News from the FDA/CDC

Triple-drug therapy proves effective in CF patients with most common mutation

Publish date: October 31, 2019

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The dream of targeted therapies for cystic fibrosis may now be reality

After 30 years, new research from Middleton et al. and others appears to be the breakthrough we’ve been waiting for in treating cystic fibrosis, wrote Francis S. Collins, MD, PhD, of the National Institutes of Health in an accompanying editorial (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMe1911602).

As one of the researchers who discovered the cystic fibrosis gene, he acknowledged the 3 decades of work that followed their discovery and the excitement that comes from being able to counter the common Phe508del CFTR mutation that afflicts so many cystic fibrosis patients. “These findings indicate that it may soon be possible to offer safe and effective molecularly targeted therapies to 90% of persons with cystic fibrosis,” he wrote.

“Yet we must not abandon the patients with cystic fibrosis who have null mutations and will not have a response to these drugs,” he added, noting that those challenges remain “substantial” and potentially will involve in vivo somatic-cell gene editing of airway epithelial cells. That said, what once was a dream 30 years ago now appears to be a reality.

Dr. Collins reported being a coinventor of the original patents on the CFTR gene, for which he donated all royalties to the Cystic Fibrosis Foundation.

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Reinforcing previous findings, a new study has determined that the next-generation corrector elexacaftor, in combination with tezacaftor and ivacaftor, can effectively treat patients with Phe508del-minimal function genotypes who did not respond to previous cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimens.

“These results provide evidence that elexacaftor-tezacaftor-ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients,” wrote Peter G. Middleton, PhD, of the University of Sydney (Australia) and his coauthors. The study was published in the New England Journal of Medicine.

To further determine if the elexacaftor-tezacaftor-ivacaftor regimen was effective and safe, the researchers launched a randomized, placebo-controlled phase 3 trial of 403 cystic fibrosis patients age 12 or older who had a single Phe508del allele. Patients in the combination group (n = 200) received 200 mg of elexacaftor once daily, 100 mg of tezacaftor once daily, and 150 mg of ivacaftor every 12 hours for 24 weeks. Patients in the other group (n = 203) received matched placebos.

At 14 weeks, patients in the combination group had a change in percentage of predicted forced expiratory volume in 1 second (FEV₁) that was 13.8 points higher than the placebo group (95% confidence interval, 12.1-15.4, P less than .001). At 24 weeks, the combination group had a predicted FEV₁ difference that was 14.3 percentage points higher (95% confidence interval, 12.7-15.8, P less than .001). The rate of pulmonary exacerbations was 63% lower (rate ratio 0.37; 95% CI, 0.25-0.55, P less than .001) and sweat chloride concentration was 41.8 mmol/L lower (95% CI, –44.4 to –39.3, P less than .001) in the combination group through 24 weeks.

At least one adverse event occurred in 93.1% of patients in the combination group and 96% of patients in the placebo group. Serious adverse events occurred in 28 patients (13.9%) in the combination group and 42 patients (20.9%) in the placebo group. There were no deaths in either group.

The study was funded by Vertex Pharmaceuticals. The authors had disclosures, including receiving personal fees and grants from various pharmaceutical companies and being on the advisory board, owning stock, or being an employee of Vertex Pharmaceuticals.

SOURCE: Middleton PG et al. 2019 Oct 31. N Engl J Med. doi: 10.1056/NEJMoa1908639.

Triple-drug therapy proves effective in CF patients with most common mutation

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