The trial is MS-SPRINT and it was a sprint to get access to the agent as both people in the USA and the UK wanted to do a trial…As is often the case the US sprinter won….
The reason there was a desire to do the trial was because of trial failure.
In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1-hypointense lesion volumes, and percent brain volume change (PBVC).
RESULTS:A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated.
CONCLUSION:Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression.
So is ibudilast a neuroprotective?
Anyway, The new trial design of Sprint has been reported
Fox RJ et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.Contemp Clin Trials. 2016 Sep;50:166-77
METHODS:SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening.
CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.
The trial will assess the outcomes and the treatment agent.
When I first heard about the UK view of it being a candidate, I did not bat an eyelid as I was not aware how it worked…..I’m not a big one for drug names…hey I didn’t know that fluoxetine was prozac:-(
But then I jogged by memory and then I felt that MS-SMART had been smart to have avoided it.
Whilst I don’t want to be a party pooper, now is a good time to get my concerns off my chest…….again. The first time in public was here
IPMSA Boston 2015. Do they Remember my concerns?…They weren’t bothered at the time and didn’t ask any questions. So all must be A OK.
Before the SPRINT trial I had heard of Ibudilast a number of years earlier. This is because some one had found it in Japan and they wanted us to do some animal experiments. I wasn’t too keen.
However, the cytokine I was concerned about was tumor necrosis factor.
So we had this paper
Sommer N, Löschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmüller A, Fontana A, et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med. 1995;1:244-8.
Fujimoto T, Sakoda S, Fujimura H, Yanagihara T. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol. 1999 Mar 1;95:35-42.
Pette M, Muraro PA, Pette DF, Dinter H, McFarland HF, Martin R.
Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones.J Neuroimmunol. 1999; 98(2):147-56
Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10.
Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Mult Scler. 2004 Oct;10(5):494-8.
OBJECTIVE:A double-blind, placebo-controlled phase II study was conducted in 168 patients, most with relapsing-remitting MS, to evaluate whether lenercept would reduce new lesions on MRI.
BACKGROUND:Tumor necrosis factor (TNF) has been implicated in MS pathogenesis, has been identified in active MS lesions, is toxic to oligodendrocytes in vitro, and worsens the severity of experimental allergic encephalomyelitis (EAE) in animals. Lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein (sTNFR-IgG p55), protects against EAE.
METHODS:Patients received 10, 50, or 100 mg of lenercept or placebo IV every 4 weeks for up to 48 weeks. MRI scans and clinicalevaluations were performed at screening, at baseline, and then every 4 weeks (immediately before dosing) through study week 24.
RESULTS:There were no significant differences between groups on any MRI study measure, but the number of lenercept-treated patients experiencing exacerbations was significantly increased compared with patients receiving placebo (p = 0.007) and their exacerbations occurred earlier (p = 0.006). Neurologic deficits tended to be more severe in the lenercept treatment groups, although this did not affect Expanded Disability Status Scale scores. Anti-lenercept antibodies were present in a substantial number of treated patients; serum lenercept trough concentrations were detectable in only a third. Adverse events that increased in frequency in treated patients included headache, nausea, abdominal pain, and hot flushes.
CONCLUSIONS:Lenercept failed to be beneficial, but insight into the role of TNF in MS exacerbations was gained.
van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.Neurology. 1996;47(6):1531-4
Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, Stürzebecher CS, Martin R.Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood–brain barrier disruption in multiple sclerosis. Mult Scler. 2009 ;15(10):1206-14. doi: 10.1177/1352458509345903.
Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective (Is it really) in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.
Studies of cytokines in multiple sclerosis (MS) have shown that immune mechanisms connected with disturbance of the synthesis of cytokines probably play critical roles in the initiation and prolongation of MS. In a double-blind, placebo-controlled trial, 45 patients with active secondary progressive MS were randomized to three groups of 15 patients, each receiving a short course of antibodies to IFN-gamma, to tumor necrosis factor (TNF)-alpha, or a placebo. After 12 months with analysis of disability (Expanded Disability Status Scale scores), accompanied by interval determinations of lymphocyte subpopulations, cytokine production levels, MRI, and evoked potentials, it was found that only patients who received antibodies to IFN-gamma showed statistically significant improvement compared to the placebo group.
So anti-TNF in SPMS did nothing (didn’t make things better)…is this the exception of the rule? We will soon find out. I really hope it is not, but…….
Myers LW, Ellison GW, Merrill JE, El Hajjar A, St Pierre B, Hijazin M, Leake BD, Bentson JR, Nuwer MR, Tourtellotte WW, Davis P, Granger D, Fahey JL. Pentoxifylline is not a promising treatment for multiple sclerosis in progression phase. Neurology. 1998; 51(5):1483-6.
So two PDE inhibitors make MS worse, should a third have been tried?
Too late now, just as it probably was when I aired my concerns about this in March 2015
But if it bad news in Paris 2017, you now know why.
If it isn’t, is it luck or Good Design?
However, I need to say now the fact that the study by Barkof et al. 2010 was not associated with worsening and is was a large trial and no worsening was reported, which is a good thing and may serve to ease my concerns
Ibudilast (AV111, MN-166) is a drug that has been used for the treatment of asthma in Japan for about 20 years and has been taken by millions of people. Maybe this needs
It appears that the effect of blocking migration inhibition factor is not a typical product of PDE4 inhibitors and there are variants of ibudilast which lack PDE4 inhibitory activity, such as AV1013 (Coy et al.2013).
The company supporting the trial will no doubt have to make an announcement to its shareholders before the results are announced at ECTRIMS.
Not long to wait now.