Date: 2017-03-30
Type of information: Granting of a Market Authorisation in Japan
Product name: Ninlaro®
Compound: ixazomib - MLN9708 - 2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid
Therapeutic area: Cancer - Oncology - Rare diseases
Action mechanism:
- proteasome inhibitor. Ixazomib (MLN9708) is an oral proteasome inhibitor, which is being studied in multiple myeloma (MM), systemic light-chain (AL) amyloidosis and other malignancies. Ixazomib was granted orphan drug designation in MM in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012.
- Ixazomib received Breakthrough Therapy status by the FDA for relapsed and/or refractory AL amyloidosis in 2014. It is also the first oral proteasome inhibitor to enter Phase 3 clinical trials. Four global Phase 3 trials are evaluaring ixazomib:
- TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM;
- TOURMALINE-AL1, investigating ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis;
- TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and
- TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant.
Company: Takeda Global Research and Development Centre (UK) Millennium Pharmaceuticals (USA - MA)
Disease: multiple myeloma
Latest news:
- • On March 30, 2017, Takeda Pharmaceutical announced
that the Japanese Ministry of Health, Labour and Welfare has approved Ninlaro® capsules (ixazomib), the first oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone, for the treatment of patients with relapsed or refractory multiple myeloma who have not responded to at least one standard therapy or who have relapsed after treatment. The decision to approve the once-weekly pill follows the Ministry of Health, Labour and Welfare’s decision to grant Ninlaro® orphan drug designation for the treatment of patients with relapsed or refractory multiple myeloma in February 2016.
- The approval is based on data from the pivotal Phase TOURMALINE-MM1 trial. The study demonstrated that Ninlaro® in combination with lenalidomide and dexamethasone, increased median progression-free survival by approximately six months, or 40 percent, in patients with relapsed or refractory multiple myeloma when compared with placebo, lenalidomide and dexamethasone (hazard ratio = 0.74, p = 0.01, median PFS = 20.6 months in the ixazomib group vs. 14.7 months in the control group, median follow-up period = 14.7 months).
- • On November 24, 2016, Takeda Pharmaceutical announced that the European Commission has granted conditional marketing authorization for Ninlaro® (ixazomib) capsules, indicated in combination with lenalidomide and dexamethasone for adult patients with multiple myeloma who have received at least one prior therapy.
- • On September 16, 2016, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the conditional approval of Ninlaro® (ixazomib) capsules in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. If the European Commission ratifies the CHMP’s opinion and authorization is granted, Ninlaro® will be the first and only oral proteasome inhibitor approved for use across the European Economic Area, which includes the 28 member states of the European Union as well as Norway, Liechtenstein and Iceland. Data from the pivotal Phase 3 trial TOURMALINE-MM1 demonstrate that the addition of Ninlaro® to lenalidomide and dexamethasone provides a significant improvement in progression-free survival when compared to placebo plus lenalidomide and dexamethasone in this patient population. Patients continue to be treated to progression in the trial, with additional evaluations planned for long-term outcomes such as overall survival. Currently licensed for use in the U.S., Canada, Israel and Venezuela, Ninlaro® is also under review for approval by a number of regulatory authorities around the world.
- • On May 27, 2016, Takeda Pharmaceutical announced that the company intends to appeal the negative opinion of the CHMP recommending the refusal of the marketing authorisation for Ninlaro®and request a re-examination by the CHMP.
- • On 26 May 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Ninlaro®, intended for the treatment of multiple myeloma. Takeda presented results from one main study involving 722 adults with multiple myeloma whose disease had not responded to or had come back after previous treatment. The study compared Ninlaro® with placebo, both taken together with the medicines lenalidomide and dexamethasone. The main measure of effectiveness was progression-free survival.
The CHMP considered that the data from the main study were insufficient to demonstrate a benefit of Ninlaro® in the treatment of multiple myeloma. The company had proposed restricting the use of the medicine to patients whose disease is more difficult to treat and had come back after one previous treatment, and to those whose disease had come back after at least two previous treatments. However, the data in these subgroups were not compelling enough and the rationale for assuming greater effectiveness in these patients was not clear.
Therefore, the CHMP was of the opinion that, based on the currently available data, the benefits of Ninlaro® did not outweigh its risks and recommended that it be refused marketing authorisation.
- • On December 11, 2015, Takeda announced that Ninlaro® (ixazomib) capsules, the first and only oral proteasome inhibitor, are now available in the United States. Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The pill can be taken at home which may reduce some of the logistical burden for patients, because administration does not require an infusion or injection at a hospital, clinic or physician’s office.
- • On November 20, 2015, the FDA granted approval for Ninlaro® (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy. This proteasome inhibitor works by blocking enzymes from multiple myeloma cells, hindering their ability to grow and survive. Ninlaro® is the first oral proteasome inhibitor and is approved in combination with Revlimid® (lenalidomide) and dexamethasone.
- The safety and efficacy of Ninlaro® were demonstrated in an international, randomized, double-blind clinical trial of 722 patients whose multiple myeloma came back after, or did not respond to, previous treatment. Study participants received either Ninlaro® in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those taking Ninlaro® lived longer without their disease worsening (average 20.6 months) compared to participants taking the other regimen (14.7 months). The most common side effects of Ninlaro® are diarrhea, constipation, low blood platelet count (thrombocytopenia), peripheral neuropathy (numbness and pain from nerve damage, usually in the hands and feet), nausea, peripheral edema (fluid under the skin causing swelling), vomiting and back pain.The FDA granted priority review and orphan drug designations for Ninlaro®.
- • On September 9, 2015, Takeda Pharmaceutical announced that the FDA has granted Priority Review status to the New Drug Application (NDA) for ixazomib, the first investigational oral proteasome inhibitor for the treatment of patients with relapsed and/or refractory multiple myeloma.
- • On August 21, 2015, Takeda Pharmaceutical announced that the European Medicines Agency (EMA) has accepted the Marketing Authorization Application (MAA) for ixazomib for the treatment of patients with relapsed and/or refractory multiple myeloma. On July 23, ixazomib was granted accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP) of the EMA, a designation reserved for those medicines deemed to be of major public health interest and, in particular, therapeutic innovation.
- The MAA submission was primarily based on the results of the first pre-specified interim analysis of the pivotal Phase 3 trial TOURMALINE-MM1, an international, randomized, double-blind, placebo controlled clinical trial of 722 patients designed to evaluate the superiority of ixazomib plus lenalidomide and dexamethasone over placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma. Patients continue to be treated to progression in this trial and will be evaluated for long-term outcomes.
In addition to the ixazomib MAA submission with the EMA, a New Drug Application for ixazomib was filed with the FDA. Additional filings in other countries are planned to begin later this fiscal year.
- • On July 14, 2015, Takeda Pharmaceutical Company announced that a New Drug Application (NDA) has been submitted to the FDA for ixazomib for the treatment of patients with relapsed and/or refractory multiple myeloma. The NDA submission was based on the pivotal Phase 3 trial TOURMALINE-MM1, an international, randomized, double-blind, placebo controlled clinical trial of 722 patients designed to evaluate the superiority of ixazomib plus lenalidomide and dexamethasone over placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma. Patients continue to be treated in this trial and evaluated for long-term outcomes. This is the first regulatory submission for ixazomib. Additional filings are planned to begin in Europe and other countries later this year.
Patents:
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2015-11-20
UE authorization: 2016-11-24
Favourable opinion UE: 2016-09-16
Favourable opinion USA:
Orphan status USA: 2011-02-18
Orphan status UE: 2011-09-27
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
Is general: Yes
