PTC Looks to Advanced Therapies

PTC Therapeutics, through its partnership with the SMA Foundation and Genentech, won approval last year for Evrysdi, the first oral therapy for the rare neurodegenerative condition spinal muscular atrophy. Now, the SMA Foundation is working with the company to discover and develop regenerative treatments that can reverse the damage done by the disease. At the same time, the company is advancing its effort on the gene therapy front following its 2018 acquisition of Agilis Biotherapeutics. We spoke to Matthew Klein, chief development officer for PTC Therapeutics, about the company’s work in SMA, its move into regenerative medicine, and its efforts to win approval in Europe and the United States for its first gene therapy.

Daniel Levine: Matt. Thanks for joining us.

Matt Klein: Thank you very much. It’s great to be here and I’m glad to have this opportunity to share with the community some of the important work PTC has been doing on a number of rare diseases, including spinal muscular atrophy (SMA) and AADC deficiency.

Daniel Levine: We’re excited to talk to you about the work PTC is doing in gene therapy. While we’re setting this up, there was news on the SMA front, that we wanted to begin with. PTC Therapeutics announced a recent agreement with the Spinal Muscular Atrophy Foundation. For listeners not familiar with SMA, what is the condition?

Matt Klein: SMA is a rare neuromuscular disease that results from a genetic defect. The result of that genetic defect is significant muscle weakness and muscle wasting. It’s often diagnosed in infancy or early childhood. If not treated, SMA is the most common genetic cause of infant death, just to give you an idea of how serious this disease is. The common feature is weakness. That could be weakness in the arms, the legs, and also weakness in the muscles that control lifting up your head and breathing. This is a very serious and significant genetic disease. There are three main types, SMA1, SMA2, and SMA3, and those refer to the age of onset and severity of disease. SMA1 is typically diagnosed in kids in the first months of life and tends to be the most severe, and SMA2 and SMA3 will be diagnosed slightly later in infancy or childhood and tend to be less severe than SMA1.

Daniel Levine: We’ve seen a fair bit of success in the area of SMA treatments, including most recently the approval of Evrysdi, which is the first oral therapy for the condition. Most people associate this drug with Genentech, but it was developed through a partnership with the SMA Foundation and PTC Therapeutics. This is a foundation that’s focused on drug development and run by a former biotech executive. How far back does that relationship go and what was it like to work with the Foundation?

Matt Klein: This is a long-standing relationship going back over a decade. In fact, Evrysdi, which was approved recently, was discovered by PTC. It was a product of our RNA innovative splicing platform that develops oral drugs that are able to modify RNA expression. When people think of manipulating genes, we think of gene therapies or antisense oligonucleotides, but with our splicing platform we’re able to develop oral drugs that can affect genetic expression. The first drug we developed was Evrysdi. As you mentioned, this was developed in collaboration with the SMA Foundation. PTC as a company was founded specifically to develop drugs for patients with rare diseases and high medical need. From the beginning, we knew that if we’re going to be successful in developing meaningful therapies for patients who desperately need them, it’s going to be a team effort between our scientists, patient foundations, and the patient communities. Therefore, from our early days of developing Evrysdi, we had a partnership with the SMA Foundation that has been incredibly successful. The ultimate development and approval occurred with the partnership with the SMA Foundation and Roche Genentech. We’re really proud of Evrysdi, it’s really a pioneering drug in terms of what it can do mechanistically in terms of splicing and it’s an incredibly important drug in terms of what it can deliver for patients with SMA. It has several advantages since it’s an oral therapy, patients can take it at home and it can travel to everywhere in the body, to the brain and to all the muscles. That’s important when you have a disease like SMA that can affect every muscle in the body. Also, since it’s an oral drug and it can be continuously dosed. So, you’re sure that you’re getting a therapy throughout your entire life. It really delivers a consistent therapeutic benefit, which is really exciting. Of course, particularly during COVID, we’re aware of how important it is to be able to have a drug that you can take at home.

Daniel Levine: In March, you announced an expanded relationship with the SMA Foundation. It’s committing $60 million in research to discover and develop regenerative treatments in neuromuscular diseases. This, in part, reflects the success that’s been seen to date in developing treatments for the disease. How will this effort differ from past efforts?

Matt Klein: Great question. While we’re incredibly excited by Evrysdi, its approval and the benefit it can deliver to patients, we view it as really a beginning. By addressing the genetic defect in the disease we’re able to slow the progression, but there’s also the thought of introducing tissue regeneration, or tissue engineering to restore any muscle that’s lost. So, while we can use our therapy to prevent further muscle wasting, this new endeavor is aimed at thinking about ways in which we can pioneer tissue regeneration and restore that muscle that was already lost before therapy was started.

Daniel Levine: What types of therapies do you expect to approve for this? Would the expectation be that these will be some type of cell or gene therapies, or will you be looking at a broader range of modalities?

Matt Klein: It’s early days. The purpose of this collaboration and funding is to look at many different approaches. I think we all know that when you think about regenerative medicine and tissue engineering, it’s complex and remains an important challenge in all of medicine. We want to make sure that we can look at every possible approach, and combination of approaches, to deliver the best outcome for patients.

Daniel Levine: What role, if any, does the SMA Foundation play beyond providing funds?

Matt Klein: I think they have an expertise that is beyond compare. It’s a foundation that’s incredibly dedicated to SMA therapies, truly understands the challenges, and has built a network of researchers and laboratories that can help solve these problems. We’re really proud to have them as a partner and to be able to work with them and leverage their decades of understanding the challenges in developing SMA therapies and knowing the right people to work with to have the highest probability of success.

Daniel Levine: Focus on regenerative medicine reflects a bigger move by PTC into new areas of medicine. In 2018, PTC acquired Agilist Biotherapeutics, which gave it a foothold in gene therapy, the lead gene therapy candidate was a gene therapy for AADC. What is AADC?

Matt Klein: Let me first just mention that we’re incredibly proud at PTC to have a diverse pipeline. We remain committed to developing important therapies for patients with rare diseases. We also realize that to develop effective therapies, you need to look at many different approaches. We have with Evrysdi a small molecule approach from our splicing platform. We have other modalities as well, and one of them is gene therapy. We believe that gene therapy is an incredibly important approach to treating genetic diseases, in particular genetic diseases that result from a single gene defect, such as AADC deficiency. AADC deficiency is a genetic disorder that results in an inability to produce dopamine and other important neurotransmitters in the brain. Basically, it’s a genetic defect that affects the enzyme that’s needed to make active dopamine as well as a couple of other neurotransmitters. Kids affected by AADC deficiency have significant defects in motor development. If you lack dopamine, your motor activity, whether that be lifting your head, sitting, walking, standing, or swallowing, are significantly impacted. This is obviously a very serious disease, which is typically diagnosed very early in life. In the most severe cases, if untreated, it results in death in childhood. What you see in some of these children, particularly those with the more common and severe variety, is that they never develop the ability to sit up, to lift their head, to crawl, and certainly not to walk or stand. We believe this disease is amenable to gene therapy, given that it’s a mutation in a single gene. If we can provide that healthy gene and get that enzyme working, we can start the production of dopamine. This is exactly what we’ve been able to do with gene therapy.

Daniel Levine: How are patients typically treated with the condition today and what’s their prognosis?

Matt Klein: Their prognosis is poor because there’s no real effective treatment. There are some patients who can get a small amount of benefit from dopamine replacement, but really that has not proven to meaningfully impact the course of disease, particularly in those with the most severe disease subtype. Those children have a very poor prognosis and will typically die in childhood.

Daniel Levine: How does the gene therapy work? What are you using for a vector and how is it delivered to the patient?

Matt Klein: PTC’s overall approach in gene therapy is utilizing something we call, targeted delivery. What we mean by targeted delivery is providing the gene that’s missing to an anatomic area in the body where it’s particularly needed. In the case of AADC deficiency, we put that deficient gene into a part of the brain called the putamen, which is ground zero for dopamine nerve function. It’s delivered through a surgical procedure known as stereotactic surgery where neurosurgeons use, if you will, a Google map that gives them a route to get safely from outside of the patient into the exact location in the brain where we need to deliver the gene therapy. When we’re able to do that procedure and deliver the gene therapy to that exact location, the putamen, where it’s needed for the nerves in the brain that are responsive for dopamine to function, we start seeing two really important things. In our clinical studies, we’ve seen an increase in dopamine production, and that’s a sure sign that we’ve delivered the gene and the gene is working. Then what we see is an improvement in motor function of the children that we treat. As I mentioned, children with AADC deficiency may not have any motor activity at all. Can’t roll over, can’t sit up, can’t crawl, and can’t walk. What we’ve seen in months to years after therapy, is first an increase in dopamine production, and then we start seeing improvement in motor function in the ability to roll over, the ability to sit up, the ability to stand, and, in some cases, the ability to walk. You can really understand that this is a potentially transformational therapy for these children.

Daniel Levine: What’s out about the safety or durability of the treatment from studies to date?

Matt Klein: That’s a really important question. When you give a gene therapy, you typically can only administer it once in the lifetime of a patient. So, durability becomes really important. We have data now out to five years, in some cases, six, seven years, and even longer where we’re observing continued dopamine production. The gene is continuing to function as we see maintenance of dopamine production and continued benefit in terms of motor function. The durability has been clear and impactful. We also have seen that over the course of the development program, the therapy has been safe and well tolerated. We’ve done a lot of work and we’re moving through the regulatory processes in Europe, in the United States, and elsewhere around the world to make sure that we can develop an approved, safe, and effective therapy.

Daniel Levine: If all goes well, when might you expect an approval for the therapy and what are the plans for marketing it?

Matt Klein: We are in a process of having an application reviewed by the European Medicines Agency. We’re on track to have approval this year in the European Union. We’re in the process of getting ready to submit our application to the FDA, which we plan to do this year as well. Then we’re going to be looking to have regulatory approval in other countries. PTC over the years has built a very strong global commercial structure that is able to provide the necessary support and essential elements in order to make these therapies available to patients wherever they’re approved. Those efforts are underway. We are also working very hard with patient foundations around the world and working very hard on physician education about making the diagnosis of AADC deficiency. It’s a challenging diagnosis. As many families affected by rare disease know, it’s often a challenge even getting a diagnosis for a rare disease. We’ve certainly seen the same thing with AADC deficiency. Our teams have worked tirelessly on education campaigns worldwide to increase awareness of AADC deficiency. We also have a number of endeavors and partnerships where we’re working to drive AADC diagnosis amongst patients suspected of having AADC deficiency. We also know that rare diseases often go underdiagnosed when there’s no therapy, because there’s no motivation to give a diagnosis when there’s no therapy. Now that we have a therapy, it becomes even more important to make accurate diagnoses of AADC deficiency.

Daniel Levine: What will this therapy mean for patients? Is there any expectation that it might reverse some of the damage done by the disease?

Matt Klein: I think one of the really important observations we’ve made in our clinical studies to date, having treated children as young as two years of age and other children in late childhood and early adolescence, is that even treatment later in childhood has resulted in significant improvement in function. So that’s a really important indication that even though you’re not one or two years old, you can still have a significant improvement in terms of motor function.

Daniel Levine: An approval would put PTC in a rare group of companies with a marketed gene therapy. What does this suggest about the future opportunity for the company?

Matt Klein: There’s a lot of understandable and appropriate hope that gene therapy can bring treatments for many different diseases, including rare diseases. Despite all the gene therapies in development, we’re still not at the point where there are many approved therapies. We’d obviously be very excited to be able to provide this therapy to patients who desperately need it. It would also be the first gene therapy ever approved with direct administration into the brain. That would be another pioneering, or unprecedented, element of this approval. PTC has other gene therapy programs in its pipeline. We have a gene therapy for Friedreich’s ataxia, which is a neuromuscular disorder. We’re going to bring our approach of targeted therapy to deliver a gene therapy to a particular area of the brain that’s significant in Friedreich’s ataxia. We have other gene therapies in development at different stages in our pipeline.

Daniel Levine: Matt Klein, chief development officer for PTC Therapeutics. Matt, thanks so much for your time today.

Matt Klein: Thank you very much, Danny.