Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the
Company), a biopharmaceutical company with marketed products and a
pipeline of development candidates, today announced that the Phase
3 RESILIENT study evaluating TNX-102 SL (cyclobenzaprine HCl
sublingual tablets) met its pre-specified primary endpoint in the
second of two positive Phase 3 clinical trials, significantly
reducing daily pain compared to placebo (p=0.00005) in participants
with fibromyalgia (Table 1). Statistically significant and
clinically meaningful results were also seen in all key secondary
endpoints related to improving sleep quality, reducing fatigue, and
improving overall fibromyalgia symptoms and function. Additionally,
as it relates to improving daily pain, treatment with TNX-102 SL
showed a robust and clinically meaningful analgesic effect size of
0.38, with rapid onset of action, separating from placebo for each
week of the study. TNX-102 SL was well tolerated with an adverse
event profile comparable to prior studies, and no new safety
signals were observed. Tonix plans to submit a New Drug Application
(NDA) to the U.S. Food and Drug Administration (FDA) in the second
half of 2024 for TNX-102 SL for the management of fibromyalgia. An
estimated 6 million to 12 million U.S. adults are living with
fibromyalgia, the majority of whom are women.
TNX-102 SL is a tablet formulation containing
2.8 mg cyclobenzaprine HCl and is a novel, centrally-acting,
non-opioid analgesic, designed to be taken once daily at bedtime
for the management of fibromyalgia. RESILIENT was a 14-week
randomized, double-blind, placebo-controlled trial of TNX-102 SL
5.6 mg, in which 457 participants with fibromyalgia were randomized
in a 1:1 ratio to TNX-102 SL or placebo across 33 sites in the U.S.
All participants received one 2.8 mg tablet of TNX-102 SL (2.8 mg)
or placebo for the first 2 weeks, which was increased to two 2.8 mg
tablets of TNX-102 SL (5.6 mg) or placebo for the remaining 12
weeks.
In December 2020, Tonix reported positive
results from the first Phase 3 RELIEF study of TNX-102 SL 5.6 mg
for the management of fibromyalgia. The RELIEF study met its
pre-specified primary endpoint, significantly reducing daily pain
compared to placebo (p=0.010) in participants with fibromyalgia,
and showing activity in key secondary endpoints.
“We believe that the positive results of
RESILIENT and RELIEF show that fibromyalgia can be successfully
treated by TNX-102 SL 5.6 mg and may provide the opportunity for
Tonix to have the first FDA-approved drug for fibromyalgia in more
than a decade,” said Seth Lederman, M.D., President and Chief
Executive Officer of Tonix Pharmaceuticals. “We are now an
important step closer to bringing a new, first-line treatment to
fibromyalgia patients that offers broad symptom relief and
favorable tolerability for chronic use and adherence. We believe
that we are well positioned to submit an NDA to the FDA under the
505(b)(2) regulatory approval pathway in the second half of 2024,
and are on track to supply the U.S. market upon FDA approval.”
Table 1. Results of Primary and
Secondary Endpoints for the Phase 3 RESILIENT Study of TNX-102
SL
|
|
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|
|
|
|
Outcome Measure at Week 14 |
|
|
Intent-to-Treat Analysis1 |
|
|
P-value |
Primary Endpoint |
|
|
|
|
|
|
Daily Pain Diary, NRS |
|
|
Mean Change from Baseline2 |
|
|
0.00005* |
|
|
|
|
|
|
|
Key Secondary Endpoints |
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|
|
|
|
|
Non-specific |
|
|
|
|
|
|
Patient Global Impression of Change |
|
|
Proportion "Much" or "Very Much Improved"3 |
|
|
<0.001* |
|
|
|
|
|
|
|
Fibromyalgia
Syndrome-Related |
|
|
|
|
|
|
FIQ-R Symptom Domain |
|
|
Mean Change from
Baseline |
|
|
<0.001* |
FIQ-R Function Domain |
|
|
Mean Change from
Baseline |
|
|
0.001* |
PROMIS Sleep Disturbance |
|
|
Mean Change from
Baseline |
|
|
<0.001* |
PROMIS Fatigue |
|
|
Mean Change from
Baseline |
|
|
<0.001* |
Daily Sleep Quality Diary, NRS |
|
|
Mean Change from
Baseline |
|
|
<0.001* |
|
|
|
|
|
|
|
Abbreviations: FIQ-R = Fibromyalgia Impact Questionnaire - Revised;
NRS = Numeric Rating Scale; PROMIS = Patient-Reported Outcomes
Measurement Information System |
*Statistically significant; to control for overall type 1 error, a
pre-specified, serial gatekeeping procedure was utilized. |
1Analysis by mixed model repeated measures with multiple imputation
unless otherwise indicated. |
2Primary endpoint analysis for FDA approvals of Cymbalta® and
Lyrica® in fibromyalgia. |
3Pearson’s chi-squared test responder analysis, with missing data
considered non-responders |
“These data are terrific news for patients with
fibromyalgia,” said Daniel J. Clauw, M.D., Professor of
Anesthesiology, Medicine and Psychiatry at the University of
Michigan. “Despite approved medications, there remains a need
for new treatment options to better address the quality of life
impacts many fibromyalgia patients experience on a chronic basis.
TNX-102 SL is a non-opioid, centrally-acting analgesic, the active
ingredient of which has a known, favorable safety profile from
decades of use. The fact that cyclobenzaprine was also beneficial
in many other key symptom domains, including sleep quality, sleep
disturbance and fatigue, will be appreciated by fibromyalgia
patients that struggle with not just pain but multiple other
symptoms.”
“These positive data from RESILIENT and
previously with RELIEF, with remarkable separation from placebo on
pain, sleep, and fatigue, add support to TNX-102 SL’s proposed
mechanism of improving sleep quality to improve the syndromal
effects of fibromyalgia,” commented Gregory Sullivan, M.D., Chief
Medical Officer of Tonix Pharmaceuticals. “The sublingual
formulation of TNX-102 SL, which uses our proprietary Protectic®
and Angstro® technologies, is integral to our treatment paradigm.
These technologies enable transmucosal delivery of cyclobenzaprine
with distinctive pharmacokinetic properties that include rapid
absorption after dosing and bypass of first-pass hepatic
metabolism. I would like to thank the RESILIENT study participants
and their families and caregivers, as well as the investigators and
their hard-working staff who all made this a highly successful
trial.”
Summary of Topline Results of the
RESILIENT Study
The RESILIENT study achieved statistical
significance on the pre-specified primary efficacy endpoint: change
from baseline in the weekly average of daily diary pain severity
numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean
[SE]: -1.8 [0.12] units) versus placebo (-1.2 [0.12] units),
analyzed by mixed model repeated measures with multiple imputation
(LS mean [SE] difference: -0.7 [0.16] units, p=0.00005, Table 1).
In addition, all pre-specified sensitivity analyses of the primary
endpoint were statistically significant (p<0.001). Figure 1
shows reduction in pain across all weeks of the 14-week study, with
nominal p<0.01 for every week. Note the rapid onset of action
with separation from placebo at Week 1 was sustained throughout all
weeks of dosing.
Abbreviations: LS = least squares; NRS =
numerical rating scale; SE = standard error
The statistically significant improvement in
pain is further substantiated when diary pain was analyzed by
another standard statistical approach, a 30 percent responder
analysis, with 45.9% on active and 27.1% on placebo having a 30
percent or greater reduction in pain (Pearson Chi-Squared Test;
difference in proportions [95% CI]: 18.8% [10.1%, 27.4%]; nominal
p<0.001).
TNX-102 SL showed statistical significance
(p≤0.001) on all six pre-specified key secondary efficacy outcome
measures (Table 1).
Consistent with the proposed mechanism that
TNX-102 SL acts in fibromyalgia through improving sleep quality,
TNX-102 SL showed statistically significant improvement of sleep by
two main measures. For the daily diary sleep quality ratings,
improvement in sleep quality for TNX-102 SL (-1.8 [0.12] units) was
significantly greater than that of placebo (-1.2 [0.12] units; LS
mean [SE] difference from placebo: -0.6 [0.17] units; p<0.001).
For the PROMIS Sleep Disturbance instrument, TNX-102 SL also
demonstrated significantly greater improvement over placebo on
T-scores (LS mean [SE] difference from placebo: -4.2 [0.79] units;
p<0.001). Fatigue is another cardinal symptom of fibromyalgia
and has a major impact on quality of life. TNX-102 SL showed
significant improvement over placebo on the PROMIS Fatigue
instrument T-scores (-3.0 [0.77] units; p<0.001).
The Fibromyalgia Impact Questionnaire – Revised
(FIQ-R) is a 21-item self-rated instrument that assesses level of
function, overall impact, and symptoms due to fibromyalgia, and the
symptoms and function domains were key secondary endpoints in
RESILENT. At Week 14 on the FIQ-R Symptoms domain, there was
significantly greater improvement with TNX-102 SL than with placebo
(LS mean [SE] difference from placebo: -7.7 [1.62], p<0.001).
Similarly, TNX-102 SL resulted in greater improvement on FIQ-R
Function (LS mean [SE] difference from placebo: -5.4 [1.66],
p=0.001). Although not a key secondary efficacy endpoint, TNX-102
SL also separated from placebo on the FIQ-R Impact domain (nominal
p=0.001). These results, along with the robust effects on improving
sleep and fatigue, suggests broad symptomatic coverage of the
syndrome of fibromyalgia.
Safety Results of the Phase 3 RESILIENT
Study
In the RESILIENT study, TNX-102 SL was well
tolerated and consistent with prior trials, with no new safety
signals observed. Among participants randomized to the TNX-102 SL
and placebo arms, 81.0% and 79.2%, respectively, completed the
14-week dosing period. As expected based on prior TNX-102 SL
studies, administration site reactions were the most commonly
reported adverse events and were higher in the TNX-102 SL treatment
group (Table 2). Hypoaesthesia oral and paraesthesia oral, or
tongue and mouth numbness or tingling, product taste abnormal
(typically a bitter aftertaste upon dosing), and tongue discomfort
were local effects nearly always temporally related to dose
administration and transiently expressed (<60 minutes) in most
occurrences. The only treatment-emergent adverse events that
occurred at a rate of 3.0% or greater in either arm were these four
oral adverse events, along with COVID-19, somnolence, and headache
(Table 2). Adverse events resulted in premature study
discontinuation in 6.1% of those who received TNX-102 SL compared
with 3.5% of placebo recipients. There were a total of seven
serious adverse events in five patients, five of which were
experienced by three patients in the placebo arm, and two of which
were in the TNX-102 SL arm. Of the two in the TNX-102 SL arm, one
was renal cancer, deemed unrelated to study drug, and the other was
acute pancreatitis with onset 14 days after dosing was completed
and reported as possibly related to study drug.
Table 2. Treatment-Emergent Adverse
Events at a Rate of 3% or Greater in Either Treatment
Arm
|
|
TNX-102 SL (N=231) |
|
Placebo (N=226) |
|
Total (N=457)* |
Administration Site Reactions |
|
N |
|
% |
|
N |
|
% |
|
N |
|
% |
Hypoaesthesia oral |
|
55 |
|
23.8% |
|
1 |
|
0.4% |
|
56 |
|
12.3% |
Product taste abnormal |
|
27 |
|
11.7% |
|
2 |
|
0.9% |
|
29 |
|
6.3% |
Paraesthesia oral |
|
16 |
|
6.9% |
|
2 |
|
0.9% |
|
18 |
|
3.9% |
Tongue discomfort |
|
16 |
|
6.9% |
|
0 |
|
0.0% |
|
16 |
|
3.5% |
Systemic |
|
|
|
|
|
|
Adverse Events |
|
N |
|
% |
|
N |
|
% |
|
N |
|
% |
COVID-19 |
|
10 |
|
4.3% |
|
7 |
|
3.1% |
|
17 |
|
3.7% |
Somnolence |
|
7 |
|
3.0% |
|
3 |
|
1.3% |
|
10 |
|
2.2% |
Headache |
|
7 |
|
3.0% |
|
4 |
|
1.8% |
|
11 |
|
2.4% |
*Safety Population
The Changes in Sexual Functioning Questionnaire
short form (CSFQ-14) served as a safety measure for assessing
potential adverse effects on sexual functioning. In females, the
total score on the CSFQ-14 at Week 14 improved (indicating better
sexual functioning) in the TNX-102 SL group compared with placebo
(nominal p=0.010 by analysis of covariance). This potentially
indicates an important tolerability advantage over
pharmacotherapeutics which potently inhibit reuptake of serotonin.
The low percentage of males in the safety population (<5%) did
not allow meaningful analysis of the CSFQ-14 data.
About the Phase 3 RESILIENT
Study
The RESILIENT study is a double-blind,
randomized, placebo-controlled trial designed to evaluate the
efficacy and safety of TNX-102 SL (cyclobenzaprine HCl sublingual
tablets) in the management of fibromyalgia. The two-arm trial
randomized 457 participants in the U.S. across 33 sites. The first
two weeks of treatment consist of a run-in period in which
participants start on TNX-102 SL 2.8 mg (1 tablet) or placebo.
Thereafter, all participants increase their dose to TNX-102 SL 5.6
mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12
weeks. The primary endpoint is the daily diary pain severity score
change (TNX-102 SL 5.6 mg vs. placebo) from baseline to Week 14
(using the weekly averages of the daily numerical rating scale
scores), analyzed by mixed model repeated measures with multiple
imputation.
For more information, see ClinicalTrials.gov
Identifier: NCT05273749.
About Fibromyalgia
Fibromyalgia is a chronic pain disorder that is
understood to result from amplified sensory and pain signaling
within the central nervous system. Fibromyalgia afflicts an
estimated 6 million to 12 million adults in the U.S., the majority
of whom are women. Symptoms of fibromyalgia include chronic
widespread pain, nonrestorative sleep, fatigue, and morning
stiffness. Other associated symptoms include cognitive dysfunction
and mood disturbances, including anxiety and depression.
Individuals suffering from fibromyalgia struggle with their daily
activities, have impaired quality of life, and frequently are
disabled. Physicians and patients report common dissatisfaction
with currently marketed products.
About TNX-102 SL
TNX-102 SL is a patented sublingual tablet
formulation of cyclobenzaprine hydrochloride which provides rapid
transmucosal absorption and reduced production of a long half-life
active metabolite, norcyclobenzaprine, due to bypass of first-pass
hepatic metabolism. As a multifunctional agent with potent binding
and antagonist activities at the 5-HT2A-serotonergic,
α1-adrenergic, H1-histaminergic, and M1-muscarinic cholinergic
receptors, TNX-102 SL is in development as a daily bedtime
treatment for fibromyalgia, fibromyalgia-type Long COVID (formally
known as post-acute sequelae of COVID-19 [PASC]), alcohol use
disorder and agitation in Alzheimer’s disease. Dr. Harvey
Moldofsky, Professor Emeritus of Psychiatry and Medicine at the
University of Toronto, founding Director of the University of
Toronto Center for Sleep and Chronobiology, first recognized the
central role of non-restorative sleep in the pathogenesis of
fibromyalgia1,2. Our program is based on the subsequent pioneering
work of Dr. Iredell W. Iglehart III, who recognized that a
sleep-focused cyclobenzaprine treatment protocol had the potential
to target non-restorative sleep and lead to improvement of
fibromyalgia at the syndromal level3. Teams led by Giorgio Reiner
at APR Applied Pharma Research S.A., a wholly-owned subsidiary of
Relief Therapeutics Holding AG, and Professor Marino Nebuloni and
Patrizia Colombo at Redox Analytical Science Srl invented and
developed these underlying technologies in collaboration with
Tonix. The United States Patent and Trademark Office (USPTO) issued
United States Patent No. 9636408 in May 2017, Patent No. 9956188 in
May 2018, Patent No. 10117936 in November 2018, Patent No.
10,357,465 in July 2019, and Patent No. 10736859 in August 2020.
The Protectic™ protective eutectic and Angstro-Technology™
formulation claimed in the patent are important elements of Tonix’s
proprietary TNX-102 SL composition. These patents are expected to
provide TNX-102 SL, upon NDA approval, with U.S. market exclusivity
until 2034/2035. In addition, Tonix has pending but not issued U.S.
patent applications directed to the transmucosal absorption of
CBP-HCl, with U.S. market exclusivity expected until 2033, for
treating major depressive disorder in fibromyalgia, with U.S.
market exclusivity expected until 2032, and for treating pain in
fibromyalgia with U.S. market exclusivity expected until 2041.
1Moldofsky H et al, Psychosom Med
1975;37:341-51.2Moldofsky H and Scarisbrick
P. Psychosom Med 1976;38:35-44.3Iglehart IW. 2003; US
Patent 6,541,523.
Tonix Pharmaceuticals Holding
Corp.*
Tonix is a biopharmaceutical company focused on
commercializing, developing, discovering and licensing therapeutics
to treat and prevent human disease and alleviate suffering. Tonix
Medicines, our commercial subsidiary, markets Zembrace® SymTouch®
(sumatriptan injection) 3 mg and Tosymra® (sumatriptan nasal spray)
10 mg under a transition services agreement with Upsher-Smith
Laboratories, LLC from whom the products were acquired on June 30,
2023. Zembrace SymTouch and Tosymra are each indicated for the
treatment of acute migraine with or without aura in adults. Tonix’s
development portfolio is composed of central nervous system (CNS),
rare disease, immunology and infectious disease product candidates.
Tonix’s CNS development portfolio includes both small molecules and
biologics to treat pain, neurologic, psychiatric and addiction
conditions. Tonix’s lead development CNS candidate, TNX-102 SL
(cyclobenzaprine HCl sublingual tablet), has completed two positive
Phase 3 studies for the management of fibromyalgia. Tonix intends
to meet with the FDA and submit an NDA for the approval of TNX-102
SL for the management of fibromyalgia in the second half of 2024.
TNX-102 SL is also being developed to treat fibromyalgia-type Long
COVID, a chronic post-acute COVID-19 condition, and topline results
were reported in the third quarter of 2023. TNX-1900 (intranasal
potentiated oxytocin) is being studied in binge eating disorder,
pediatric obesity, bone health in autism and social anxiety
disorder by academic collaborators under investigator-initiated
INDs. TNX-1300 (cocaine esterase) is a biologic designed to treat
cocaine intoxication and has been granted Breakthrough Therapy
designation by the FDA. A Phase 2 study of TNX-1300 is expected to
be initiated in the first quarter of 2024 Tonix’s rare disease
development portfolio includes TNX-2900 (intranasal potentiated
oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has
been granted Orphan Drug designation by the FDA. Tonix’s immunology
development portfolio includes biologics to address organ
transplant rejection, autoimmunity and cancer, including TNX-1500,
which is a humanized monoclonal antibody targeting CD40-ligand
(CD40L or CD154) being developed for the prevention of allograft
rejection and for the treatment of autoimmune diseases. A Phase 1
study of TNX-1500 was initiated in the third quarter of 2023.
Tonix’s infectious disease pipeline includes TNX-801, a vaccine in
development to prevent smallpox and mpox. TNX-801 also serves as
the live virus vaccine platform or recombinant pox vaccine platform
for other infectious diseases, including TNX-1800, in development
as a vaccine to protect against COVID-19. During the fourth quarter
of 2023, TNX-1800 was selected by the U.S. National Institutes of
Health (NIH), National Institute of Allergy and Infectious Diseases
(NIAID) Project NextGen for inclusion in Phase 1 clinical trials.
The infectious disease development portfolio also includes TNX-3900
and TNX-4000, which are classes of broad-spectrum small molecule
oral antivirals.
*Tonix’s product development candidates are
investigational new drugs or biologics and have not been approved
for any indication.
Zembrace SymTouch and Tosymra are registered
trademarks of Tonix Medicines. All other marks are property of
their respective owners.
This press release and further information about
Tonix can be found at www.tonixpharma.com.
About Redox - Analytical Science Srl
Redox is an independent CRO company
headquartered in Monza- Italy with R&D activities and customer
analytical support to pharmaceutical companies for more than 30
years. From more than 25 years the analytical activities have been
certified by national and international agencies (European
Medicines Agency, the Italian Medicines Agency (AIFA), FDA, and
etc). One of the main activities is the development of new drug
products in order to improve the pharmaceutical actions and at the
same time improve the stability and reducing the cost of the new
drug substance. Several unique and sophisticated analytical
techniques and equipment are used in support to research and
development strategies with the focus to reach the best and
effective pharmaceutical formulation in a short time frame. More
than 30 professional people are dedicated to our efforts and many
projects are ongoing in collaboration with the pharmaceutical
industry as well as with Italian and international
Universities.
Further information about Redox can be found at
www.labredox.com.
About APR Applied Pharma Research S.A.,
a wholly-owned subsidiary of Relief Therapeutics Holding
AG
Relief Therapeutics is a commercial-stage
biopharmaceutical company committed to advancing treatment
paradigms and delivering improvements in efficacy, safety, and
convenience to benefit the lives of patients living with select
specialty and rare diseases. Relief Therapeutics' portfolio offers
a balanced mix of marketed, revenue-generating products, our
proprietary, globally patented Physiomimic™ and TEHCLO™ platform
technologies and a targeted clinical development pipeline
consisting of risk-mitigated assets focused in three core
therapeutic areas: rare metabolic disorders, rare skin diseases and
rare respiratory diseases. In addition, Relief Therapeutics is
commercializing several legacy products via licensing and
distribution partners. Relief Therapeutics' mission is to provide
therapeutic relief to those suffering from rare diseases and is
being advanced by an international team of well-established,
experienced biopharma industry leaders with extensive research,
development and rare disease expertise. Relief Therapeutics is
headquartered in Geneva, with additional offices in Balerna,
Switzerland, Offenbach am Main, Germany and Monza, Italy. Relief
Therapeutics is listed on the SIX Swiss Exchange under the symbol
RLF.
Further information about APR can be found at
www.relieftherapeutics.com or by following Relief Therapeutics on
LinkedIn and Twitter.
Forward Looking Statements
Certain statements in this press release are
forward-looking within the meaning of the Private Securities
Litigation Reform Act of 1995. These statements may be identified
by the use of forward-looking words such as “anticipate,”
“believe,” “forecast,” “estimate,” “expect,” and “intend,” among
others. These forward-looking statements are based on Tonix's
current expectations and actual results could differ materially.
There are a number of factors that could cause actual events to
differ materially from those indicated by such forward-looking
statements. These factors include, but are not limited to, risks
related to the failure to obtain FDA clearances or approvals and
noncompliance with FDA regulations; risks related to the failure to
successfully market any of our products; risks related to the
timing and progress of clinical development of our product
candidates; our need for additional financing; uncertainties of
patent protection and litigation; uncertainties of government or
third party payor reimbursement; limited research and development
efforts and dependence upon third parties; and substantial
competition. As with any pharmaceutical under development, there
are significant risks in the development, regulatory approval and
commercialization of new products. Tonix does not undertake an
obligation to update or revise any forward-looking statement.
Investors should read the risk factors set forth in the Annual
Report on Form 10-K for the year ended December 31, 2022, as filed
with the Securities and Exchange Commission (the “SEC”) on March
13, 2023, and periodic reports filed with the SEC on or after the
date thereof. All of Tonix's forward-looking statements are
expressly qualified by all such risk factors and other cautionary
statements. The information set forth herein speaks only as of the
date thereof.
Investor Contact
Jessica MorrisTonix
Pharmaceuticalsinvestor.relations@tonixpharma.com (862)
904-8182
Peter VozzoICR Westwickepeter.vozzo@westwicke.com (443)
213-0505
Media Contact
Ben ShannonICR
Westwickeben.shannon@westwicke.com443-213-0495
A photo accompanying this announcement is available at
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