Type of information: Granting of a Market Authorisation in the US
Product name: Alunbrig® (brigatinib - AP26113)
Therapeutic area: Cancer - Oncology
- kinase inhibitor/tyrosine kinase inhibitor. Brigatinib (AP26113) is an investigational, targeted cancer medicine discovered internally at Ariad Pharmaceuticals. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) that is resistant to crizotinib.
- Brigatinib received Breakthrough Therapy designation from the FDA in October 2014 for the treatment of patients with ALK+ NSCLC that is resistant to crizotinib on the basis of an ongoing Phase 1/2 trial. Brigatinib is currently being evaluated in the global Phase 2 ALTA trial that is anticipated to form the basis for its initial regulatory review.
- Brigatinib was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC.
- Brigatinig is now part of Takeda's portfolio. The Japanese company has acquired Ariad Pharmaceuticals in February 2017.
Company: Ariad Pharmaceuticals (USA - MA) now Takeda Pharmaceutical (Japan)
Disease: patients with ALK+ non-small cell lung cancer (NSCLC) who are resistant to crizotinib
- • On April 28, 2017, Takeda Pharmaceutical announced that Alunbrig® (brigatinib) has received accelerated approval from the FDA for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The FDA approval was primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of brigatinib in adults. This ongoing, two-arm, open-label, multicenter trial enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of Alunbrig® once daily (n=112) or 180 mg once daily following a seven-day lead-in of 90 mg once daily (n=110).
- The recommended dosing regimen for Alunbrig® is 90 mg orally once daily for the first 7 days. If 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily. With a median follow-up of 8 months (range 0.1 - 20.2), results demonstrated that of the patients who received the recommended dosing regimen, 53 percent achieved a confirmed overall response (OR) as assessed by IRC and 54 percent as assessed by Investigator. At the recommended dosing regimen, the median duration of response was 13.8 months as assessed by IRC and 11.1 months by Investigator assessment. Additionally, at the recommended dosing regimen, 67 percent of patients with measurable brain metastases (n=18) achieved a confirmed intracranial OR by IRC assessment.
- The warnings and precautions for Alunbrig® are: interstitial lung disease (ILD)/pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase (CPK) elevation, pancreatic enzyme elevation, hyperglycemia and embryo-fetal toxicity. Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90?180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90?180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90?180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
At the recommended dosing regimen, the most common adverse reactions with Alunbrig® were nausea, diarrhea, fatigue, cough, and headache.
- • On February 6, 2017, Ariad Pharmaceuticals announced the submission of a Marketing Authorization Application for brigatinib, to the European Medicines Agency (EMA). Ariad is seeking marketing approval in the European Union of brigatinib in adult patients with anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC) who have been previously treated with crizotinib. The submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. Results from the ALTA trial and central nervous system (CNS) activity in the ALTA and Phase 1/2 trials were reported at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) in December 2016. In the ALTA trial, 222 patients received either 90 mg of brigatinib once per day (QD) continuously or 180 mg QD, preceded by a lead-in dose of 90 mg QD for seven days. Data from the ALTA trial demonstrated that of 110 patients on the 180-mg regimen QD with a seven-day lead-in at 90 mg QD with a median follow-up of 11.0 months, 55 percent achieved confirmed objective response as assessed by the investigator. In this arm, the median progression-free survival (PFS) was 15.6 months in this post-crizotinib setting, by both investigator and independent review committee (IRC) assessment. Additionally, in this arm, 67 percent (12/18) of patients with measurable brain metastases achieved a confirmed intracranial objective response.
- • On October 31, 2016, Ariad Pharmaceuticals announced that the FDA has accepted for review the New Drug Application (NDA) for brigatinib, in patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who have progressed on crizotinib. The FDA granted Ariad’s request for Priority Review and has set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA).
- • On August 30, 2016, Ariad Pharmaceuticals announced it has completed the rolling submission of the New Drug Application (NDA) for brigatinib, to the FDA. The NDA submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. Data from the ALTA trial, in which patients who had experienced disease progression on crizotinib therapy were randomized to one of two brigatinib regimens, were presented at the 2016 Meeting of the American Society of Clinical Oncology ( ASCO ). With a median follow-up of 8.3 months, the data show that, for patients treated with the 180 mg regimen with a seven day lead-in at 90 mg (Arm B), 54 percent achieved an investigator-assessed confirmed objective response, the trial's primary endpoint. In this arm, the median progression free survival (PFS) exceeded one year (12.9 months). Additionally, a 67% confirmed intracranial objective response rate was achieved in patients with measurable brain metastases.
- • On June 17, 2016, Ariad Pharmaceuticals announced the initiation of a New Drug Application (NDA) submission for its investigational anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, to the FDA. The company is seeking U.S. marketing approval of brigatinib for patients with ALK+ non-small cell lung cancer (NSCLC) who are resistant to crizotinib. The rolling NDA submission is expected to be complete in the third quarter of 2016.
Patents: * On April 22, 2015, Ariad Pharmaceuticals announced the issuance of its first U.S. patent on its ALK inhibitor, brigatinib. The United States Patent and Trademark Office granted U.S. Patent No. 9,012,462 under the title, "Phosphorous Derivatives as Kinase Inhibitors." The patent provides composition-of-matter protection through at least December 30, 2030 for ARIAD's investigational ALK inhibitor, brigatinib. Additional patent applications covering brigatinib are pending in the U.S. and in other countries.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE: 2017-02-06
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-04-28
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: