Press Release: Tolebrutinib demonstrated a 31% delay in time to
onset of confirmed disability progression in non-relapsing
secondary progressive multiple sclerosis phase 3 study
Tolebrutinib demonstrated a 31% delay in time
to onset of confirmed disability progression in non-relapsing
secondary progressive multiple sclerosis phase 3 study
- Data presented at
ECTRIMS show that tolebrutinib, a brain-penetrant BTK inhibitor,
addresses disability accumulation that occurs independently from
relapse activity
- Global regulatory submissions will
begin in H2 2024
Paris, September 20,
2024. Positive results from the HERCULES phase 3 study in
people with non-relapsing secondary progressive multiple sclerosis
(nrSPMS) demonstrated that tolebrutinib delayed the time to onset
of 6-month confirmed disability progression (CDP) by 31% compared
to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Further analysis
of secondary endpoints demonstrated that the number of participants
who experienced confirmed disability improvement increased by
nearly two-fold, 10% with tolebrutinib compared to 5% with placebo
(HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021). These results were
presented today as a late-breaking presentation at the European
Committee for Treatment and Research in Multiple Sclerosis
(ECTRIMS) 2024 conference in Copenhagen, Denmark.
Robert Fox, MD
Vice Chair of Research at Cleveland Clinic’s Neurological
Institute, Cleveland, Ohio and Chair of the HERCULES Global
Steering Committee
“Secondary progressive multiple sclerosis is characterized by
insidious worsening of disability over time, independent of
relapses, and represents a critical unmet need because we
don’t have effective treatments. The results of
HERCULES show clearly that tolebrutinib delayed
disability progression in people with nrSPMS – and
some people even improved disability – by
uniquely targeting the biological processes driving disease
progression in the brain.” Dr. Fox is a paid advisor to Sanofi for
the HERCULES trial.
Based on preliminary analysis of the HERCULES
study, there was a slight increase in tolebrutinib-treated patients
of some adverse events. Liver enzyme elevations (>3xULN) were
observed in 4.1% of participants receiving tolebrutinib compared
with 1.6% in the placebo group, a side effect also reported with
other BTK inhibitors in MS. A small (0.5%) proportion of
participants in the tolebrutinib group experienced peak ALT
increases of >20xULN, all occurring within the first 90 days of
treatment. All but one case of liver enzyme elevations resolved
without further medical intervention. Prior to the implementation
of the revised study protocol with more stringent monitoring, one
participant in the tolebrutinib arm received a liver transplant and
died due to post-operative complications. To date, the
implementation of more frequent monitoring has mitigated such
serious liver sequelae. Other deaths in the trial were assessed as
unrelated to treatment by investigator; deaths were even across the
placebo and tolebrutinib arms at 0.3%.
Adverse events (≥10%*) |
tolebrutinib
N=752 (%) |
placebo
N=375 (%) |
COVID-19 infections |
192 (25.5%) |
85 (22.7%) |
Urinary tract infections |
85 (11.3%) |
49 (13.1%) |
*For participants receiving tolebrutinib
Houman Ashrafian, MD,
PhD
Head of Research & Development, Sanofi
“With no treatment options currently available for the broad
population of patients with secondary progressive multiple
sclerosis, tolebrutinib has demonstrated its ability to delay
disability by targeting underlying drivers of the disease. We look
forward to discussing these results with healthcare authorities
and are eager to see the results of tolebrutinib in primary
progressive MS when they become available next year. We extend
our deepest appreciation to the study participants, their families,
and the healthcare professionals involved in these
trials.”
The GEMINI 1 and 2 phase 3 study results of
tolebrutinib compared to Aubagio (teriflunomide), a
standard-of-care treatment, in participants with relapsing multiple
sclerosis (RMS) were also presented today as a late-breaking
presentation at ECTRIMS. Both studies did not meet their primary
endpoints of statistically significant improvement in annualized
relapse rates (ARR) compared to Aubagio. However, in the key
secondary endpoint, a pooled analysis of data from GEMINI 1 and 2,
tolebrutinib delayed the time to onset of 6-month confirmed
disability worsening (CDW) by 29% (HR 0.71; 95% CI: 0.53-0.95;
nominal p=0.023). The results of the 29% delay in CDW endpoint in
participants with RMS are in line with the 31% delay in CDP
observed in participants with nrSPMS. The significant impact of
tolebrutinib on disability accumulation versus Aubagio, in the
absence of a statistically superior impact on relapses, suggests
that tolebrutinib may address smoldering neuroinflammation, which
manifests as progression independent of relapses.
Furthermore, results showed historically low ARR in
the Aubagio arm in both GEMINI 1 and 2, and no difference was
observed between Aubagio and tolebrutinib in a pooled analysis.
These relapse rates amount to approximately 1 relapse every 8
years.
|
tolebrutinib ARR |
Aubagio ARR |
GEMINI 1
(adjusted rate ratio 1.06; 95% CI: 0.80 to 1.39; p=0.67) |
0.13 |
0.12 |
GEMINI 2
(adjusted rate ratio 1.00; 95% CI: 0.75 to 1.32; p=0.98) |
0.11 |
0.11 |
Pooled analysis
(adjusted rate ratio 1.03; 95% CI: 0.84 to 1.25; p=0.80) |
0.12 |
0.12 |
In preliminary analysis of the GEMINI 1 and 2
pooled safety data, adverse events observed between the
tolebrutinib and Aubagio arms were generally balanced. Liver enzyme
elevations (>3x ULN) were observed in 5.6% of participants
receiving tolebrutinib compared with 6.3% of participants receiving
Aubagio, a side effect reported with other BTK inhibitors in MS and
resolved without further medical intervention. A small (0.5%)
proportion of participants in the tolebrutinib group experienced
peak ALT increases of >20xULN, all occurring within the first 90
days of treatment. Deaths were balanced across the Aubagio and
tolebrutinib arms, at 0.2% and 0.1% respectively, and were assessed
as unrelated to treatment by investigator.
Adverse events (≥10%*) |
Tolebrutinib
N=933 (%) |
Aubagio
N=939 (%) |
COVID-19 infections |
225 (24.1%) |
252 (26.8%) |
Nasopharyngitis |
119 (12.8%) |
105 (11.2%) |
Headache |
117 (12.5%) |
98 (10.4%) |
*For participants receiving tolebrutinib
Study results will form the basis for future
discussions with global regulatory authorities with submissions
starting in H2 2024. Tolebrutinib is currently under clinical
investigation, and its safety and efficacy have not been evaluated
by any regulatory authority.
The PERSEUS phase 3 study in primary progressive MS
is currently ongoing with study results anticipated in H2 2025.
About Multiple Sclerosis
Multiple sclerosis is a chronic, immune-mediated, neurodegenerative
disease that results in accumulation of irreversible disabilities
over time. The physical and cognitive disability impairments
translate into gradual deterioration of health status and lower
quality of life, impacting patients’ care and life expectancy.
Disability accumulation remains the significant unmet medical need
in MS. To date, the primary target of current therapies has been
peripheral B and T cells, while innate immunity, which is believed
to drive disability accumulation, remains largely unaddressed by
current therapies. Currently approved, or medicines being tested
for MS mainly target the adaptive immune system and/or do not act
directly within the central nervous system (CNS) to drive clinical
benefit.
RMS refers to people with MS who experience
episodes of new or worsening symptoms (known as relapses) followed
by periods of partial or complete recovery. nrSPMS refers to people
with MS who have stopped experiencing confirmed relapses but
continue to experience accumulation of disability, experienced as
symptoms such as fatigue, cognition impairment, balance and gait
impairment, loss of bowel and/or bladder function, sexual
disfunction, amongst others.
About HERCULES
HERCULES (NCT04411641) was a double-blind randomized phase 3
clinical study evaluating the efficacy and safety of tolebrutinib
in participants with nrSPMS. nrSPMS was defined at baseline as
having a SPMS diagnosis with an expanded disability status scale
(EDSS) between 3.0 and 6.5, no clinical relapses for the previous
24 months and documented evidence of disability accumulation in the
previous 12 months. Participants were randomized (2:1) to receive
either an oral daily dose of tolebrutinib or matching placebo for
up to approximately 48 months.
The primary endpoint was 6-month CDP defined as the
increase of ≥1.0 point from the baseline EDSS score when the
baseline score is ≤5.0, or the increase of ≥0.5 point when the
baseline EDSS score was >5.0. Secondary endpoints included
3-month change in 9 hole peg test and T25-FW test, time to onset of
3-month CDP as assessed by EDSS score, total number of new or
enlarging T2 hyperintense lesions as detected by MRI, change in
cognitive function at the EOS compared to baseline as assessed by
the Symbol Digit Modalities Test and by the California Verbal
Learning Test as well as the safety and tolerability of
tolebrutinib.
About GEMINI 1 and 2
GEMINI 1 (clinical study identifier: NCT04410978) and GEMINI 2
(clinical study identifier: NCT04410991) were double-blind
randomized phase 3 clinical studies evaluating the efficacy and
safety of tolebrutinib compared to Aubagio in participants with
relapsing forms of MS. Participants were randomized in both studies
(1:1) to receive either tolebrutinib and placebo daily or 14mg
Aubagio and placebo.
The primary endpoint for both studies was the
annualized relapse rate for up to approximately 36 months defined
as the number of confirmed adjudicated protocol defined relapses.
Secondary endpoints included time to onset of CDW, confirmed over
at least 6 months, defined as an increase of ≥1.5 points from the
baseline EDSS score when the baseline score is 0, an increase of
≥1.0 point from the baseline EDSS score when the baseline score is
0.5 to ≤5.5 or an increase of ≥0.5 point from the baseline EDSS
score when the baseline score was >5.5 in addition to the total
number of new and/or enlarging T2 hyperintense lesions as detected
by MRI from baseline through the end of study, the total number of
Gd-enhancing T1 hyperintense lesions as detected by MRI from
baseline through the end of study and the safety and tolerability
of tolebrutinib.
About tolebrutinib
Tolebrutinib is an investigational, oral, brain-penetrant, and
bioactive Bruton’s tyrosine kinase (BTK) inhibitor that achieves
CSF concentrations predicted to modulate B lymphocytes and
disease-associated microglia. Tolebrutinib is being evaluated in
phase 3 clinical studies for the treatment of various forms of
multiple sclerosis and its safety and efficacy have not been
evaluated by any regulatory authority worldwide. For more
information on tolebrutinib clinical studies, please visit
www.clinicaltrials.gov.
About Sanofi
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