In an interview with PharmaShots, Dr. Robert Koenekoop, MD, PhD, Professor of Pediatric Surgery, Human Genetics and Adult Ophthalmology at McGill University's Montreal Children's Hospital shared his views on the clinical data of the trial and shed light on how RNA therapies work in eye disorders?

Shots:

• QR-421a demonstrated a concordant benefit in multiple measures of vision including visual activity, visual fields, and retinal imaging. QR-421a was also observed to be safe and well-tolerated with no SAEs reported
• QR-421a targets the underlying cause of the genetic disease with the intent to stop vision loss in people with Usher syndrome and retinitis pigmentosa due to USH2A exon 13 mutations
• ProQR has built a platform to develop highly targeted therapies to address the underlying cause of inherited retinal diseases to stop or reverse vision loss

Tuba:   Can you shed some light on Usher Syndrome Type 2a and Non-Syndromic Retinitis Pigmentosa?

Dr. Koenekoop: Usher syndrome is a genetic condition characterized by both hearing loss up to deafness and the progressive loss of vision. The vision loss can also occur without hearing loss in a related disease called non-syndromic retinitis pigmentosa (nsRP).

Usher syndrome type 2a is caused most often by mutations in the USH2A gene. This gene is responsible for the formation of the Usherin protein. The mutation results in a dysfunctional Usherin protein and disrupts a process called phototransduction in the light-detecting cells (rod and cone photoreceptors) in the retina, causing RP. People with Usher syndrome type 2a are usually born with hearing loss and start to have progressive vision loss during adolescence.

People living with RP experience a gradual decline in their vision because both photoreceptor cell types  'rods and cones'  degenerate and die. Night blindness is followed by visual field loss and visual acuity loss, which may eventually result in complete blindness. RP is one of the most heterogeneous genetic conditions, known to be caused by more than 60 genes, and affects approximately 1 in 3,000 to 1 in 4,000 individuals worldwide.

Tuba:   Discuss QR-421a in detail (including its RoA, its type, etc), along with its mechanism of action.

Dr. Koenekoop: QR-421a is an investigational RNA therapy developed by ProQR Therapeutics that aims to stop vision loss in people with RP and Usher syndrome due to mutation(s) in a specific part of the USH2A gene, called exon 13, which is one of the most common locations for mutations in the USH2A gene. It is administered as an intravitreal injection (directly into the eye).

QR-421a works by binding to the mutated USH2A RNA to exclude exon 13 from the RNA. This approach is known as exon skipping. The cells in the retina can then produce a slightly shorter but functional USH2A protein, without the mutation(s).

Tuba:   Unveil the study design of P-I/II Stellar study.

Dr. Koenekoop: The Stellar trial is a randomized, sham-controlled, single ascending dose, global, multicenter, 24-month study. The study includes a total of 20 patients, of which 14 received a single dose of QR-421a and six received a single sham procedure for masking.

The 14 QR-421a-treated patients enrolled varied in their disease stage and were classified into two groups; advanced patients (defined as patients with baseline visual acuity of <70 letters, or equivalent to LogMAR 0.3, or worse than 20/40 on a Snellen chart) and early to moderate patients (visual acuity of >70 letters, or better than 20/40 Snellen). Six patients had advanced disease and eight patients had early to moderate disease.

Three different dose levels were studied. The population also varied in disease characteristics with both Usher syndrome (n=7) and nsRP (n=7) and genetic background with both USH2A mutations in exon 13 (n= 9) and other subjects who have one USH2A mutation in exon 13 (n=5) and the other mutation elsewhere in the gene. The majority of the patients were followed for up to 48 weeks, with one patient followed up to 96 weeks.

Tuba:   Discuss the safety and efficacy data of QR-421a in P-I/II Stellar trial.

Source: ProQR

Dr. Koenekoop: QR-421a was observed to be well tolerated at all doses. There were no serious adverse events reported and no inflammation was observed. One patient had to worsen pre-existing cataracts in both the treated and untreated eyes; both were deemed not treatment-related by the investigator. One patient had a progression of pre-existing cystoid macular edema (CME) that was managed with standard of care. Both cataracts and CME are associated with a high rate of occurrence in the natural history of this disease.

Best-corrected visual acuity, or BCVA, is a measure of central vision, or sharpness of sight, as measured on an Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart. In advanced patients, the primary measure of efficacy is BCVA. In early-moderate patients, the primary measure of efficacy is a measurement of visual fields by static perimetry. QR-421a-treated patients responded on endpoints consistent with their disease stage in both advanced and early to moderate patient populations after a single injection.

All three doses studied in the Stellar trial were observed to be active as predicted by the preclinical data. No differences were observed based on patients having one or two exons 13 mutations in USH2A, or having Usher syndrome or non-syndromic RP. These findings were consistent with the preclinical data for QR-421a.

Tuba:   What are your plans to advance QR-421a in other clinical studies?

Dr. Koenekoop: On the basis of these findings, ProQR plans to conduct two pivotal Phase 2/3 clinical trials with the Sirius trial evaluating QR-421a in patients with advanced vision loss, and the Celeste trial evaluating QR-421a in patients with early-moderate vision loss. Based on initial Regulatory guidance, ProQR plans to submit protocols to start two Phase 2/3 trials. Each trial could potentially serve as the sole registration trial depending on the findings. Pending finalization of the study designs with Regulatory authorities, the trials are expected to start before year-end 2021. Both trials are expected to be conducted at global centers of excellence.

Tuba:   How do RNA therapies work specifically in eye disorders?

Dr. Koenekoop: RNA stands for ribonucleic acid and it is an essential component of all living cells. RNA is used for 'translation' ,the process in which proteins are created in a cell. RNA itself is produced from DNA, in a process called 'transcription'. 

An RNA therapy is designed to correct the mistake, or mutation, in the RNA of someone with a genetic disease. This process is novel and is called genetic editing. By correcting the mistake, the RNA can then be used to create the protein that the cell needs and without the mutation(s), taking away the underlying cause of the disease. 

For a drug to work it first has to get into the body. RNA therapies work best if they are delivered directly to the affected organ. In the case of retinal diseases, RNA therapies can be injected into the vitreous of the eye, which is a cavity filled with a jelly-like fluid. This delivery method is known as an intravitreal injection. Intravitreal injection is one of the most commonly performed procedures for eye diseases. The procedure is performed by eye doctors (Ophthalmologists) for common conditions such as age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion in adults and in infants with retinopathy of prematurity. Intravitreal delivery is different from sub-retinal injection used for gene therapy which requires complicated retinal surgery and is local. 

Tuba:   QR-421a has the potential to stabilize vision. Justify the statement.

Dr. Koenekoop: Best-corrected visual acuity, or BCVA, is a measure of central vision, or sharpness of sight, as measured on an Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart.

In the Stellar trial, across all treated patients (n=14), a mean benefit of 6.0 letters was observed at week 48 in the treated eyes compared to the untreated (contralateral) eyes after a single injection.

Among advanced disease patients (n=6), a mean benefit of 9.3 letters was observed at week 48 in the treated eyes as compared to the untreated eyes, and the benefit was maintained for >12 months. All six advanced patients had a benefit in the treatment eye, whereas none of the patients in the sham group had a benefit in the treatment eye. The sham-treated control patients continued to lose their visual acuity.

These results support the belief that QR-421a has the potential to stabilize vision for patients with Usher syndrome and non-syndromic RP due to USH2A exon 13 mutations.

Tuba:   What does this drug mean for people living with Usher syndrome and retinitis pigmentosa?

Dr. Koenekoop: QR-421a represents what may be the first approved therapy to stabilize vision for people living with Usher syndrome and non-syndromic RP due to USH2A exon 13 mutations. ProQR looks forward to advancing this drug candidate to pivotal testing to potentially help these patients in dire need.

Tuba:   As there are no treatments for the rare blindness disorder, what motivates ProQR to work in this space?

Dr. Koenekoop: This remains the sole focus of the company today. ProQR has built a platform to develop highly targeted therapies to address the underlying cause of inherited retinal diseases to stop or reverse vision loss.

About Author:

At McGill University, he is currently Professor of Pediatric Surgery, Human Genetics and Adult Ophthalmology. He saw the light in the retina clinic and finished his residency in Ophthalmology at McGill and his Ocular Genetics and Pediatric Ophthalmology Fellowships at Johns Hopkins University.

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