In Cystic Fibrosis Failure, Eloxx Sees Silver Lining for Alport Syndrome

Kidney exam

After reporting a failed clinical trial of ELX-02 for cystic fibrosis (CF), Eloxx Pharmaceuticals plans to shift its focus and use the drug to treat Alport syndrome, a rare kidney disease.

The Phase II trial of ELX-02, in combination with Vertex's Kalydeco (ivacaftor) in Class 1 CF patients who have at least one nonsense mutation, failed to hit the primary efficacy endpoints. But because ELX-02 is preferentially taken up in the kidneys, the company believes it may be effective in patients with Alport syndrome.

"The trial demonstrated ELX-02 was active, but it was difficult to get appropriate levels into the necessary tissues, Sumit Aggarwal, president and CEO of Eloxx, told BioSpace.

Aggarwal added that "the bridge between activity and clinical efficacy was a bridge too far," and that variability in the data confounded the result.

In the trial, no improvements were seen with the ivacaftor combination. There were signs of activity in patients with higher baseline sweat chloride levels showing increased responses by the SCC test. These included changes from baseline in sweat chloride concentration (SCC) and percent forced expiratory volume (FEV1).

Aggarwal suggested the data were potentially confounded by unexpectedly high variability in sweat chloride and lung function measurements, which may have been caused by very low drug exposures in the lung.

The steady-state levels of the drug in the lungs of study participants were, on average, 20% of the lowest levels ever seen in preclinical testing. Eloxx had expected lung drug exposure with inhaled dosing to be at least 50-fold higher than with subcutaneous delivery.

Alport syndrome is a genetic disease marked by kidney disease, hearing loss and abnormalities of the eye. It is caused by mutations in the COL4A3, COL4A4 and COL4A5 genes, which code for a component of type IV collagen protein, which plays a key role in the kidneys.

ELX-02 is a small molecule engineered to restore the production of full-length functional proteins. It belongs to a class of drugs called aminoglycosides that have preferential uptake in the kidneys. The drug appears to slow down ribosomes enough so that instead of truncated proteins, it causes fully formed proteins. It previously received FDA Fast Track designation for CF patients with nonsense mutations.

Another drug in the company's pipeline is ZKN013. Aggarwal said Eloxx plans to submit an Investigational New Drug (IND) application to the FDA for this drug by the end of the year.

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