Trial in Remyelination is safe in humans

You want to hear about remyelination trials and here is one. The idea that there are naturally occurring antibodies that promote remyelination was suggested by the group of Moses Rodriguez at the Mayo clinic many, many years ago. 

They then generated an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. Apparently the antibody is well-endowed with strong anti-apoptotic and pro-proliferative effects on oligodendrocytes.

So this study says it is safe in humans

However, I must admit that I find the whole approach very weird. 

We know that to promote remyelination that the treatment has to enter the brain and bind the oligodendrocytes.

In the Lingo-1 studies they injected massive amounts of antibody such as up to 100mg/kg, which was was about 99.9% excluded from the target. But that tiny percent apparently did something. 

In this current study they used 50 to 100th less antibody and amazing 99.997%  was excluded although this increased to about 99.95 at 1mg/kg and 99.5 at 2mg/kg so again most of what injected went no where useful.

Surely the starting point needs to develop agents that get into the brain.  Maybe I'm just being thick again.

However, I guess other people think differently

Eisen A, Greenberg BM, Bowen JD, Arnold DL, Caggiano AO. A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. Mult Scler J Exp Transl Clin. 2017 Nov 21;3(4):2055217317743097.

OBJECTIVE:The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).
METHODS:Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.
RESULTS: rHIgM22 was well tolerated with no clinically significant safety signals. Non-compartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0-Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.
CONCLUSIONS: Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Remyelination studies: Publishing the data after pharma has dumped the idea

Positive data for a target for remyelination.

I suspect you are hearing about it after clinical development has been stopped.

Chen Y, Zhen W, Guo T, Zhao Y, Liu A, Rubio JP, Krull D, Richardson JC, Lu H, Wang R. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination.PLoS One. 2017 Dec 18;12(12):e0189380.

BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo.
METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS.
RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists (deliver a negative signal) of H3R but not neutral antagonists (receptor blockers) promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis.
CONCLUSIONS: From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis

               Hrh3 histamine 3 receptor expression from BrainSeq

We have heard of anti-cholingeric/muscarinic receptor drugs (acetyl choline (nerve transmitter) receptor) promoting remyelination. These include clemastine. However this is also an anti-histamine drug and blocks the Histamine 1 receptor. 

In this study they find that Histamine receptor 3 inhibiting drugs promote remyelination. 

Oligodendrocyte differentiation is regulated through the cAMP/CREB/HDAC1/Hes-5 pathway. Constitutively active H3R inhibits cAMP increase, which would otherwise activate PKA phosphorylation of CREB leading to oligodendrocyte differentiation through HDAC1 and Hes-5. AC, adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate, CREB, cAMP response elements; H3R, histamine receptor 3; HDAC, Histone deacetylase. MBP, myelin basic protein; OL, oligodendrocyte; OPC, oligodendrocyte precursor cell; P, phosphate; PKA, protein kinase A.

Now before you get too excited, I have reported on this before when it was presented at ECTRIMS:

http://multiple-sclerosis-research.blogspot.com/2014/09/news-from-actrimsectrims-2014-pharma-in.html

If you read that post you can see that the clinical trial with the clinical candidate drug GSK239512 was already underway 3 years ago. 

The logic of the approach is that, histamine H3 receptor antagonism has been proposed to increase cholinergic signaling.

Between 2007 and 2014, GSK conducted six clinical trials on this compound, three in Alzheimer's, two in multiple sclerosis, and one in schizophrenia.

The antagonist improved episodic memory but not other cognitive domains or clinical measures in Alzheimers. 

The results in MS were published:

Schwartzbach CJ, Grove RA, Brown R, Tompson D, Then Bergh F, Arnold DL.Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017 Feb;264(2):304-315.

Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

http://multiple-sclerosis-research.blogspot.com/2016/12/researchspeak-remyelination-study.html

So a positive effect great.....so what is happening?

So we look to the side effects it caused predominantly headaches, dizziness, and problems sleeping (Grove et al., 2014). As of November 2015, this compound was no longer listed in GSK’s development pipeline. So it was dumped.

I think this will be the problem for most of the remyelinating drugs, as the targets people are finding e.g. RXR are all used in other important bodily functions and so blocking or activating them will have side-effects. This does not surprise me as the body uses the same signalling molecules to do many things, because this is not where the specificity of the activity is located. However, will probably hamper long-term use of such agents. 

Importantly, we have yet to answer the question. Do you need long-term treatment to remyelinate or will a pulse of treatment get the differentiation/maturation arrested oligodendrocyte precursor cells the kick they need to become myelinating cells?

The animal models used can't answer this question as they naturally remyelinate anyway, but it is an essential question that needs answering.

It is quite common for Pharma to not publish their data until after they have lost interest in a project. This keeps it secret so their competitors don't get an advantage.

So back to the drawing board.

An internal cell signalling molecule found to support remyelination

Do you want to know about cell signalling and how the oligodendrocyte knows when to make myelin or not?




The protein tyrosine phosphatase Shp2 regulates oligodendrocyte differentiation and early myelination and contributes to timely remyelination. Ahrendsen JT, Harlow DE, Finseth LT, Bourne JN, Hickey SP, Gould EA, Culp CM, Macklin WB. J Neurosci. 2017 pii: 2864-16.

Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mTOR and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis.

SIGNIFICANCE STATEMENT In the present study, we show that the protein phosphatase Shp2 is an important mediator of oligodendrocyte differentiation and myelination, both during developmental myelination as well as in myelin regeneration. We provide important insight into the signaling mechanisms regulating myelination and propose that Shp2 acts as a transient brake to the developmental myelination process. Furthermore, we show that Shp2 regulates oligodendrocyte differentiation following demyelination and therefore has important therapeutic implications in diseases such as multiple sclerosis

                                     Expression from Brain seq
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), SHP-2, or protein-tyrosine phosphatase 2C (PTP-2C) is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. 

This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. 

Mutations in this gene are a cause of Noonan syndrome and Leopard syndrome as well as acute myeloid leukemia.

Is this going to be a good target for remyelination without side-effects, one would think this will be unlikely as the molecule is expressed at high levels all over the place. 

This feature seems to be common for many of the remyelination .pathways. However do we need to treat long term or give a pulse treatment?

We dont know...becuase we are not testing for this. The models used naturally repair without any treatment so all we are seeing in an enhanced repair. People never look at what happens in a model where there is chronic demyelination yet we jump from these simple models straight into human trials.

Is it surprising that we often struggle to see benefit.

Remyelination....a reality

Good news from repair studies! 

A few years ago Jonah Chan and his team developed a neat screening assay to show myelination (making myelin) by myelin-forming cells (oligodendrocytes). 


They did a screen of many drugs and pulled out one of the best called clemastine. This was shown to stimulate myelin formation and in animal models it helped to speed up the remyelination process.

http://multiple-sclerosis-research.blogspot.com/2016/10/remyelination-enhancement-by-clemastine.html

Clemastine is old type of anti-histamine (anti-itch) that has fallen out of favour, because it induces fatigue and drowsiness. It is used for drying you up when you have a streaming eyes or nose. 

Now they have done a trial in MS and claim that it causes remyelination.

This was seen by an increase in nerve impulse conduction speeds because demyelination slows them down, so if you remyelinate the nerve impulse speed increases.

So in this study people took a placebo for 2 months and then the drug for three months, or the drug for 3 months followed by the placebo.

The nerve impulse speeds increased by 2,000th of a second.

So the trial worked.

Here's the abstract:

Green et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.Lancet. 2017. pii: S0140-6736(17)32346-2.

BACKGROUND: Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.

METHODS: We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients were randomly to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. The trial is registered with ClinicalTrials.gov, number NCT02040298.

FINDINGS: Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048)  Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION: To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.

So there you have it: a positive effect, moving ideas from animals to humans, so great news!

But before you rush down to the chemist (if you have not done this already) here are a few questions to consider: 

1. What are ProfG, DrK, NDG and Dr MnM going to say when you say "Give me clemastine"? 

It is licensed for use in humans. It costs a few pence, so NICE isn't going to waste any sleep over this one. 

2. What is Biogen going to do with anti-LINGO, costing thousands if clemastine does it?

3. What are the MS charities going to do next?
     Another trial? Then What?

4. Why was there no-dose response?

Because the dose used is massive, compared to what's usually prescribed. So will a repeat study be needed before it can it be prescribed off-label as the 5.36mg dose used in the trial, is twice that normally used (2.68mg). No wonder the participants got fatigue. 

5. If you get fatigue are you going to take the drug, long-term?

6. Do you even need to take it long term or just as a pulse therapy? 

7. (Importantly) are the results clinically meaningful?

Questions, questions questions.

More from the Neuros will be forthcoming...