BTK inhibitor also shows promise in slowly evolving lesions

Tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, reduced new active brain lesions on MRI in people with relapsing multiple sclerosis (MS), a phase IIb placebo-controlled, crossover dose-finding trial found.

“Twelve weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated,” reported Daniel Reich, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and co-authors.

“Reduction of acute inflammation, combined with the potential to modulate the immune response within the central nervous system (CNS), provides a scientific rationale to pursue phase III clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis,” the researchers wrote in Lancet Neurology.

“In addition to the treatment effect shown in patients with relapsing multiple sclerosis, exploratory analysis of slowly evolving lesions raises the possibility that investigation of tolebrutinib in patients with progressive disease, in which chronic neuroinflammation is well documented, is warranted,” they added.

Tolebrutinib is a small-molecule oral inhibitor of BTK, an enzyme expressed in cells with roles in inflammation in MS including B lymphocytes and microglia. Phase III trials of tolebrutinib are ongoing in both relapsing and progressive multiple sclerosis.

Reich and colleagues studied adults 18-55 years old at 40 centers in Europe and North America with either relapsing-remitting or relapsing secondary progressive MS (2017 McDonald criteria with 2020 clarifications), enrolled between May 2019 and January 2020. People with primary progressive MS or a diagnosis of secondary progressive MS without relapse were excluded. Participants had at least one of the following: one or more relapses in the previous year, two relapses within the previous 2 years, or one or more active gadolinium-enhancing brain lesion in the 6 months before screening.

MRI measures of disease activity predictive of reductions in relapse rates including T2-weighted fluid-attenuation inversion recovery and gadolinium-enhanced T1-weighted scans were acquired at screening and every 4 weeks over 16 weeks.

Two cohorts were defined. Cohort 1 received tolebrutinib for 12 weeks then placebo for 4 weeks, while cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Both cohorts tested multiple doses; the combined total participants by dose were 5 mg (n=33), 15 mg (n=32), 30 mg (n=33), and 60 mg (n=32).

The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected after 12 weeks of tolebrutinib treatment, assessed at week 12 for cohort 1 and at week 4 and week 16 for cohort 2.

For a total of 126 patients in modified intention to treat analysis, the researchers found:

  • At treatment week 12, MRI showed a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean lesions per patient for placebo 1.03; 5 mg 1.39; 15 mg 0.77; 30 mg 0.76; 60 mg 0.13; P=0.03)
  • One serious adverse event required hospital admission due to a multiple sclerosis relapse. The most common non-serious adverse event during treatment was headache (in 3% of the 5 mg group, 9% of the 15 mg group, 3% of the 30 mg group, and 13% of the 60 mg group). No treatment-related deaths or discontinuations were seen.

In an accompanying editorial, Jorge Correale, MD, of the Institute for Neurological Research in Buenos Aires, Argentina, noted that the “results support the rationale to pursue the phase III studies of tolebrutinib in relapsing remitting and progressive forms of multiple sclerosis that are ongoing.”

Tyrosine kinases, including BTK, mediate phosphorylation of tyrosine residues on signaling pathway molecules and have roles in cell reproduction, differentiation, growth, metabolism, and apoptosis. BTK, expressed by B cells and myeloid cells, has been implicated in the inflammation of MS.

Prior work on BTK inhibitors in MS has led to ongoing evaluation of multiple agents. In a phase II evaluation, evobrutinib reduced 12-24 week enhancing lesions versus placebo but had no effect on annualized relapse rate or disability progression. Other agents include enebrutinib, orelabrutinib, and BIIB09.

Reich and colleagues also undertook exploratory analysis of paramagnetic rim and slowly evolving lesions. “These chronic lesions, relatively resistant to approved therapies, are associated with activated microglia and are correlated with disability accumulation,” they noted.

About 50% of patients with available susceptibility-weighted imaging had paramagnetic rim lesions (myelin and axon injury with activated microglia). Analysis of slowly evolving lesions suggested “a longer course of treatment is likely to be necessary to assess whether BTK-driven modulation of CNS-resident microglia, infiltrating macrophages, and B lymphocytes trapped behind the blood–brain barrier would translate to clinical benefit related to slowing or halting of disability accumulation,” the researchers observed.

“Inhibitors of Bruton’s tyrosine kinase, such as the irreversible inhibitors evobrutinib, tolebrutininb, and orelabrutinib, and the reversible inhibitors fenebrutinib and BIIB091, might provide therapeutic benefits for patients,” the editorialist noted.

“However, whether BTK inhibitors will be more efficacious than monoclonal antibodies remains to be established,” Correale added. “Furthermore, Bruton’s tyrosine kinase inhibitors might inhibit tyrosine kinases not involved in multiple sclerosis, potentially damaging unrelated tissue.”

Limitations of the study included small sample sizes per dosing group, and a relatively short treatment period.

BTK Inhibitors, Covid-19 Infections, and Covid-19 Vaccinations

With BTK inhibitors poised to become part of the armamentarium against MS, what guidance is there for MS patients vis-a-vis BTK inhibitors, Covid-19, and Covid vaccines? BreakingMED reached out to James Bowen, MD, Medical Director of the Multiple Sclerosis Center at the Swedish Neuroscience Institute in Seattle, for his insight.

“This is very complicated. The simple response is that we have no data about Covid in MS patients treated with BTK inhibitors,” he told BreakingMED in an email correspondence. “The not-so-simple response is as follows: BTK inhibitors cause widespread changes in a number of metabolic pathways that are involved with immune responses. These effects alter B-cell activity, but also T-cell responses, cytokines, dendritic cells, and others. Due to these widespread effects, one might postulate that this could increase the risk of Covid in patients treated with BTK inhibitors. It might also decrease the effectiveness of Covid vaccines.”

Bowen did note that they are in the process of evaluating the effects of BTK inhibitors on people with severe Covid infection.

“This is based on the premise that activation of the immune system may be responsible for some of the damage caused by the virus, particularly related to lung involvement. Preliminary data from some of these studies indicates that once a person has Covid, BTK inhibitors may have decreased oxygen requirements and decreased hospitalization rates,” he noted, adding that “These studies do not address whether patients who are already taking BTK inhibitors are at greater or lesser risk of getting Covid, or once they get Covid whether it puts them at higher or lower risk of severe disease.

“It is a completely different question as to whether BTK inhibitors that patients are taking long-term for other diseases ha[ve] an impact on the rate of getting Covid or the severity of symptoms should they get Covid. There is one paper that described decreased antibody responses in chronic lymphocytic leukemia patients treated with BTK inhibitors.

“Of course, patients with CLL already have some degree of immunosuppression from their disease, but the BTK inhibitor appears to add further immunosuppression. Furthermore, it could be that those treated with BTK inhibitors were the ones with more severe CLL, so it is difficult to prove which was the cause of the decreased antibody responses,” said Bowen.

“Another fact that makes interpretation of th[ese] data difficult is that there is more to immunity than antibody titers,” he went on to explain. “T cells are also important in protection from viral infections. T cell function is more difficult to measure than antibody titers, so it is not studied as often. So, we don’t really know whether vaccinating patients who are taking a BTK inhibitor but who do not have hematologic cancers have completely inadequate immune protection, poor B cell but competent T cell response, or adequate responses in both B and T cell protection to the virus.”

Vaccine Recommendations

The FDA recently recommended a third dose of the Covid-19 mRNA vaccines for immunocompromised individuals. Bowen clarified this recommendation for BreakingMED and outlined the potential interactions between BTK-inhibitors and vaccines for patients with MS. He noted that “the CDC guidance that followed has a clause that states: ’Active treatment with high-dose corticosteroids or other drugs that may suppress your immune response.’ This [a BTK inhibitor] would fit into the category of one of those other drugs that ’may’ suppress your immune system.”

He also addressed the confusion between an additional dose versus a booster dose.

“The FDA approved a third dose of vaccine for immunocompromised patients. This is different than a booster,” he wrote. “A third dose is intended as part of the initial course of vaccination. Most people get two doses of the mRNA vaccines, but immunosuppressed patients need three doses. A booster would be needed later if immunity wanes over time. Rumors are that the FDA may approved a booster dose for everyone in the U.S. on about September 20, and this booster would be given about 8 months after their initial course of immunization. So, this means that people on immunosuppressants would get three initial doses, and then get an additional booster dose 8 months after their third initial dose.”

  1. Tolebrutinib, an investigational Bruton’s tyrosine kinase inhibitor, reduced new active brain lesions on MRI in people with relapsing multiple sclerosis, in a phase IIb trial.

  2. BTK inhibitors are promising investigational treatments. In the era of Covid-19, understanding the mechanism of action for these drugs is critical for optimal treatment of MS patients.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by Sanofi.

Reich is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke and has received research support from Vertex.

Correale reported receiving consulting or speaking fees from Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme; research support from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme; and support for attending meetings or travel from Merck and Biogen.

Cat ID: 36

Topic ID: 82,36,730,36,192,925