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Combination Trial of Ivacaftor and Eloxx’s ELX-02 in Cystic Fibrosis Fails to Reach Statistical Significance

September 15, 2022

Eloxx Pharmaceuticals reported topline results from the phase 2 clinical trial of ELX-02 in combination with ivacaftor in Class 1 cystic fibrosis patients with at least one nonsense mutation, which found that the combination was well tolerated but did not achieve statistical significance for efficacy endpoints, including changes from baseline in sweat chloride concentration (SCC) and percent forced expiratory volume (FEV1).

Photo: Sumit Aggarwal, president and CEO of Eloxx

“We are disappointed that ELX-02 failed to achieve statistical significance for its key efficacy endpoints in this phase 2 trial in combination with ivacaftor for the treatment of Class 1 CF. Despite this setback, we were pleased to observe that ELX-02 was well tolerated and demonstrated additional evidence of activity in this underserved patient population. We will work closely with the CF Foundation, as it has generously supported this trial, to determine the next steps in the development of ELX-02 for CF,” said Sumit Aggarwal, president and CEO of Eloxx.

Cystic fibrosis (CF) is an inherited condition caused by mutations in the CFTR gene and is inherited in an autosomal recessive fashion that causes mucus to build up and clog some organs in the body, particularly in the lungs and pancreas. When mucus clogs the lungs, it can make breathing very difficult. The thick mucus also causes bacteria to get stuck in the airways, which causes inflammation and infections. Over time, mucus buildup and infections can lead to permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs. Mucus can also block the digestive tract and pancreas, leading to digestive problems.

CF patients with a Class 1 nonsense mutation remain highly underserved with no approved disease modifying therapies. An estimated 10-12 percent of CF patients are Class 1 patients with one or both alleles harboring nonsense mutations, leading to less than full length CFTR proteins on the cell membrane in these patients.

Eloxx’s lead investigational product candidate, ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins. The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for ELX-02 for the treatment of CF patients with nonsense mutations. In addition, ELX-02 has also been granted Orphan Drug designation for the treatment of CF patients with nonsense mutations by the FDA and orphan medicinal product designation by the European Commission.

Despite this failure, the company plans to initiate a proof-of-concept trial for ELX-02 in Alport syndrome, a rare kidney disease, later this year. “Given the likelihood of increased drug exposure, as ELX-02 is preferentially taken up in the kidneys, we believe ELX-02 is well suited to potentially deliver transformative results in these patients,” said Aggarwal.

The phase 2 combination clinical trial of ELX-02 was designed to evaluate safety and assess biological activity in G542X nonsense mutation Class 1 CF patients as monotherapy and in combination with ivacaftor. The trial included a 1-week monotherapy period (1.5 mg/kg daily subcutaneous) followed by a four-week combination period (1.5 mg/kg daily subcutaneous and 150 mg ivacaftor twice daily).

Topline results showed that ELX-02 was generally well tolerated in the trial, with no treatment-related serious adverse events noted; overall, the study did not achieve statistical significance for efficacy endpoints including changes from baseline in SCC and FEV1; and no incremental improvement was observed with ivacaftor combination.

Evidence of activity for ELX-02 was observed, as patients with higher baseline sweat chloride levels demonstrated increased responses as indicated by SCC, but trial results were potentially confounded by high variability in sweat chloride and lung function measurement.

Eloxx believes this variability could have been caused by very low drug exposures in the lung. Steady state lung drug levels in patients from this trial were on average 20 percent of the lowest levels at which drug activity has previously been seen in preclinical testing. Lung drug exposure with inhaled delivery of ELX-02 is expected to be at least 50-fold greater than with subcutaneous delivery.

Author: Rare Daily Staff

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