EXECUTIVE INTERVIEW – Eloxx Pharmaceuticals: Developing Rare Disease Drugs for Nonsense Mutations


Led by a management team experienced in the development of rare disease therapeutics, Eloxx Pharmaceuticals is a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel therapeutics to treat cystic fibrosis (CF), cystinosis, inherited retinal disorders, and other diseases caused by nonsense mutations limiting production of functional proteins. Drug Development & Delivery recently interviewed Bob Ward, Chairman and CEO at Eloxx Pharmaceuticals, to discuss nonsense mutations and how his company’s goal is to bring safe and effective therapies to children and adults suffering from genetic diseases as quickly as possible.

Q: What are nonsense mutations, and what is Eloxx working on to address the rare diseases associated with them?

A: Worldwide, approximately 4% of all babies are born with a genetic disease or major birth defect. Of those, about 12% of all mutations reported are caused by an anomaly known as a nonsense mutation. These variations introduce premature stop codons in the reading frame of a gene, which can halt or stunt the production of a protein. Consequently, most nonsense mutations result in missing or nonfunctional proteins.

Nonsense mutations have been identified in about 1,800 rare and ultra-rare diseases, often patients with these mutations lack the ability to make essential proteins and have few, if any, treatment options. The vast majority of these are terrible diseases.

Our lead investigational compound, ELX-02, is in the early stages of development for CF and has the potential to be the first disease-modifying therapy for CF patients with nonsense mutations in one or both alleles. Preclinical studies have demonstrated that ELX-02 is a potent read-through-inducing drug in several models of genetic disease caused by nonsense mutations, including CF, cystinosis, mucopolysaccharidosis type I (MPS I), Rett syndrome Duchenne muscular dystrophy, and inherited retinal disorders. ELX-02 is an investigational drug that has not been approved by any global regulatory body. Eloxx’s preclinical candidate pool consists of a library of novel ERSG drug candidates identified based on read-through potential. Eloxx recently announced a new program focused on rare ocular genetic disorders.

Q: What is your lead candidate, and review for our readers what is in the pipeline?

A: Our lead investigational compound, ELX-02, is a eukaryotic ribosomal selective glycoside (ERSG) designed to restore the production of protein through reading-through a premature stop codon and enabling the production of sufficient amounts of full-length functional CFTR protein to restore activity.

Currently our clinical programs for ELX-02 are focused on development for CF and cystinosis patients with diagnosed nonsense mutations on one or both alleles. These patients have a high unmet medical need, a high burden of disease and few, if any, treatment options. Our CTA in Belgium for CF has been approved, and our IND in the US for cystinosis is open. Our Phase 2 program has been given a score of “high priority” by the European Cystic Fibrosis Society-Clinical Trial Network (ECFS-CTN). We expect to initiate Phase 2 clinical trials in CF and cystinosis and report top line data in 2019.

Eloxx’s preclinical candidate pool consists of a library of novel ERSG drug candidates identified based on read-through potential. Eloxx recently announced a new program focused on rare ocular genetic disorders.

We are the leader in the development of eukaryotic ribosomal selective glycosides (ERSG) aimed at treating rare and ultra-rare premature stop codon diseases.

Q: Can you review Eloxx’s current R&D strategy?

A: Our research and development strategy is to target rare or ultra-rare diseases in which a high unmet medical need, nonsense mutation bearing patient population has been identified. We focus on clinical indications in which established preclinical read-through or personalized medicine experiments are predictive of clinical activity, and there is a definable path for Orphan Drug development, regulatory approval, patient access, and commercialization.

Our current clinical focus is on CF and cystinosis where we are advancing our lead investigational drug candidate, ELX-02, a eukaryotic ribosomal selective glycoside (ERSG). Eloxx’s preclinical candidate pool consists of a library of novel ERSG drug candidates identified based on read-through potential. Eloxx recently announced a new program focused on inherited retinal disorders.

Q: What types of other diseases could Eloxx Pharma’s platform potentially target?

A: More than 1,800 genetic diseases involve nonsense mutations that impair the production of essential proteins. Translational read-through is directed at restoring the production of full length functional proteins by overcoming the premature stop codon and the associated nonsense-mediated decay.

Q: What are organoids, and what is Eloxx doing with them from a research standpoint?

A: Organoids are tiny, self-organized three-dimensional tissue cultures that are derived from patient stem cells. The HUB, a nonprofit organization associated with the Utrecht University, has developed the organoid model and is testing all drugs approved and in development of CF. Eloxx is working with the HUB on a series of studies using CF patient-derived organoids and an FIS swelling assay, which is being broadly used in CF as a complement to the human bronchial epithelial cell model to understand how different cystic fibrosis mutations respond to ELX-02.

At the North American Cystic Fibrosis Conference (NACFC) in Denver this past October, we shared new data generated in the organoid model that demonstrates the reproducibility of the assay and its dependence on CFTR activity. ELX-02 is the first investigational compound to show these beneficial effects in organoids derived from patients with nonsense mutations. At NACFC, we shared positive data demonstrating that ELX-02 showed dose responsive increases in CFTR function and Mrna expression when tested in a correlative assay using organoids from CF patients with homozygous and heterozygous nonsense mutations. The FIS swelling was consistent across a range of concentrations of the swelling-inducing agent, forskolin, and did not saturate in the timeframe of the assay. Significant dose-responsive increases in CFTR were demonstrated for ELX-02 in a functional assay using nanoStringTM technology. ELX-02 mediated organoid swelling was found to correlate with increased CFTR mRNA, with elevations to levels at or above wild-type. ELX-02 appears to increase the steady state concentrations of CFTR mRNA, suggesting that ELX-02 may be modulating nonsense-mediated decay.

We are encouraged by the data that showed it is possible to restore CFTR and mRNA to normal levels in patients with nonsense mutations with ELX-02 to normal levels. These data are important as mRNA is required by the cell to make CFTR protein. By enabling read-though, mRNA is no longer being degraded by nonsense-mediated decay.

Q: What are the next critical steps for Eloxx?

A: We’re pleased that our CTA in Belgium for CF is approved and that ELX-02 has been granted Orphan Drug Designation by EMA. Our IND for the US for cystinosis is open, and the FDA has also granted ELX-02 Orphan Drug Designation.

We expect to initiate Phase II trials this year, and we are on track to report top line data in 2019. We are very encouraged, as ELX-02 is the only read-through agent to have demonstrated substantial activity in CF patient-derived organoids bearing nonsense mutations. We believe the consistent positive data meaningfully de-risk our planned Phase 2 studies.

We’re pleased to have initiated a new program focusing on inherited retinal diseases and with the emerging favorable tolerability profile demonstrated by several compounds from our library. We are currently in IND-enabling studies and plan to advance an additional molecule into development in an inherited retinal disorder, and we have entered into a broad strategic partnership with the Foundation Fighting Blindness.

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