Eloxx Pharmaceuticals Reports Positive Topline Results in CF
November 17, 2021
Eloxx Pharmaceuticals reported positive topline results from the monotherapy arms of its phase 2 clinical trial of ELX-02 in Class 1 cystic fibrosis patients with at least one G542X nonsense allele mutation.
Cystic fibrosis (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.
ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins. The U.S. Food and Drug Administration has granted Fast Track designation for ELX-02. 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 Medicines Agency.
“We are highly encouraged with the topline results from the monotherapy 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,” said Sumit Aggarwal, president and CEO of Eloxx.
The phase 2 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.
ELX-02 was generally well tolerated in the trial, with no treatment-related serious adverse events noted.
The study met a key secondary endpoint by showing a statistically significant reduction in mean sweat chloride of 5.4 mmol/L after one week of therapy for ELX-02 dosed at 1.5mg/kg/day.
Short term reductions in sweat chloride have been shown to correlate with biologic activity of the CFTR protein and translate to lung function improvement over the long term.
A potential dose response trend was also seen in mean sweat chloride reduction, with a stronger dose response trend in the subset of patients (post-hoc) that completed the 1.5mg/kg/day dosing.
The reduction in mean sweat chloride in Class 1 CF patients with nonsense mutations who received 1.5mg/kg/day in the trial is similar to the activity in Class 1 CF patient organoids treated with ELX-02 in preclinical experiments.
As expected, no change was observed in forced expiratory volume (FEV1) due to short treatment duration.
While the trial was not designed as a longer-term efficacy study and did not compare ELX-02 to any other agent, results from prior phase 2 trials with FDA-approved agents for CF can serve as a contextual reference for the level of sweat chloride reduction observed and its potential clinical relevance.
Results of a phase 2 study with lumacaftor and lumacaftor/ivacaftor combination (Orkambi), an FDA-approved combination CF agent, demonstrated 4.1mmol/L to 5.1 mmol/L reductions in sweat chloride over two- and three-week study durations in Class 2 CF patients with HomF50del mutations.
Results of a phase 2 study with tezacoftor/ivacaftor combination (Symdeko), an FDA-approved combination CF agent, demonstrated a 1.8mmol/L to 5.2 mmol/L reduction in sweat chloride over 28 days in Class 2 CF patients with HomF50del mutations.
Treatment with both these agents resulted in improved lung function as measured by forced expiratory volume (FEV1) with longer treatment duration in subsequent phase 3 trials with Orkambi and Symdeko.
First patient dosing has occurred in the expansion arm of the phase 2 trial, which includes a combination of ELX-02 and Kalydeco (ivacaftor), a CFTR protein potentiator. In preclinical studies, Class 1 CF patient organoids had a 2- to 3-fold higher swelling response with a combination of ELX-02 and Kalydeco than with ELX-02 as a monotherapy. Topline results are expected by the end of the first half of 2022.
“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, head of Research and Development of Eloxx.
Eloxx has also begun evaluation of inhaled (nebulizer-based) delivery of the current subcutaneous formulation of ELX-02. Eloxx believes that inhaled delivery has the potential to further improve the activity of ELX-02 as a single agent and in combination with other drugs given potential for increased drug exposure in the lung versus plasma. Prior animal studies have shown a 19-fold increase in ELX-02 exposure at a similar dose when administered as an inhalation agent versus subcutaneously.
The company said it expects to submit an Investigational New Drug application the second half of 2022.
Author: Rare Daily Staff
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