BACKGROUND: VSN16R is an opener of neural, big-conductance, calcium-activated, potassium channels. We report the results of a phase 2a trial of twice daily oral tablet therapy in people with spasticity due to multiple sclerosis (MS).
METHODS: Subjects had confirmed diagnosis of MS, spasticity reported as ≥ 4 on the spasticity numerical rating scale (NRS) and modified Ashworth scale ≥2 in 2 or more lower limb muscle groups. Participants entered (i) a hospital-based, placebo-controlled, single ascending dose (SAD) group (100mg, 200mg, 400mg and 800mg) to assess pharmacokinetics (n=10), safety and drug tolerability (n=~50) and (ii) a second group (Total n=156) to receive either a maximum-tolerated dose or up to 400mg BID of VSN16R capsules or matching placebo. The primary end-point was a reduction of spasticity as measured by the NRS, with secondary-outcomes including reduction of modified Ashworth and Tardieu Spasticity Scales, Penn spasm scale and 10m walk following treatment.
RESULTS: Pharmacokinetics and relative lack of adverse events in the single ascending dose, (SAD) safety phase were consistent with phase I safety studies in healthy individuals and all people tolerated the single 800mg dose. Therefore, all people were assigned to 400mg BID during the efficacy arm. Among the people who received VSN16R the change in the NRS was -0.9 ± 1.50 in the VSN16R 400mg BID group and -1.1 ± 1.52 in the placebo group, giving a non-significant treatment difference of +0.20 (95% CI: -0.2 to +0.7, p=0.3434). There was no significant effect on the secondary endpoints. However, post-hoc analysis of people who responded (>30% inhibition of the NRS) to the 800mg dose in the SAD phase demonstrated a significant (p<0.02) inhibition in the NRS compared those receiving placebo during the multiple dosing arm. The drug was not associated with any sedation. Reported adverse effects were inconsistent and generally mild, although Escherichia urinary tract infections occurred in 12/77 people compared to 0/79 people treated with placebo.
CONCLUSIONS: VSN16R at the dose of 400mg bid did not show activity in reducing spasticity in MS patients. VSN16R had a very good safety profile. Due to short half-life of VSN16R further studies with higher doses and slow-release formulation may be warranted. (ClinicalTrials.gov number NCT02542787. EU trials register Number: 2014-004412-11).
What went wrong?
1. The idea was a dud?
2. Humans do not use the same channel?
3. The trial design was wrong?
It was highly complicated trial, perhaps too complicated as it slowed recruitment, but it was designed to show safety in people with MS and if there was activity it was designed to capture it. It was two trials in one. The multiple dosing trial was aimed to test efficacy on the maximum tolerated dose based on the first trial, which was a safety study to see how much people with MS would tolerate.
This was based on the levels set by the phase I trial where people could take up to 800mg a day as a single dose or a month of twice a day 400mg. Perhaps, this was where the problem lay as we could only test so many doses due to costs and we started low and perhaps did not escalate enough. However we were trying to be safe.
In the trials everyone tested could tolerate 800mg and so after the first 50 people with MS had taken the drug this part was stopped and every one went into the main part of the trial to start with 400mg twice a day.
I met a participant on the first
part of trial ages ago who told me that they thought the drug may do something at the 800mg dose but not the lower doses.
If, we hacked the data to answer a very specific question and we looked at those people who responded (More than a 30% improvement) to the 800mg dose and asked what happened when they got 400mg twice daily or placebo. There was actually a statistically significant effect of the drug on the spasticity scale.
Is this chance or real? We would need another study to do this. Some people clearly did better, but was it the placebo-effect?
The drug was on the whole well-tolerated, and lacked the sedating effect you would associate with drugs like baclofen. The only issue that cropped up was that there were were more bladder infections reported. Was this because the bladder was being relaxed? I don't know.
4. The dose was too low. See Above. Mice tolerated the equivalent of about 200 times more than was used in the trial. At 1-2mg/kg used in the mouse the effect lasted about 1.5-3hours. However humans get a much higher concentration in the blood than a mouse for the equivalent dose suggesting we were not too low. However did enough get into the spinal cord and brain? It would depend on the concentration needed at the human channels in the CNS and we don't know how much got into the human brain. In one scenario only the 800mg dose would only have a high enough blood level to reach the brain for about 3 hours.
5. The drug did last long enough. This is perhaps part of the problem, as there was a rapid elimination of the drug so that only low concentrations persisted. With more resource this could have been addressed.
So we have had our shot and have been found wanting. Sorry.
Ipsen Pharmaceuticals, France, who donated money as part of a pre-licencing deal that allowed the trial to occur, have declined to exercise their option to buy Canbex Therapeutics and its Assets.
What next?....Learn from the mistakes, dust ourselves down and try Plan B, Plan C
COI: We are shareholders and consultants of Canbex therapeutics.
It is not all bad news
ECTRIMS 2018 P629 - FLX-787 significantly reduces muscle cramp/spasm frequency and improves spasticity in a phase 2 study (Flex-201) in patients with multiple sclerosis
1Royal Melbourne Hospital, Parkville, VIC, Australia, 2Flex Pharma, Boston, MA, United StatesIntroduction: FLX-787 is believed to dampen α-motor neuron and reflex hyperexcitability by chemical neurostimulation. In this process, TRPA1/TRPV1 coactivation in the oropharynx and esophagus leads to excitatory sensory input to stimulate brainstem nuclei and subsequently descending spinal tracts to inhibit hyperexcitability. The Flex-201 study was initiated in patients with Multiple Sclerosis (MS) to evaluate the safety and efficacy of FLX-787 in a disease state where the symptoms of cramps, spasms and spasticity are prevalent.
CoI A competitor:-(
Objectives: To assess in an exploratory Phase 2 study: 1.)the frequency of cramps/spasms and associated-pain in MS patients; 2.)the efficacy of FLX-787 in treating cramps/spasms, pain and spasticity; 3.)the safety and tolerability of FLX-787.
Methods: Flex-201 was a multicenter, randomized, blinded, cross-over study which investigated the effects of FLX-787 in 57 MS patients with symptoms of spasticity, spasms and cramps versus inactive control. A daily questionnaire capturing cramp/spasm events, pain, stiffness and spasticity was administered using an interactive voice response system (IVRS). IVRS data, as well as in-clinic end-of-period assessments of spasticity, were analyzed.
Results: Analysis of the parallel portion of the study in the per-protocol population (n=45) showed that FLX-787 treatment caused a 27.3% reduction (p=0.0010) in the total number of cramps/spasms relative to baseline and a 42.5% reduction in total pain intensity (p=0.0486). Patients experienced a median increase of 1.4 cramp free days over the course of treatment (p=0.0457). Importantly, FLX-787 treatment caused a 1-point decrease relative to inactive control of the CGI-C spasticity score rated as a total improvement being entirely due to drug treatment (p=0.0427). CGI-C spasticity responders comprised 25% of the population and demonstrated a 2-point improvement on total modified Ashworth scale (p=0.025) and a 1-point improvement by NRS (0-10 scale) for spasticity (p=0.053). FLX-787 was generally well tolerated and resulted in infrequent GI-related adverse events (diarrhea and nausea).
Conclusion: This is the first report of FLX-787 being well-tolerated, safe and effective in treating common MS symptoms including cramps/spasms, pain and spasticity. These findings are similar to FLX-787 mediated reductions in cramp frequency associated with ALS and nocturnal leg cramps and suggest a broad applicability of FLX-787 across many neurological disorders.