Date: 2012-04-21
Type of information: Granting of a Market Authorisation in the EU
Product name: Jakafi® (USA)/Jakavi® (UE)
Compound: ruxolitinib
Therapeutic area: Rare diseases
Action mechanism: kinase inhibitor. Jakafi® inhibits enzymes called JAK 1 and 2 (Janus Associated Kinase) that are involved in regulating blood and immunological functioning. Myelofibrosis is associated with the deregulation of JAK 1 and 2. Novartis and Incyte Corporation have a worldwide collaboration and license agreement for Jakafi® - INC424 (ruxolitinib).
Company: Incyte (USA - DE) ) Novartis (Switzerland)
Disease: myelofibrosis
chronic idiopathic myelofibrosis
myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia
Latest news: * On August 19, 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) announced the results of ruxolitinib's early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG). Ruxolitinib (Jakavi®) has been approved since August 2012 for the treatment of adults with myelofibrosis. IQWiG has examined whether this new drug offers an added benefit over the appropriate comparator therapy specified by the Federal Joint Committee (G-BA). According to the results, there is an indication of considerable added benefit in comparison with "best supportive care" (BSC) because ruxolitinib is better at relieving symptoms. Moreover, a hint of an added benefit with regard to survival can be derived from the dossier. Its extent is non-quantifiable, however. Stem cell transplantation is currently the only option to cure myelofibrosis. Ruxolitinib aims to relieve the symptoms of myelofibrosis. This drug is an option for patients with so-called primary or secondary myelofibrosis whose spleen is already enlarged (splenomegaly) or who have other disease-related symptoms. The G-BA specified "best supportive care" (BSC) as appropriate comparator therapy. In its assessment, IQWiG could include one randomized controlled trial (RCT) conducted in 89 centres in Australia, Canada and the United States (COMFORT-I). The 309 patients in total were either treated with ruxolitinib plus BSC or with placebo plus BSC. The first analysis (primary analysis) was conducted in 2010 after all patients had been treated for 24 weeks and half of them for 36 weeks. Then all participants were unblinded and could switch to the ruxolitinib arm of the study. If their spleen volume had increased by more than 25%, they could also switch earlier. A 3-year analysis was conducted in 2013. The study was prolonged to 2015, however, to obtain long-term data. With regard to survival time, the differences between the two treatment groups were not statistically significant in favour of ruxolitinib in all of the four analysis dates. Because of the high proportion of patients who switched treatment, the survival advantage of ruxolitinib is rather underestimated. Overall, IQWiG therefore considers there to be a hint of an added benefit. The extent of this added benefit is unclear, however. A disease-specific questionnaire (MFSAF v2.0) was used to record symptoms in the COMFORT-I study. This instrument comprises myelofibrosis symptoms and aggregates them to one value (total symptom score, [TSS]). In the ruxolitinib + BSC group, considerably more patients than in the placebo + BSC group reported that their symptoms have improved. Regarding the occurrence of leukaemia (leukaemic transformation), a typical late complication, there were no differences between the two treatment groups in the study. For the outcome "morbidity", IQWiG therefore recognizes an indication of an added benefit with the extent "considerable". The dossier contained no evaluable data on quality of life. Quality of life was recorded in the study using an instrument developed for cancer (EORTC QLQ-C30). However, different proportions of participants in the two treatment groups remained unconsidered in the analysis. As the difference of the missing values was more than 20 percentage points, no reliable conclusions can be derived from the results. For the same reason, the data on symptoms that were also recorded with EORTC QLQ-C30 are also not evaluable. Only limited conclusions can be drawn on side effects. This is mainly due to the fact that typical symptoms of myelofibrosis, such as night sweats, were also recorded as "adverse events". This means that it remains unclear whether these were side effects of the drug or symptoms of the underlying condition. Such events that are not clearly attributable allow no informative conclusions on side effects. Although greater harm from ruxolitinib can also not be ruled out completely, the available data contain no signs of harm of a magnitude that might justify downgrading the added benefit as a whole. Hence the positive effects with regard to symptom relief (indication) and prolongation of life (hint) remain. Overall, IQWiG therefore regards there to be an indication of considerable added benefit of ruxolitinib in comparison with BSC. Ruxolitinib has the status "orphan drug". According to §35a (1), Sentence 10, Social Code Book V [SGB V]), the medical added benefit is regarded as proven if a drug has been approved, as long as the yearly turnover in the statutory health insurance (SHI) funds does not exceed 50 million euros. In this case, the G-BA only has to determine the extent of added benefit. The G-BA made this decision on ruxolitinib in March 2013. In 2013, ruxolitinib was the first drug for rare diseases to exceed the 50 million euro threshold. The G-BA therefore requested the drug manufacturer to submit proof of the added benefit of ruxolitinib in comparison with the appropriate comparator therapy in a dossier, and commissioned IQWiG with the assessment. The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G?BA then decides on the extent of the added benefit, thus completing the early benefit assessment. * On August 28, 2012, Novartis has received approval from the European Commission for Jakavi® 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. The European Commission's decision was based on positive findings from the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) clinical trial program. The efficacy and safety of Jakavi® in the treatment of patients with myelofibrosis was established in clinical studies, including the two pivotal Phase III trials - COMFORT-I and COMFORT-II. Chronic inflammation through elevated cytokine levels is one of the primary consequences of dysregulated JAK 1 and JAK 2 signaling, and may be a major contributor to morbidity and mortality of patients with myeloproliferative neoplasms such as myelofibrosis. In one pivotal Phase III study, Jakavi® was shown to alter the clinical course of myelofibrosis by reversing symptom progression and splenomegaly, thus improving quality of life and potentially impacting overall survival. * On April 19 2012, the CHMP adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Jakavi®, 5, 15, 20mg, tablet intended for the treatment of chronic idiopathic myelofibrosis and treatment of myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. The benefits with Jakavi® are its ability to reduce the size of the spleen by at least 35 % and to treat other symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. The most common side effects are thrombocytopenia, anaemia and bleeding. A pharmacovigilance plan for Jakavi® will be implemented as part of the marketing authorisation. This positive opinion triggers a $40 million payment for Incyte Corporation. A second payment of $60 million would be earned once Novartis achieves reimbursement and pricing approval in specific EU countries.
Patents:
Submission of marketing authorization application USA : 2011-06-06
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2011-11-16
UE authorization: 2012-08-28
Favourable opinion UE: 2012-04-19
Favourable opinion USA:
Orphan status USA: 2008-09-05
Orphan status UE: 2008-11-07
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
