News for the US has surfaced that says we are on the way.
This is a repeat trial but this time in seondary progressive MS. This repeats what was found in relapsing remitting disease.
This study shows that brain shrinkage is slowed, but not halted, by ibudilast.
This is a drug made for asthma, which has been repurposed for use in MS.
This is a drug made for asthma, which has been repurposed for use in MS.
Ibudilast is a phophodiesterase 4 (PDE4) inhibitor. These agents block tumor necrosis factor (TNF) and so could be anti-inflammatory, indeed that is part of their use in the lung diseases.
However, we know that TNF blockers have been shown to make MS worse or even trigger MS in people treated for arthritis with these drugs. Indeed trials with rolipram a PDE4 inhibitor was stopped because of disease worsening.
This has not occurred with Ibudilast...Why?
This has not occurred with Ibudilast...Why?
Simple answer is...I don't know. I had hoped that CNS penetration may be an answer as anti-TNF has low CNS penetration, butrolipram and ibudilast get in the brain
However, it tells us that not all drugs are created equally, but what is the difference?
Ibudilast inhibits TNF but also block a macrophage migration factor (MIF) also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase.
Is this the key difference?
Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Naismith RT, Ashokkumar A, Barnes J, Ecklund D, Klingner E, Koepp M, Long JD, Natarajan S, Thornell B, Yankey J, Bermel RA, Debbins JP, Huang X, Jagodnik P, Lowe MJ, Nakamura K, Narayanan S, Sakaie KE, Thoomukuntla B, Zhou X, Krieger S, Alvarez E, Apperson M, Bashir K, Cohen BA, Coyle PK, Delgado S, Dewitt LD, Flores A, Giesser BS, Goldman MD, Jubelt B, Lava N, Lynch SG, Moses H, Ontaneda D, Perumal JS, Racke M, Repovic P, Riley CS, Severson C, Shinnar S, Suski V, Weinstock-Guttman B, Yadav V, Zabeti A; NN102/SPRINT-MS Trial Investigators. N Engl J Med. 2018 ;379(9):846-855.
Background There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.
Methods We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.
Results Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.
Conclusions In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression.
However, it tells us that not all drugs are created equally, but what is the difference?
Is this the key difference?
Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Naismith RT, Ashokkumar A, Barnes J, Ecklund D, Klingner E, Koepp M, Long JD, Natarajan S, Thornell B, Yankey J, Bermel RA, Debbins JP, Huang X, Jagodnik P, Lowe MJ, Nakamura K, Narayanan S, Sakaie KE, Thoomukuntla B, Zhou X, Krieger S, Alvarez E, Apperson M, Bashir K, Cohen BA, Coyle PK, Delgado S, Dewitt LD, Flores A, Giesser BS, Goldman MD, Jubelt B, Lava N, Lynch SG, Moses H, Ontaneda D, Perumal JS, Racke M, Repovic P, Riley CS, Severson C, Shinnar S, Suski V, Weinstock-Guttman B, Yadav V, Zabeti A; NN102/SPRINT-MS Trial Investigators. N Engl J Med. 2018 ;379(9):846-855.
Background There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.
Methods We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.
Results Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.
Conclusions In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression.
Gastrointestinal side effects are a common problem of PDE4-inhibitors and shows some efficacy. So what next?
Clearly a phase III will be needed to show clinical benefit. But that means a 2-3 year trial and a 5-6year wait. Is this any better that a statin. However one thing we know and thatt is that ibudilast does not inhibit relapsing disease .
To my mind we need to learn from this and rather than plough on with a sub-optimal clinical trial with a single neuroprotective compound.
It would be sensible to add this on top of an induction treatment like rituximab/ocrelizumab, cladribine or CD52, so you remove the immune-mediated neurodegeneration element occuring in progressive MS as well.
Not to do this is simply pandering to the academic neurologists, but we need to remember that it is not their brain they are not saving, it is your brain they are not saving.
So if you are thinking of doing a trial in advanced MS, you simply have to ask why are we not thinking this way.
Will pharma follow in the Ibudilast trail?
If they do, what aspects of ibudilast need to be replicated as PDE4 activity alone is not enough.
I will be off to eat my hat as I was concerned of disease worsening by this approach, but shows that sometimes you have to stop procrastinating and "bite the bullet" and do the trial