Real World Data Confirm RPE65-IRD Gene Therapy Voretigene Neparvovec Efficacy in Improving Light Sensitivity

Bart P. Leroy, MD, PhD

Spark Therapeutics’ voretigene neparvovec (Luxturna) was originally approved by the FDA in December 2017 and by the European Medicines Agency (EMA) in 2018 for the treatment of inherited retinal dystrophy related to mutations in the RPE65 gene.^1,2 It was the first gene therapy to be approved by both the FDA and the EMA for the treatment of a genetic disease.

Following up on the success seen in the pivotal phase 3 clinical trial (NCT00999609), several postmarketing studies have been launched to verify the safety and efficacy of the gene therapy in real world settings. One such study, data from which were presented in a poster at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, 2023, in New Orleans, Louisiana, evaluated the treatment in 10 Belgian patients.³

CGTLive™ spoke with Bart P. Leroy, MD, PhD, the head of the Department of Ophthalmology at the Center for Medical Genetics, Ghent University Hospital, who coauthored the poster, to discuss the importance of verifying results from the gene therapy’s clinical trials in real world settings.

CGTLive: What was the main intent behind your study that was presented at ARVO’s 2023 conference?

Bart P. Leroy, MD, PhD: Obviously we wanted to know what is going on with the patients and whether we have results that actually mimic what was reported in the phase 3 pivotal trial that led to the market authorization for Luxturna both in the United States and the European Union. On the other hand, we also have some obligations. In Belgium, we have a national health service that reimburses Luxturna—it’s a lot of money paid for by society. So society wants to know: do we give another round of reimbursements from 2024 onwards? And that's why we’re gathering the data. Our National Health Service asked us, as the National Center in Belgium, to collect as many data as possible. And then the other reason is that EMA actually asked for a postmarketing study; a phase 4 study. So, we have an obligation to gather data and upload them onto a European system that is funded by Novartis Pharmaceuticals, the holders of the rights in the EU. So, on the 1 hand, we just want to be responsible with public money, and on the other hand, there's an obligation, both from a National Health Service and an EMA standpoint.

Can you give an overview of the methods used in the study?

The essence of the study was looking at a couple of outcome measures: best corrected visual acuity (BCVA) with logMAR scales; we also looked at Goldman visual fields performed in a manual fashion; and then, in addition, we also did full-field sensitivity testing (FST), where we performed a test using 3 lights. We did FST with red light, which mostly will stimulate the cone function; we did it with blue light, which is mostly stimulating the rods of the retina; and then we did it with white light, which is a general way of doing FSTs.

We did not actually expect the BCVA to go up much based on the phase 3 trial results. The phase 3 trial results that led to the market authorization for Luxturna showed no statistically significant improvement of BCVA, but did show improvements of the Goldman visual fields, and we clearly saw that there were improvements on mobility tests. The mobility test is something that takes a lot of time; it takes different light levels, and you observe how a patient goes from point A to point B at the different light levels. A good surrogate of that outcome measure, and much easier to perform in a daily practice setting, is the FST. So,it's a surrogate for mobility in activities of daily living.

What were the key results of the study?

The essence of the results of our study showed that the BCVA indeed does not improve. We're talking about 19 eyes of 10 patients after 6 months, so this is early, and we have generated more data since the cutoff date. Since then, I can definitely say that the results are very similar. And so we did not see an improvement of BCVA, as we thought was going to happen.

With the Goldman visual fields, I think we have a bit too little data to actually have meaningful, statistically significant results. But with FST we saw a serious improvement of retinal function: mostly the rods, but certainly also the cones. And this translates, if you look at activities of daily living, into a patient being much more capable of navigating at lower light levels in daily life.

For example, a patient told me a story, she said: ‘All of a sudden, Dr. Leroy, I am capable of seeing the slices of bread when I'm preparing the sandwiches for lunch for my son at school with normal lighting conditions—whereas before that I basically touched everything and I didn't really see what I was doing.’ And now she's able to do this. And this was a patient who was 40 years old when her first eye was treated. So, people with considerable evolution of disease already do benefit from this innovative treatment.

Transcript edited for clarity.

REFERENCES
1. FDA approves Spark Therapeutics’ LUXTURNA™ (voretigene neparvovec-rzyl), a one-time gene therapy for patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. News release. Spark Therapeutics. December 19, 2017. Accessed April 26, 2023. https://sparktx.com/press_releases/fda-approves-spark-therapeutics-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-for-patients-with-confirmed-biallelic-rpe65-mutation-associated-retinal-dystrophy/
2. European Commission approves Spark Therapeutics’ LUXTURNA® (voretigene neparvovec), a one-time gene therapy for inherited retinal disease caused by confirmed biallelic RPE65 mutations. News release. Spark Therapeutics. November 23, 2018. Accessed April 24, 2023. https://sparktx.com/press_releases/european-commission-approves-spark-therapeutics-luxturna-voretigene-neparvovec-a-one-time-gene-therapy-for-inherited-retinal-disease-caused-by-confirmed-biallelic-rpe65-mutations/
3. Hertens L, Cauwenbergh CV, den Broeck FV, et al. Results of Belgian patients with RPE65-related inherited retinal dystrophy 6 months after treatment with voretigene neparvovec. Presented at: Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting. April 23-27, 2023; New Orleans, LA. Abstract #762 – C0363