Vertex Pharmaceuticals Incorporated, a global biotechnology company, announced that the Therapeutic Goods Administration (TGA) of Australia has approved Orkambi 200/125 (lumacaftor 200mg and ivacaftor 125mg), the first medicine to treat the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have two copies of the F508del mutation.

In Australia, there are approximately 1,000 people with CF ages 12 and older who have two copies of this mutation. The Australian reimbursement process for Orkambi is already underway as part of the parallel regulatory and reimbursement processes between the TGA and the Pharmaceutical Benefits Advisory Committee (PBAC).

"We are pleased that the Therapeutic Goods Administration has recognised the ‘meaningful clinical benefit' offered by Orkambi," said Simon Bedson, senior vice president and international general manager for Vertex. "Today's approval is an important step toward making Orkambi available for eligible Australians who do not currently have a medicine to treat the underlying cause of their disease."

The TGA approval is based on previously announced data from two 24-week global phase 3 studies, TRAFFIC and TRANSPORT, and additional interim 24-week data from the subsequent extension study, PROGRESS, in people with CF ages 12 and older who have two copies of the F508del mutation and were already being treated with standard-of-care medicines. In the TRAFFIC and TRANSPORT studies, which enrolled more than 1,100 patients and were the largest CF studies ever conducted, those treated with the combination of lumacaftor and ivacaftor experienced significant improvements in lung function. Patients also experienced improvements in body mass index (BMI) and reductions in pulmonary exacerbations (acute lung infections), including those requiring hospitalisations and intravenous antibiotic use. Interim data from PROGRESS showed that these improvements were sustained through 48 total weeks of treatment (24 weeks in TRAFFIC/TRANSPORT + 24 weeks in PROGRESS). In addition, the pattern and magnitude of response observed after the initiation of combination treatment across all patients who received placebo in TRAFFIC and TRANSPORT and subsequently received a combination regimen in PROGRESS were similar to those seen among patients who received a combination regimen in TRAFFIC and TRANSPORT.

The combination of lumacaftor and ivacaftor was generally well tolerated in all three studies. In TRAFFIC and TRANSPORT, the most common adverse events included shortness of breath and/or chest tightness, upper respiratory tract infection (common cold) and gastrointestinal symptoms (including nausea, diarrhea, or gas). In the extension study, the safety and tolerability results, including the type and frequency of adverse events and serious adverse events, were consistent with those observed in TRAFFIC and TRANSPORT, and no new safety concerns were identified. Over 48 weeks, the most common adverse events were infective pulmonary exacerbation, cough and increased sputum. The incidence of serious adverse events during PROGRESS was generally similar to TRAFFIC and TRANSPORT.

Orkambi 200/125 is indicated for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.

Orkambiis only for use in patients who possess two copies of the F508del mutation in the CFTR gene. The safety and efficacy of Orkambiin children aged less than 12 years have not been established. Orkambi should be used with caution in patients with advanced liver disease and only if the benefits are expected to outweigh risks. If Orkambi is used in patients with advanced liver disease, they should be closely monitored after the initiation of treatment and the dose should be reduced. Assessment of liver function tests is recommended before initiation, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Caution is recommended when administering Orkambi to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease. Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of Orkambi compared to those who received placebo. Clinical experience in patients with percent predicted FEV1 (ppFEV1) < 40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. Menstrual abnormalities (amenorrhoea, dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and polymenorrhoea) were more common in Orkambi treated female patients than in placebo. These menstrual abnormalities were more frequent in the subset of female patients who were taking hormonal contraceptives. Increased blood pressure has been observed in some patients treated with Orkambi. Blood pressure should be monitored periodically in all patients during treatment. Lumacaftor is a strong inducer of CYP3A; administration of  Orkambi may decrease systemic exposure of medicinal products which are substrates of CYP3A, which may decrease their therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. Orkambi may substantially decrease hormonal contraceptive exposure, reducing effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi. Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes; use of Orkambi with strong CYP3A inducers, such as rifampicin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of Orkambi. Therefore, co-administration with strong CYP3A inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]) is not recommended. Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with Orkambi. Orkambi has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended.