The Guantlet is thrown down and we have to see proof of the pudding


ProfG and I were taking about the times many many years ago when we tried to get a trial of a Brutons tyrosine kinase inhibitor and sad to say there was not much interest by the company so fast forward about a decade and the race is on to cross the line and get approval. The major hurdle is to get positive data in the trials and there are alot in the hunt and there are three that are most advanced evobrutinib, fenebrutinib, and tolebrutinib. So which is best?.

Which targets the CNS the most and this is important because targeting microglia is important. Although there is a bias as the study is down by the makers of tolebrutinib, they have given a challenge.

ACTRIMS 2022 P162. Comparative CNS Pharmacology of Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating MS

T. J. Turner;
Neurology Development, Sanofi, Cambridge, MA

Background: Designing drugs with a goal of modulating neuroinflammation within the CNS represents a paradigm shift for disease modification in multiple sclerosis (MS). Tolebrutinib is a covalent BTK inhibitor designed and selected based on maximizing both potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells of interest.
Objectives: To evaluate the current BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency for to block BTK-dependent signaling and exposure in the CNS.
Methods: We applied a translational approach to the problem, employing in vitro kinase assays (to determine relative potency to inhibit BTK kinase activity), cellular activation assays (to evaluate the ability to block BTK signaling in microglia and B cells), and pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus (Macaca fascicularis) to estimate the ability of three BTK inhibitors (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS. All three molecules were synthesized and validated by Sanofi Integrated Drug Discovery.
Results: In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib (Kinact/Ki values of 4.37 x 10-3 and 6.82 x 10-5 nM-1*s-1, respectively). Fenebrutinib, a classical reversible antagonist had a Ki value of 4.7 nM. Because of the slow off-rate (1.54 x 10-5 s-1), the first order rate constant of association was also very slow (3.28 x 103 M-1 * s-1), consistent with a slow approach to steady-state relative to covalent BTKi’s. Estimates of cellular potency (measuring antigen-stimulated B cell activation) were largely consistent with the in vitro kinase assays, with an estimated IC50 of 0.7 nM for tolebrutinib against 34.5nM for evobrutinib and 2.9nM for fenebrutinib. To translate the in vitro findings to the in vivo pharmacokinetics, we observed that evobrutinib, fenebrutinib, and tolebrutinib achieved similar levels of exposure in the CSF after oral doses of 10 mg/kg for each candidate. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp,uu CSF=0.40) exceeded the estimated cellular potency by >10 fold, while evobrutinib (3.2 ng/mL) (kp,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the estimated IC50 values.
Conclusions: To achieve pharmacological activity within the CNS, four criteria must be met. 1) The cellular target must be expressed in CNS-resident cells, 2) those cells must be involved in the pathophysiology, 3) the drug must cross the blood brain barrier to engage the target, and 4) inhibiting the target leads to a pharmacological benefit. We conclude that tolebrutinib is the only late-stage candidate that meets each of the first three criteria. Evidence of clinical benefit attributed to the fourth criterion awaits validation in ongoing Phase 3 clinical trials.

COI Multiple non relevant

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  • Hello again! Thank you for everything you do. I was diagnosed 14ish years ago and initially took betaseron and had at least six attacks. Then Tysabri which I continued to progress on, albeit without actual new lesions, but clinically. Then Rituxan, with same results and then I did I.V.I.G. while waiting for Lemtrada’s FDA approval (after being denied the first time “here” in United States. I went from an EDSS score of 7 to a 2.5 within six months and continued to quantifiably actually improve in almost every way. Eighteen-ish months after round two I had a clinical relapse (again no new lesions) but old lesions “flaring” up, particularly spinal ones. After a third round, I went back to my 2.5 EDSS post Lemtrada self. Now two years after round three, I have some new things come up, but also similar to the previous clinical attack. I’m awaiting results of a (new for me) “fancy” GE 3T MRI.
    I am not expecting any sort of medical advice, just any input from others before going to neurologist follow up appointment. I did do five days of 1000ml of IV steroids a couple months ago, and then (despite vaccination and booster for Covid-19) came down with the omicron version a week later, sooooo many appointments were pushed forward.
    I think a round 4 Lemtrada, but not sure if neurologist is onboard with it. Neuro nurse practitioner assistant keeps bringing up Ocrevus, which I feel would be redundant/useless considering how badly I crashed on Rituxan.
    Is the concept behind the BTK drugs to repair and/or halt regression OR just be another type of DMT?
    I’ve been following BTK, and other clinical trials, but because of Lemtrada, I’m always booted out.
    My neurologist has me down as relapsing remitting, because here in the U.S. any other designation limits the drug choices for insurance reasons.
    Thank you in advance.

    • I aways say after alemtuzumab check that it is stll depleting….if it isnt it may not be working….Steroids are a risk for COVID.

      The concept with BTK inhibitors is to (a) block B cell activity to inhibit relapses and (b) block macrophages/microglia to limit progression there are some reports of it increasing remyelination but if it blocks macrophage function you wouldnt expect this, so we have to wait for more data

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