JAK2 inhibitor for myelofibrosis: Q&A with Sanofi

Sanofi is testing a new drug for myelofibrosis and is presenting details of a phase II study at the American Society of Hematology's annual meeting this week. I asked Tal Zaks, M.D., Ph.D., VP, Oncology Clinical Development, Sanofi Oncology to provide further insights regarding myelofibrosis and the company's JAK2 inhibitor, code-named SAR302503.In this interview (conducted by email) Dr. Zaks describes the disease, existing treatment strategies and treatment gaps. He also comments on the delicate topics of head-to-head comparisons with ruxolitinib (a competing JAK2 inhibitor) and affordability.1. How many people are affected?Myelofibrosis (MF) is a rare, debilitating and life-threatening progressive malignant blood disease characterized by abnormal blood cell production and fibrosis (scarring) within the bone marrow.  Scarring in the bone marrow interferes with blood cell production; the spleen and liver try to produce and store extra blood cells which can cause these organs to become enlarged.Most patients with MF have greatly enlarged spleens that can result in a range of symptoms with dramatic impact on quality of life.  These include fatigue, abdominal pain, night sweats, feeling full without eating, cough or shortness of breath and decreased physical activity.  Other signs and symptoms of MF include anemia, thrombocytopenia, weight loss and severe itching.Primary MF is one of the three main types of slow growing malignant hematologic diseases called myeloproliferative neoplasms that cause blood cells to grow abnormally in the bone marrow.  The other two are polycythemia vera (PV) and essential thrombocythemia (ET) and can precede the development of secondary myelofibrosis. PV and ET are characterized by too much production of red blood cells and platelets, whereas in MF there is not enough blood being produced by the bone marrow. All three types are characterized by genetic mutations in the JAK2 enzyme leading to abnormally activated JAK2 signaling in the cells that produce blood components.The exact prevalence of MF, PV and ET is not known. The latest research, presented at the 2012 American Society of Hematology Annual Meeting, estimates that the prevalence of MF ranges from 4.2 to 5.6 per 100,000 people in the U.S., or approximately 15,000 patients, suggesting that the prevalence is higher than has been reported to date. Prevalence estimates in Europe are less clear.2. What are the existing treatment strategies?There is an unmet need for new MF treatments.  Most available therapies are palliative, providing some relief of symptoms, but do not impact the underlying disease. The primary goal of the treatment is to control symptoms, including low blood counts and the size of the spleen. Treatment may involve blood transfusions, radiation and chemotherapy, recombinant erythropoietin to help stimulate red blood cell production, and spleen removal. Bone marrow transplants are the only treatment that can cure MF, but have significant risks.3.  What are the treatment gaps that Sanofi's development-stage JAK2 inhibitor is meant to address?Currently, there are limited treatment options for patients with MF.  Most available therapies are used to manage symptoms, and none have been shown to reduce or reverse the underlying disease.   Many patients do not respond to currently available therapies, and even among those who initially respond, many discontinue treatment due to intolerance or resistance.SAR302503 is a selective JAK2 inhibitor  that has shown activity in patients with myelofibrosis from the initial phase I study. New Phase II data presented at the 2012 American Society of Hematology Annual Meeting help define the relationship between the dose ofSAR302503, its ability to inhibit molecular signaling of JAK2 in the blood of the patients, and its ability to ameliorate the spleen size and alleviate symptoms.  These data also confirm a very good pharmacological profile that allows once-a-day dosing. The pivotal Phase III study, JAKARTA, is currently underway; enrollment of 289 patients has been completed and results are expected in the second quarter of 2013.4. What is the best-case expectation for the drug and how many patients will it be relevant for?Sanofi does not publicly speculate about potential sales.  There remains a substantial unmet need for effective and safe treatments for people with primary and secondary MF.  We believe SAR302503 may provide a benefit for patients with these difficult-to-treat diseases.5. Does Sanofi intend to compare this new drug head-to-head with Ruxolitinib? If so, when? If not, how will doctors and patients be able to decide which one to use?The Phase III pivotal study has been designed with similar endpoints to those that led to the approval of ruxolitinib and will be able to clearly demonstrate the safety and efficacy of SAR302503. There are no plans for a head-to-head trial at this time; however, a Phase II trial is underway evaluating SAR302503 in patients who were previously treated with ruxolitinib but who either could no longer tolerate ruxolitinib or are resistant to it, although results won’t be available for a few years.6. Hematology is a fairly small specialty in terms of number of physicians and patients, yet it seems to be attracting a lot of interest lately from pharma companies and from Wall Street in particular.  Why is that?Hematology is an area where we believe we can bring a substantial benefit to patients. Unlike other cancers, there is a close correlation between the clonal origin of the cancer cell, the molecular aberration unique to the cancer, and the clinical sequelae of the disease.  For example, hyperactivation of JAK2 in blood progenitor cells that produce red blood cells and platelets is associated with conditions of both marrow overproduction (MF and ET) and underproduction of these blood components, with the expected clinical outcomes (i.e., excessive tendency to clots in the former and excessive tendency to fatigue and bleeding in the latter). Consequently, the ability to therapeutically inhibit JAK2 signaling in the appropriate disease and patient population enables more rational and rapid drug development. This is exemplified by the development of SAR302503, which has progressed quite rapidly from Phase I to Phase III.This correlation is not unique to JAK2; as can be seen from our hematology pipeline, Sanofi is developing a broad range of treatments for various hematologic malignancies including myelofibrosis (MF), acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukemia (ALL).7. This product seems like it has the potential to be helpful to patients, but also a drug that would need to be used for a long period of time and that would be expensive. What are your thoughts about the affordability of this kind of therapy in an era of health reform in the US and economic challenges in Europe?Myeloproliferative neoplasms are chronic, progressive diseases and thus require long-term treatment.  New research to be presented by Wang et al., at this year’s ASH annual meeting shows that MF is associated with a significant burden of illness, incurring about five times the health care expenditures than similarly matched patients without MF.  MF patients had higher overall comorbidities (mean CCI of 2.1 vs. 0.9), were hospitalized more often (34% vs. 11%), had higher number of average hospital days (7 vs. 1 day), and had more outpatient office visits (58 vs. 22).MF-associated medical resource utilization and the corresponding expenditures for those services are substantive.  Today, treatment for MF is largely palliative using a variety of medicines and other medical interventions.   New and more effective treatments, especially those that may modify the course of the disease, have the potential to significantly reduce the burden of illness associated with MF.One of our top priorities at Sanofi is to provide rapid and broad access to our medicines by demonstrating their value to both patients and payors; consequently, we integrate direct input from payors into our clinical development plans. Once a drug is approved and launched, Sanofi has programs to provide assistance to patients having difficulty accessing their medications.  These include a comprehensive patient access program called Patient Connection, which provides product-support services for indigent and functionally uninsured patients for future dates of service, reimbursement-support services to practice managers, a Drug Replacement Program (DRP) for insured patients who have been denied coverage and alternative services to assist patients and caregivers.