myelofibrosis

Jakafi: First and only FDA-approved agent for myelofibrosis.

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Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis—collectively known as myelofibrosis diseases.1

Identifying intermediate or high-risk myelofibrosis2-4

In order for a patient to be classified as having intermediate or high-risk myelofibrosis, he or she must have 1 or more of the following characteristics:

  • Age >65 years
  • Presence of constitutional symptoms
  • Hemoglobin <10 g/dL
  • White blood cell count >25 × 109/L
  • Blood blasts ≥1%
  • Platelet counts <100 × 109/L
  • Unfavorable karyotype*
  • Red cell transfusion dependence

Jakafi significantly reduces spleen volume and improves symptoms of myelofibrosis

In both phase III studies, a significantly higher proportion of patients receiving Jakafi achieved a ≥35% reduction in spleen volume vs those receiving placebo or best available therapy.1 Learn more about splenomegaly efficacy.

  • Superior reductions in spleen volume vs placebo1,5
    • 41.9% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at Week 24 vs 0.7% of patients receiving placebo (P < 0.0001)1,5
  • Superior reductions in spleen volume vs best available therapy1,6
    • 28.5% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at 48 weeks vs 0% of patients receiving best available therapy (P < 0.0001)1,6

Significantly more patients receiving Jakafi achieved a ≥50% improvement in symptoms vs those receiving placebo.1,5 Learn more about symptoms efficacy.

  • Superior improvements in symptoms vs placebo1,5
    • 45.9% of patients receiving Jakafi achieved a ≥50% improvement in Total Symptom Score (TSS)† vs 5.3% of patients receiving placebo (P < 0.0001) at Week 241,5

Responses were seen in patients regardless of JAK2V617F mutational status.5

  • Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo5
  • Patients with myelofibrosis have dysregulated Janus kinase (JAK) signaling, regardless of the presence or absence of the JAK2V617F mutation7

Safety profile of Jakafi

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Serious bacterial, mycobacterial, fungal and viral infections may occur. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache.

Similar and low discontinuation rates were observed in both the Jakafi and placebo arms (11% and 10.6%, respectively).1

Dosing for Jakafi based on platelet counts1

Starting dose for Jakafi is based on platelet counts. Dosing should be modified based on

  • Patient response
  • The presence of thrombocytopenia
  • Organ impairment
  • Concomitant administration of CYP3A4 inhibitors
  • Anemia and neutropenia

*Unfavorable karyotype: complex karyotype or sole or two abnormalities that include +8, –7/7q-, i(17q), –5/5q-, 12p-, inv(3), or 11q23 rearrangement.

†At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1

Important Safety Information

  • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
  • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary
  • Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi
  • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery
  • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache
  • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment
  • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate
  • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy
  • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Source: http://www.jakafi.com

Two-year data show new Novartis drug Jakavi® significantly reduced myelofibrosis disease burden and suggest overall survival advantage.

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  • Jakavi demonstrated rapid reductions in spleen size and improved quality of life in Phase III studies, with results sustained over two years

 

  • COMFORT-II follow-up results show Jakavi may improve overall survival vs. best available therapy

 

  • MF is a life-threatening blood cancer associated with progressive, debilitating symptoms that severely impact quality of life and reduce overall survival

 

  • Until recently, treatment options have been very limited – Jakavi is now approved in the EU and Canada with additional worldwide regulatory filings underway 

 

Novartis today announced long-term follow-up data from the COMFORT-I and COMFORT-II Phase III studies in myelofibrosis. In these studies, Jakavi® (INC424, ruxolitinib) treatment resulted in sustained reductions in spleen size, a hallmark of myelofibrosis, while also improving quality of life and extending overall survival compared to placebo or the best available therapy (BAT).

 

Results are being presented at the 54th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta.

 

A two-year follow-up analysis of COMFORT-II showed Jakavi was associated with sustained reductions in splenomegaly (enlarged spleen). Overall, 48.3% of patients treated with Jakavi achieved a >=35% reduction in spleen volume, and the majority of reductions were sustained with continued treatment over two years. In a rigorous intent-to-treat analysis, Jakavi-treated patients showed an overall survival advantage compared to patients receiving BAT (HR=0.51; 95% CI, 0.26-0.99; p=0.041)[1], which was defined by protocol as any commercially available agent (monotherapy or in combination) or no therapy at all. A total of 61.6% of BAT patients switched to Jakavi treatment, but remained categorized as BAT patients during the follow-up analyses[1].

 

“As these Phase III studies continue over the long term, it is encouraging to see how treatment with Jakavi consistently alleviates the myelofibrosis disease burden and may improve overall survival,” said Dr. Francisco Cervantes, Hematology Department, Hospital Clínic, IDIBAPS, University of Barcelona. “Just one year ago, we didn’t have a truly effective treatment to offer our patients with myelofibrosis. Now, it appears we can significantly improve a patient’s quality of life while also potentially extending their life.”

 

In COMFORT-I, which compared the use of Jakavi versus placebo, researchers presented long-term follow-up data evaluating the efficacy and safety of Jakavi. Similar to COMFORT-II, Jakavi was associated with sustained reductions in spleen volume. Mean spleen volume reduction in the Jakavi arm was 31.6% at week 24, and maintained through week 96 (34.9%)[2]. Among patients with a >=35% reduction in spleen volume, response was maintained with a median duration of 108 weeks. The study demonstrated a continued overall survival benefit in favor of Jakavi, as 83% of patients on Jakavi survived at the 102 week follow-up period, compared to 73% of patients on placebo (HR=0.58; 95% CI, 0.36-0.95; p=0.028)[2]. Overall survival favored Jakavi across subgroups, including starting dose as well as baseline risk status and hemoglobin[2].

 

“The COMFORT program, which supported the European Commission approval for Jakavi, is the most extensive clinical trial program in myelofibrosis to date and continues to demonstrate significant results for Jakavi-treated patients,” said Hervé Hoppenot, President, Novartis Oncology. “We are encouraged by these findings and look forward to evaluating how Jakavi may help patients with other myeloproliferative neoplasms associated with a similar mechanism of disease.”

 

Myelofibrosis develops when uncontrolled signaling in the JAK pathway – which regulates blood cell production – causes bone marrow scarring and faulty blood cell production, resulting in severe complications. Jakavi directly targets an underlying mechanism of myelofibrosis, significantly reducing splenomegaly and improving debilitating symptoms regardless of JAK mutational status, disease subtype or any prior treatment, including hydroxyurea[3],[4],[5],[6].

 

While Jakavi has proven to provide patient benefits regardless of mutational status, an analysis of patients with the JAK2V617F mutation within the COMFORT-II study was also presented at ASH. Findings demonstrate the disease-modifying effects of Jakavi.  Patients bearing the JAK2V617F mutation who received Jakavi had greater reductions in the presence of cancerous cells with the mutated JAK2V617F allele (allele burden) compared with BAT[5]. Allele burden reductions among Jakavi-treated patients were gradual and sustained over the duration of the study, whereas BAT-treated patients demonstrated zero reductions. Among patients with >=20% allele burden reduction, sustained spleen volume reductions were observed to week 72[5].

 

COMFORT-II Long-Term Study Background

The COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study randomized 219 patients to receive Jakavi (15 or 20 mg BID) or BAT (2:1 randomization for Jakavi vs. BAT). A total of 73.3% (107/146) of patients in the Jakavi arm entered the extension phase vs. 61.6% (45/73) in the BAT arm, and 55.5% (81/146) of those originally randomized to Jakavi remained on treatment at the time of this analysis[1]. Overall survival was estimated using the Kaplan-Meier method. In the analysis of COMFORT-II data examining JAK2V617 allele burden reduction, allele burden was measured from blood samples using allele-specific quantitative real-time polymerase chain reaction (qPCR)[5].

 

No specific long-term safety signals emerged during the two-year follow-up period. In the primary analysis of the COMFORT-II study published in The New England Journal of Medicine in February 2012 (median treatment duration of 50.1 weeks; Jakavi, 51.4 weeks; BAT, 45.1 weeks), the most common grade 3/4 hematologic adverse events (AEs) in either arm (Jakavi, BAT) were anemia (42.4%; 31.4%) and thrombocytopenia (8.3%; 7.2%), and were manageable with either dose reduction or occasional interruption[4]. In the Jakavi arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to the BAT from week 24 onward[4].

 

One patient in each arm discontinued for thrombocytopenia, and no patients discontinued for anemia. One week after discontinuing Jakavi, these patients experienced a return of myelofibrosis symptoms that were present before initiating therapy. Since the core study has completed, all patients either entered the extension phase or discontinued from the study. A total of 107 of the 146 patients on Jakavi entered the extension phase in addition to 45 of the 73 patients previously treated with BAT (median treatment duration of 83.3 weeks; Jakavi, 111.4 weeks [randomized and extension phases]; BAT, 45.1 weeks [randomized treatment only per primary analysis]. Grade 3/4 hematologic abnormalities in the extension phase for Jakavi were consistent with the primary analysis: anemia (40.4%); lymphopenia (22.6%) and thrombocytopenia (9.6%)[1].

 

COMFORT-I Long-Term Study Background

This study randomized 309 patients to Jakavi or placebo. The primary analysis occurred when all patients completed 24 weeks of therapy, and all patients receiving placebo were eligible to cross over to Jakavi after the primary analysis. Quality of life was evaluated beyond week 24 using the European Organization for Research and Treatment of Cancer QoL Questionnaire-Core 30, and overall survival was assessed according to original randomized treatment[2].

 

The AE profile with long-term treatment is consistent with what has been previously reported[2]. Of 34 patients randomized to Jakavi who discontinued after the primary analysis, 4 discontinued for an AE. In patients who continued on Jakavi therapy, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in 12 and 5 patients, respectively. One patient discontinued for anemia. Overall, among all patients randomized to Jakavi, grade 3 and 4 anemia – regardless of baseline hemoglobin – was reported in 37.4% and 14.8% of patients, respectively. Similarly, grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of patients, respectively. These rates were similar to those reported in the primary analysis. By week 36, the proportion of patients receiving red blood cell transfusions decreased to the level seen with placebo and remained stable thereafter[2].

 

Rates of non-hematologic AEs adjusted for increased follow-up duration remained similar to those seen at the time of the primary data analysis[2]. No additional cases of acute myeloid leukemia (AML) in patients randomized to Jakavi were reported. Two patients originally randomized to placebo developed AML, 21 and 178 days after crossover to Jakavi. There continued to be no reports of a withdrawal syndrome after Jakavi discontinuation[2].

 

About Myelofibrosis

Myelofibrosis is a life-threatening blood cancer with a poor prognosis and limited treatment options[7],[8]. Studies show that patients with myelofibrosis have a decreased life expectancy, with a median overall survival of 5.7 years[9]. Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and transplant-related mortalityand is available to less than 5% of patients who are young and fit enough to undergo the procedure[10].

 

About Jakavi  

Jakavi® (INC424, ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases[4] and was approved by the European Commission in August 2012 for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Jakavi is available in more than 30 countries including the European Union and Canada, with additional global regulatory filings underway.

 

Novartis licensed INC424 (ruxolitinib) from Incyte Corporation for development and commercialization outside the United States. Both the European Commission and the US Food and Drug Administration (FDA) granted INC424 (ruxolitinib) orphan drug status for myelofibrosis. Jakavi is marketed in the United States by Incyte Corporation under the name Jakafi® for the treatment of patients with intermediate or high-risk myelofibrosis.

 

The recommended starting dose for Jakavi is 15 mg twice daily for patients with a platelet count between 100,000cubic millimeters (mm3) and 200,000 mm3,and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily and patients should be titrated cautiously[11].

 

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation.

 

Jakavi® Important Safety Information

Jakavi® can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with severe hepatic or renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed.

 

The most common adverse drug reactions, occurring at any level of severity (incidence >10%) are urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransaminase increased, asparte aminotransferase increased, bruising, bleeding and increased blood pressure. Other common adverse drug reactions (incidence 1 to 10%) are herpes zoster, weight gain, flatulence and tuberculosis (1%).

 

Please see full Prescribing Information for Jakavi available at www.jakavi.com.

 

References

[1] Cervantes, F, et al. Long-Term Safety, Efficacy, and Survival Findings From COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF).  Blood. 2012. Abstract #801. American Society of Hematology (ASH) 2012 Annual Meeting. Atlanta, GA.

[2] Verstovsek S et al. Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I. Blood. 2012. Abstract #800. ASH 2012 Annual Meeting. Atlanta, GA.

[3] 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.

[4] 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.

[5] Vannucchi A, Kiladjian JJ, Gisslinger H, et al. Reductions in JAK2V617F Allele Burden with Ruxolitinib Treatment in COMFORT-II, a Phase III Study Comparing the Safety and Efficacy of Ruxolitinib to Best Available Therapy (BAT). 2012. Abstract #802. ASH 2012. Annual Meeting, Atlanta, GA.

[6] Harrison C, Kiladjian JJ, Gisslinger H, et al. Association of Cytokine Levels and Reductions in Spleen Size in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib to Best Available Therapy (BAT). Abstract # 6625. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.

[7] 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(12):1117-1127.

[8] 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.

[9] Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.

[10] 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.

[11] JAKAVI [Summary of Product Characteristics]. Basel, Switzerland: Novartis Pharma AG; 2012.

Source: Novartis newsletter.

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

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Results of the COMFORT-I and COMFORT-II trials show INC424 significantly reduced disease burden in patients with myelofibrosis

  • Myelofibrosis is a life-threatening blood cancer associated with progressive, debilitating symptoms that severely impact quality of life and reduce survival
  • These data provided the basis for worldwide regulatory filings with first actions expected in the second half of 2012

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.

Source: Novartis Release

 

 

 

 

 

 

 

 

New Phase III data shows Novartis JAK inhibitor INC424 significantly reduced disease burden in patients with myelofibrosis

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Novartis today announced additional results from two pivotal Phase III trials evaluating Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in myelofibrosis. These data demonstrate the important potential role of INC424 in treating patients with myelofibrosis, a life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms.

Results are being presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego. Novartis and Incyte Corporation have a worldwide collaboration and license agreement for INC424.

A post-hoc analysis from the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study evaluated patient-reported health-related quality of life (HRQoL) measures for INC424 versus best available therapy (BAT). The results showed a substantial improvement in HRQoL and myelofibrosis symptoms compared with baseline for patients receiving INC424 but remained the same or worsened for patients receiving BAT. Results were based on a broad range of validated QoL instruments.[1]

“Myelofibrosis is a life-shortening disease with symptoms that significantly compromise patients’ everyday lives,” said Claire Harrison, MD, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, lead investigator for the COMFORT-II study. “As a result, therapies that address the severe burden of myelofibrosis are urgently needed. Data from large Phase III studies continue to show INC424 alleviates the manifestations and associated symptoms of myelofibrosis, potentially representing a major advance.”

In the second Phase III study, COMFORT-I researchers evaluated INC424 versus placebo in symptom improvement and spleen volume reduction, as well as overall survival. Results showed that patients receiving INC424 had higher response rates based on reductions in spleen volume and Total Symptom Score (TSS). The TSS evaluated changes in symptoms, such as abdominal discomfort, pain under the ribs on the left side, early satiety, itching, night sweats and bone or muscle pain. These benefits were consistent across all patient subgroups, including myelofibrosis disease subtype, age, risk group, presence or absence of JAK2 mutation, hemoglobin, spleen size and TSS.

In the COMFORT-I updated analysis, INC424 also demonstrated an overall survival advantage over placebo. A total of 13 INC424 and 24 placebo patients died during the study or during extended follow up after median follow up of 51 and 52 weeks, respectively, representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). Survival was estimated by the Kaplan-Meier method.[2]

“These data reinforce the dramatic effect INC424 has on improving the overall quality of life of patients battling this debilitating blood cancer,” said Hervé Hoppenot, President, Novartis Oncology. “We are committed to developing innovative therapies to address this unmet patient need and further support our ongoing research in myelofibrosis and other myeloproliferative neoplasms.”

COMFORT-II Predictors of Response and Post-Hoc HRQoL Study Details
A detailed analysis of predictors of spleen response in various patient subsets indicated that INC424 was more effective than BAT for all patient subgroups. In particular, responses to INC424 occurred and were superior to BAT regardless of the JAK2 mutation status.

The COMFORT-II study included an assessment of HRQoL and myelofibrosis symptoms using validated instruments, including the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym). Scores from these instruments were measured at baseline and weeks 8, 16, 24 and 48. A total of 219 patients were included in two treatment groups: INC424 (n=146) and BAT (n=73).

Based on a detailed analysis of the patterns of change of QoL scales over time, and compared with the BAT arm, INC424-treated patients experienced significant improvement in Global Health Status/QoL and in symptoms measured by the FACT-Lym symptom subscale including pain, swelling, fever, night sweats, itching, trouble sleeping, fatigue, weight loss, loss of appetite and trouble concentrating compared to BAT. In addition, the EORTC QLQ-30 showed that treatment differences in physical functioning, role functioning, fatigue and appetite loss were significantly better for INC424-treated patients as early as week 8 (p<0.05), and this effect was sustained throughout 48 weeks (p<0.05).[1]

The COMFORT-II trial was conducted by Novartis in Europe.

COMFORT-I Study Details for Symptom and Overall Survival Analyses
Patients were randomized to start INC424 or placebo at doses of 15 mg or 20 mg PO BID, depending on baseline platelet count (100-200 X109/L or >200X109/L, respectively). A total of 309 patients were randomized, 155 to INC424 and 154 to placebo. The dose was optimized for efficacy and safety during treatment.[2]

The COMFORT-I study was conducted by collaboration partner Incyte Corporation in the US, Canada and Australia.

About Myelofibrosis
Myelofibrosis is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, such as fatigue, night sweats and pruritus, poor quality of life, weight loss as well as shortened survival.[4] In the EU, the disease affects about 0.75 out of every 100,000 people annually.[5],[6] In the US, myelofibrosis affects about 1.5 out of every 100,000 people annually.[7] 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.[8],[9] Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality.[10] The five-year survival rate after transplantation is approximately 50%.[10]

About INC424 (ruxolitinib)
The investigational compound INC424 is an oral inhibitor of the JAK1 and JAK2 tyrosine kinases.[3] As part of Novartis’ clinical development program, INC424 is being investigated in primary myelofibrosis as well as post-polycythemia vera myelofibrosis (PPV-MF) and post-essential thrombocythemia myelofibrosis (PET-MF). INC424 is also being investigated in clinical trials for the treatment of polycythemia vera (PV).

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 Food and Drug Administration (FDA) have granted INC424 orphan drug status for myelofibrosis, and INC424 was recently approved by the FDA in the US under the name Jakafi(TM).

Source:Novartic release