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NICE Issues Preliminary Guidance To Not Recommend Jakavi™ In The Treatment Of Rare Blood Cancer As Not Cost-Effective

today expressed disappointment at the National Institute for Health and Clinical Excellence’s (NICE) preliminary recommendation to not recommend Jakavi™ (INC424, ruxolitinib) for the treatment of disease-related () or symptoms in adult patients with primary (also known as chronic idiopathic ), post-polycythaemia vera or post-essential thrombocythaemia [i].

The NICE appraisal committee concluded that ruxolitinib was clinically effective in reducing spleen size and reducing debilitating symptoms such as extreme fatigue, bone pain, insomnia and uncontrollable itching, which are associated with myelofibrosis, but could not be considered cost-effective when compared to next best available therapy1.

The NICE Committee considered ruxolitinib to be an innovative treatment for patients with splenomegaly and myelofibrosis and also acknowledged that ruxolitinib provided a ‘step change’ in treating splenomegaly and symptoms in patients with myelofibrosis.

“The lives of patients affected by myelofibrosis are improved with ruxolitinib therapy. In many cases this improvement is dramatic with long lasting tangible benefits. There is now increasing evidence that ruxolitinib therapy also prolongs survival in this difficult disease where we have previously had very limited options”, said Professor Claire Harrison, consultant haematologist and co-founder of patient charity, MPD Voice. “This decision is disappointing for patients, their families and clinicians. However the work of NICE is crucial and we will work with NICE as well as patients and clinicians to ensure that as drugs are developed that appropriate information is gathered so that important new groundbreaking treatments like ruxolitinib are made available where appropriate to patients in the UK.”

These are preliminary recommendations and will be reviewed following a public consultation period. A second appraisal committee meeting is scheduled for the 13 March 2013 with final guidance expected in June 2013.

“We believe that ruxolitinib has the potential to improve patient quality of life and address the underlying causes of the disease. We are encouraged that the Committee considers ruxolitinib to be an innovative treatment and Novartis is committed to working alongside clinicians and patient groups in this area to address all queries raised by NICE”, said Panos Alexakos, Oncology General Manager, Novartis UK & Ireland.

The UK marketing approval of ruxolitinib was based on positive findings from the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) clinical trial programme, the first comprehensive clinical programme in myelofibrosis[ii],[iii]. In one pivotal Phase III study, ruxolitinib was shown to provide significant clinical benefit by decreasing spleen size, improving symptoms and impacting overall survival (OS)2. None of the currently available treatments specifically target the underlying molecular defect that drives this disease3. NICE reiterated the statistical significance of results demonstrated in the COMFORT-I and COMFORT-II trials.

The draft guidance follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on 19 April 2012, recommending marketing authorisation for ruxolitinib in Europe[iv] and European Commission approval on 28 August 2012. The European approval was followed by UK availability in September 2012.

About Myelofibrosis

Myelofibrosis is a life-threatening blood cancer with a poor prognosis and limited treatment options[v],3. Studies show that patients with myelofibrosis have a decreased life expectancy, with a median survival of 5.7 years[vi]. Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and transplant-related mortality and is available to 10% or less patients in the UK[vii].

About Jakavi

Jakavi (INC424, ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinase5. The recommended starting dose for Jakavi is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimetres (mm3) and 200,000mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy[viii].

Novartis licensed INC424 (ruxolitinib) from Incyte for development and potential commercialisation outside the US. Incyte has retained rights for the development and commercialisation of INC424 (ruxolitinib) in the US. Both the European Commission and the US Food and Drug Administration (FDA) granted INC424 (ruxolitinib) orphan drug status for myelofibrosis. Incyte received FDA approval for INC424 (ruxolitinib) in November 2011 under the name Jakafi for the treatment of patients with intermediate or high-risk myelofibrosis.

About the COMFORT studies

The efficacy and safety of ruxolitinib in the treatment of patients with myelofibrosis was established in clinical studies, including the two pivotal Phase III trials – COMFORT I and COMFORT II.

COMFORT-I demonstrated that 41.9% of ruxolitinib treated patients achieved at least a 35% reduction (roughly equivalent to a reduction in palpable spleen size by 50%) in spleen volume at 24 weeks from baseline compared to 0.7% of patients in the placebo group (p<0.001). An analysis of COMFORT-I data at 51 weeks of treatment shows ruxolitinib treatment resulted in an significant survival advantage for patients who received ruxolitinib versus placebo (hazard ratio=0.50 [95% confidence interval: 0.25, 0.98])2.

In COMFORT-II, ruxolitinib produced a volumetric spleen size reduction of 35% or greater in 28% of patients compared to 0% of patients in the best available therapy (BAT) group at 48 weeks (p<0.001). The BAT is any commercially available agent (such as monotherapy or in combination) or no therapy at all. At week 24, 32% of patients treated with ruxolitinib 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. Additionally, ruxolitinib was associated with improvements in myelofibrosis symptoms at each evaluation as compared with the BAT group3. Continuous ruxolitinib therapy also provided a marked and durable improvement in overall quality of life measures, functioning and symptoms, including loss of appetite, dyspnoea (shortness of breath), fatigue, insomnia and pain, at week 48, compared to a worsening of symptoms in BAT-treated patients3. Ruxolitinib showed modest toxicity as compared with the BAT, with increased frequency of anaemia and thrombocytopaenia. Pneumonia was the only SAE reported in ≥5% of patients in either group (ruxolitinib, 1%; BAT, 5%)3.

In COMFORT-I the most frequently reported grade 3 or higher adverse events were haematologic. One patient in each study discontinued treatment for thrombocytopaenia or for anaemia, respectively. The most common non-haematologic adverse events of any grade reported for patients receiving ruxolitinib or placebo, respectively, were fatigue (25% vs. 34%), diarrhoea (23% vs. 21%), peripheral oedema (19% vs. 22%) and ecchymosis (19% vs. 9%). After interruption of ruxolitinib treatment, MF-related symptoms gradually returned to baseline levels over a period of 1 week2. COMFORT-I was conducted in the US by Incyte under the worldwide collaboration and license agreement for INC424 (ruxolitinib).

Jakavi Important Safety Information8

Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood counts monitoring is recommended. Dose reduction or interruption may be required in patients with severe hepatic or renal impairment or in patients developing haematologic adverse reactions such as thrombocytopaenia, anaemia and neutropaenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP2C9 enzymes (e.g. fluconozole). 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 (incidence >10%) are urinary tract infections, anaemia, thrombocytopaenia, neutropaenia, hypercholesterolaemia, dizziness, headache, increased alanine aminotransaminase, increased asparte aminotransferase, bruising and bleeding. Other common adverse drug reactions (incidence 1 to 10%) are herpes zoster, weight gain and flatulence.