Trial builds on prior compelling efficacy data
in xanomeline and suggests enhanced safety and tolerability with
novel KarXT combination approach
Initiation of Phase 2 clinical trial planned
for 2017
Karuna Pharmaceuticals, focused on targeting muscarinic
receptors for the treatment of central nervous system (CNS)
disorders and a subsidiary of PureTech Health (LSE: PRTC), today
announced positive results from a tolerability proof-of-concept
study of its proprietary product, KarXT. In the study, KarXT
(xanomeline plus trospium chloride), which is being developed as a
novel antipsychotic for schizophrenia and Alzheimer’s disease, was
found to be generally well-tolerated and have superior tolerability
to xanomeline alone. Based on these positive safety results and
previous efficacy data on xanomeline, which is exclusively licensed
to Karuna from Eli Lilly, Karuna intends to initiate a Phase 2
clinical trial of KarXT in 2017.
“We are extremely pleased with these results, which provide a
clear proof-of-concept that the KarXT approach improves the
tolerability of xanomeline and move us closer toward our goal of
developing the first truly novel antipsychotic agent in more than
sixty years for patients with schizophrenia or Alzheimer’s,” said
Andrew Miller, Ph.D., Karuna’s CEO. “Given the strong efficacy data
shown in previous clinical trials with xanomeline, our goal was to
demonstrate the improved tolerability of KarXT compared to
xanomeline. Now we look forward to initiating a Phase 2 trial in
2017 to replicate the efficacy previously observed with xanomeline
with this greatly improved product profile.”
In the 70 subject, double-blind, placebo-controlled trial,
participants received either placebo or trospium chloride during a
two-day run-in period before receiving xanomeline plus placebo or
xanomeline plus trospium chloride (KarXT) for seven days. Safety
and tolerability were analyzed using adverse event incidence rates
with a prespecified focus on the cholinergic adverse events that
were previously observed with xanomeline alone and hindered
development efforts: diarrhea, nausea, vomiting, excessive sweating
and excessive salivation. A series of visual analogue scales (VAS)
were also piloted to track each cholinergic adverse event.
KarXT was shown to reduce the incidence of prespecified
cholinergic adverse events by a statistically significant and
clinically meaningful extent (46% p=0.016) compared to xanomeline
alone and each individual cholinergic adverse event was reported at
a lower rate in the KarXT treatment arm. No severe or serious
adverse events were reported. VAS scores (maximum weekly composite
VAS) were reduced by 42% in the KarXT treatment arm, but this
measure was not statistically significant (p=0.31). The low VAS
score in the xanomeline-only arm (3.82 out of 100, reduced to 2.29
in the KarXT arm) indicates that the VAS score was not a
sufficiently sensitive metric, likely due to the episodic nature of
the cholinergic adverse events.
The placebo-only group during the two-day run-in period also
served to indicate the baseline cholinergic adverse reporting rate
in the study population, which was 32%. This rate is similar to the
cholinergic adverse event rate of the KarXT treatment arm during
the active phase of the study (34% vs 32%, respectively),
indicating an excellent tolerability profile in the KarXT treatment
arm.
“For many years, researchers have been excited about the
therapeutic application of muscarinic agonists. The impressive
tolerability data reported in this study, together with the
previous compelling efficacy data generated with xanomeline,
highlight the great potential of this novel approach to targeting
muscarinic receptors and unlocking the development of a
first-in-class medicine,” said Alan Breier, M.D., Professor of
Psychiatry at Indiana University, Karuna Chief Clinical Advisor,
and former Chief Medical Officer at Eli Lilly. “Patients with
Alzheimer’s and schizophrenia are in dire need of new treatments,
and KarXT may offer a potentially transformative new path towards
treating these serious and debilitating diseases.”
KarXT combines xanomeline, a novel clinical-stage muscarinic
acetylcholine receptor agonist, with trospium chloride, a
muscarinic antagonist, and is being developed to selectively target
muscarinic receptors in the CNS. Exclusively licensed to Karuna,
xanomeline has demonstrated robust efficacy in reducing psychosis
in both schizophrenia and Alzheimer’s disease in previous studies;
however, it has been associated with side effects that have limited
its development. The results of the KarXT proof-of-concept study
indicate that the addition of trospium chloride results in improved
tolerability of xanomeline. Based on these positive safety results
and previous efficacy data on xanomeline, Karuna intends to
initiate a Phase 2 clinical trial of KarXT in 2017.
This announcement contains inside information for the purposes
of Article 7 of Regulation (EU) 596/2014.
About KarunaKaruna is a clinical-stage drug development
company targeting muscarinic receptors for the treatment of central
nervous system (CNS) disorders and a subsidiary of PureTech Health.
Karuna's lead program, KarXT, is a product candidate consisting of
xanomeline, a novel muscarinic
acetylcholine receptor agonist that has demonstrated efficacy in
placebo-controlled human trials in schizophrenia and Alzheimer’s
disease, and trospium chloride,
an FDA-approved and well-established muscarinic receptor antagonist
that has been shown not to enter the CNS.
Schizophrenia is a severe and chronic mental health disorder
that affects more than 21 million people worldwide. The disease is
characterized by profound disruptions in thinking, affecting
language, perception and the sense of self, and it typically
includes psychotic episodes. Antipsychotics are the mainstay
therapy for the treatment of schizophrenia; however, significant
unmet needs remain due to the limited efficacy and potential
serious side effects associated with current antipsychotic
medications.
Alzheimer’s disease is a chronic, progressive, neurodegenerative
disorder characterized by loss of memory and other important mental
functions. The type, severity, sequence and progression of mental
changes vary widely, and it represents an enormous burden on
victims of the disease and their families. Alzheimer’s is the most
common form of dementia in people over the age of 65, and it is
estimated to affect more than 5 million Americans. It is the sixth
leading cause of death in the United States, and there is currently
no cure.
Karuna’s Board of Directors includes Ben Shapiro, M.D., former
Executive Vice President of Research for Merck & PureTech
Health Non-Executive Director; Edmund Harrigan, M.D., former Senior
Vice President for Worldwide Safety and Regulatory, Head of
Worldwide Business Development at Pfizer; and Atul Pande, M.D.,
Former Senior Vice President, Head of Neuroscience and Senior
Advisor, Pharmaceutical R&D at GlaxoSmithKline & PureTech
Health Senior Advisor. Karuna’s Chief Clinical Advisor is Alan
Breier, M.D., the former Chief Medical Officer at Eli
Lilly. Karuna has a worldwide exclusive license for xanomeline
and has a patent portfolio more broadly covering selective
muscarinic targeting enabled by the KarXT approach. For more
information, visit www.karunapharma.com.
PureTech Health plc (PRTC.L) owns 79.6% of Karuna on a diluted
basis as of June 30, 2016, plus potential product royalties as a
co-inventor of the KarXT platform. The ownership calculation
includes issued and outstanding shares as well as options to
purchase shares and written commitments to issue shares or options,
but excludes unallocated shares authorized to be issued pursuant to
equity incentive plans and any convertible debt.
About PureTech HealthPureTech Health (PureTech
Health plc, PRTC.L) is a cross-disciplinary biopharma company
creating 21st century medicines that modulate the adaptive human
systems. Our therapies target the immune, nervous, and
gastro-intestinal systems by addressing the underlying
pathophysiology of disease from a systems perspective rather than
through a single receptor or pathway. We are advancing more than 20
clinical studies across our pipeline, with multiple human
proof-of-concept studies and pivotal or registration studies
expected to read out in the next two years. PureTech Health’s rich
and growing research and development pipeline has been developed in
collaboration with some of the world’s leading scientific experts,
who along with PureTech's experienced team and board analyses more
than 650 scientific discoveries per year to identify and advance
the opportunities we believe hold the most promise for patients.
This process places PureTech Health on the cutting edge of
ground-breaking science and technological innovation and leads the
Company between and beyond existing disciplines. For more
information, visit www.puretechhealth.com or connect with us on
Twitter.
Forward Looking StatementThis press release contains
statements that are or may be forward-looking statements, including
statements that relate to the company's future prospects,
developments and strategies. The forward-looking statements are
based on current expectations and are subject to known and unknown
risks and uncertainties that could cause actual results,
performance and achievements to differ materially from current
expectations, including, but not limited to, those risks and
uncertainties described in the risk factors included in the
regulatory filings for PureTech Health plc. These forward-looking
statements are based on assumptions regarding the present and
future business strategies of the company and the environment in
which it will operate in the future. Each forward-looking statement
speaks only as at the date of this press release. Except as
required by law and regulatory requirements, neither the company
nor any other party intends to update or revise these
forward-looking statements, whether as a result of new information,
future events or otherwise.
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PureTechMedia:Allison Mead, +1
617-651-3156amead@puretechhealth.comorInvestors:Graham
Morrell, +1 617-986-1659gm@puretechhealth.com
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