How did you feel when you got the results?
“My feelings can be best described by talking about one of the patients, a 42-year old fella who had been born with LCA10. Within years of birth he was already down to just tunnel vision, but he was still able to read and function with glasses until his early twenties. By the time he entered the study, he could only distinguish light from dark. We then gave him the treatment, and when he came back after four weeks, he was able to see bright lights in different colors.
He was scheduled to come in another month, but after two weeks he called his doctor and said he was able to read signs. That was something he hadn’t done in twenty years. Then when he came in for his second treatment he was reading letters on an eye chart, for the first time since he was a kid. That’s tremendous. It was great for the company too, because it’s really fortunate to see everything we work for come together so early on in the process.
We did this study with 11 patients and got very consistent responses, so we’re going to move to the next phase. We will start a seamless adaptive Phase 2/3 clinical study that could be the last study we have to do before we get market approval. That it’s an adaptive study means that we can adapt the design as we go, based on what we learn. This makes it a modern study design that has been done before, but it’s the first time it would be applied in an eye disease. With rare diseases and small patient groups it’s essential to be flexible in study design, and thankfully the regulators are enthusiastic and willing to listen.”
Seeing the success of sepofarsen, what’s your vision for ProQR in eye diseases?
“We’re at a stage now where we want to go both narrow and deep. Now that we’ve shown that our RNA therapy had an effect on LCA10, we want to exploit that. We are doing an extensive search to make an inventory of all genetic eye diseases, and select the ones that can be fixed using our toolbox of RNA therapies. This would give us a theoretical playing field. At the same time, we need to learn more about patients, because a lot of people with vision problems don’t know what genetic mutation is causing their disease.
This is why we work with foundations like Foundation Fighting Blindness who provide genetic testing to patients. We could probably end up with a list of hundreds of diseases that we could potentially target, but then we have to prioritize.
The eye is a very good treatment area for RNA therapies. One major issue with RNA therapies in general is that it’s difficult to deliver it intact to the relevant tissue, but in the eye this problem doesn’t exist. We can just inject it into the liquid in the eye, actually a common procedure that is used for many drugs nowadays. The RNA therapy then automatically spreads and enters all of the retinal cells, where it can act.
Another reason is that we have a very good and novel system to test potential therapies in. We can take stem cells from a patient’s skin and grow these into ‘retina in a dish’, what we call the optic-cup organoid model. This means we can test drugs in a very relevant setting, and the results suggest that it can predict what the drug can do in the real eye. A nice benefit is that these organoid models reduce the need for animal testing too. Besides looking narrowly at LCA, we are also taking a broader perspective on retinal diseases. For example, we have started a clinical study in patients with vision loss due to Usher syndrome. This disease is the most common cause of combined deafness and blindness. This drug, QR-421a, uses exon skipping, a different mode of action to hopefully restore the vision loss that these patients experience. We are expecting to report the first results from this study in 2020.”
For another eye disease, autosomal dominant retinitis pigmentosa (adRP), you have licensed a program from Ionis. What’s the story there?
“There are a few reasons really. Firstly, adRP patients go through a stage of tunnel vision and ending with complete blindness and there is no therapy available to them. This made me enthusiastic about trying to make a difference.
Secondly, the disease progresses more slowly which means that measuring the effect of the disease and the therapy takes a long time. Ionis, the partner that discovered the drug, had just followed a group of patients closely for two years to map the progression. We can now use that knowledge and save time in testing the drug. This helps the patients quicker.
The third reason is that the disease is caused by a very different type of mutation than we have thus far targeted. The type of RNA therapy is therefore different too, which gives us a chance to learn to work with it. Instead of repairing the RNA like we do for LCA and Usher, in adRP, we are trying to selectively break down the mutated version of the RNA that creates a toxic protein, and not the healthy one. The work on adRP also made me realize that with such subtle differences, we need to rethink what we measure in our clinical study too. What actually matters to the patient? I think we should measure, for example, if a therapy lets them run an errand quicker, or allows them to drive a car.
We are also exploring the possibilities of virtual reality for this. Our aspiration for eye therapies is that we want to start at least one new program a year, for the foreseeable future. Once we get the first programs I just described done, and we’ve established the potential of RNA therapies in the eye, then the next step is to get to what we call N=1 studies. To scale down from rare diseases with a few thousand patients in the world to diseases with only hundreds and, finally being able to treat versions of the disease that are so rare that it affects perhaps just one patient in the whole world. Obviously, this will blur the boundary between study and treatment, so we need to find a way to treat individual patients with a new drug in a safe way while tracking their well-being. Once we have figured that out, we will be able to help a lot more patients.”