With limited treatments available, the discovery of mutations in Janus kinase 2 (JAK 2) in 2005 was a major step forward for scientists in search of new therapies for myeloproliferative neoplasms (MPNs).
With limited treatments available, the discovery of mutations in Janus kinase 2 (JAK2) in 2005 was a major step forward for scientists in search of new therapies for myeloproliferative neoplasms (MPNs).
MPNs are a group of related disorders in which blood cells grow abnormally in the bone marrow, with the 3 main types being polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). PV and ET are characterized by excessive production of blood elements (red blood cells and platelets, respectively), whereas MF is characterized by scarring (fibrosis) and insufficient production of blood in the bone marrow and concurrent production and storage of blood elements in the spleen and liver, with consequential enlargement of the spleen. Patients with PV and ET have a propensity for abnormal blood clots, and may progress to MF or acute myeloid leukemia; the clinical burden of MF is a consequence of the enlarged spleen (abdominal pain, feeling full without eating), low blood counts (anemia), or systemic symptoms (night sweats, weight loss, itching, fatigue), as well as symptoms associated with massive spleen enlargement (abdominal pain, inability to eat full meals, bone pain). These symptoms have a profound impact on the patient’s quality of life, and disease progression is ultimately associated with increased mortality.
Despite the divergent clinical spectrum, all 3 MPNs are characterized molecularly by dysregulated activation of the JAK2 signaling pathway. This occurs most commonly as a function of an activating mutation in the JAK2 kinase itself, which is present in a varying portion of patients with MF (65%), PV (96%) and ET (55%). Activated JAK2 represents a therapeutic target, and indeed the benefit of inhibiting JAK2 has been translated from the ability to impact disease models of MF in mice to improving symptoms and reversing spleen enlargement in patients.
Sanofi is developing a novel, selective, once-daily, oral JAK2 inhibitor (SAR302503) for these 3 diseases, with a phase 3 trial in MF nearing completion. Rapidly progressing from phase 1 to phase 3, early clinical trials demonstrated that the compound is active in MF patients with both wild type and mutated JAK2. New data from a phase 2 study on Sanofi’s JAK2 inhibitor (SAR302503) presented in December 2012 at the American Society of Hematology Annual Meeting in Atlanta, showed that study patients treated with the compound had reversed spleen size and improved disease symptoms. Thirty-one patients were randomly assigned to 3 different once-daily doses (300 mg, 400 mg, and 500 mg), with the following results:
The results demonstrated a correlation between dose and exposure, the ability to inhibit the JAK2 pathway in blood cells from patients, and the likelihood of achieving a reversal of spleen enlargement. They also confirmed a pharmacological profile that is consistent with a once-daily oral dosing, and provide further support for the choice of doses (400 mg and 500 mg) of the Sanofi JAK2 inhibitor used in the pivotal phase 3 JAKARTA trial. Moshe Talpaz, MD, of the University of Michigan who was the lead investigator of the phase 2 study, called the phase 2 results “encouraging.” He also stated, “There are existing treatment gaps for patients with these debilitating blood disorders, and specifically targeting the JAK2 enzyme appears to offer a promising approach.”
PHASE 3 STUDY
The phase 3 JAKARTA study, which completed enrollment in 9 months, will evaluate the efficacy and safety of 400-mg and 500-mg doses of SAR302503 versus placebo in reducing spleen size and improving MF symptoms. “There are few treatments available, so people living with these terrible diseases need new and effective options, especially those that target the underlying disease process,” notes MPN Research Foundation Chairman and PV patient, Robert Rosen. JAKARTA will explore the potential of the Sanofi JAK2 inhibitor to reduce or reverse bone marrow fibrosis-a critical gap in MF treatment and an effect that has not yet been demonstrated with any JAK inhibitor-and results are expected by mid-2013.