All JAKed Up and No Place to Go: A Critical Evaluation of the Role of JAK2 Inhibitors

JAK therapies and their origins were recently discussed in an educational session at the 17th Annual International congress on Hematologic Malignancies on February 15-17, 2013, in NYC.

Myeloproliferative disorders (MPD) have long been treated with non-specific agents to minimize symptoms. Splenomegaly in myelofibrosis (MF) can lead to severe pain; anemia and other cytopenias as a result of polycythemia vera (PV) can increase risk of infection and bring about fatigue, pruritis, night sweats, and bone pain; and the high abnormal platelet levels associated with essential thrombocythemia (ET) can increase bleeding risk in patients. Patients may lose weight and have below-normal cholesterol levels as a result of poor appetite in MPD. These disorders may leave patients with a poor quality of life;, therefore, proper control of disease and symptoms is a goal of treatment.

The discovery of a mutation in the protein Janus kinase 2 (JAK2) has led to further drug development for myelofibrosis, polycythemia vera, and essential thrombocytopenia. Novel JAK2 inhibitors were designed to target the cells with specific JAK2V617F mutations througha sophisticated mechanism of action that spares healthy, normal cells. Decreased splenomegaly and related pain, potential splenic infarction, exacerbation of low blood counts, and other symptoms have been reported with the use of these therapies. The first JAK2 inhibitor for myeloproliferative disorders—ruxolitinib—was approved by the FDA in 2011.

Treatment options for myelofibrosis include watchful waiting, bone marrow transplant, and pharmacotherapies including JAK2 inhibitors. The best available pharmacotherapy for MF prior to introduction of JAK2 inhibitors was historically focused on symptomatic relief. Androgens, erythropoietin, and thalidomide was used for anemia; hydroxyurea, busulfan and 2-CDA or medical interventions such as splenectomy or radiation was used to treat splenomegaly; and lenalidomide could also be given for anemia and spleen dysfunction.

Phase III trials COMFORT I and COMFORT II assessed the first JAK2 inhibitor (ruxolitinib) against placebo and against best available therapy, respectively. In COMFORT I, 41.9% of patients taking ruxolitinib saw a nearly 35% reduction in spleen volume, compared with 0.7% of placebo patients, many of whom experienced an increase in spleen volume. COMFORT II demonstrated similar results, with 28% of patients taking ruxolitinib achieved a nearly 35% reduction in spleen volume, compared with 0% of patients in the best available therapy group. Based on symptom response scores,researchers also concluded that quality of life and symptoms such as fatigue, insomnia, appetite loss, and dyspnea improved with ruxolitinib. Ruxolitinib patients from the COMFORT I trial also demonstrated a favorable survival profile.

Additional agents are being continuously added to the pipeline since the emergence of ruxolitinib. One investigational JAK2 inhibitor undergoing Phase I clinical trials with sanofi-aventis, SAR302503, resulted in a dose dependent increase in spleen response. YM Biosciences Inc is investigating another agent, CYT387, which is implicated in blood transfusion independence. When given either once or twice daily, this agent elicits favorable transfusion independence rates between 57% and 75%. Another highly selective JAK2 inhibitor, pacritinib, from Cell Therapeutics Inc, has shown to significantly reduce splenomegaly in MF patients and has been associated with fewer blood count-related adverse effects. Although the JAK2 inhibitors don’t have a curative function in MF, they have improved the quality of life for many patients and display a favorable survival profile..

PV and ET are two related disorders linked to poor quality of life. Patients are prone to thrombosis and therefore classic management of these conditions includes a regimen of low-dose aspirin and aggressive CVD risk control. Various additional treatments are used to decrease risk of phlebotomy, enlarged spleen, and other severe symptoms in PV. There were no major breakthroughs in treatment until ruxolitinib in demonstrated phlebotomy-free disease in 74% of patients for nearly 144 weeks in Phase II studies of PV. Ruxoiltinib use resulted in normalization of white blood cell and platelet counts and improved pruritis, night sweats, and bone pain within 4 weeks of treatment initiation. In a 2010 study, patients underwent significant abnormal platelet count reduction of nearly 50% from baseline after 21 months of treatment with JAK2 inhibitors. The efficacy and safety of JAK2 inhibitors to treat PV and ET will be studies in future trials. Until then, research on the mechanistic pathways involved with these disorders may shed light on development of new drug moieties.

Adverse effects are always a concern with new pharmacologic agents, and minimizing toxicity is a priority. In general, JAK2 inhibitors may cause anemia, diarrhea, nausea, decreased platelets, increased lipase, headache, dizziness, and other neuropathies. Clinical trials suggest that hematologic toxicity is more common with ruxolitinib and SAR302503, which may influence their uptake. Pacritinib and CYT387 are associated with fewer adverse effects and could potentially become preferred agents, barring any future issues regarding their safety and efficacy. Initiation of an agent should be personalized, and clinicians must weigh the risks of toxicity with the benefits of treatment before selecting an agent.

The introduction of targeted therapies in oncology could lead to the discovery of valuable new treatments. Ongoing clinical trials in 2013 with MF patients include several new agents from various pharmaceutical companies and combination regimens with ruxolitinib and a variety of adjuncts. Selected clinical trials in PV and ET patients with JAK2 inhibitors and pegylated interferon are also expected in 2013. Curative pharmacologic treatments have not been discovered, but sophisticated drug development has led to a wave of potential new therapies.

References

1. Vertovsek S. Therapeutic potential of JAK2 inhibitors. ASH Education Book. Jan 1 2009;2009(1):636-642