There are too many ECTRIMS 2024 highlights to cover in one newsletter. However, the top of the list of highlights was the positive tolebrutinib results in non-relapsing (inactive) secondary progressive MS. At the bottom was the negative, but not unexpected, simvastatin trial in SPMS.

Tolebrutinib

Tolebrutinib, a second-generation BTK inhibitor (BTKi), has a dual mode of action in MS. It inhibits BTK in B-cells and is an anti-inflammatory therapy. In both the relapsing and non-relapsing progressive MS trials, it had a relatively modest impact on relapses and focal MRI activity and more or less matched the anti-inflammatory effects of evobrutinib, the first BTKi (see paper below). Both tolebrutinib and evobrutinib were not shown to be superior to teriflunomide in suppressing relapse and focal Gd-enhanced MRI activity.

Teriflunomide, however, was superior to tolebrutinib in suppressing Gd-enhancing lesions but not new T2 lesions. This would indicate that new Gd-enhancing lesions are less likely to form chronic T2 lesions in subjects treated with tolebrutinib. This suggests that tolebrutinib is changing the biology of how MS lesions evolve; i.e. it is doing something to the acute Gd-enhancing lesions that makes it less likely to leave a scar or new T2 lesion. Based on this preliminary observation, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse outcomes. These data have yet to be analysed. It will be interesting to see if these MRI findings also apply to blood neurofilament levels, i.e. if new Gd-enhancing lesions are less likely to form new T2 lesions on tolebrutinib subjects on tolebrutinib should have lower NFL levels associated with Gd-enhancing scans than those occurring in patients on teriflunomide or placebo.

However, despite being inferior to teriflunomide in suppressing focal inflammatory activity, tolebrutinib was superior to it when it came to disability progression., i.e. it has a robust impact on smouldering MS-associated worsening (SAW) but not relapses.

Tolebrutinib, therefore, dissociates relapses from disability progression and proves that these two processes are likely to be independent of each other with the caveat that relapses can be associated with some disability progression called relapse-associated worsening or RAW. This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib. I hope biomarker data can support the recovery of function data.

How do you explain tolebrutinib’s effect on smouldering MS and its moderate impact on focal inflammatory activity? Tolebrutinib is a CNS penetrant BTKi and will inhibit CNS resident B-cells and plasmablasts. In addition, it downregulates and inhibits microglia and macrophages via the so-called Fc-gamma III receptor. So, this agent tackles some CNS processes that drive smouldering MS and may switch microglia into a regulatory phenotype that promotes remyelination and recovery of function.

Notably, the data on reduced disability progression and recovery of function on tolebrutinib was not associated with a significant impact on brain volume loss. This needs to be explained. Brain volume is a complex measure, and a shrinking in the volume of microglia may confound any protection of volume by reduced neuroaxonal loss. Therefore, we will have to wait for more detailed analyses of regional brain volume and other MRI metrics from these studies to interpret this data. What is clear is that simply using brain volume alone as a biomarker does not explain what is happening at the tissue level.

Please note that tolebrutinib and the other BTKIs are associated with liver toxicity. Hence, if they get to the clinic, they will require frequent blood monitoring for the first 3-6 months to prevent severe drug-induced liver injury (DILI).

What about other BTK’s?

The phase 2 extension data of fenebrutinib, another BTKi in phase 3, was presented as an ePoster. Compared to tolebrutinib, fenebrutinib is much more effective at suppressing Gd-enhancing lesions. Based on this data, I would give fenebrutinib a ~87.5% (range 75-95%) of being superior to teriflunomide in suppressing relapses and focal MRI activity. The billion-dollar question is whether or not it will have an impact on smouldering MS pathology to a similar degree to tolebrutinib.

I raised this question with a pharmacologist and got the following response.

‘Fenebrutinib differs from tolebrutinib in that fenebrutinib is a non-covalent reversible inhibitor that targets the “open” conformation of the enzyme and acts to trap BTK in an inactive conformation. Fenebrutinib is reasonably potent, more so than evobrutinib, but about 9-fold less potent than tolebrutinib. From a PK perspective, tolebrutinib has a very short half-life (~90 min), while fenebrutinib is ~4-6 hrs. Because tolebrutinib is covalent, the PD actions are long-lasting, and enzyme activity recovers after the last dose within 5-7 days as new enzyme is synthesized (protein turnover). Fenebrutinib is a classical competitive inhibitor, so to maintain “coverage” in vivo, relatively high doses are needed, given twice daily. Fenebrutinib has a “long residency time”, meaning that the off-rate is slow. The consequence of nanomolar potency with slow dissociation means that the steady-state is defined by the off-rate. When measured in a model system, occupancy of BTK within cells is driven primarily by C trough, with estimates being that fenebrutinib is likely to have modest occupancy within the CNS. Interestingly, remibrutinib is also a hybrid covalent inhibitor that targets the same open conformation as fenebrutinib but also reacts with the C481 residue to form a thioether adduct like tolebrutinib evobrutinib, ibrutinib, etc.’

The proof will be in the trial results. You may be interested in knowing that fenebrutinib is being compared to ocrelizumab in a primary progressive trial. Ocrelizumab is setting a high bar, and if fenebrutinib is superior to ocrelizumab in PPMS, this will further prove the need to target CNS mechanisms to slow down SAW.

After deep thinking about this data this weekend, I will be optimistic and give fenebrutinib a 40% chance (range 30-50%) of being superior to ocrelizumab in PPMS. The latter is based on its superior anti-inflammatory effect to tolebrutinib and the fact that it does get into the CNS at a level likely to inhibit BTK in both B-cells and microglia. If I am proven correct about fenebrutinib, this would be great news for pwPPMS.

The dark horse is remibrutinib. We have no detailed PK and PD data on its CNS effects. However, the news on the ECTRIMS grapevine is that remibrutinib does not have a clear liver toxicity signal. If that is the case and it is as effective as tolebrutinib and fenebrutinib, it may just win the battle of the BTKi’s on safety.

How will the BTKi’s be used in clinical practice?

It is too early to speculate. But if the regulators’ license tolebrutinib to reduce SAW in non-active SPMS, it will be used as a monotherapy in more advanced MS. However, as SAW or PIRA occurs very early in the course of MS I suspect we will be identifying SAW early and switching patients early from other DMTs onto tolebrutinib in early MS. In other words, the diagnosis of SPMS will move to an earlier time in the course of MS. Going forward, tolebrutinib may be best used as part of an induction-maintenance protocol after an anti-CD20 or immune reconstitution therapy.

You can download my ECTRIMS slides from here.

Papers of interest

Turner et al. Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. Drugs R D. 2024 Jun;24(2):263-274.

Background and objectives: Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS.

Results: In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a Ki value of 4.7 nM and slow off-rate (1.54 x 10-5 s-1), also had an association rate 1760-fold slower (0.00245 μM-1 * s-1). Estimates of cellular potency were largely consistent with the in vitro kinase assays, with an estimated IC50 of 0.7 nM for tolebrutinib against...