Nabiximols is an oral spray containing two of the main compounds found in the cannabis plant that is approved in some countries for easing spasticity in people with multiple sclerosis (MS).
The therapy is approved under the brand name Sativex in 25 countries, including Canada and most of Europe, for reducing involuntary muscle spasms and stiffness. It is used as an add-on therapy to manage such symptoms in MS patients who failed to respond to other anti-spastic treatments.
Nabiximols has not been approved for use in the U.S.
Nabiximols is being developed by GW Pharmaceuticals, now part of Jazz Pharmaceuticals.
Spasticity is one of the most common symptoms in people with MS, and refers to an abnormal increase in muscle tone or stiffness and involuntary muscle spasms. It is due to an imbalance in signals from the nervous system.
About 90% of MS patients experience some form of spasticity at some point in their lifetime.
The main ingredients in nabiximols are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), both of which are compounds found in the cannabis plant. THC is the main psychoactive compound responsible for the “high” associated with recreational cannabis use. CBD, meanwhile, does not induce a “high,” but is thought to have other biological effects, including anxiety-relieving and anti-inflammatory properties.
The mechanisms of action for nabiximols remain incompletely understood. But it is thought the medication may help to balance out nerve signals in MS, thus prompting muscles to relax and ultimately easing spasticity.
These cannabis compounds are poorly absorbed when administered orally. Delivery into the mucosa in the mouth — its mucous membrane lining or “skin” — and under the tongue is believed to increase their absorption and the levels in circulation in the body.
Nabiximols is available in a liquid solution that is designed to be sprayed into the mouth. Each spray delivers about 100 microliters of the solution, which contain 2.7 mg of THC and 2.5 mg of CBD.
In MS patients, Nabiximols has been studied at doses of up to 48 sprays per day. However, its prescribing information in the U.K. recommends patients start with one spray per day, then gradually increase the number of daily sprays over the course of a few weeks. This enables patients to find a dosage that offers symptom relief without unacceptable side effects.
The maximum number of sprays per day should not exceed 12, according to the label.
Initial pivotal Phase 3 trials of nabiximols (NCT01610700 and NCT01599234), conducted in the U.K. and involving nearly 500 participants, showed questionable or no benefits in MS patients. Researchers postulated, however, that negative results from individuals who did not respond to the therapy could be masking potential benefits in others.
Thus, they designed a clinical trial with a two-step recruitment process: only patients who responded to the therapy in an initial period were allowed to remain in the trials and continue receiving treatment.
The European GWSP0604 Phase 3 trial (NCT00681538) enrolled 572 MS patients with moderate-to-severe spasticity that had not fully resolved with anti-spasticity medications.
In the first four weeks, all participants were given nabiximols to identify early responders, or those with a 20% or greater reduction in spasticity scores. These scores were assessed with the MS spasticity Numerical Rating Scale (NRS), in which patients rate the severity of their spasticity-related symptoms over the last 24 hours on a scale of 0 to 10.
Then the 241 participants who showed early signs of spasticity easing were randomly assigned to nabiximols or a placebo for 12 weeks. Most patients continued receiving a fixed dose of their standard spasticity treatments as well during this period.
Results showed that spasticity scores were significantly different between patients who continued on nabiximols versus those who switched to the placebo. Those continuing nabiximols experienced a further reduction of 0.04 points in their NRS scores, while those who switched saw their spasticity increase by about 0.81 points.
The proportion of patients with at least a 30% improvement in spasticity also was significantly higher with nabiximols (74% vs. 51%). Moreover, patients given the medication reported significantly fewer spasms per day and had less trouble sleeping due to spasticity than those on the placebo.
A Phase 2 clinical trial called SAVANT enrolled 191 MS patients with moderate-to-severe spasticity that failed to improve after treatment with at least two standard anti-spasticity medications. Such medications included baclofen, tizanidine, or dantrolene.
The trial’s design was similar to that of GWSP0604, with two notable exceptions. First, there was a wash-out period after identifying responders, in which participants were given time for the initial medication to be eliminated from the body. Secondly, participants were allowed to adjust the dosage of their other spasticity-controlling medicines during the trial.
Results from SAVANT showed that significantly more participants given nabiximols than placebo (77.4% vs. 32.1%) experienced a 30% or greater improvement in spasticity scores. Nabiximols also lowered the average spasticity and pain scores, as well as the severity of spasms and trouble sleeping, compared with a placebo.
Researchers then conducted a Phase 3 trial (NCT00702468) to determine how long it took from nabiximols discontinuation for patients to experience worsening in spasticity scores.
The trial enrolled 36 MS patients who had been using nabiximols to manage spasticity for at least 12 weeks. On average, the participants had been using nabiximols for more than three years before the trial started. Participants were randomly assigned to continue taking nabiximols or switch to a placebo for four weeks.
Over the five-week study, less than half (44%) of the participants given nabiximols experienced treatment failure, defined as a 20% or higher increase in NRS scores. Conversely, nearly all (94%) of those given the placebo had treatment failure. Patient-reported assessments of overall health also favored nabiximols.
The RELEASE MSS1 (NCT04657666) enrolled 68 MS patients who had a marked increase in muscle tone on at least two of six leg muscles, as determined using a clinician-administered assessment called the Modified Ashworth Scale (MAS).
The study consisted of two treatment phases, each including a seven-day “baseline” period followed by three weeks of treatment. During the baseline period, designed to gauge current treatment effectiveness, participants used an electronic diary to record spasticity scores and daily numbers of muscle spasms while on their routine anti-spasticity medications. Then, participants were randomly assigned to receive nabiximols or a placebo for three weeks, with the number of sprays adjusted during the first two weeks (up to 12 sprays per day).
The second treatment phase had the same design, but participants switched groups — those on placebo moved to nabiximols and vice versa. The study’s main goal was to determine whether nabiximols could reduce spasticity in the legs, as measured by Lower Limb Muscle Tone-6, or the average MAS scores in the six leg muscles.
Top-line results showed that the trial did not meet its goal of showing a significant reduction in leg spasticity. No new safety signals related to nabiximols were reported.
Jazz Pharmaceuticals is running two other Phase 3 clinical trials to further evaluate the safety and effectiveness of nabiximols for the treatment of MS-related spasticity.
The RELEASE MSS5 (NCT04984278) trial, which is expected to enroll about 190 participants, uses the same design as the MSS1 trial and also will assess the effect of treatment on lower limb spasticity based on MAS scores.
The other trial, RELEASE MSS3 (NCT04203498), is expected to enroll 446 adults. Participants will first undergo a 28-day “baseline” period, in which they will record spasticity scores while on their routine treatment. Then they will be randomly assigned to take nabiximols or a placebo for 12 weeks, with the number of sprays also adjusted during the first two weeks.
That study’s main goal is to assess the effect of nabiximols treatment on daily spasm counts. Secondary measures include changes in mean spasticity scores and overall safety.
According to the MS Trust, side effects from nabiximols are most common when starting treatment, and tend to wear off after a few days. The most common side effects associated with the therapy include:
Some of these side effects, such as dizziness or drowsiness, may make it unsafe to drive or operate heavy machinery.
Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
Nabiximols is not approved to treat multiple sclerosis in the U.S., but in Canada and much of Europe, the medication is authorized to help ease disease-related spasticity in MS. It is indicated for patients who do not respond to standard spasticity therapies. Treatment is thought to ease spasticity by helping to normalize imbalanced nervous system signals that cause muscles to tighten.
Nabiximols is now being tested for multiple sclerosis-related spasticity in three Phase 3 clinical trials. If trial results are positive, it is possible that they may support applications seeking the medication’s approval by the U.S. Food and Drug Administration. However, it is currently too early to know if or when nabiximols might be approved for use in the U.S.
Nabiximols has not been well-studied in pregnant patients. The medication’s label in the U.K. recommends that all patients with the ability to reproduce use effective contraception while on nabiximols and for at least three months after stopping treatment. Notably, nabiximols may reduce the effectiveness of hormonal birth control methods, so other methods (e.g., barriers such as condoms) should be used. Nabiximols should be used during pregnancy only if the benefits of treatment outweigh the potential risks to the fetus.
In the SAVANT Phase 2 and GWSP0604 Phase 3 trials, participants were treated with nabiximols for four weeks to identify those who appeared to benefit from the therapy. More than half of patients were deemed “responders,” defined as those who experienced a 20% or higher improvement in spasticity scores — meaning an easing of spasticity symptoms — after four weeks.
Neither hair loss nor weight gain has been reported as side effects of nabiximols in clinical studies. Patients who experience unexpected effects of treatment are advised to discuss these with their healthcare team.
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