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



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









Dabigatran Associated with Increased Bleeding During Atrial Fibrillation Ablation

Until the effects of dabigatran use during ablation are clearer, it should be withheld for at least 24 hours before the procedure.

In warfarin recipients with therapeutic international normalized ratios (INRs), uninterrupted warfarin treatment during radiofrequency ablation for atrial fibrillation (AF) has relatively convincingly been shown to reduce both thromboembolic and bleeding events. Dabigatran is increasingly prescribed as an alternative to warfarin in patients with nonvalvular AF. However, dabigatran’s half life ranges from 12 to 14 hours and is prolonged in patients with renal insufficiency. Given the lack of an antidote to reverse its effects, the drug’s safety and efficacy during ablation are not clear.

Investigators used prospective data from a multicenter registry to compare the results of AF ablation in 145 patients taking dabigatran with the results in a matched cohort of 145 warfarin recipients with therapeutic INRs. Dabigatran was withheld on the day of surgery and restarted 3 hours after ablation; warfarin treatment was uninterrupted. The rate of major bleeding (pericardial tamponade) was 6% with dabigatran and 1% with warfarin (P=0.009). The rate of thromboembolic complications was also higher with dabigatran than with warfarin (2% vs. 0%), but this difference was not statistically significant.

Comment: These findings are by no means definitive. All of the warfarin patients had therapeutic international normalized ratios — a more realistic control group would have been a matched sample of all warfarin recipients. The optimal role of dabigatran in patients with atrial fibrillation undergoing ablation has yet to be determined. We need more data before we open the floodgates, and an editorialist describes a number of alternative strategies for anticoagulation during AF ablation. Still, this report does provide some practical guidance: Dabigatran should be discontinued before the day of the ablation, probably for at least 24 hours.

Source: Journal Watch Cardiology

Cost-Effectiveness of Adult Pneumococcal Vaccines.

Mathematical modeling indicates that the new adult pneumococcal conjugate vaccine could be more cost-effective than the current pneumococcal polysaccharide product.

Although the 23-valent pneumococcal polysaccharide (PPSV23) has been licensed for adults since 1983, its effectiveness against nonbacteremic pneumococcal pneumonia (NPP) is still unresolved. The 7-valent pneumococcal conjugate vaccine, introduced in 2000 for routine childhood immunization, showed clear benefit in preventing both NPP and invasive pneumococcal disease; it was replaced in 2010 by a 13-valent conjugate vaccine (PCV13). This vaccine was recently licensed for use in adults.

Using a Markov state-transition model, researchers examined the cost-effectiveness of various adult vaccination strategies with PPSV23 and PCV13. Simulations involved hypothetical cohorts of U.S. 50-year-olds; data sources included the CDC Active Bacterial Core surveillance, the National Health Interview Survey, the National Hospital Discharge Survey, and the Nationwide Inpatient Sample.

In the basic model, assuming vaccination at age 65 (or at younger ages for high-risk individuals), PCV13 would be more cost-effective than PPSV23 (US$28,900 vs. $34,600 per quality-adjusted life-year [QALY] gained). Giving PCV13 routinely at ages 50 and 65 would be still more protective but at a cost of $45,100 per QALY gained. However, sensitivity analyses showed these estimates to be highly dependent on PCV13 effectiveness against NPP, vaccine costs, and indirect effects of childhood PCV13 vaccination (i.e., herd immunity, shifts in pneumococcal serotype distribution).

Comment: Although we still don’t know the best adult pneumococcal vaccination strategy, the present analysis highlights the data needed to make this determination. Information on PCV13 effectiveness against NPP and the indirect effects of childhood PCV13 vaccination on adult pneumococcal disease rates should be available fairly soon.

Source: Journal Watch Infectious Diseases

FDA Approves First Quadrivalent Flu Vaccine .

The FDA has approved a quadrivalent vaccine (FluMist Quadrivalent) for seasonal flu prevention in people aged 2 to 49 years. The new formulation, which will be administered intranasally, contains two strains each of influenza A and influenza B. Previous vaccines contained two influenza A strains and only one B strain.

Approval was based on three studies comprising some 4000 adults and children in which immune responses to the quadrivalent formulation were similar to those of the trivalent one (FluMist).

Common side effects include headache and sore throat in adults and stuffy or runny nose in all ages.

Source: FDA news

Nicotine Patch No Better Than Placebo in Helping Pregnant Smokers Quit

The nicotine patch is no better than placebo in helping pregnant smokers abstain from cigarettes until delivery, according to a New England Journal of Medicine study.

Some 1000 pregnant smokers between 12 and 24 weeks’ gestation were randomized to receive 8 weeks of nicotine-replacement or placebo patches. All participants also received behavioral counseling before randomization and several times during the intervention period.

The primary outcome — abstinence until childbirth — did not differ significantly between the nicotine and placebo groups (9% and 8%, respectively). Adverse pregnancy and birth outcomes generally did not differ between the groups, although low adherence rates (3%–7%) limited safety assessments.

An editorialist, citing previous studies with similar outcomes, concludes: “Pending more data on the efficacy and safety of nicotine-replacement therapy during pregnancy, this therapy cannot be recommended with any clinical certainty.”

In an interview with Clinical Conversations, study author Dr. Tim Coleman said, “Women should really … try very hard [to quit] with behavioral support alone.”


Internet-Based Therapy Effective in Treating Teens with Chronic Fatigue Syndrome

Specialized Internet-based cognitive-behavioral therapy appears to effectively treat chronic fatigue syndrome in teenagers, according to a Lancet study.

Some 140 Dutch patients aged 12 to 18 years with chronic fatigue were randomized to either usual care or an Internet-based intervention consisting of a cognitive-behavioral therapy module and e-mails with a therapist. On average, teens and parents in the intervention group logged in to the module 255 times and e-mailed the therapist 90 times during 6 months of treatment.

The intervention group had better results than the control group in all three primary outcomes: full school attendance (75% vs. 16%), lack of severe fatigue (85% vs. 27%), and normal physical functioning (78% vs. 20%). The improvements persisted at 12 months, and members of the control group who crossed over to the intervention group at 6 months also saw improvements by month 12.

Commentators write: “With chronic fatigue syndrome now identified as a common cause of long-term school absence, an accessible and flexible treatment for adolescents is most welcome.”


Colonoscopy Decreases Cancer Deaths.

More evidence that colonoscopic polypectomy prevents deaths from colorectal cance.

In 1993, the National Polyp Study, a large, randomized, controlled trial — initially designed to test 1-year versus 3-year colonoscopic postpolypectomy surveillance intervals in patients who had adenomas removed — reported that the cohort had 76% to 90% lower incidence of colorectal cancer than reference populations. Now, long-term follow-up data on mortality from colorectal cancer are reported for this cohort.

The current study included 2602 patients with adenomas (adenoma cohort) and 773 patients with nonadenomatous polyps (nonadenoma cohort) who had undergone colonoscopic polypectomy at seven clinical centers between 1980 and 1990 for diagnostic purposes. Deaths in the cohort were identified from the National Death Index. U.S. national cancer surveillance data were used to calculate death rates from colorectal cancer in the general population. The patients with nonadenomatous polyps comprised an internal control group.

During a median follow-up of 15.8 years, 1246 deaths occurred in the adenoma cohort (48%), including 12 deaths from colorectal cancer, compared with 25.4 expected deaths from colorectal cancer in the general population. This 53% reduction in mortality from colorectal cancer in the adenoma cohort was similar between follow-up periods (<10 years and 10 years). Mortality reduction was similar between the adenoma and nonadenoma cohorts during the first 10 years. After 10 years, when surveillance for the adenoma cohort was not organized, mortality rose in the adenoma cohort relative to the nonadenoma cohort.

Comment: This study provides additional evidence that colonoscopic polypectomy prevents colorectal cancer deaths — in this instance, in a cohort of patients with adenomas. This cohort was high risk, with 57% having advanced adenomas at baseline examination. The contrast between the similar reductions in mortality between the adenoma and nonadenoma cohorts in the first 10 years and the difference in mortality between these groups after 10 years underscores the importance and benefit of close colonoscopic surveillance in patients with advanced adenomas.

Source: Journal Watch Gastroenterology

A meta-analysis shows that dopamine is associated with increased risk for death and arrhythmic events compared with norepinephrine.

Although current guidelines recommend either dopamine or norepinephrine as the vasopressors of choice for septic shock, a recent meta-analysis of six interventional studies suggested that norepinephrine is the superior agent. Investigators conducted a meta-analysis of the same six interventional studies — excluding patients with nonseptic shock — and five observational studies; the analysis involved a total of 2768 adult patients.

Observational studies showed significant heterogeneity in results overall and no difference in mortality between patients treated with dopamine and those treated with norepinephrine. After exclusion of one trial that accounted for the heterogeneity, dopamine was associated with an increased risk for death at 28 days over norepinephrine (relative risk, 1.23). Interventional trials were homogeneous and likewise showed a significantly increased risk for death with dopamine use (RR, 1.12). Two interventional studies that reported arrhythmic events showed a significant increase in these events in the dopamine groups (RR, 2.34).

An editorialist suggests that dopamine, a more powerful β-agonist than norepinephrine, could still be considered in patients with septic shock, hypotension (systolic blood pressure <90 mm Hg), and either a low cardiac index (<2.5 L/minute/m2) or low heart rate (<90 beats per minute).

Comment: This study supports norepinephrine as the vasopressor of choice for adult patients with septic shock. Dopamine is relegated to a secondary role, perhaps to be used when cardiac output is insufficient despite optimal use of norepinephrine.

Source:  Journal Watch Emergency Medicine.