MMJ-001 is currently in a dose-ranging trial, with a planned study for spasticity in primary progressive MS. The trial's principal investigator spoke about how it will be assessed.
Bianca Weinstock-Guttman, MD
Recently, MMJ International Holdings announced that it was seeking a Fast Track designation from the FDA for MMJ-001, its cannabis-based pharmaceutical candidate for the treatment of multiple sclerosis (MS).1
The company is planning a dose-ranging study, in which it plans to compare its formulation of both tetrahydrocannabinol (THC) and cannabidiol (CBD) with placebo. It has stated that it anticipates the trial will be positive in demonstrating a safe and tolerable dose and that it plans to conduct trials in patients with primary progressive MS (PPMS).
Bianca Weinstock-Guttman, MD, a professor of neurology at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, as well as the executive director of the New York State MS Consortium, has been announced as the principal investigator for the trial in PPMS. So, to find out more about the plans for the trial and what has been learned thus far about the application of marijuana-derived products in MS, NeurologyLive spoke with her in an interview.
Bianca Weinstock-Guttman, MD: Cannabis appears to be beneficial for spasticity and additional symptoms in MS patients. In a very clear evaluation and review from the National Academies of Sciences in 2016, they looked on the benefit of marijuana on many different diseases and symptoms, and MS spasticity is clearly showing a benefit through all the studies. So, there is a clear suggestion, and this is also why we have medical marijuana approved for MS patients for spasticity and also pain, which is available in many states now. The issue is that the medical marijuana available today is only available through dispensaries. There is really not much proof or assessment of the dosages that each sample includes, and there’s not a pharma-assessed study, and the FDA doesn’t have much control of it.
The benefit of marijuana is clearly known based on many studies for the symptoms of MS, on spasticity and pain. There are many other benefits for sleep, on symptoms of anxiety, and it’s well known that CBD is approved for some types of epilepsy. Now the problem for the different medical marijuana products is the concentration between THC and CBD, or either one alone. The problem concerns related to THC alone are the psychoactive effects, meaning the cognitive issues, feeling this high, disassociation, and the interference with day-to-day activities, primarily driving. This is a primary concern for children aged 11 to 18 years, that still have a developing brain. There’s also a rare, but serious concern for people that have a family history of schizophrenia. Now CBD, on the other hand, is known to have a certain effect on spasticity pain and anxiety. CBD can actually decrease the adverse effects of the THC. This is why the products coming up now are really considering a combination between THC and CBD, first is because the CBD may decrease the adverse effects, especially the psychoactive effects, of the THC, but also, in a lower dosage, can actually potentiate the THC. On, one hand, you can go higher on the THC, as the CBD might neutralize the adverse effects. But some of the effects of the THC may also increase with adding on CBD.
The product, first of all, will be fully overseen because it is a pharma-based assessment, everything has to be assessed under FDA supervision. There is a product that is called nabiximols (Sativex) that is approved for spasticity in many countries in Europe and Canada, but not in the US. This is given as an oral spray—it has a very bad taste as I understand—but the FDA didn’t approve it. It didn’t approve it because in any kind of study, you have to have a certain outcome measure, and the FDA is very strict about what you are exactly measuring to prove the benefit of a certain product. Now for spasticity, primarily the effectiveness is considered by a scale, called the Ashworth scale. Most of the medication that we have today available for spasticity in MS and in other diseases that affect the central nervous system are were approved after having a benefit on the Ashworth scale, based on the practitioner assessment. Nabiximols didn’t show this benefit.
Now that is also a problem because many times, in MS especially, our assessments are not perfect ones. The one that they used is the so-called MRS, the medical rating scale, in which the patient is rating the spasticity. Sure enough, a symptom that’s coming from a patient is more important than what we say, but at the same time, the regulatory agencies want to have something objective. In general, for an FDA approved medication we have to follow their recommendations and rules. You have to have the primary outcome in the phase 3 trial. In order to be approved for spasticity, the FDA wanted to have us use the Ashworth scale, meaning the practitioner-assessed outcome. For this study, it’s a preliminary phase 2 trial, we’ll probably still use the NRS as the primary outcome based on all the data that we have today, but we will also have to include the Ashworth scale as well. Then, we can determine if the benefit is positive on a larger scale in a phase 3 trial.
For MMJ-001, the amount is very important and so is the ratio. For Sativex, the ratio is 1:1 for THC to CBD and MMJ-001 will be 2:1, so CBD will be double the THC, going up to 4 pills a day. On the one side, you’ll have the possibility to go a higher dosage, decreasing the possible adverse effects related to the THC.
Besides spasticity, we will look for many other effects. One of the effects they found in one of the studies for marijuana in MS, clearly showed, objectively, a benefit on the bladder function and this is clearly understood because the issues with the bladder are coming from the muscle problem. If you treat spasticity, you also have a benefit on the bladder. But at the same time the cannabinoid products have a lot of effects on a lot of receptors, not only in the central nervous system but the peripheral nervous system and the autonomic nervous system, because both bowel and bladder are controlled by the autonomic nervous system.
But the benefit we’re looking for will be primarily on moderate to severe spasticity in patients who actually have failed the medications that we have available—baclofen, gabapentin, and benzos. Sometimes, it’s not sufficient for a patient and often if you’re going on higher dosages there are more adverse effects, and some people are very sensitive to low dosages for a certain reason—we don’t know why. The primary group will be patients with progressive disease. These patients have a much higher frequency of moderate-to-severe spasticity, they may be older, and many of our patients with progressive diseases also have increased risk for comorbidities—hypertension, diabetes, and such, and all this may bring only new problems from the medication that they’re already on. It’s a more complex patient, and that could really be a benefit for patients to have a different product that may have better efficacy.
We will also look at pain because it may have a real benefit with pain. Pain itself and pain from spasticity because many patients actually have pain from their spasticity. There may also be benefits for sleep, as one of the primary concerns of MS patients is fatigue, and often the fatigue is related to effected sleep. By improving sleep, you may also have a benefit on improving fatigue and daily activities. We’re also looking on different cognitive assessments in our patients and anxiety, as that may also have a benefit from the CBD.
1. MMJ Files FDA Fast Track Approval Application For Cannabis Multiple Sclerosis Drug [press release]. Reston, VA: MMJ International Holdings; Published February 13, 2019. markets.businessinsider.com/news/stocks/mmj-files-fda-fast-track-approval-application-for-cannabis-multiple-sclerosis-drug-1027948379. Accessed February 13, 2019.