The proprietary formulation of aspirin and fumaric acid addresses issues with pretreating fumarate flush, a bothersome side effect of popular MS disease-modifying therapy Tecfidera.
Joseph Habboushe, MD, MBA
For patients with multiple sclerosis (MS), slowing disease progression and reducing relapses remain top priorities of treatment. However, MS-associated symptoms and treatment side effects can be as troublesome as the disease itself, significantly impacting patient quality of life.
Fumarate flush, the itching, skin-burning side effect associated with dimethyl fumarate (Tecfidera; Biogen) treatment, affects upwards of 40% of patients and is equally uncomfortable and embarrassing. The only current solution to avoid flush is to pre-treat with aspirin 30 minutes prior to administration — a directive that is often ignored or viewed as an inconvenience by patients.
In an effort to solve this issue, Joseph Habboushe, MD, MBA, an emergency medicine physician at NYU Langone and founder of Vitalis Pharmaceuticals, developed a proprietary formulation of aspirin and combined it with fumarate, in turn improving the pharmacokinetics of fumaric acid. Data from a pilot study of 18 patients showed a 63% reduction in flush compared to fumarate alone in patients who received the combination drug.
The drug, which has received orphan status from the FDA, will be the subject of a phase 3 clinical trial this year. In order to learn more about the novel drug and its potential in the MS space, NeurologyLive spoke with Habboushe in an interview.
Joseph Habboushe, MD: Tecfidera, the biggest oral multiple sclerosis (MS) drug, has 2 main side effects, gastrointestinal side effects and fumarate flush. The discontinuation rates are about the same, but the flushing side effect, which is a burning of the skin which is actually the exact same skin reaction that is seen with high-dose niacin, is actually much more prevalent. In Biogen’s original Tecfidera study, about 40% of patients had fumarate flush and in some real-world studies it actually goes much beyond that. Although niacin flush is the exact same flush that is seen with fumaric acid and through the same mechanism, it’s a bit ironic that the fumarate flush is somehow being a bit ignored. That may partially be because MS is a much more severe disease, so there's a little bit of an expectation that these patients should just deal with the side effects. The downside of an MS patient who has this flush not taking their medication, due to discontinuing or just skipping doses, which we know happens, is so much worse for an MS patient who is treating a very bad chronic disease. It affects a lot of people, but it has been downplayed a lot. It's painful, but it's burdensome in a different way. When you have the flush, everyone can see it, and you can imagine patients who are on fumarates, oral medications for MS, are typically early on in their disease process, so they're more or less living a normal life, but suddenly they're becoming bright red twice a day. That means that they constantly have to face this conversation of, “Why are you red?” Some patients will skip doses when they’re at work or when they're going on out for social reasons. So it’s both physically a problem but also psychologically, because people don't want to have to deal with talking about their disease all the time. I think it's a very important patient-centered side effect that has been mostly down-played, partially because there wasn't a solution to it before.
For as long as we’ve known that high-dose niacin is good for cholesterol, we've known that pre-treating niacin or fumaric acid with aspirin actually reduces the flush significantly. Tecfidera’s drug label advises patients to take an aspirin 30 minutes before. The problem is up until now, we haven't been able to take aspirin at the same time. It won't reduce the flush; you have pretreat and the vast majority of patients won't do that timing. Our core technology is a specialized aspirin formulation that allows you to co-formulate and take it at the same time and yet still reduce the flush.
There's a bunch of clinical, patient-centered benefits, which is what I get the most excited about because I'm a practicing emergency physician and I love dreaming up ways to try to help these patients, but in addition to that, there is an interesting other benefit related to Tecfidera’s patents. Between mid 2020s and early 2028, it only has 1 patent keeping generics off the market. This patent is called the 514 patent. The interesting thing with our drug is its somewhat unique and we believe we get around that patent. Whether or not that patent gets thrown out, we may be able to enter the market and start helping patients sooner. The clinical benefits are several. One is reducing the most common side effect, which is flush, but in addition to that, aspirin has been shown to help some other aspects of MS. MS-related fatigue, which affects a lot of patients, and MS exercise intolerance. Aspirin has been shown in several studies both to reduce fatigue and reduce exercise intolerance in MS, and in other studies, aspirin has been shown to actually reduce MS endpoints themselves, including disease flare ups. The idea here is that we have this drug that we believe gets get around the Tecfidera patent so we can enter the market and start helping patients; we can reduce the most common side effect and maybe we can show benefit in MS-related fatigue and exercise tolerance. And maybe head-to-head against Tecfidera, if it ends up being a superior drug because aspirin has some additional efficacy. It has all these potential upsides in addition to the upside we already know, which is the flush reduction.
Right now, we're developing this aspirin-fumaric acid combination drug, but that same aspirin formulation is being used in development for other drugs outside of MS. This aspirin formulation that we have is proprietary, and we have patents on it. We have put in combination with fumaric acid here, and with a high-dose niacin for cholesterol, as well as with an oral ketamine. Ketamine is only approved IM [intramuscularly], IV [intravenously] and intranasally, but we are studying it in an oral formulation with our aspirin formulation to reduce the pain and replace the blood thinners that are used after surgery. Specifically for knee replacements and hip replacements that are now being done on an outpatient basis, we are looking for a powerful opiate replacement that also replaces the injectable blood thinner. The big picture is we're trying to use the same specialized aspirin formulation that seems to work in a really interesting way in a few different areas. If ends up being efficacious within MS fatigue and exercise tolerance, there's no reason we can’t develop it specifically for use outside of fumaric acid.
The beautiful thing with our development is that because we are using a category of drug that is already approved by the FDA, our clinical path for approval is quite short because we can show that we are bioequivalent to the drug that's on the market. Because of that, we have a fairly short and predictable clinical path for approval. We know we reduce the flush; in our early studies, we showed a 63% flush reduction, which frankly was much better than I had ever expected it to be. Our hope is that we can start our phase 3, pivotal studies at the end of the year, and then submit our NDA some time in 2021. That would be for the first label, which will be for the reduction of acute flush. Then there would be a potential path to expand the label for chronic flush, and then studying to reduce MS-related fatigue and exercise intolerance, which would be not that long of a study. The head-to-head study against Tecfidera would be a little bit longer than that. But again, since aspirin by itself seems to have some benefits, and the combination proved to be better than dimethyl fumarate alone, then you would have a new best-in-class drug. All in all, I would predict 2022 to be the time that we can potentially submit an NDA for chronic flush, and for the fatigue and exercise intolerance indications, maybe a bit after that for the head-to-head if the results turn out the way we hope.
Transcript edited for clarity
Vitalis Pharmaceuticals Announces Results of Type C Meeting with FDA for VTS-72 [news release]. New York, NY: Vitalis Pharmaceuticals. January 7, 2020. finance.yahoo.com/news/vitalis-pharmaceuticals-announces-results-type-130010366.html. January 10, 2020.