You say why dont you lot do anything for PPMS, if you don’t try, you can’t fail. Laquinimod was a rather useless DMT as far as relapsing MS was concerned and it was pitted against beta interferon in a trial and it lost, but it looked like if affected brain volume. So a trial in PPMS was done and here are the results….Sorry trial has failed.
Sadly this could have been the perfect drug to use in combination with a DMT that stopped peripheral inflammation. But no it was done as single entity and it failed. We (ProfK) and I had noticed that the manufactureres were filling patents on combinations of laquinimoid with every DMT so laquinimod and DMF, Laquinimod and copaxone and used dodgey EAE experiments to justify the combination was better than the single treatment……They even did a combination of cannabinoid and laquinimod and baclofen and laquinimod. Baclofen is an anti-symptomatic so why would it work as an immunosuppressive in EAE…However, give enough of it the animals get sent to sleep as it is sedating, the animals get so stressed they will make a steroid response, which will stop EAE.
However they had missed one combination and this was cladribine and laquinimod, which would have been the best combination. At that time cladribine was on the maggot pile but we were using it off-label in MS, so ProfK and I got on of the bods in the commercial department to write a patent, so we didn’t pay any lawyers fee and so saved £5,000, which we filed and then went to the manufacturers of laquinimod to see it they wanted the patent……..They didn’t:-). I guess they were stopping others filling the space and did them a favour. I suppose we could have sold it to Merck…but as laquinimod is no destined for the maggot pile, it is not worth the paper it was written on.
However this seemed to have been the last foray of the manufacturers of Copaxone to do MS trials….After this, a lot of the MS left and sponsorship of MS meetings were cut. IS this disenguagement from MS?
A randomized, placebo-controlled phase 2 trial of laquinimod in primary progressive multiple sclerosis.Giovannoni G, Knappertz V, Steinerman JR, Tansy AP, Li T, Krieger S, Uccelli A, Uitdehaag BMJ, Montalban X, Hartung HP, Sormani MP, Cree BAC, Lublin F, Barkhof F.Neurology. 2020 Jul 10:10.1212/WNL.0000000000010284. doi: 10.1212/WNL.0000000000010284.
Objective: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).
Methods: In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events.
Results: 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%).
Conclusions: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.
COI: ProfG is lead investigatoer