ProQR Therapeutics, a company specializing in the treatment of inherited retinal degenerations (IRDs), released 3-month interim data from its 24-month phase 1/2 STELLAR trial to treat a specific form of retinitis pigmentosa.¹ This trial adds to the positive news in the world of IRDs, which was forever changed after the FDA approval of voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics). The target of this study is exon 13 of the USH2A gene, and while this study applies to a very specific cohort of patients, early released data demonstrate safety of a single intravitreal injection with possible functional and structural improvements that require further study to corroborate. Retinal Physician asked some expert clinicians in the field to review the available data and provide their insights. We are also fortunate to have a representative from ProQR weigh in on the results and implications of these preliminary data.

Charles C. Wykoff, MD, PhD, Retina Consultants of Houston, Retina Consultants of America, Blanton Eye Institute, and Houston Methodist Hospital

Inherited retinal diseases remain a tremendous unmet need in retina. This field was forever transformed by the FDA approval of Luxturna in 2017 for patients with biallelic RPE65 mutation-associated IRD; this was the first step in what I believe will be many positive developments in this space over the months and years to come. Despite this momentous advance, however, the vast majority of patients with IRDs remain without options for treatment. Fortunately, many pharmaceutical and device programs in development hold great promise for expanding our treatment options for IRDs.

The phase 1/2 STELLAR trial of QR-421a (ProQR Therapeutics) in adults with IRDs due to USH2A exon 13 mutations included patients who were homozygous as well as heterozygous and patients with and without Usher syndrome. The recently released, planned 3-month interim analysis represented single-injection data from 14 patients, 8 actively treated and 6 receiving a sham procedure.

QR-421a dosing reportedly led to “evidence of activity” in 25% of treated eyes, ranging from reported functional benefit to, most tantalizing to me, reported changes detected through anatomic assessment by OCT of the “photoreceptor ellipsoid zone.” I would very much like to see these data, especially the structural changes observed. I would like to have seen a larger proportion of patients responding favorably to the treatment, but it is highly encouraging that there appears to be a positive signal. Hopefully, additional data will help to clarify who is more likely to be a responder so that the development pathway can focus on that subset. Ultimately, this is a 24-month study with planned dose escalation included, and I look forward to additional results and longer-term data.

It is also not a surprise that ProQR is predicting that COVID-19 will impact development timelines. This is an unfortunate reality that we are seeing across most, if not all, programs in development.

Daniel Chao, MD, PhD, Shiley Eye Institute, University of California San Diego

Although very early, this interim analysis looks encouraging. This trial looks at very specific mutations in exon 13 of the USH2A gene, that result in mutant RNA thereby causing syndromic and non-syndromic retinitis pigmentosa. ProQR uses an antisense oligonucleotide to bind to the exon containing the mutation(s), acting as a steric hinderer for the RNA splicing machinery, thus allowing for “exon skipping,” leading to restoration of RNA transcript. The scientific rationale behind this approach is strong, and ProQR also has encouraging results from another early clinical trial using an antisense oligonucleotide for exon skipping in patients with Leber congenital amaurosis type 10 (LCA10) with a specific mutation of CEP290, suggesting this approach may work in humans.

In this first-in-human safety study, there do not appear to be any serious dose-limiting adverse events seen in the study. The fact that 2 patients showed improvements out of 8 is preliminary but encouraging. That there are multiple endpoints, both functional, such as dark-adapted chromatic visual fields and full-field stimulus testing, and structural, such as stabilization of OCT vs progression in sham, makes these data more believable. I especially like the use of dark-adapted chromatic visual fields as an endpoint, as this is a biomarker of rod function, whereas all the other outcomes are primarily focused on the cones. Given that rod death occurs before cone death in retinitis pigmentosa, this may be a more sensitive endpoint and may be able to detect subtle changes in progression. Another interesting observation was that benefit was seen in both homozygous as well as heterozygous mutations of USH2A, increasing the number of potential patients that may benefit from this treatment.

The COVID-19 pandemic has had a profound effect on clinical trial recruitment and enrollment worldwide. I applaud the company for suspending recruitment of new patients at this time out of caution for patient safety. Fortunately, these patients with rare mutations can be identified ahead of time and are generally highly motivated to be a part of such studies given the lack of treatments, so I anticipate recruitment to occur rapidly after the COVID-19 situation stabilizes.

I am encouraged by the results seen in this small number of patients and look forward to seeing long-term results as well as the initiation of a properly powered and designed phase 3 study. Design of a neuroprotection trial in retinitis pigmentosa is complicated and a challenge for all in the field. I look forward to seeing how ProQR tackles the trial design, as this may strongly influence other clinical trial designs in the space. What should the primary endpoint be (structural or functional)? What will be the length of the trial? Fortunately, the Foundation Fighting Blindness has performed extensive natural history studies (RUSH2A), which will greatly aid addressing these questions. Another key question is, how durable is the effect of a single injection of an ASO? Also, what will the data look like with multiple injections? Perhaps the most important question is, even if one can see statistically significant differences in these highly sensitive endpoints, does this provide clinically meaningful functional benefit to patients? I look forward to seeing additional results in the future.

Aniz Girach, MD, Chief Medical Officer, ProQR Therapeutics, Netherlands

The whole field of IRD has been very excited to see the 3-month interim analyses from the QR-421 STELLAR trial, which show that the drug was well tolerated and did not have any serious adverse events. We were also delighted to find that in this slowly progressive and degenerative disease, where stabilization of disease or vision is seen as a positive outcome, we saw evidence of target engagement and efficacy benefit (including improvement of vision) in multiple cases. We look forward to reviewing future data from this trial, with a potential of being able to help patients with this blindness-causing condition. RP

REFERENCE

1. ProQR Therapeutics. ProQR announces positive findings from an interim analysis in the phase 1/2 trial of QR-421a for Usher syndrome and provides business update. Accessed May 7, 2020. https://ir.proqr.com/news-releases/news-release-details/proqr-announces-positive-findings-interim-analysis-phase-12