News & Analysis News From the Food and Drug Administration Clarithromycin-Resistant H pylori sis, the first triple-combination therapy that tion, sweat chloride concentration, and re- Faces New Foe treats the underlying cause of most pa- spiratory quality of life compared with the The FDA has approved a combination drug tients’ disease has received FDA approval. tezacaftor-ivacaftor group. for Helicobacter pylori infection that’s Marketed as Trikafta, the drug com- Serious adverse events associated with designed to address high rates of resistance bines elexacaftor, tezacaftor, and ivacaftor. Trikafta in both trials were rash and influ- to standard clarithromycin-based treat- The trio improves the function of the abnor- enza. Common adverse events included ment, according to manufacturer RedHill mal cystic fibrosis transmembrane conduc- headache, upper respiratory tract infec- Biopharma Ltd of Tel Aviv, Israel. In 2017, tance regulator (CFTR) protein resulting tion, abdominal pain, diarrhea, and in- the World Health Organization designated from a genetic mutation that’s responsible creased liver enzymes. the need for new antibiotics against H pylori for about 90% of cystic fibrosis cases. The as a high priority. drug is indicated for patients aged 12 years A combination of the antibiotics rifabu- or older who have at least 1 copy of the An FDA report has offered a snapshot of tin and amoxicillin along with the proton F508del CFTR mutation. drugs subject to shortages in recent years: pump inhibitor omeprazole magnesium, they’re often sterile injectables that have a the drug is marketed as Talicia. In a phase 3 generic version and have been on the mar- trial, 119 patients with H pylori infection ket perhaps for decades. But once they oc- were randomized to receive Talicia or pla- cur, why do the shortages persist? In a word, cebo for 14 days. Infection was eradicated economics. in 89.4% of patients in the treatment group The report comes after members of Con- compared with 2.7% in the placebo group. gress in 2018 urged the FDA to convene a In a confirmatory phase 3 trial, a RedHill task force to examine the issue and offer po- statement noted that H pylori was eradi- tential solutions. In response, officials from cated in 84% of patients in the Talicia the FDA and several other federal agencies group compared with 58% in a group that analyzed 163 drugs that were in short sup- received amoxicillin and omeprazole. ply from 2013 to 2017 and compared them Treatment with 2 CFTR modulators is ef- Adverse reactions included nausea, vomit- with more readily available drugs. ing, and nasal congestion. fectiveforpeoplewithcysticfibrosiswhoare “Shortage drugs were more likely to be “The clinical studies for Talicia demon- homozygous for that mutation. But those relatively low-price and financially unattract- strated high efficacy in eradication of who have a single F508del allele and an- ive drugs,” former Acting Commissioner Ned H pylori,” lead investigator David Y. Graham, other CFTR mutation—about 2000 are Sharpless, MD, and Janet Woodcock, MD, di- MD, of the Baylor College of Medicine in known—have no options to treat the under- rector of the FDA’s Center for Drug Evalua- Houston, said in a statement. The studies lying disease. These mutations are called tion and Research, wrote in a statement. “found zero resistance to rifabutin and minimal function because they result in Sharpless and Woodcock indicated that showed 17% resistance to clarithromycin, a either no CFTR protein production or non- prices rarely increased after shortages be- current standard-of-care macrolide antibi- response to CFTR modulators. gan and production subsequently didn’t rise otic, consistent with current data showing Efficacy was demonstrated in 2 phase 3 to meet demand. Many manufacturers, they trials involving patients with cystic fibrosis. that clarithromycin-containing therapies noted, discontinued drugs that no longer fail in approximately 25%-40% of cases,” In 1 trial, 403 patients with F508del mini- were profitable. mal function genotypes were randomized he added. “These results suggest a broken market- A2017 meta-analysis reported that to receive the triple-drug combination place,” they wrote. or placebo. After 24 weeks, the treated 4.4 billion people—more than half the Although solutions aren’t easy,Sharpless world’s population—had H pylori infection patients had improvements in lung func- and Woodcock recommended that data be tion, pulmonary exacerbations, sweat chlo- in 2015. Prevalence in the US general popu- gathered to quantify the effects of short- lation was 35.6%, but more than doubled ride concentration, and respiratory-related ages, a rating system be developed to quality of life. to 74.8% among Alaska Natives. Nigeria’s inform purchasers and consumers about 87.7% prevalence was the world’s highest; In the other trial, 107 patients who were manufacturers’ quality management, and 18.9% in Switzerland was the lowest. homozygous for the F508del mutation were contracting methods be updated to pro- randomized to receive Trikafta or 2 of its vide manufacturers, especially producers components, tezacaftor and ivacaftor. Af- of older generic drugs, with sustainable Patients With Cystic Fibrosis Have New Triple-Drug Combination ter 4 weeks, the investigators said that pa- returns. − Rebecca Voelker, MSJ Thirty years after investigators discovered tients treated with the 3-drug combination Note: Source references are available through the genetic defect that causes cystic fibro- embedded hyperlinks in the article text online. had “clinically robust” benefits in lung func- 2068 JAMA December 3, 2019 Volume 322, Number 21 (Reprinted) jama.com © 2019 American Medical Association. All rights reserved. James Cavallini/sciencesource.com
JAMA – American Medical Association
Published: Dec 3, 2019
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