Will we be joining the Glee Club?

W

You asked what do I think about the news of the mastitinib trial? I guess we have to wait and see what happens when it is presented at AAN at ECTRIMS but they are reporting activity on one dose (4.5mg/kg) in PPMS and non-relapsing SPMS. This could be good news if true, but it could also be part of a buy-me report for the company. Importantly for me the higher dose was not reported to work, so alarm bells ring when a dose-response is not seen as it could mean dosing will be an issue. The heaviest man compared to the lightest woman is going to be twice the lightest woman so if the dose response is bell-shaped (doesn’t work at low and high dose) it makes things difficult. However, I must say it is weird that for many MS drugs weight/size is not part of the dosing plan.

Anyway what am I on about.

tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an “on” or “off” switch in many cellular functions. Tyrosine kinases are a subclass of protein kinase.

The phosphate group is attached to the amino acid tyrosine on the protein. Tyrosine kinases are a subgroup of the larger class of protein kinases that attach phosphate groups to other amino acids (serine and threonine). Phosphorylation of proteins by kinases is an important mechanism in communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division.

Protein kinases can become mutated, stuck in the “on” position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Therefore, kinase inhibitors, such as imatinib, are often effective cancer treatments.

However imatinib, which is known as Gleevec is probably not going to go far, as it has seemed to cause demyelination, so we won’t be joining the Glee club.

CNS demyelination after initiating the tyrosine kinase inhibitor imatinib: A report of two cases. Rotstein DL, Sawicka K, Bharatha A, Montalban X, Lipton JH. Mult Scler. 2019 Dec 17:1352458519892914. doi: 10.1177/1352458519892914. [Epub ahead of print]. This is the first report of cases of multifocal central nervous system (CNS) demyelination following exposure to imatinib. One case was severe with bilateral optic neuritis and transverse myelitis that was AQP4 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG negative and improved after plasma exchange and withdrawal of imatinib. The second case involved a unilateral optic neuritis with magnetic resonance imaging (MRI) brain confirming other demyelinating lesions. Although the mechanism is unknown, demyelination on imatinib could be related to activation of previously normal T-cells.

However, the interest is in Masitinib. Masitinib is less toxic than imatinib, because it is more selective towards tyrosine kinase targets

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumours in animals, specifically dogs. Masitinib has been studied for several human conditions including melanomamultiple myelomagastrointestinal cancerpancreatic cancerAlzheimer diseasemultiple sclerosisrheumatoid arthritismastocytosis, and amyotrophic lateral sclerosis.

There appeared to be some positive impact in ALS

Mora S et al. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Jul 7:1-10. doi: 10.1080/21678421.2019.1632346. [Epub ahead of print] Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

In that study there was a slowing of progression but it came with more side-effects. This has been trialled in MS and the preliminary results have been leaked by the company who have filed a dose patent. These are always challenged, because the dose was obvious and so not inventive, but it gives pharma life and gives lawyers a shed load of money.

The original trial was NCT01450488 using a 3mg/kg and 6mg/kg, which is the same as in the terminated rheumatoid arthritis trial and originally had 35 planned participants. This was published

Vermersch P et al. BMC Neurol. 2012; 12: 36.Published online 2012 Jun 12. doi: 10.1186/1471-2377-12-36PMCID: PMC3467179PMID: 22691628 Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study Prof G will be happy as the major effect was a change (improvement) in hand function. The most common side effects being asthenia (loss of strength and/or energy occurring in about 40% of people), rash, nausea, oedema (fluid retention) and diarrhoea.

The new trial NCT01433497 was A 96 Week, Prospective, Multicentre, Randomized, Double-blind, Placebo-controlled, 2 Parallel-groups, Phase 3 Study to Compare Efficacy and Safety of Masitinib 4.5 mg/kg/Day Versus Placebo in the Treatment of Patients With Primary Progressive or Relapse-free Secondary Progressive Multiple Sclerosis. This has a dose escalation to 6mg/kg.

If I accept it is working and it tell us that we can modify “non-active” progressive MS.

Then big question I ask is what is the logic from the mechanism of action or was it just thrown in on the off chance. Brutons tyrosine kinase is another kinase and this was selected becuase it is B cell selective. There is some debate on how good this will be but that’s another story. However, I suspect the route lies with it being anti-immunological and there is a suggestion that metalloproteinases are inhibited. Spleen tyrosine kinase (STY) is another tyrosine kinase that is present in B cells and has cropped up in MS studies. However how does masitinib work? That is the key question. Answer I don’t know and will have to do some more work, but here is a quick look.

Masitinib inhibits the receptor tyrosine kinase c-Kit . It also inhibits the platelet derived growth factor receptor (PDGFR), lymphocyte-specific protein tyrosine kinase (Lck), focal adhesion kinase (FAK) and fibroblast growth factor receptor 3 (FGFR3).

Expression of c-kit (below) shows it is present at low levels on immune and brain cells although there are high levels on CD34+ stem cells which are the cells that make new immune cells

PDGFa expression

This pdgfa highly expressed in rodent glial cells


However the beta form of the Pdgf receptor is more expressed on microglia

PDGFB

Also if we look at masitinib it is more selective for the Pdgfb form

Have they lucked out and got a microglial modulator

Expression of Lck (below) targets T cells

but on a closer look there is expression in B cells, but it is low in plasma cells (antibody secreting cells) and can be seen in B and T cell areas in lymph glands (www.proteinatlas.org)

Present in B and T cell areas

FAK is all over the place but high on immune cells and brain (but enough other places to expect side effects of any inhibitor)

Add FGF3 is expressed in the brain fibroblasts and elsewhere

But there does not seem to be much on the brain cells

So the big question is if masitinib really works, how is it working?. If it targets multiple myeloma it hits B cells, but I doubt that is the answer. However, we will need to get more specific if we can as it will reduce the side effect profile. However, if true progressive MS is being modifyied and if we can do it once we can do it again, importantly we can do it better if we ensure that the peripheral immune response is also dealt with!

I am surprised that so many so called opinion leaders don’t get it and they are happy to do one sub-optimal trial that may not work after another. This is street-light science…where they do what is easy to do not what is logical to do. Maybe French company with a neuroprotector can team up with a French company with a disease modifying drug:-), maybe French with Swiss or American even. I suspect I will be long gone by the time it happens. If you want to see the advantage of this approach look at Neurofilaments and see how they pummet when an effective DMT is used, Neurofilaments are released due to nerve damage, but the major damaging influence is the active immune system, after this has been removed the so called real MS does not produce much neurofilaments, so targeting this alone and you are missing a trick or importantly a primary endpoint in your trial.

COI Multiple but none relevant

About the author

MouseDoctor

4 comments

Leave a Reply to lucas Cancel reply

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives