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#Post#: 4539--------------------------------------------------
Tolebrutinib for nonrelapsing SPMS?
DIR By: agate
Date: September 3, 2024, 8:52 pm
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Sanofi press release about tolebrutinib (September 2, 2024):
HTML https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875
#Post#: 4541--------------------------------------------------
Tolebrutinib fails 2 in trio of phase 3 MS trials but pharma
still plans FDA filing (FierceBiotech)
DIR By: agate
Date: September 5, 2024, 1:11 am
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From FierceBiotech (September 2, 2024)--"Sanofi's tolebrutinib
fails 2 in trio of phase 3 MS trials, but pharma still plans FDA
filing":
HTML https://www.fiercebiotech.com/biotech/sanofis-tolebrutinib-fails-2-trio-phase-3-ms-trials-pharma-still-plans-fda-filing
#Post#: 4564--------------------------------------------------
(ECTRIMS) Tolebrutinib slows disability in non-relapsing SPMS
DIR By: agate
Date: September 21, 2024, 6:30 pm
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From MedPage Today (September 20, 2024)--"Tolebrutinib slows
disability in non-relapsing secondary progressive MS":
HTML https://bit.ly/3BmoIWy
#Post#: 4587--------------------------------------------------
Tolebrutinib, fenebrutinib, remibrutinib
DIR By: agate
Date: October 16, 2024, 1:00 am
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From Managed Health Care Executive (October 14, 2024)--"It's
Been a Bumpy Ride for the BTK Inhibitors for MS":
HTML https://www.managedhealthcareexecutive.com/view/it-s-been-a-bumpy-ride-for-the-btk-inhibitors-for-ms
#Post#: 4769--------------------------------------------------
(NEJM) Tolebrutinib in nonrelapsing SPMS
DIR By: agate
Date: April 10, 2025, 1:10 am
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From the New England Journal of Medicine (April 10,
2025)--"Tolebrutinib in nonrelapsing secondary progressive
multiple sclerosis":
HTML https://www.nejm.org/doi/full/10.1056/NEJMoa2415988?query=TOC#
Under "Adverse Events" there is this:
--- Quote ---
> The incidence of death was similar in the two groups [the
tolebrutinib group and the placebo group]. In the tolebrutinib
group, one participant had liver failure that was assessed as
being related to tolebrutinib; this participant died as a result
of postoperative complications related to a liver
transplantation.
--- End Quote ---
#Post#: 4782--------------------------------------------------
(MedPage Today) Tolebrutinib benefits nonrelapsing SPMS
DIR By: agate
Date: April 23, 2025, 1:13 am
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My own reaction to the news about tolebrutinib is lukewarm at
best but it is getting some attention lately, particularly with
Sanofi's claim that this is "the very first time we have
identified a treatment that is effective for this form of MS."
From MedPage Today (April 14, 2025)--"Tolebrutinib benefits
nonrelapsing secondary progressive MS":
HTML https://tinyurl.com/y2zfyvep
#Post#: 4805--------------------------------------------------
(NEJM editorial) Progress toward mitigating disability
progression in MS
DIR By: agate
Date: May 14, 2025, 7:46 pm
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This should provide access to the full article. From the New
England Journal of Medicine, editorial by Peter A. Calabresi, MD
(May 14, 2025)--"Progress toward mitigating disability
progression in multiple sclerosis":
HTML https://www.nejm.org/doi/full/10.1056/NEJMe2503891?query=TOC
If that link doesn't get you there, here is the editorial
(emphasis added):
(New England Journal of Medicine Editorial) "Progress toward
Mitigating Disability Progression in Multiple Sclerosis" by
Peter A. Calabresi, MD:
Multiple sclerosis is the most common cause of progressive
neurologic disability in young adults. There had been no
treatments for the disease, except for glucocorticoids, which
were used for more than 25 years before they were shown to
reduce the duration and severity of acute relapses but to have
no benefit with respect to the accumulation of disability. Then,
in 1993, interferon beta was shown to reduce the frequency of
relapses and the number and area of lesions on T2-weighted
magnetic resonance imaging (MRI) of the brain.
Since then, more than 20 additional drugs have been approved
for multiple sclerosis, predominantly for relapsing forms of the
disease. These compounds mostly modulate the peripheral immune
system and minimally target existing lesions in the brain and
meninges. As a result, persons with multiple sclerosis who are
treated with these drugs have few new clinical exacerbations;
however, the lesions that form before treatment often remain
chronically active and continue to cause progressive tissue
damage and disability. The pathogenesis of secondary progressive
multiple sclerosis, which is characterized by insidious disease
progression in the absence of new infiltration of peripheral
immune cells, involves reactive gliosis (microglia and
astroglia), chronic demyelination, and neuroaxonal injury.
In this issue of the Journal, three landmark clinical trials
provide evidence that a brain-penetrant Bruton’s tyrosine kinase
(BTK) inhibitor, tolebrutinib, may slow disability progression
in multiple sclerosis. Investigators report the efficacy of
tolebrutinib in relapsing multiple sclerosis (the GEMINI 1 and
GEMINI 2 trials) and secondary progressive multiple sclerosis
(the HERCULES trial).
BTK inhibitors are being tested in several trials in
immune-mediated diseases because the enzyme is important for
B-cell activation. BTK is also expressed in myeloid lineage
cells, including reactive microglia. Tolebrutinib was designed
to be brain-penetrant to suppress B cells both in the periphery
and the meninges, as well as in activated microglia at the edge
of chronic active lesions.
The HERCULES trial, which recruited participants with secondary
progressive multiple sclerosis and no recent clinical relapses,
assessed the efficacy of tolebrutinib as compared with placebo
in the absence of classic inflammatory disease. The percentage
of participants who had confirmed disability progression that
was sustained for at least 3 months and for at least 6 months
was smaller in the tolebrutinib group than in the placebo group.
The rate of new or enlarging lesions on T2-weighted MRI was
lower in the tolebrutinib group than in the placebo group, a
finding that suggests that there was a component of active
inflammation in this trial population, despite attempts to
recruit participants with noninflammatory progressive multiple
sclerosis.
The GEMINI trials were active-comparator trials for ethical
reasons (because there are effective therapies known to reduce
relapse rates).
The two trials compared tolebrutinib with teriflunomide and
involved participants with relapsing forms of multiple
sclerosis. There was no significant difference between the two
drugs in the annualized relapse rate or the number of new or
enlarging lesions on T2-weighted MRI. This result is consistent
with the results of another recently completed trial of a BTK
inhibitor (evobrutinib) for the treatment of relapsing multiple
sclerosis that acts in the periphery. Nonetheless, despite the
absence of any additional beneficial effect on acute
inflammation-mediated clinical events or acute inflammatory
activity on MRI (as compared with teriflunomide), there was
apparent slowing of confirmed disability progression with
tolebrutinib, which, when viewed in the context of the HERCULES
trial, suggests that tolebrutinib may target chronic
inflammation in the central nervous system.
Caution in the interpretation of these results is indicated,
pending further data analyses from these trials and ongoing
studies of BTK inhibitors in progressive multiple sclerosis.
Progression independent of relapse activity has been widely
cited as an important outcome in studies in multiple sclerosis,
but it does not capture subclinical MRI activity and accumulated
lesion load on T2-weighted MRI that are known to be more
prevalent than relapses and to predict future disease
progression. Progression in the absence of relapses and new
lesion formation on MRI is more sensitive in determining whether
the mechanisms underlying disease progression are new
inflammatory infiltrates (new or gadolinium-enhancing lesions)
or the insidious neurodegenerative process for which we need new
therapies.
Participants in the HERCULES trial were enrolled because they
were having progression despite previously receiving available
disease-modifying therapies for multiple sclerosis. However,
more than 70% of the participants were only receiving first-line
therapy, and in many cases these drugs are only partially
effective at reducing inflammation. Furthermore, for patients
who are receiving stronger therapies, the withdrawal of these
therapies could lead to delayed reactivation of inflammatory
disease. A total of 13% of the participants had
gadolinium-enhancing lesions at baseline, and new lesions on MRI
were observed in participants during the trial. Therefore, some
of the observed effects on disability progression may be
attributable to antiinflammatory effects akin to what has been
seen with existing multiple sclerosis drugs when assessed in
persons with progressive multiple sclerosis who have
superimposed relapses or MRI activity. Indeed, the reduction in
new and enlarging lesions with tolebrutinib could support this
notion. The absence of an apparent effect of tolebrutinib on MRI
activity in the GEMINI studies argues against the possibility
that new lesions on T2-weighted MRI were the sole driver of
disease progression in the HERCULES trial. BTK is expressed at
the edge of chronic active lesions, which can be assessed with
the use of susceptibility-weighted imaging to detect iron-laden
microglia in phase rim lesions, which are known to predict worse
outcomes in multiple sclerosis.
Analysis of the susceptibility-weighted imaging data in these
trials may help discern whether there was a greater treatment
effect in the participants with phase rim lesions than in those
without them and would strongly support the concept that
tolebrutinib was indeed, in part, targeting activated microglia
in chronic active lesions.A serious safety concern, related to
BTK inhibitors as a class when tested in persons with multiple
sclerosis, has been markedly elevated levels of
aminotransferases. These events led to the Food and Drug
Administration placing a temporary hold on all the ongoing BTK
inhibitor studies until it was determined that the vast majority
of the most serious cases were occurring in the first 12 weeks
of treatment but were reversible if detected rapidly through
more frequent laboratory testing. If these data are replicated
in ongoing studies, and BTK inhibitors are approved for
progressive multiple sclerosis, clinicians will need to grapple
with when and how to use these drugs, which may have less robust
antiinflammatory activity than the available monoclonal
antibodies, but which could be directly targeting the
pathogenesis of insidious progression in persons with multiple
sclerosis. Clinical trials are warranted to evaluate the added
benefits of initiating combination therapy from the onset of
disease, which could enable targeting of both inflammation and
neurodegeneration.
[Reference notes omitted]
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