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New Breakthroughs Offer Hope for Patients with Cystic Fibrosis to Breathe Easier

Two preliminary trials have found that either of two triple-drug regimens could potentially benefit 90 percent of people with cystic fibrosis. The short-term trials found that the drug combinations improved adult patients’ lung function over four weeks. But experts said they were optimistic the results will hold up in the larger, longer-term trials already underway.

Researchers point to a  triple-drug approach could open up new options to nearly all cystic fibrosis patients. “This is not a cure for cystic fibrosis,” stressed Dr. Steven Rowe, a director of the Cystic Fibrosis Research Center at the University of Alabama at Birmingham and leader of one of the trials. “But it could be game-changing.” Both new trials focused on those two groups of patients. The results are published in the Oct. 18 New England Journal of Medicine, to coincide with the researchers’ presentation at a North American Cystic Fibrosis meeting, in Denver.

Rowe’s team tested a combination of two available CFTR modulators — tezakaftor and ivakaftor — plus an experimental one, known as VX-659. The other trial used the same existing drugs, along with a similar new drug, dubbed VX-445. The Cystic Fibrosis Foundation helped fund the work through a grant to Vertex Pharmaceuticals, Inc., which is developing both experimental drugs.

Cystic fibrosis (CF) is a genetic disorder that causes persistent lung infections. Over time, extensive lung damage leads to respiratory failure. At one time, children with CF usually died before they reached school age. But with improved treatments, the typical life expectancy is now about 40 years, according to the Cystic Fibrosis Foundation.

Cystic fibrosis is caused by various mutations in a gene called CFTR. In the past several years, drugs that target those underlying genetics have become available. Known as CFTR modulators, they were heralded as a major advance in treating the disorder.

However, they work well only for a small number of people with certain CFTR mutations, explained Rowe. “The most common mutation that causes cystic fibrosis is called F508del — and it has proven tougher to tackle, Rowe said.

About half of people with CF carry two copies of the mutation (one inherited from each parent). For them, a combination of two existing CFTR modulators can ease breathing problems — but the overall effects are only “modest,” Rowe said.

Then there’s the 30 percent of CF patients who carry only one copy of F508del, plus another defect known as a “minimal-function” mutation. For them, the existing CFTR modulators do not work at all.

Early Hope

Rowe’s team randomly assigned 54 adults with cystic fibrosis to either take the triple-drug regimen or be in a comparison group. In the comparison group, patients with one F508del mutation took placebo pills, while patients with two copies of the mutation took tezakaftor and ivakaftor alone.

After four weeks, the trial found, the triple-drug therapy had improved lung function in patients with both types of mutations. Their performance on a test called FEV1 rose by as much as 13 percentage points, on average — what Rowe described as a “pronounced improvement.”

The other trial had nearly identical results. This is the first time, Rowe said, that CFTR modulator therapy has “pushed the needle” for patients with one F508del mutation.

An editorial published with the studies said they “represent a major breakthrough.”

Now the questions are whether the improved lung function can be sustained, and whether the drugs prevent symptom exacerbations and other complications, wrote Dr. Fernando Holguin, of the University of Colorado, Aurora.

New Treatments on the Horizon

Eloxx Pharmaceuticals, Inc.,  a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel therapeutics to treat cystic fibrosis, cystinosis and other diseases caused by nonsense mutations limiting production of functional proteins,  announced positive data demonstrating that ELX-02 showed significant increases in CFTR functional assay (P<0.0001) and mRNA levels (P<0.05) across multiple CFTR nonsense mutations in cystic fibrosis patient-derived organoids. ELX-02 demonstrated significant forskolin-induced swelling (FIS) in cystic fibrosis patient-derived organoids carrying homozygous and compound heterozygous CFTR nonsense mutations. These findings were presented at the North American Cystic Fibrosis Conference in Denver, Colorado.

Recent work with cystic fibrosis patient-derived organoids have extended the potential applications of the FIS assay to include use in stratifying patient disease severity (1) and as a potential predictor of CF patient response to drug therapy (2).

Eloxx plans to initiate a Phase 2 study in cystic fibrosis patients carrying at least one G542X mutation. The European Cystic Fibrosis Society-Clinical Trial Network has reviewed the program and assigned a “high priority” rating. Eloxx expects to report top-line data from the Phase 2 study in 2019.

In a Poster presentation titled “Measuring mRNA levels in cystic fibrosis organoids with nonsense mutations following treatment with ELX-02,” presented by Neal Sharpe, Ph.D., V. P. Translational Science, Eloxx reported that:

  • ELX-02 demonstrated dose responsive increase in CFTR function and mRNA expression when tested in a correlative assay using organoids from cystic fibrosis patients with homozygous and heterozygous nonsense mutations. The FIS swelling was consistent across a range of concentrations of the swelling inducing agent, forskolin, and did not saturate in the timeframe of the assay. Additionally, the swelling response was demonstrated to be dependent on CFTR activity and the presence of a nonsense mutation. The response demonstrated is consistent with levels potentially predictive of clinical efficacy.
  • Using nanoString™ technology, ELX-02 mediated organoid swelling was found to correlate with increased CFTR mRNA, with elevations above wild-type. ELX-02 appears to increase the steady state concentrations of CFTR mRNA suggesting that ELX-02 may be modulating nonsense mediated decay.
  • The increased CFTR function demonstrated with ELX-02 was further enhanced with the addition of a potentiator and corrector in some organoids derived from patients with heterozygous nonsense mutations.
  • These data demonstrate that ELX-02 promotes translation of functional CFTR and support continuing development of ELX-02 in patients with cystic fibrosis.

“We are extremely pleased with the emerging profile of ELX-02, as the first read-through agent to demonstrate increases in CFTR function and mRNA in organoids derived from cystic fibrosis patients with nonsense mutations,” said Neal Sharpe, Ph.D., Vice President of Translational Sciences at Eloxx. “There is a high unmet medical need among the estimated 13% of cystic fibrosis patients with a nonsense mutation, as they have a high burden of disease and few, if any, treatment options.”

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