NeuroVoices: Francesco Saccà, MD, PhD, on Crossing Over Dimethyl Fumarate in Friedriech Ataxia

Fracesco Saccà, MD, PhD

In neurology, there are several benefits to repurposing drugs in other disease areas. For instance, it may show greater efficacy in different condition, it can lead to more cost-effective solutions, and shed light on novel disease mechanisms or pathways, potentially leading to new therapeutic approaches. For patients with Friedreich ataxia (FA), an autosomal recessive neurodegenerative disorder, there is only 1 approved therapy, omaveloxolone (Skyclarys; Biogen), that has shown to improve patient’s clinical outcomes.

In the latter half of 2023, investigators announced a new phase 2 study assessing the use of dimethyl fumarate (DMF), an approved product for relapsing multiple sclerosis and psoriasis in Europe, in patients with FA. The study, which two sequential 12-week phases, assesses whether DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. FA, which is typically associated with several developmental features, is caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently ATP production abnormalities.

Led by Fracesco Saccà, MD, PhD, the study features 40 patients with FA who are randomly assigned 1:1 to either DMF or placebo, followed by an open-label treatment of just DMF. As part of a new iteration of NeuroVoices, Saccà, an associate professor of neurology at the University of Naples, sat down to discuss the trial and how its conducted. He spoke on the mechanism of action of DMF, previous observations that led to the trial, and why it differs from the previously approved omaveloxolone. Furthermore, he spoke on the clinical end points of the study and what he would consider as a “successful” study.

NeurologyLive: Can you provide some background on the origin of this study and how it came to be?

Francesco Saccà, MD: It's kind of really difficult to explain, it's been a struggle to start with this trial in Friedrich ataxia. We started thinking about the trial probably seven or eight years ago, and we were not able to find support financial support for the study. Then, once we had the financial support, we didn't have a pharmaceutical company available to donate dimethyl fumarate, or at least to, sell it to us at a decent price because dimethyl fumarate has a very high price. After six or seven years of trying around and moving things around, we had a support from the Italian Ministry of Health that specifically supports investigator-initiated trials. We also received support from FARA, the Friedreich Ataxia Research Alliance in the US. And we also had the opportunity of donation from Almirall, which is a pharmaceutical company based in Europe, that donated the study drug and placebo for the trial. We managed to put everything together, and we had approval from the National Ethics Committee in Italy. At the end of last year, we enrolled the first patient in this trial. It's been a long journey until the beginning of the trial itself.

How is this trial conducted? Talk a little bit about the details of it.

First of all, dimethyl fumarate has this ability to do two things. One is to increase frataxin mRNA and protein. The primary endpoint of this trial is the ability of dimethyl fumarate to increase frataxin mRNA. Why mRNA and not protein? Because mRNA is easy. The methods behind that work way better, it's easier to measure an increase in protection mRNA than protein, but protein is a secondary endpoint. We will look at both of them. Dimethyl fumurate is also able to stimulate Nfr2, which is what omaveloxolone, the only approved drug for FA, does. DMF kind of has both abilities. Other secondary endpoints will be the ability of DMF to improve clinical signs of the disease and to increase the VO2 max, or oxygen consumption, at the cardiopulmonary exercise test, which is a test that we set up specifically for patients with Friedreich ataxia. The way its set up is with the upper limbs, not lower limb so that you can effectively have many more patients being able to perform the test as with a normal exercise bike. Other secondary endpoints will be safety and tolerability of the study drug as well as clinical scales, like the MFARs, which is the American scale, and the SARA, which is the European scale for ataxia. Other clinical measures will include the nine-hole peg test, the patter rate test, and quality of life measures.

As an approved product for relapsing multiple sclerosis, why do we believe dimethyl fumarate can be successful in this patient group?

I would like to start from the end. We use dimethyl fumarate for relapsing MS, but we also have an approval in Europe for psoriasis. That is the compound that we are using. Almirall produces DMF that is approved for psoriasis. Since I follow patients with multiple sclerosis too, we had blood samples taken before and after dimethyl fumarate in this patient group. The dosing was kind of part of our routine practice. What we saw was that this dose ( ) of dimethyl fumarate, which is the one that we are using [in the study], is able to increase frataxin expression by 85% in patients with MS, which is a lot. Plus 85% means that patients could reach the same expression level as healthy carriers, which have half of what our healthy individuals have. Apart from that, DMF is also able to increase frataxin expression in a specific way to Friedreich ataxia. Its linked to the silencing of the gene, it enhances expression. I would say there’s a higher chance that in patients with FA, we might see an even higher increase [in frataxin] after DMF. Of course, this is theory, we have to prove that. But if we look at the experiments that have been conducted in cells from patients with FA, or in animal models, the increase in frataxin expression is sometimes 2-3-fold of the baseline. There’s a high chance that in this trial, we might see even more than 85% as we saw previously in patients with multiple sclerosis, hopefully.

Some therapies have shown change in frataxin but fail to impact clinical scales, do we believe that could be the case with dimethyl fumarate?

This is a good point. I think that omaveloxolone is not able to increase frataxin, but is still of some benefit for patients. This benefit occurs quite quickly after therapy initiation. That's why many clinicians think that there is a symptomatic effect there. It’s probably linked to the fact that omaveloxolone is able to stimulate Nrf2. By doing that, there is probably an improvement in mitochondrial energetics in general and patients are getting better. DMF is able to stimulate Nrf2 as well. By doing this, there is a higher chance that you are acting on two different pathways here: increasing frataxin, which is a historical target of many of the therapies and clinical trials we've seen in the past. But there is also a chance that it is stimulating Nrf2 and it might bring a symptomatic improvement in the short term and probably even longer term. It might do two things in one compound.

Hopefully, we will be able to see both frataxin increase and clinical improvement. Clinical improvement has not been something that has ever been a target of therapies in the past. We've always looked at therapies and their ability to increase frataxin, and then in time, reduce the chance of disease progression. That's the historical view. But I think that omaveloxolone kind of changed things because we saw for the first time that an improvement is possible in these patients, probably because a lot of the clinical signs that we see are due not only to neurodegeneration, but also to a reduced energy production in the mitochondria. We’ve done some tests with the cardiopulmonary exercise test, and our caveat there is that patients’ energetics are so poor that they switch very early to an anaerobic metabolism. It could be that if you act on that, not only by increasing frataxin, but also by enhancing energy production in the mitochondria, you might have very quick improvement in some of the signs, which is what we see with omaveloxolone.

What would you consider for this study to be successful?

Well, the primary endpoint is the primary endpoint, so that means a success, even if all of the secondary endpoints fail. We want to see that DMF is able to increase frataxin expression, because this means a lot. It's not like increasing a clinical scale or improving some of the other parameters, because this is the type of innovation that we really need, we need to see an increase in frataxin. And I strongly believe in that. That is what will probably bring in a future disease modifying therapy in the real sense of it. But I mean, it would be ideal to see this coupled with some increase in mitochondrial biogenesis genes, some increase on the cardiopulmonary exercise test. I'm not expecting it to in such short trial, which altogether, is just six months. I'm not expecting differences between treatment and placebo patients on the clinical scales, but we are already planning an extension phase of the study so we could hypothetically follow up these 40 patients for up to one year, and then match them to historical cohorts to see if there is some slowing of the disease progression on clinical scales. But I'm focused on the primary endpoint, because that is what we're looking for. That will be real innovation because meeting that endpoint with an already available and approved treatment means a lot. Also, the pricing of it is very positive, because it's already available. And it could be available to a lot of clinical centers here in Europe and in the US.

What goes into patient selection for a trial like this?

We didn't have very strict inclusion criteria because since the primary endpoint is frataxin expression, we're not including patients in a phase three trial where you would typically look at progression on the MFARs or SARA. Because at that point, it makes sense to exclude some of the outliers, some of those patients that do not have a propensity to progress. That's the key factor. But here, since we have a biochemical endpoint or molecular endpoint, we're just interested in having a classic FA, so no point mutations, because we don't know exactly how dimethyl fumarate could behave with these patients. But apart from that, there are no exclusion criteria, except for the ones that apply to DMF. This includes infectious diseases, panic failure, kidney failure, or cardiological heart diseases that are not typical for FA, or that the investigators view are not compatible with the DMF therapy. Apart from that, we're not excluding patients based on the MFARs, SARA score, disease duration, or an age. There are no filters there.

Do you have any timeline of when the study might conclude?

We completed the enrollment in February. All 40 patients were enrolled. We are expecting to have the last patient last visit by the end of July. This means that we could probably get some data, at least the primary and many of the secondary endpoints, by September or October of this year. By the end of the year, we will close the entire analysis.

Transcript edited for clarity.