ELX-02 Lowers Sweat Chloride in Patients With G542X Mutation, Trials Find

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by Marta Figueiredo PhD |

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ELX-02 for nonsense mutations | Cystic Fibrosis News Today | clinical trial illustration

Eloxx Pharmaceuticals’ experimental therapy ELX-02 was generally safe and resulted in a significant reduction in sweat chloride levels — a biomarker of cystic fibrosis (CF) — in patients carrying the most common CF-causing nonsense mutation, according to top-line data from a Phase 2 clinical program.

While the short duration of treatment (one week) did not allow significant changes in lung function to be detected, findings suggest that the therapy improved the activity of CFTR, the faulty protein in CF, to levels similar to those of approved therapies for other CF-causing mutations.

As such, Eloxx believes ELX-02 will lead to gains in lung function with long-term treatment.

“We are highly encouraged with the topline results from the [single therapy] arms of our Phase 2 trial, and believe that ELX-02, if approved, has potential to transform the lives of Class 1 CF patients with nonsense mutations, who do not have any available therapies,” Sumit Aggarwal, Eloxx’s president and CEO, said in a press release.

ELX-02 in combination with the approved therapy Kalydeco (ivacaftor) is also being evaluated in the Phase 2 clinical program, and top-line study results are expected by mid-2022.

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“With dosing of the first patient, we have now advanced ELX-02 into the Phase 2 combination study and have begun preparations for Phase 3 clinical development,” said Vijay Modur MD, PhD, Eloxx’s head of research & development.

According to a company webcast detailing trial findings and planned next steps, the launch of the Phase 3 trial is expected by late 2022 or early 2023.

CF is caused by different types of mutations in the CFTR gene, all resulting in the production of a faulty CFTR protein. Since CFTR controls the flow of water and ions through cells, these mutations lead to the excessive production of mucus in several organs, such as the lungs, and salty sweat.

ELX-02 is designed to treat people with CF due to nonsense mutations, which are the cause of about 10–12% of all cases and of which G542X is the most common. Nonsense mutations cause an early stop signal in an intermediate molecule in protein production, resulting in a shorter, non-functional CFTR protein.

Administered as an under-the-skin-injection, ELX-02 works by helping the ribosome — the cells’ protein-building machinery — ignore the premature stop signal (a process called read-through) to generate a full-length, working CFTR protein.

The therapy was designated an orphan drug in the U.S., an orphan medicinal product in Europe, and given fast track designation in the U.S. These designations are meant to accelerate its clinical development and regulatory review.

ELX-02 is being tested in CF patients carrying least one G542X mutation in two parallel open-label Phase 2 clinical trials — EL-012 (NCT04135495)  in the U.S., and EL-004 (NCT04126473) in Australia, Germany, and Israel.

Up to 20 participants, ages 18 and older in EL-012 and 16 and older in EL-004, received four treatment regimens with escalating daily doses of ELX-02 at 0.3, 0.75, and 1.5 mg/kg, and then a dose of up to 3 mg/kg. Each of the first three regimens was given for seven days, with the last having a treatment duration of two weeks.

The trials’ main goals were to assess the therapy’s safety, tolerability, pharmacokinetics (its movement into, through, and out of the body). Secondary goals included changes in the levels of chloride (a component of salt) in sweat, a biomarker of CFTR function, and in lung function from baseline (study’s start) to the last day of each treatment regimen.

Baseline sweat chloride was defined as the average between values at study start and those prior to initiation of each regimen.

Top-line results showed that ELX-02 was generally safe and well tolerated, with no treatment-related serious adverse events reported. The most common adverse events were mild to moderate injection-site reactions, which led to treatment discontinuation in three patients (two at the highest dose group).

One week of daily treatment with 1.5 mg/kg of ELX-02 resulted in a significant drop in sweat chloride of 5.4 milimol per liter (mmol/L), which was similar to those reported over the short-term in previous Phase 2 trials of approved therapies for CF patients with other types of mutations, Eloxx noted.

Specifically, two to three weeks of treatment with lumacaftor (VX-809) and Orkambi (lumacaftor/ivacaftor) resulted in a 4.1 to 5.1 mmol/L reduction in sweat chloride levels, while nearly a month of treatment with Symdeko (tezacaftor/ivacaftor) dropped the levels by up to 5.2 mmol/L.

Eloxx also noted that the effect of the 1.5mg/kg dose on patients’ sweat chloride levels was consistent with ELX-02’s activity previously seen in lab-grown organoids, or 3D mini-organs, derived from CF patients with at least one G542X mutation.

No significant sweat chloride changes were observed with the other three dose regimens. Notably, inconsistent dosing and fewer patients completing the highest and final dose regimen limited the ability to draw meaningful conclusions, the company noted in the webcast, adding that no doses between 1.5 mg/kg and 3 mg/kg will be further evaluated.

No changes were evident in patients’ lung function, but this was likely due to the short treatment duration, the company stated in the release.

Given that longer treatment with either Orkambi or Symdeko in subsequent Phase 3 trials was associated with lung function improvements, ELX-02’s use over a longer time may result in similar benefits.

Combination therapy

Based on these findings and on previous organoid data suggesting that a combination of ELX-02 and Kalydeco may be more effective, the Phase 2 trials will now test this combination in up to 30 CF patients carrying G542X or other nonsense mutations.

Those enrolled will receive one week of treatment with ELX-02 alone at its now-established optimal dose (1.5 mg/kg per day), followed by four weeks of ELX-02 plus Kalydeco, given as a 150 mg tablet twice a day. The trials’ combination therapy part will have the same goals as the completed single therapy part.

The trials may be actively recruiting; more information on U.S. sites can be found here and on those outside the U.S. can be found here.

Eloxx is also evaluating an inhaled formulation of ELX-02, since the company believes that inhaled delivery might further improve the therapy’s activity, both as a single agent and in combination with other therapies. Late next year, the company expects to file an application for permission to initiate clinical trials testing the new formulation in the U.S.


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