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#Post#: 4539--------------------------------------------------
Tolebrutinib for nonrelapsing SPMS?
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 sti
ll plans FDA filing (FierceBiotech)
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
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
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
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][font=otnejmquadraat]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[/font].[/quote]
#Post#: 4782--------------------------------------------------
(MedPage Today) Tolebrutinib benefits nonrelapsing SPMS
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":
[font=minion-pro]
HTML https://tinyurl.com/y2zfyvep[/font]
#Post#: 4805--------------------------------------------------
(NEJM editorial) Progress toward mitigating disability progressi
on in MS
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):
[font=arial](New England Journal of Medicine Editorial)
"Progress toward Mitigating Disability Progression in Multiple
Sclerosis" by Peter A. Calabresi, MD:[/font]
[font=arial]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.[/font]
[font=arial] 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.[/font]
[font=arial]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)[/font][font=arial]
and secondary progressive multiple sclerosis (the HERCULES
trial).[/font]
[font=arial] BTK inhibitors are being tested in several trials
in immune-mediated diseases because the enzyme is important for
B-cell activation.[/font][font=arial] BTK is also expressed in
myeloid lineage cells, including reactive
microglia.[/font][font=arial] 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.[/font]
[font=arial]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.[/font]
[font=arial]The GEMINI trials were active-comparator trials for
ethical reasons (because there are effective therapies known to
reduce relapse rates). [/font]
[font=arial]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.[/font][font=arial] 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.[/font]
[font=arial]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.[/font][font=arial] 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.[/font]
[font=arial]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.[/font]
[font=arial] 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.[/font][font=arial]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.[/font]
[font=arial][Reference notes omitted][/font]
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