidate novel pathways for therapeutic intervention. 2- Preclinical data on novel JAK2 specific type II inhibitor NVP-CHZ868 To date, all JAK inhibitors in development fall within the so called Type I family. Recently, a new compound named NVP-CHZ868 was identified as a type II JAK inhibitor. This class of inhibitors binds to the kinase in a manner that is distinct from the first generation drugs and thus is postulated to have different effect on JAK activity. In this presentation, Dr. Meyer, working with Dr. Levine performed pre-clinical experiments to assess the activity of NVP-CHZ868. They found that the drug is very potent both in cultured cells and in animal models: treatment of either the Mpl or Jak2 mutant mice led to near complete resolution of the disease with significant reductions in splenomegaly, bone marrow fibrosis and the mutant allele burden. The drug was also active against JAK2 mutant cells that developed a form of resistance to ruxolitinib, suggesting that it may provide an important therapeutic advance. The next step will be to perform a clinical trial in patients.

5 3- Preclinical studies to evaluate the anti-mpn activity of a thrombopoietin (TPO) antagonist Based on reports, which show that the TPO, the cytokine that binds MPL and activates JAK/STAT signaling, is required for myelofibrosis, Drs. Wang and colleagues, with support of the MPN Research Foundation, studied the effect of an inhibitor of TPO signaling on primary human MPN cells in culture and in an animal model. They discovered that the compound reduced growth and induced cell death of MPN cells, and that it also interfered with the ability of MPN stem cells to engraft in recipient mice. These results indicate that this drug can target the leukemia stem cell population and may provide a novel therapeutic strategy for myelofibrosis PROGNOSTIC SCORING SYSTEMS Two talks addressed the need to expand the current prognostic scoring system for the primary myelofibrosis to incorporate cytogenetic and/or molecular data. First, Dr. Vannucchi and colleagues proposed a new scoring system named MIPSS, which incorporates the status (i.e. wild-type versus mutant) of several MPN-associated genes including ASXL1 and SRSF2. This method appears to be better at predicting survival than the IPSS (International prognostic scoring system). Second, Dr. Tefferi and colleagues proposed a model named GPSS, which would include not only molecular data, but also cytogenetic data. This genetics based prognostic scoring system also appears to be an advance over the IPPS model. Given the rapid advances in defining the genetics of the MPNs, the time is ripe to refine the scoring system. These revised protocols may be practice-changing in that they would aid physicians and patients in determining the best course of therapy. SUMMARY In summary, the 2014 ASH meeting provided important updates to novel therapies and biologic studies in the MPNs. There have been rapid advances in moving combination studies form the laboratory to the clinic. Moreover, every new biologic discovery brings us closer to designing new and more potent therapies. Finally, it should be noted that the meeting included six full sessions dedicated to the MPNs and that all of these sessions were well attended. Thus, there continues to be strong interest in the MPNs among scientists, clinicians and industry. In the coming year, watch for a number of phase 2 and phase 3 studies of novel agents for treatment of myelofibrosis.