ELX-02 Plus Kalydeco Fails to Reach Trial’s Efficacy Goals

The trial tested the combo in CF caused by nonsense mutations

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with ELX-02 in combination with Kalydeco (ivacaftor) was well-tolerated, but failed to meet efficacy goals in a clinical trial that tested the combo in people with cystic fibrosis (CF) caused by nonsense mutations.

Eloxx Pharmaceuticals, the company developing ELX-02, says the lack of efficacy may be due to low amounts of the medication getting where it is needed in patients’ bodies. The company stated that next steps for the therapy in CF will be decided following discussions with the CF Foundation, which has helped to fund the development of ELX-02.

“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,” Sumit Aggarwal, president and CEO of Eloxx, said in a press release.

CF is caused by mutations in the CFTR gene that provides instructions for making the CFTR protein, which helps regulate the flow of water and salt in and out of cells. There are several types of CF-causing mutations; about 10% of patients have disease caused by nonsense mutations.

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Nonsense mutations result in a “stop” signal midway through the CFTR gene, ultimately resulting in the production of a truncated version of the CFTR protein that gets rapidly degraded by cells. ELX-02 was designed to help the cellular protein-making machinery “read through” this abnormal signal to generate a full-length, functional CFTR protein.

In this clinical trial, CF patients harboring the most common CF-causing nonsense mutation, called G542X, were treated for one week with ELX-02, given daily via subcutaneous (under-the-skin) injection at a dosage of 1.5 mg/kg. Then for the next four weeks, participants continued ELX-02 treatment and also were given Kalydeco (150 mg twice daily).

Kalydeco is an approved CFTR modulator therapy sold by Vertex Pharmaceuticals. It can help improve the functionality of the CFTR protein by “propping open” the gate-like protein, allowing easier flow of water and salts.

No serious side effects

Top-line results announced by Eloxx showed that the combination therapy was well-tolerated overall, with no serious side effects related to the treatment reported.

Efficacy measures in the study included sweat chloride content (an assessment of CFTR function) and forced expiratory volume, a measure of lung function. Results showed no significant changes in these measurements overall. Sweat chloride measures showed a significant response among patients who initially had higher (worse) values.

According to Eloxx, the trial results were muddied by high variability in these efficacy measurements, which may partly explain the lack of significant results.

The company also noted that the average concentration of ELX-02 in patients’ lungs was 2 micromolar, which is just 20% of the minimum concentration that was needed to achieve therapeutic activity in preclinical tests. Dosing of ELX-02 by inhalation directly into the lungs, rather than injection under the skin, is expected to increase medication exposure by at least 50 times, according to Eloxx.

The company now is planning to start clinical testing of ELX-02 in Alport syndrome, a rare genetic disorder that affects the kidneys, among other complications.

“Given the safety and evidence of activity we have observed to date with ELX-02, including in this trial, we look forward to initiating a proof-of-concept trial for ELX-02 in Alport syndrome … 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,” Aggarwal said.