Investigational drug gives sight to patient with inherited form of blindness 

A patient with childhood blindness has gained vision after a single injection of sepofarsen, an investigational RNA therapy.

The patient had a rare genetic disorder known as Leber congenital amaurosis (LCA) that affects the retina and often causes severe visual impairment. Injection of sepofarsen led to measurable changes in the fovea, a depression in the retina where eyesight is sharpest.

The research was published in Nature Medicine.

The drug was developed by ProQR (Leiden, Netherlands), which has a Phase 2/3 clinical trial underway for sepofarsen involving 36 participants.

Scientists at the University of Pennsylvania had found in 2018 that injections of sepofarsen administered every three months led to continued vision improvement in 10 study participants. One participant with the ability to perceive light gained 20/400 vision. That research was also published in Nature Medicine.

“The sponsor of the clinical trial (ProQR) had guessed that sepofarsen would be cleared from the retina in about 2–3 months,” said Artur V. Cideciyan, a research professor of ophthalmology at the Scheie Eye Institute at the University of Pennsylvania. “Therefore the clinical trial was designed with injections planned every three months.”

That sepofarsen clinical trial began in October of 2017.

The University of Pennsylvania has had an ongoing Phase 1/2 clinical trial related to sepofarsen since November 2017.

LCA occurs in two or three newborns out of 100,000, making it one of the most common causes of childhood blindness.

LCA patients often have a mutation in the CEP290 gene, which is responsible for encoding a protein within the transition zone of the rod photoreceptors in the eye. The p.Cys998X mutation is commonly linked to the disorder. Overall, however, there are more than 20 different genes that cause LCA.

Sepofarsen can increase CEP290 levels in the eye’s photoreceptors to improve retinal function.

“Our results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations,” said Cideciyan. “Importantly, we established a comparator for currently-ongoing gene-editing therapies for the same disease, which will allow comparison of the relative merits of two different interventions.”

When asked what led the group to sepofarsen, Cideciyan said that the drug, a small (17 nucleotide) anti-sense oligonucleotide (ASO) molecule was “specifically designed for the exact mutation these patients have as an extreme example of personalized medicine.”

ProQR has developed other ASOs for two other forms of inherited retinal degeneration. “One for P23H mutations in the Rhodopsin gene that causes autosomal dominant retinitis pigmentosa, and another one for Exon 13 mutations in the USH2A gene that causes autosomal recessive forms of Usher syndrome or retinitis pigmentosa,” Cideciyan said. “Both are currently in clinical trials. It remains to be seen how different diseases with different molecular defects respond to ASO therapies.”

In the recent case report, a patient treated with injectable sepofarsen demonstrated considerable vision improvement after one month, with visual acuity peaking between two and three months after the initial injection.

Visual improvements persisted 15 months after treatment.

FDA and EMA have granted orphan drug designation to sepofarsen. FDA has also awarded fast track designation status to the drug.

University of Pennsylvania researchers are also continuing their research on sepofarsen and other similar therapies.

“We continue to evaluate promising gene-based therapies in early phase clinical trials for different forms of inherited retinal degeneration,” Cideciyan said.