The only therapy available for a disease with a clear unmet medical need will not be made available to UK patients

Novartis today expressed disappointment at the National Institute for Health and Clinical Excellence's (NICE) decision to publish final guidance not recommending ruxolitinib (INC424, Jakavi™) for the treatment of disease-related splenomegaly (enlarged spleen) or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis[i]. This follows the Final Appraisal Determination (FAD) issued in April 2013.

Novartis intends to request an early review of NICE's decision taking into account additional data that has recently been announced at the European Haematology Association congress in Stockholm, which provides further clinical evidence of the benefits associated with ruxolitinib.

"Novartis does not agree with the final guidance which does not consider ruxolitinib to be a cost-effective use of NHS resources, considering the clinical effectiveness of ruxolitinib in reducing spleen size and reducing debilitating symptoms such as extreme fatigue, bone pain, insomnia and uncontrollable itching, which are associated with myelofibrosis. Our priority is to continue dialogue with NICE and the NHS to ensure patients have the most clinically effective and innovative treatment options available to them," said Panos Alexakos, Oncology General Manager, Novartis UK & Ireland.

Patients are currently able to access ruxolitinib through the Cancer Drugs Fund. There is, however, uncertainty around access for future patients as the Cancer Drugs Fund may come to an end in 2014 and there is no direction as to how treatments will be funded after this. Novartis is committed to requesting a re-review of the data by NICE at the earliest opportunity and is working with other companies to ensure that a potential lag time does not exist between the completion of the review and the Cancer Drugs Fund drawing to a close.

"This is extremely disappointing news for patients and the myelofibrosis community at large. We have fought painstakingly to make ruxolitinib available in the UK and for the needs of myelofibrosis patients with limited treatment options", said Professor Claire Harrison, consultant haematologist and co-founder of patient charity, MPD Voice. "We will continue to collaborate with NICE and the NHS to support patients at most risk from this life-threatening disease".

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. Furthermore, there is now longer-term follow up data of the Phase III trials which demonstrates ongoing significant clinical benefit. NICE reiterated the statistical significance of results demonstrated in the COMFORT-I and COMFORT-II trials.

This guidance denies patients long-term secure access to a clinically effective treatment that is already approved and being made available to patients across select European countries.

The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on 19 April 2012, which recommended 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 options3,[v]. 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 kinase3. The recommended starting dose for Jakavi is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimetres (mm3) and 200,000 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[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 a 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 breastfeed.

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.