Dr Dorenbaum, can you tell us a bit about what you do at Reneo?
We're a US- and UK-based company that specialises in developing drugs for diseases that are rare and difficult to treat. We have a very experienced and dedicated team, who have worked together on many successful programs in the past. Often we find that big drug companies will make a business decision to halt development of a drug, even when it has the potential to treat rare diseases, because they don't see it as being profitable enough. Our approach is to acquire these products at a stage when a lot of the costly early research has already been done, and look at how they can be used to help patients with rare diseases like mitochondrial disease.
Can you explain how this new drug works?
The drug we are trialling belongs to a group of medicines called PPAR agonists. PPAR (or peroxisome proliferator-activated receptors) is a receptor that sits just outside the cell nucleus and controls the activation of genes inside the nucleus. If you stimulate this particular receptor with a medicine that we call a PPAR agonist, it increases the activity of the PPAR. This is like turning on a switch for certain genes in the cell, including those involved in promoting the growth and activity of mitochondria that help the body manage energy more efficiently. So this is a really interesting drug to try with patients with mitochondrial myopathy, who typically have alterations in their mitochondria.
Did you face any big challenges getting this drug to trial?
One of the hardest things about developing drugs for rare diseases is finding a sufficient number of patients to make the trial effective. If there are too many variables in the process it's difficult to tell if the drugs works or not. With mitochondrial diseases, even patients with the same genetic mutations can present with very different clinical courses, so trying to find a uniform patient cohort is difficult. The disease is rare, which we should be grateful for of course, but from the perspective of drug development the more patients there are, the easier it is to set up an effective clinical trial.
How important is the role of patients in new drug development?
I've been doing this for about 30 years, and what I've learned is that although I'm an expert in developing drugs, I'm not an expert in the disease. Likewise, physicians are experts in treating the disease, but they are not experts in the disease itself. It's patients who are the experts. They are the ones who really understand the issues affecting people with these diseases. We rely on sources like The Lily Foundation to put us in touch with patients, so we can engage with them and their families, and learn from them what problems they have and how to tackle them. Patients are an essential part of the process.
Where is the trial going to be based?
We're working with Newcastle University and UCL, two centres of excellence in the UK where there is a really great understanding of mitochondrial diseases. We feel that by collaborating with these experts we will be able to do the first stages of our program in a much better way. The tradition of studying neurological diseases at UCL dates back centuries, and Newcastle do a remarkable job too, they have a very large program that specialises in mitochondrial disease research. So we are very privileged to be working with these two centres.
Could this drug be given to children as well as adults?
I advocate very strongly for early development of drugs for children. However, there are important safety guidelines we need to follow, and children aren't old enough to provide the informed consent necessary to enrol in new drug trials. It's important to first study the effectiveness and safety of the medication in adults, before moving on to children. We have established a really good relationship with the MHRA, the regulatory agency for patient trials in the UK, and they have allowed us to lower the age at which we start treatment to 16 years of age. So while we are limited to recruiting patients 16 years and older for now, we are really focused on being able to treat the paediatric population in the future.
What stage is the trial at now, and what does it involve?
We are all set to go. We have gone through all the regulatory stages, and patient enrolment is now underway. Patients aged 16 and older can enrol at UCL or Newcastle. It's an open label trial, meaning all patients will be treated with the same drug and will know exactly the drug and quantity they are taking. Our approach is to treat patients for three months, monitoring them for safety and efficacy of the drug. Patients will take daily capsules containing the medication, and will be seen at home or be required to attend follow-up consultations with their clinic, and do some tests. They will be monitored very carefully.
How optimistic are you that the drug will get results?
I anticipate good results for some patients. However, due to the variable nature of mitochondrial disease it is possible the drug will not be effective for everyone. The drug could help overcome some of the genetic defects in patients but it is too early to predict how many patients will receive benefit. At this stage we are planning on an open-label study so that all participants will get the drug for 12 weeks. This will help us determine the patients for whom the drug is safe and potentially efficacious. While there will be some patients who will not respond to this medication, we are optimistic that others might see a marked improvement in their energy levels, and in the quality of their lives. If we can achieve this, then the hard work of everyone involved in the project – doctors, researchers, patients and their families – will have been worthwhile.