Two Phase III studies of Novartis drug INC424 published in NEJM show significant clinical benefit for patients with myelofibrosis

The New England Journal of Medicine (NEJM) today published the results of the two Phase III trials that found treatment with the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) significantly reduced disease burden in patients with myelofibrosis[1],[2]. The results of COMFORT-I and COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) were first presented at the 47th American Society of Clinical Oncology (ASCO) annual meeting in June 2011.

Myelofibrosis is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, such as fatigue, night sweats and intractable pruritus (itching), poor quality of life and weight loss, as well as shortened survival[3].

“Patients living with this malignant disease have a poor quality of life and experience multiple debilitating symptoms,” said Claire Harrison, MD, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, lead investigator for the COMFORT-II study. “Results from these trials are significant because they demonstrate the potential INC424 has to impact the manifestation of the disease and become a new standard of care for many patients with myelofibrosis.”

In the COMFORT-II trial, INC424 produced a volumetric spleen size reduction of 35% or greater (roughly equivalent to a reduction in palpable spleen size by 50%) in 28% of patients compared to 0% of patients in the best available therapy (BAT) group at 48 weeks (p<0.001). At week 24, 32% of patients treated with INC424 demonstrated a 35% or greater volumetric spleen size reduction compared to 0% of patients treated with the BAT (p<0.001) for the key secondary endpoint[1]. Additionally, INC424 was associated with improvements in myelofibrosis symptoms at each evaluation as compared to the BAT[1].

Continuous INC424 therapy also provided a marked and durable improvement in overall quality of life measures, functioning and symptoms, including appetite loss, dyspnea (shortness of breath), fatigue, insomnia and pain, at week 48, compared to a worsening of symptoms in BAT-treated patients[1]. INC424 showed modest toxicity as compared with the BAT, with increased frequency of anemia and thrombocytopenia. The most frequently reported serious adverse event (SAE) was anemia for both groups (INC424, 5%; BAT, 4%). Pneumonia was the only SAE reported in >=5% of patients in either group (INC424, 1%; BAT, 5%). These findings are consistent with previous investigation of INC424[4].

The COMFORT-I trial, conducted by Incyte Corporation, demonstrated that 41.9% of INC424 treated patients achieved at least a 35% reduction in spleen volume at 24 weeks from baseline compared to 0.7% of patients in the placebo group (p<0.0001). Additionally, an early analysis of COMFORT-I data shows INC424 treatment resulted in an overall survival benefit as compared to placebo (hazard ratio=0.50 [95% confidence interval: 0.25, 0.98]). For patients taking INC424, the most frequently reported grade 3 or higher adverse events were hematologic. Only one patient in each group discontinued for thrombocytopenia and for anemia, respectively. The most common non-hematologic adverse events of any grade reported for patients receiving INC424 or placebo respectively were fatigue (25% vs 34%), diarrhea (23% vs 21%), peripheral edema (19% vs 22%) and ecchymosis (19% vs 9%)[2].

“The COMFORT data provided the basis for worldwide regulatory filings and we expect to hear from the regulatory authorities beginning in the second half of 2012,” said Hervé Hoppenot, President, Novartis Oncology. “We are getting closer to achieving our goal of bringing innovative, pathway-based compounds to patients with myelofibrosis.”

Novartis and Incyte Corporation have a worldwide collaboration and license agreement for INC424. Incyte received US Food and Drug Administration (FDA) approval for INC424 in November 2011 under the name Jakafi(TM) for the treatment of patients with intermediate or high-risk myelofibrosis. INC424 will be marketed by Incyte in the US.

COMFORT-II trial details

COMFORT-II is a randomized, open-label, Phase III trial of INC424 versus the BAT that enrolled 219 patients with primary myelofibrosis (MF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 56 study locations. Two-thirds of the patients enrolled received INC424 (starting dose 15 or 20 mg twice daily) and one-third received the investigator-selected BAT[1].

The primary endpoint for COMFORT-II was the proportion of patients achieving a reduction in spleen volume of 35% or more from baseline at week 48 as measured by MRI (or CT scan in applicable patients). Patients continue to receive INC424 therapy beyond week 48 to determine longer-term outcomes of efficacy and safety[1]. The study was not powered to detect a statistically significant effect on overall survival.

COMFORT-II was conducted by Novartis in Europe.

COMFORT-I trial details

COMFORT-I is the first Phase III trial of INC424 and is a randomized, double-blind, placebo-controlled trial that enrolled 309 patients with primary MF, PPV-MF or PET-MF, conducted by Incyte in 89 study locations. Half of the patients enrolled received INC424 (starting dose 15 or 20 mg twice daily) and half received placebo. The primary endpoint was the proportion of patients achieving a reduction in spleen volume of 35% or more from baseline at week 24 as measured by MRI (or CT scan in applicable patients)[2].

COMFORT-I was conducted by Incyte in the US, Canada and Australia.

About Myelofibrosis

In the EU, the disease affects about 0.75 out of every 100,000 people annually[5],[6]. Myelofibrosis has a poor prognosis and limited treatment options[3],[4].

Studies show that within 10 years of diagnosis, up to approximately 20% of myelofibrosis patients progress to fatal secondary acute myelogenous leukemia, which is virtually untreatable[7],[8]. Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality[9]. The five-year survival rate after transplantation is approximately 30%[9].

About INC424

INC424 is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases[4]. As part of the Novartis clinical development program, INC424 is being investigated in primary MF as well as PPV-MF and PET-MF. INC424 is also being investigated in clinical trials for the treatment of polycythemia vera (PV)[10].

Novartis licensed INC424 from Incyte for development and potential commercialization outside the US. Incyte has retained rights for the development and potential commercialization of INC424 in the US. Both the European Commission (EC) and the US FDA granted INC424 orphan drug status for myelofibrosis.

References

1. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. New Eng J Med. 2012: March 1;366:787-98.
2. Verstovsek S, Mesa RA, Gotlib J, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. New Eng J Med. 2012: March 1;366:799-807.
3. Mesa RA, Schwagera S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.
4. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 & JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010 September 16;363:1117-1127.
5. Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica. 2009; 94(6):865-869.
6. McNally RJQ, Rowland D, Roman E, Cartwright RA. Age and sex distributions of hematological malignancies in the U.K. Hematol Oncol. 1997;15:173-189.
7. Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemia. Cancer Res. 2010;70(2):447-452.
8. Beer PA, Green AR. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.
9. Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514-1522.
10. National Institutes of Health. Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: The RESPONSE Trial. Available at http://www.clinicaltrials.gov/ct2/show/NCT01243944?term=ruxolitinib&rank=14. Accessed January 31, 2012.