ProQRThe rare disease biotech ProQR (NSDQ:PRQR) has a mission of reversing blindness from inherited retinal diseases. The company seems to be on track to realize that ambition, having recently announced promising data in treating a condition known as Leber congenital amaurosis type 10 in clinical studies.

One patient with the childhood form of blindness gained durable vision improvement after a single injection of ProQR’s investigational RNA therapy sepofarsen. That case study was published in Nature Medicine and featured in Drug Discovery & Development.

To learn more about the company behind sepofarsen, we spoke with its CEO, Daniel de Boer. In the following interview, De Boer shed light on ProQR’s approach to treating genetic forms of blindness, sharing how the firm can grow artificial retinas.

Drug Discovery & Development: What led you to found ProQR Therapeutics?

Daniel De Boer

Daniel De Boer

De Boer: I started this company in 2012 for a very personal reason. A few years earlier, one of my children was born and diagnosed with a rare genetic disease. No drugs were available to treat it, so I decided to start ProQR Therapeutics to develop RNA therapeutics for rare genetic diseases. That’s still our mission today.

DDD: What was your background before founding the company?

De Boer: I was an IT entrepreneur before starting ProQR. One of those tech companies I ran happened to be called “RNA Systems,” but the name was a coincidence. When I founded ProQR, that was my first experience with pharma.

DDD: How did ProQR’s focus on blindness emerge?

De Boer: We started with the broad objective of developing medicines for rare genetic diseases. Our founding scientific hypothesis was to use RNA oligonucleotides to target genetic mutations in the RNA to restore normal protein function. And we did that in multiple therapeutic areas, but we’ve focused the company on inherited retinal diseases over the years. We’re targeting a group of diseases that lead to blindness as a result of genetic mutations in the retina.

DDD: Could you give an overview of your pipeline?

De Boer: We currently have four drugs in clinical trials, of which two are now in the pivotal stage. Beyond that, we have a few dozen molecules in preclinical stages based on the same platform, targeting mutations that lead to genetic forms of eye diseases. It’s a broadly applicable platform with a lot of potential to extrapolate from one program to the next.

Our lead program is sepofarsen, which is for Leber’s congenital amaurosis type 10 (LCA10). We are currently in a pivotal study that’s fully enrolled. We’ll have a primary data readout in the first half of next year.

In this program and earlier studies, we have seen some pretty compelling improvements in vision in patients who live with this very aggressive form of retinal blindness.

We published two different papers related to sepofarsen in Nature. The most recent publication involved an early-stage patient who participated in the trial and was given sepofarsen and saw some pretty remarkable improvement in vision.

This patient was homozygous for the mutation we are targeting. After a single injection, we saw vision improvements relating to more than 20 different endpoints. They all concordantly moved in the same direction. That’s important because the merit of this platform technology is that we can treat the entire retina due to the broad distribution throughout the eye. We have seen functional improvements in the peripheral retina, which provides hope that sepofarsen can treat several different stages of the disease.

DDD: What is the regulatory status of sepofarsen?

De Boer: Sepofarsen has an orphan drug designation on both sides of the Atlantic. It has a rare pediatric disease and fast-track designation in the U.S. In Europe, we have PRIME designation, which is similar to fast track. I think we are well-positioned from a regulatory perspective to get an accelerated review of a submission.

We’re in the midst of a Phase 3 study. This study is fully enrolled and is designed to serve as the sole registration trial for this program. We anticipate having the primary readout for that in the first half of next year. And on the back of that, we plan to submit globally for approval, focusing on Europe and the U.S.

DDD: How did ProQR establish a partnership with the University of Pennsylvania to explore new treatments for inherited retinal diseases?

De Boer: We partnered with them to execute this exploratory Phase 1/2 study to learn about the disease.

We were the first ever to do a clinical trial related to LCA10. University of Pennsylvania researchers Dr. Artur V. Cideciyan and Dr. Samuel G. Jacobson are both experts in inherited retinal diseases, focusing on early-onset variants. So LCA10 is an interesting area for them. We partnered with them to understand the disease and treat patients and work together to understand the impact of sepofarsen on this particular population.

DDD: Your company has stated that it vows to reverse blindness. That’s a big mission statement. Can you share more about it?

De Boer: We’re privileged to have such a mission and big objectives that we can work on every day. We are over the moon with the data we’ve seen in our clinical trials. It seems that we can help people who live with these diseases.

The genesis of this company was very personal. I think that inspires how we think about our mission and our responsibility toward the communities we serve.

We’re patient-focused. We get a lot of inspiration from the people who live with these diseases.

Some of these patients have had physicians tell them, ‘There’s nothing we can do to the retina. There are currently no approved therapies we can use to treat your particular disease, but we can point you to people that can help you to live with visual impairment.’

But this narrative is now starting to change for people diagnosed with Leber congenital amaurosis, Usher syndrome and retinitis pigmentosa. We can start to look toward something that could help them preserve or even improve their vision. Hope is very important for people who have received such a diagnosis.

We hope to deliver on that ambition and provide people with much better vision.

Ultimately, our objective is that patients are diagnosed early enough in life to start treating them before they actually lose vision. Imagine if you can treat kids who are starting to lose vision and prevent them from becoming visually impaired. They could have a normal school career and normal development as a child. I think that would have a major impact on our world.

DDD: What is your strategy for building out your executive team?

De Boer: Over the past few years, we’ve reinforced our leadership team with some heavyweights on the ophthalmology development side.

Our latest addition has been Dr. Naveed Shams, who joined us from Santen (OTCMKTS:SNPHY), a large Japanese pharma company primarily focused on ophthalmology. Before that, he was involved in multiple different drug approvals. He was a lead developer on Lucentis, which is still one of the most important ophthalmology drugs.

In addition to Dr. Shams, our chief medical officer, Dr. Aniz Girach, joined us about two and a half years ago. Dr. Girach also has significant experience in developing ophthalmic drugs and has several approvals under his belt, including in inherited retinal diseases.

DDD: What can you share about your company’s proprietary RNA repair platform technology?

De Boer: We use single-stranded RNA oligonucleotides as the modality for therapeutics. These are synthesized oligonucleotides — chemically modified oligonucleotides — that interact with mutated messenger RNA in cells. That interaction essentially provides the cell with the information to restore normal protein expression.

The mechanisms that we use vary quite a bit depending on the type of mutation. We use splice switching and exon skipping and repeat targeting, and other mechanisms. And we’ve also invented some novel mechanisms that allow us to do individual-based editing in the messenger RNA. We are using mechanisms that are present in the cell to individually change nucleotides in RNA. That allows us to — in a microsurgical way — correct messenger RNA and restore protein function in mutations involving the retina.

We specialize in genetic forms of blindness. We have built an arsenal of preclinical translational models that can help us to predict how a drug will behave in the clinic.

For example, we can grow human retinas in the lab. We can take a skin biopsy from an individual and grow their personal retina in a dish in the lab. Subsequently, we can test drugs on this retina to understand what the right dose is and understand how potent the therapeutic will be. This approach has allowed us to increase the probability of success for therapeutics that we take to the clinic.

We are validating [artificial retinas] as a predictive tool across different mutations and diseases. And so far, our model has been successful two out of two times with both sepofarsen for LCA10 and QR 421-a for Usher syndrome. The model has predicted the activity of the drug and the correct dose for the clinical trial. So, once we further validate it, this model will become even more predictive and can allow us to think about accelerated development pathways.

DDD: Could you give an overview of the investigational RNA therapy QR-421a that might stop vision loss in people with retinitis pigmentosa and Usher syndrome?

Daniel de Boer: QR421a targets mutations in exon 13 of the USH2A gene.

One phenotype associated with such mutations is called retinitis pigmentosa, which leads to vision loss. Another phenotype leads to both vision loss and hearing loss, which is called Usher’s syndrome, but it’s caused by mutations in the same part of the gene. We can use one therapeutic to target both phenotypes.

In a Phase 1/2 clinical trial, we had 20 patients with this mutation in exon 13 in the USH2A  gene. We saw some really encouraging results where the people who were treated with the drug, it stabilized their vision in the treated eye versus a continued decline in the untreated side. Some even had their vision improve in their treated eye.