A positive trial on Ashworth Scale in Spasticity

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Spasticity is a common problem in multiple Sclerosis and is caused by muscle contraction due to over excited nerves. Baclofen stimulates inhibitory nerves and so is sedative and causes muscle relaxation, cannabis blocks nerve excitation and so is sedative and may cause muscle relaxation. Why do I say “may”…well it is because it is not been proven to the standards that the US regulators want. They want Sativex to cause a reduction in spasticity as seen on the Ashworth Scale….which is the gold standard spasticity scale….but is a crude tool that has kept Spasticity research in the Stone-Age.

Sativex (Nabiximols) has repeated not shown to have an effect there. I suspect because the dose is wrong. Sativex is given at doses that don’t get you high or at least are aimed at doses that don’t get you high. If you are not getting “high” the dose is not optimal and so subtherapeutic. This is because the receptors that cause spasticity relief are the same as those that get you “high” but they are in different parts of the brain, so if you are not getting the high signal you are not getting enough of the muscle relaxing signal. I think many of you know this and that is why you take cannabis (and get high) at night and get the benefit of muscle relaxation and sleep induction.

Baclofen is sedative and this is perhaps why it works better in spasticity. When we were developing VSN16R for spasticity, which blocked pathological nerve excitation, we had to compare VSN16R to baclofen to try and get investor support. This was bad in two ways one it compared VSN16R to a “cheap as chips” drug creating the idea that you couldn’t ask a high price and two we never got as good a result with baclofen in stopping nerve transmission. I think this is because we were working with a drug where the animals were not unconscious, but all the positive data reported in the literature with baclofen was done at crazy baclofen doses where the animals were asleep and there was never a dose response reported. Our trial in MS failed, it was too complicated and we tried to do too much, the dose was probably lower than it needed to be and the drug didn’t last long enough. If only we had developed VSN16S slighlty less potent than VSN16R but lasted way longer. We suffered the problem of academic drug development and sadly you only “get one bite of the Cherry” and we missed our chance.

With pharma you may get more than one chance if you have deep pockets or if you go under due to the failure but have a firesale to divest your assets to another company who may then develop your drug. I think todays post may be this.

Baclofen is a drug that stimulates the gamma aminobutyric acid (GABA) B receptors which mediates a major inhibitory signal for nerve transmission. Baclofen is used to treat spasticity, but its two main weaknesses in my opinion are the side-effects which are sedating and not surprising as you are switching off nerve function, which is why it is used to inhibit spasticity (muscle stiffness). It is also why it is used as an intrathecal pump, with the idea that a low dose stops spinal cord induced spasticity, whilst limiting brain-induced drowsiness. The second issue with baclofen is that it brokendown very quickly and it has a half-life of roughly 2–4 hours; it therefore needs to be administered frequently throughout the day to control spasticity appropriately.

Arbaclofen (XP19986) becomes baclofen when it is metabolised and is absorbed better in the intestine than baclofen and so was also designed to be extended release and so avoiding peaks (going to cause side-effects) and troughs (drug stops working). It was promising for spasticity. Nance et al. Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.. 2011;49:974. Yet by 2013 the manufacters at the time called Xenoport terminated development in spastcity because it failed in trials

XenoPort Reports Top-Line Results of Phase 3 Trial of Arbaclofen Placarbil for Spasticity in Multiple Sclerosis Patients The trial was unsuccessful in demonstrating that arbaclofen placarbil provided statistically significant improvement relative to placebo in the co-primary endpoints of the study.

The trial was a 13-week, multicenter, randomized, double-blind, placebo-controlled study that enrolled 228 subjects in 30 sites in the United States. There was a one-week placebo run-in period, two weeks of up-titration, eight weeks at the maintenance dose and two weeks of down-titration. Eligible subjects were randomized to one of four arms: 15 mg, 30 mg or 45 mg of AP or placebo dosed twice a day (BID) with food. The first of the co-primary endpoints for the study was the time-matched change from baseline in Maximum Ashworth score (six hours post-dose time point) at the end of the maintenance dose period. The muscle group in the lower limbs with the highest Ashworth score at baseline was followed throughout the trial. Subjects entering the trial were required to have a Maximum Ashworth score of two or greater prior to entering the study and at the end of the placebo run-in period, which served as baseline. The second co-primary endpoint was the score on the 7-point Patient Global Impression of Change scale at the end of the maintenance period. The co-primary endpoint analysis plan examined the differences of the 30 and 45 mg BID groups from the placebo group. The co-primary endpoints and dose groups were analyzed independently. Comparison of the AP groups to the placebo group did not reach statistical significance on either of the co-primary endpoints for either of the AP doses. The most commonly reported adverse event was somnolence (drowsiness…2%, 7%, 16% and 21% for placebo, 15, 30 and 45 mg AP BID, respectively).

The results do not seem to be published at the time and the trial was not reported on clinicaltrial.gov.

Xenoport sunk and was bought by Abor Pharmaceuticals in 2016.

The next I know about arbaclofen is that it is being developed by a company called Osmotica and trials are being developed in MS.

Arbaclofen Extended Release that involes the Osmodex® drug delivery system and is being studied for the treatment of spasticity resulting from multiple sclerosis.

This trial appears on clinical trials.gov as Trial (NCT03290131) a trial of 536 people taking 40mg or 80mg of arbaclofen extened release tablet or placebo from 30 sites in Eastern Europe and was first reported in 2017 and is completed and reported in 2022.

Then there is another trial NCT03319732 of 80mg in USA in over 350 people reported started in 2017

Importantly then there is another trial NCT01743651 (apparently started in 2012) in 48 sites in the USA plus Russia and Ukraine with over 350 people testing placebo, baclofen (80mg split 4 times a day) and Arbaclofen (40mg split into twice a day).

One suspects that Xenoport passed Arbaclofen onto Osmotica and maybe they did abit more on the formulation or maybe just changed the dose as an apparent negative becomes an apparent positive.

Okuda DA et al. Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients with Multiple Sclerosis: A Randomized, Placebo-Controlled Clinical Trial. SSRN 2022

Objective: Evaluate the efficacy and safety of arbaclofen extended-release (ER) tablets in patients with multiple sclerosis (MS)-related spasticity.

Methods: In a multicenter, double-blind, placebo-controlled study, adults with MS-related spasticity were randomized to arbaclofen ER 40 mg/day, arbaclofen ER 80 mg/day, or placebo for 12 weeks. Co-primary end points were the change from baseline to Week 12 in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb (TNmAS-MAL) score and the Clinical Global Impression of Change (CGIC) score. A hierarchical testing procedure was used to evaluate the co-primary end points; analyses for the 80 mg/day group were considered inferential only if the  arbaclofen ER 40 mg/day and placebo groups demonstrated a statistically significant difference (P≤0∙05) for both end points.

Results: 536 patients were included in the study. At Week 12,…..mean change from baseline in TNmAS-MAL score was –1∙67 (95% confidence interval [CI]: –1∙97, –1∙36) and –1∙28 (95% CI: –1∙57, –0∙99) in the arbaclofen ER 40 mg/day and placebo groups, respectively (mean difference, –0∙39; P<0∙048). Improvements were seen in mean CGIC scores for both the arbaclofen ER 40 mg/day and placebo groups, however no statistically significant difference was observed between them (LS mean difference, –0∙10; P=0∙43). Most adverse events were of mild-moderate severity.

Conclusions: Administration of arbaclofen ER 40 mg/day for 12 weeks significantly reduced MS-related spasticity compared with placebo. Although arbaclofen ER 40 mg/day improved CGIC scores, a significance difference from placebo was not observed.

In additon there is this

Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients with Multiple Sclerosis: An Open-Label Extension Study SSRN

Methods: In a 52-week, open-label, multicenter study, adults with a Total Numeric-transformed Modified Ashworth Scale (TNmAS) score ≥2 in the most-affected limb (MAL) received oral arbaclofen ER titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen ER safety and tolerability. Secondary objectives included an assessment of efficacy using the TNmAS-MAL, the Patient Global Impression of Change (PGIC), and Expanded Disability Status Scale (EDSS).

Results: Of 323 patients enrolled, 218 (67∙5%) completed 1 year of treatment. Most patients (74∙0%) achieved an arbaclofen ER maintenance dose of 80 mg/day. At least one treatment-emergent adverse event (TEAE) was reported by 148 patients (80∙4%). The most common adverse events (AEs) were (n patients [%]): muscle weakness (24 [13∙0]), urinary tract infection (21 [11∙4]), somnolence (18 [9∙8]), dizziness (16 [8∙7]), pollakiuria (12 [6∙5]), and asthenia (11 [6∙0]). Most AEs were of mild-moderate severity. Twenty-eight serious AEs were reported. No deaths occurred during the study. Overall, 14∙6% of patients discontinued due to AEs, primarily muscle weakness, MS relapse, asthenia, and nausea. Evidence of improvement in MS-related spasticity was observed across arbaclofen ER dosages.

Conclusions: Arbaclofen ER treatment (up to 80 mg/day) was well-tolerated and improved spasticity in adults for 1 year.

So this a positive with a difference of P<0.048 which is pretty pretty close to the P=0.05 = no difference mark and the secondary main outcome is not significant. In the other (extension ) study they must have been so excited…they forgot to put the results of the anti-spastic in the abstract. At 28 weeks the difference was TNmAS-MAL was -0.7 and at 6 weeks it was -0.1 (apparently after drug taper).

Osmotica has become RVL pharmaceuticals. Will it arrive on the Market?….Have a look at RVL’s pipeline

COI: None now

Disclaimer. This are the sole views of the author

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MouseDoctor

6 comments

  • No its not coming to market because RVL is “focused developing and commercializing eyecare and medical aesthetics products.” I have been searching for a better spasticity drug other than baclofen and arbaclofen looked good, but the company couldn’t commercialize it. Their website went from a picture of a pill shooting out drug through a tiny hole (which was their gimmick/patented protection for extended release) to a smiling naked woman showing how her eyes are all better now thanks to RVL. Ugh

    Its criminal that they bought the company and are apparently abandoning the drug.

    What about dantrolene? Our PA waved it off as an “old drug” with side effects but if we can’t handle baclofen, and tizanidine doesn’t last more than an hour and has rebound, well why not try dantrolene? May as well.

  • Very interesting. I’ve gotten great results with Baclofen but of course the issue is increase in weakness and finding it’s benefits wear out regularly. In addition to it, I have found treatment with Botox and shockwave therapy to really help, particularly with managing pain. Immediately after shockwave therapy the difference can be seen in my legs – the treated leg moves smoothly while the untreated once is jerky and shaky due to hip flexor tightness.

  • After so many years since Baclofen was approved, we have no new drugs. The investment has been in modifications to existing drugs such as Baclofen and Tizanidine. Nothing novel in them. Perhaps new ones should be first trialed in SCI, since they don’t have brain involvement and it is a static disorder.

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