Tolebrutinib 96-Week MRI Results Promising for the Investigational BTK Inhibitor

A 60-mg daily dose of the investigational Bruton tyrosine kinase inhibitor tolebrutinb (SAR442168), in the long-term safety (LTS) extension study from Sanofi, held new gadolinium (Gd)-enhancing lesions at bay and demonstrated a favorable safety, tolerability, magnetic resonance imaging (MRI), and annual relapse rate (ARR) profile among patients with relapsing multiple sclerosis (RMS), according to 96-week data presented in 2 posters this week at the American Academy of Neurology annual meeting.^1,2

The long-term safety extension study is part of the ongoing phase 2b dose-finding trial.^3,4 Results through week 120 also were presented yesterday. The 60-mg daily tolebrutinib dose is currently under investigation in the phase 3 GEMINI 1 and 2 trials for RMS and the phase 3 PERSEUS and HERCULES trials for progressive MS^.5-8

MRI, Efficacy, and Safety Outcomes¹

This subanalysis of data from the LTS study was conducted among patients with relapsing multiple sclerosis (RMS) with highly active disease (HAD). For this analysis, HAD was defined as 1 or more disease relapses in the year prior to study inclusion screening and at least 1 Gd-enhancing lesion seen via MRI in the 6 months prior to screening or 9 or more T2 lesions at baseline or 2 or more relapses in the year prior to screening.

According to the study authors, “HAD is associated with a more aggressive disease course and can be difficult to treat.”

Of the 125 patients who were part of the LTS study, 60 met the HAD criteria at baseline, and 59 transitioned from Part A to Part B. The mean (SD) age of the patients with HAD was 36.2 (9.6) years, 63% were female, and the mean symptom onset was 7.2 (7.7) years. At baseline, relapses in the previous year and previous 2 years were 1.5 (0.7) and 1.1 (1.1), respectively; Expanded Disability Status Scale (EDSS) score was 2.4 (1.1); T2 lesion volume, 13.1 (13.6) cm³; and total Gd-enhancing lesions, 1.8 (4.1). Forty-one percent had Gd-enhancing lesions, incidence of severe treatment-emergent adverse events (TEAEs) was comparable to the overall study population (3.3% vs 5.6%, respectively); and no TEAEs led to study discontinuation or death. The most common TEAEs were COVID-19 (20%; all mild or moderate cases) and nasopharyngitis (17.0%).

Lesions were evaluated 3 ways among the patients with HAD and compared with the overall study population:

• New Gd-enhancing lesions at week 96 vs week 72
• New/enlarging T2 lesions at week 96 vs week 72
• T2 lesion volume change at week 96 vs baseline

For new Gd-enhancing lesions, the totals at week 96 were 0.23 among the patients with HAD and 0.31 in the overall study population. The corresponding totals for new/enlarging T2 lesions were 2.77 and 2.13; both low, according to the study authors. T2 lesion volume was considered unchanged, at 0.05 and 0.38.

In addition, at the week 96 cutoff, EDSS scores were stable, the ARR was 0.10 (95% CI, 0.02-0.66), and the relapse-free rate was 92.9%; there also were no reports of participants having 1, 2, or 4 or more relapses, but 7.1% did report 3 relapses. Among those with HAD who received the 60-mg daily dose of tolebrutinib for at least 8 weeks, the ARR was 0.18 (95% CI, 0.10-0.33).

MRI Outcomes²

In this subanalysis of the LTS study, MRI outcomes were evaluated on 5 fronts:

• New Gd-enhancing T1 lesions
• New/enlarging T2 lesions
• T2 lesion volume change from baseline
• Volume of slowly enhancing lesions (SLEs)
• Number of paramagnetic rim lesions (PRLs)

“New/enlarging T2 lesions were identified from sequential scans using a semi-automated process of joint timepoint segmentation, followed by manual correction as necessary, and SELs were identified as contiguous areas of the baseline unenhancing T2 lesion mask that showed constant and concentric local expansion from baseline to week 96,” the study authors explained. “Local expansion was determined by Jacobian analysis, and PRLs were manually identified on susceptibility-weighted images generated from six 3D-gradient echo phase images in a subset of participants at sites with sufficient imaging capability.

Compared with prior scan results, through week 96, new Gd-enhancing T1 lesions among those who received the 60-mg tolebrutinib dose remained low, hovering between 0.0 and 0.5 from weeks 0 through 96 of the LTS study. This type of lesion was also reduced in all the other study arms (5-, 15-, or 30-mg daily dose) from weeks 48 through 96.

For new/enlarging T2 lesions, measured per month, this total also remained low. The highest total, reported at week 12, was approximately 2 lesions per month among those receiving the 5-mg daily dose. From weeks 24 through 48, lesions totals were reduced for the 5-, 15-, and 30-mg dose arms, while they very slightly rose for the 60-mg arm. From weeks 48 through 96, however, the mean totals in all arms were comparable. At week 96 for the 60-mg dose, the mean (SE) was 0.36 (0.11) vs 0.53 (0.20) seen at week 0.

The positive trend continued when looking at T2 lesion volume change from baseline. Overall, the mean (SD) change remained low from weeks 0 through 96: 0.38 (2.11) cm³ at the 60-mg dose. The highest volume was seen among those receiving the 5-mg daily dose, but this did not rise above 2.5 cm³ for this analysis of the LTS study, and volumes in all other doses remained below 2.0cm³ for weeks 0 to 96 .

At week 96, for SLEs, median (IQR) lesion volume was again lowest in the 60-mg arm compared with the other 3 arms:

• 60 mg: 245 (87-939) mm³
• 5 mg: 248 (84-420) mm³
• 15 mg: 258 (66-906) mm³
• 30 mg: 570 (133.5-1011) mm³

Compared with baseline in the original study’s double-blind period among study participants who also had scans at week 96 of the LTS study, total PRLs did not change in 18 patients and were reduced to 0 from 1 lesion in 2 patients. Three patients did report new PRLs at week 96, but these were in the smaller-dose arms:

• 5 mg: 1 patient reported 1 lesion
• 15 mg: 1 patient reported 2 lesions
• 30 mg: 1 patient reported 3 lesions

“All new PRL corresponded to new T2 lesions that appeared on study,” the authors noted.

The authors of both analyses emphasized the importance of both a longer follow-up in the ongoing extension study of tolebrutinib and data from the 4 phase 3 trials underway to add to the BTK inhibitor’s safety and efficacy profile for people living with MS.

References

1. Fox RJ, Oh J, Arnold DL, et al. MRI, efficacy, and safety of tolebrutinib in patients with highly active disease (HAD): 2-year data from the phase 2b long-term safety (LTS) study. Presented at: AAN 2023; April 22-27, 2023; Boston, MA. Accessed April 25, 2023. https://cattendee.abstractsonline.com/meeting/10872/Presentation/7445

2. Reich DS, Traboulsee A, Syed S, Xu Z, Turner TJ, Arnold DL. MRI outcomes from the long-term extension study of tolebrutinib in patients with relapsing multiple sclerosis: 2-year results. Presented at: AAN 2023; April 22-27, 2023; Boston, MA. Accessed April 25, 2023. https://cattendee.abstractsonline.com/meeting/10872/Presentation/7441

3. Dose-finding Study for SAR442168 in Relapsing Multiple Sclerosis. ClinicalTrials.gov. Updated March 8, 2023. Accessed April 24, 2023. https://clinicaltrials.gov/ct2/show/NCT03889639

4. Long Term Safety and Efficacy Study of Tolebrutinib (SAR442168) in Participants With Relapsing Multiple Sclerosis. ClinicalTrials.gov. Updated April 24, 2023. Accessed April 24, 2023. https://clinicaltrials.gov/ct2/show/NCT03996291

5. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1). ClinicalTrials.gov. Updated August 8, 2022. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04410978

6. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2). ClinicalTrials.gov. Updated August 8, 2022. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04410991

7. Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS). ClinicalTrials.gov. Updated February 1, 2023. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04458051

8. Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES). ClinicalTrials.gov. Updated February 10, 2023. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04411641