Michael A. Singer, MD: For this month’s Retina Minute, I have the honor of interviewing my dear friend Robert A. Sisk, MD, FACS, FASRS, from Cincinnati, Ohio, who on Saturday afternoon presented the first clinical trial results from the VISTA study of laru-zova (Beacon Therapeutics) for patients with X-linked retinitis pigmentosa (XLRP). Why don’t you tell our readers about the molecule, the condition, and the study?
Robert A. Sisk, MD, FACS, FASRS: Sure. XLRP accounts for about 20% of retinitis pigmentosa, and RPGR accounts for about 80% of those cases. The RPGR gene can cause retinitis pigmentosa or cone dystrophy, and there can be affected females, but the VISTA study focused on affected male patients. Laru-zova is a codon-optimized AAV2 gene augmentation therapy for males aged 12 to 50 years with XLRP from pathogenic variants in RPGR.
From the earlier clinical development with the phase 1/2 HORIZON trial, we found that patients who had an intact ellipsoid band on OCT and detectable microperimetry with intact fixation tended to have the best outcomes in terms of ellipsoid zone preservation and microperimetry improvement. Those became parameters for selection of patients for the phase 3 VISTA study. Two doses were investigated, which were similar to the higher dose validated in the phase 2 SKYLINE study, and those were compared with an untreated control group.
Dr. Singer: How is this medication delivered?
Dr. Sisk: It’s a subretinal injection that’s intended to treat the entire macula, which is the area where the cells would be most preserved in a retinal degeneration like retinitis pigmentosa.
Dr. Singer: What were the findings in VISTA?
Dr. Sisk: Two different groups were studied—there was a US study and a European study. The US study looked at low-luminance visual acuity (LLVA) as the primary endpoint, and they found that 25% of patients had a 3-line gain in LLVA compared with controls. The European study looked at 10-letter, or 2-line, gains, and they found that about 50% of patients had that improvement. The primary endpoint for the European study was microperimetry, and there was a statistically significant improvement in microperimetry in the treated eyes vs the untreated eyes in both dose cohorts.
Dr. Singer: This is fascinating. Obviously, every time you do a subretinal injection after vitrectomy, we always worry about safety, so tell me about safety.
Dr. Sisk: In general, the drug is very well tolerated. It does require steroid prophylaxis. Patients routinely receive oral, sub-Tenon, and topical steroids. As a result of that, it was common to see increased intraocular pressure in about 30% of patients. But in the VISTA study, it was all manageable with topical antihypertensives, and no patients required any sort of surgical intervention for glaucoma.
In HORIZON, retinal pigment epithelium (RPE) changes were observed with the highest dose, but thankfully these were rare in SKYLINE and VISTA patients. Another factor may be improvements in manufacturing, with a higher proportion of full capsids and fewer empty capsids, allowing greater efficiency from a lower overall capsid dose. So, in general, the drug appears to be well tolerated.
There is a modest amount of vision impairment during the first 2 weeks after surgery, which is typical for a patient who receives a subretinal injection involving the macula.
Dr. Singer: Why do you think the safety profile was better in these subsequent trials than we’ve seen in other subretinal surgeries?
Dr. Sisk: Beacon Therapeutics had a vigorous surgical training program for the surgeon investigators including lectures, animal wet labs, one-on-one proctoring, and regular videoconference discussion of surgical cases. We learned from each other accelerating our learning curve to the benefit of our patients.
I’d also highlight the vector design and manufacturing process, which are geared towards efficient transfection and reduced inflammation. Beyond that, the Beacon trials used the right amount of steroid prophylaxis. There’s a trend in gene therapy trials to reduce steroid prophylaxis, but that comes at the risk of allowing inflammatory complications. If there’s adequate control, immune-mediated damage to the retina is prevented. But on the opposite side, steroids raise intraocular pressure, which is usually more manageable than inflammation and temporary.
Dr. Singer: What’s the next step for Beacon Therapeutics?
Dr. Sisk: The next step is that the company is filing for the biologics license application (BLA), and hopefully the US Food and Drug Administration (FDA) will look favorably upon the data. If it moves forward to approval, it would be the first gene therapy since voretigene (Luxturna; Spark Therapeutics) to be approved.
Future plans could include looking at treating other populations affected by RPGR, such as female patients or patients with cone dystrophy, but that’s still up to the company.
Dr. Singer: This is fascinating. You said it very well: We haven’t had anything since Luxturna. This patient population is severely debilitated. Most of these therapies are just based on maintaining vision. The fact that this actually increased vision is super exciting and obviously provides hope for our patients. Is there anything else that I didn’t ask you that you want to add?
Dr. Sisk: Well, I think we’re going to be more impressed with the long-term results from this type of gene therapy. Luxturna has been the standard, and people expect any subsequent gene therapy to have a tremendous amount of initial vision gain as a result. But you have to remember that Luxturna was addressing a defect in the phototransduction cascade. So you’re taking an almost nonfunctional visual system and restoring it.
In this situation, RPGR is expressed in cone photoreceptors, and so that’s probably why we’re seeing the improvements in low-luminance visual acuity and microperimetry. But over time, what we should see is preservation of those photoreceptors compared with untreated eyes. And so the differences that we’re seeing at year 1 may become more substantial with longer-term follow-up if we do have patients in whom only 1 eye is treated.
Dr. Singer: I think that’s true, and not just for patients with inherited retinal diseases (IRDs). We’ve seen similar things with geographic atrophy, where over time the curves diverge and, as a result, the treatment effect is more impressive going forward. This is fascinating, and I am very excited to learn about this. I’m thrilled because it could be a new option for this patient population, which has had very limited treatment options.
Dr. Sisk: Thanks so much, Michael. RP
