News & analysis
News in brief
FDA approves first-in-class NK3 receptor
antagonist for hot flushes
The FDA has approved Astellas’s
fezolinetant for moderate-
to-severe hot flushes in
menopause. The small molecule
is the first neurokinin 3 receptor
(NK3R) antagonist to market,
and the first non-hormonal
treatment to address the neural
signalling underlying hot
flushes. The FDA approved the
antidepressant paroxetine, a
selective serotonin reuptake
inhibitor, for hot flushes in 2013.
NK3R is a tachykinin recep-
tor that is mainly expressed
in the central nervous system
and that first attracted interest
from drug developers in the
1990s as a target for next-
generation antipsychotics.
Trials of NK3R antagonists
disappointed in this setting, but
the target was resurrected for
menopause after it was impli-
cated in hormone-mediated
thermoregulation.
In 2011, one team showed that
NK3R activation triggers hot-
flush-like changes in rats. Others
found evidence of importance
in humans too, including a 2015
report that the NK3R-activating
ligand neurokinin B induces hot
flushes when administered to
pre-menopausal women, and a
2017 study showing that varia-
tion in the gene for NK3R could
account for the variability in hot
flush severity in menopausal
women.
Astellas acquired fezolinetant
in 2017 by buying the biotech
Ogeda, for up to €800 million,
based on promising phase II
data.
Astellas has since demon-
strated the efficacy of fezolin-
etant in two phase III trials, in
nature reviews drug discovery
1,022 women with moderate-
to-severe hot flushes. Trial
participants had on average
around 10–12 flushes per day
at baseline. The now-approved
dose of fezolinetant reduced hot
flush frequency by over 2 flushes
per day compared to placebo, at
4 weeks and 12 weeks, meeting
both co-primary endpoints,
showed results in The Lancet
and The Journal of Clinical
Endocrinology & Metabolism.
Common side effects
included abdominal pain, diar-
rhoea, insomnia, back pain,
hot flush and increased hepatic
transaminases.
Hot flushes affect 80% of men-
opausal women and can include
periods of sweating, flushing
and chills. “The key impact will
be in women who cannot, or
do not want to, take hormone
therapy,” wrote University of
Exeter endocrinologist Julia
Prague in The Lancet. Head-
to-head studies of fezolinetant
versus other treatment options
would be helpful, she added.
Analysts forecast sales of
US$1.9 billion by 2028 for fezo-
linetant, according to Evaluate
Pharma.
Bayer/KaNDY Therapeutics’
elinzanetant, a dual NK1R and
NK3R antagonist licensed from
GSK, is in phase III for hot flushes
in menopause. Sojournix’s NK3R
antagonist SJX-653, licensed
from Lundbeck, is in phase II in
this setting. Acer Therapeutics
recently paused development of
osanetant, an NK3R antagonist
acquired from Sanofi, in various
settings.
Asher Mullard
News in brief
PD1 agonist antibody passes first phase II
trial for autoimmune disease
Results from a phase II trial of
Eli Lilly’s PD1-targeted peresoli-
mab in refractory rheumatoid
arthritis have raised hopes
for the immune checkpoint
agonist in autoimmune and
autoinflammatory diseases.
Immune checkpoint inhibi-
tors that block PD1 signalling
to unleash T cells on cancers
have transformed the oncology
landscape. But these therapeu-
tics can cause immune-related
adverse events that resemble
autoimmune diseases. Immune-
dampening PD1 signalling is
also downregulated in the joints
of patients with rheumatoid
arthritis. Agonistic antibodies
that boost PD1 signalling —
pumping the brakes on T cell
activity — might therefore
provide therapeutic benefit in
this disease.
Lilly tested this hypothesis in
a placebo-controlled phase II
trial of its PD1 agonist peresoli-
mab in 98 adults with moderate-
to-severe rheumatoid arthritis
and inadequate response to
prior therapies. The primary
efficacy endpoint was the
change from baseline to week 12
in the DAS28-CRP, an assess-
ment of joint tenderness, joint
swelling, the patient’s global
assessment of disease activ-
ity and serum levels of high-
sensitivity C-reactive protein. At
week 12, patients who received
700 mg of peresolimab had on
average a −1.09-point placebo-
adjusted improvement on the
9.4-point DAS28-CRP scale,
investigators reported in The
New England Journal of Medicine
(NEJM).
Peresolimab recipients were
also more likely to achieve
ACR20, but not ACR50 or
ACR70 — improvements from
baseline of 20%, 50%, and 70%
Volume 22 | July 2023 | 526–527 | 526
or more, respectively, in a core
set of rheumatoid arthritis
measures.
Researchers did not identify
any safety signals.
“This trial opens a refreshing
new chapter in the treatment
of rheumatoid arthritis and
introduces an approach that
might also be applied to the
treatment of other autoimmune
diseases that are driven by
antigen-activated lymphocytes,”
wrote rheumatologists Ellen
Gravallese, from Brigham and
Women’s Hospital, and Ranjeny
Thomas, from the Frazer
Institute, in an Editorial in NEJM.
The trial might have been
too short and small to assess
whether the T-cell-dampening
antibody increases the risk of
cancer, they cautioned.
Lilly is running another
phase II trial of peresolimab in
moderate-to-severe rheumatoid
arthritis, and is considering its
options for other autoimmune
diseases.
AnaptysBio is set to start
phase II trials of its PD1 agonist
rosnilimab in rheumatoid arthri-
tis and in another indication
later this year.
Bristol Myers Squibb/Celgene’s
contender CC-90006, licensed
from AnaptysBio, was in phase I
for psoriasis, but Bristol Myers
Squibb no longer lists CC-90006
in its pipeline. This antibody
“was based on early under-
standing of agonism and by
today’s standards is not a potent
molecule,” said a spokesman
for AnaptysBio.
Merck & Co. and Gilead
recently acquired preclinical
PD1 agonists in their respec-
tive acquisitions of Pandion
Therapeutics and MiroBio.
Asher Mullard