Lineage Announces Pipeline Expansion To Include Auditory Neuronal Cell Therapy For Treatment Of Hearing Loss

Research, News, and Market Data on Lineage Cell Therapeutics

 

• Expansion of Pipeline Into a Third Neuronal Cell Type Builds on Existing Capabilities
• Intellectual Property Has Been Filed Covering Composition and Methods for Generating Auditory Neuronal Progenitors
• Hearing Loss Afflicts More Than 5% of the Population; More Than 430 Million People

CARLSBAD, Calif.–(BUSINESS WIRE)–Mar. 21, 2022– 

Lineage Cell Therapeutics, Inc.
 (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, today announced that the Company is expanding its novel cell therapy pipeline to include a new investigational product candidate, an auditory neuronal cell transplant for the treatment of hearing loss, with an initial focus on the treatment of auditory neuropathy spectrum disorders. To support this new therapeutic effort, Lineage has filed for intellectual property covering the composition and methods for generating auditory neuronal progenitors which may be capable of functioning as sensory neurons and the connecting neuronal ganglion cells of the ear, and to methods of treatment that employ these cells for the potential treatment of auditory neuropathy. According to the 
World Health Organization, hearing loss currently afflicts over 5% of the world’s population, or more than 430 million people, and by 2050 it is estimated that one in every ten people, or more than 700 million people, will have disabling hearing loss.

“Hearing loss is a major sensory deficit which affects an enormous number of individuals worldwide, yet current approaches leave much room for improvement. I am pleased to be advising Lineage and providing insights and experience in the launch of this new endeavor and working toward developing cell-based solutions for this condition,” stated 
Stefan Heller, Ph.D., Edward C. and  Amy H. Sewall Professor, 
Stanford University School of Medicine, 
Department of Otolaryngology – Head & 
Neck Surgery and Institute for Stem Cell Biology and Regenerative Medicine ISCBRM.

“We are excited to announce this new, internally-developed initiative for Lineage, and to do it so quickly following the partnership we announced with Roche and 
Genentech for our lead program, OpRegen^®, in a deal worth up to 
$670M USD,” added  Brian Culley, Lineage CEO. “Many patients with sensorineural hearing loss are poorly addressed, cannot benefit from cochlear implants, and/or have no FDA-approved treatment options. Similar to OpRegen, which has demonstrated to be able to replace and restore retinal pigment epithelium cells in patients with vision loss, and OPC1, which similarly replaces oligodendrocytes for the treatment of spinal cord injury, replacing auditory neurons or augmenting an existing but damaged auditory neuron population may provide a benefit beyond the reach of alternate approaches such as prostheses. We believe auditory neuronal transplants represent a unique opportunity to leverage our knowhow and capabilities in cellular differentiation into a fourth indication with a large unmet need. In addition to the speed with which the team created this new program from our internal technology, we have done so with a modest investment of capital so far, because we were able to take advantage of our established manufacturing infrastructure and broad knowhow in the expansion and differentiation of pluripotent cells. This is another example of the efficiency and versatility of our technology platform, which is gaining broader awareness, and which offers us a favorable competitive position in the emerging fields of regenerative medicine and anti-aging technologies.”

Auditory neuropathy is a hearing disorder in which the inner ear successfully detects sound but has a problem with sending signals from the ear to the brain. Current state of the art medical knowledge suggests that auditory neuropathies play a substantial role in hearing impairments and deafness. Hearing depends on a series of complex steps that change sound waves in the air into electrical signals. The auditory nerve then carries these signals to the brain. Outer hair cells help amplify sound vibrations entering the inner ear from the middle ear. When hearing is working normally, the inner hair cells convert these vibrations into electrical signals that travel as nerve impulses to the brain, where the brain interprets the impulses as sound. Auditory neuropathy can be caused by a number of factors including: (i) damage to the auditory neurons that transmit sound information from the inner hair cells – specialized sensory cells in the inner ear – to the brain; (ii) damage to the inner hair cells themselves; (iii) inherited genes with mutations or suffering damage to the auditory system, either of which may result in faulty connections between the inner hair cells and the auditory nerve, which leads from the inner ear to the brain; or (iv) damage to the auditory nerve itself. Researchers are still seeking effective treatments for those affected with auditory neuropathy.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineage’s programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineage’s clinical programs are in markets with billion dollar opportunities and include four allogeneic (“off-the-shelf”) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, which is now being developed under a worldwide collaboration with Roche and 
Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineage’s VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer and (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy. For more information, please visit www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as “believe,” “aim,” “may,” “will,” “estimate,” “continue,” “anticipate,” “design,” “intend,” “expect,” “could,” “can,” “plan,” “potential,” “predict,” “seek,” “should,” “would,” “contemplate,” “project,” “target,” “tend to,” or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the collaboration and license agreement with Roche and 
Genentech and activities expected to occur thereunder, the upfront, milestone and royalty consideration payable to Lineage and Lineage’s planned use of proceeds therefrom; the potential benefits of treatment with OpRegen, the potential success of other existing partnerships and collaborations, the broad potential for Lineage’s regenerative medicine platform and Lineage’s ability to expand the same; Lineage’s plans to advance its spinal cord injury, oncology and auditory neuron programs and announce new disease settings where it plans to deploy its technology; the projected timing of milestones of future studies, including their initiation and completion, the projected timing of interactions with the FDA to discuss product designation, manufacturing plans and improvements, and later-stage clinical development; the potential opportunities for the establishment or expansion of strategic partnerships and collaborations and the timing thereof, and the potential for Lineage’s investigational allogeneic cell therapies to generate clinical outcomes beyond the reach of traditional methods and provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineage’s actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, but not limited to, the risk that competing alternative therapies may adversely impact the commercial potential of OpRegen, which could materially adversely affect the milestone and royalty payments payable to Lineage under the collaboration and license agreement, the risk that Roche and 
Genentech may not be successful in completing further clinical trials for OpRegen and/or obtaining regulatory approval for OpRegen in any particular jurisdiction, the risk that Lineage might not succeed in developing products and technologies that are useful in medicine and demonstrate the requisite safety and efficacy to achieve regulatory approval in accordance with its projected timing, or at all; the risk that Lineage may not be able to manufacture sufficient clinical and, if approved, commercial quantities of its product candidates in accordance with current good manufacturing practice; the risks related to Lineage’s dependence on other third parties, and Lineage’s ability to establish and maintain its collaborations with these third parties; the risk that government-imposed bans or restrictions and religious, moral, and ethical concerns about the use of hES cells could prevent Lineage or its partners from developing and successfully marketing its stem cell product candidates; the risk that Lineage’s intellectual property may be insufficient to protect its products; the risk that the COVID-19 pandemic or geopolitical events may directly or indirectly cause significant delays in and substantially increase the cost of development of Lineage’s product candidates, as well as heighten other risks and uncertainties related to Lineage’s business and operations; risks and uncertainties inherent in Lineage’s business and other risks discussed in Lineage’s filings with the 
Securities and Exchange Commission (SEC). Lineage’s forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading “Risk Factors” in Lineage’s periodic reports with the 
SEC, including Lineage’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the 
SEC and its other reports, which are available from the SEC’s website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Lineage Cell Therapeutics, Inc. IR
Ioana C. Hone
(ir@lineagecell.com)
(442) 287-8963

Solebury Trout IR
Mike Biega
(Mbiega@soleburytrout.com)
(617) 221-9660

Russo Partners – Media Relations
Nic Johnson or  David Schull
Nic.johnson@russopartnersllc.com
David.schull@russopartnersllc.com
(212) 845-4242

Source: 
Lineage Cell Therapeutics, Inc.

Tonix Pharmaceuticals Announces Phase 3 RALLY Study Results for TNX-102 SL 5.6 mg for the Management of Fibromyalgia

Research, News, and Market Data on Tonix Pharmaceuticals

 

As Expected Based on Interim Analysis Results Reported in July 2021, TNX-102 SL Did Not Achieve Statistical Significance Over Placebo on the Primary Endpoint of Reduction in Daily Pain in RALLY Study

Relative to the Previous Positive Phase 3 Study (RELIEF), RALLY had an Unexpected Increase in Study Participant Adverse Event-Related Discontinuations in both Drug and Placebo Groups

TNX-102 SL Generally Well Tolerated with Overall Adverse Event Profile Comparable to Prior Studies; No New Safety Signals Observed

Confirmatory Phase 3 Study RESILIENT for the Management of Fibromyalgia Planning to Enroll Participants Imminently

CHATHAM, N.J., March 21, 2022 (GLOBE NEWSWIRE) — Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced that, as expected based on previously reported pre-specified interim analysis results, TNX-102 SL (cyclobenzaprine HCl sublingual tablets)¹ did not achieve statistical significance on the primary endpoint of reducing fibromyalgia (FM) daily pain at Week 14 compared to placebo (p=0.115) in the Phase 3 RALLY study. RALLY was a 14-week randomized, double-blind, placebo-controlled trial of TNX-102 SL 5.6 mg, in which 514 participants with FM were randomized in a 1:1 ratio across 36 U.S. sites. All participants received TNX-102 SL 2.8 mg or placebo for the first two weeks, which was increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. Tonix reported interim analysis results of RALLY in July 2021 at which time the Independent Data Monitoring Committee recommended stopping the study as it was unlikely to succeed on the primary endpoint for the planned full sample. The Company therefore stopped enrollment of new participants while continuing those enrolled at that time to completion.

TNX-102 SL is in mid-Phase 3 development for the management of fibromyalgia. In December 2020, Tonix reported positive results from the Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of FM (primary endpoint, p=0.010). FM is a pain disorder characterized by chronic widespread pain, non-restorative sleep, fatigue, and impaired cognition. Approximately one-fourth of FM patients resort to prescription opioids for analgesia². TNX-102 SL is a centrally acting analgesic that has the potential to be a new non-addictive, non-opioid bedtime medication for the management of FM. Cyclobenzaprine, the active ingredient of TNX-102 SL, has no recognized potential for addiction.

“The positive outcome of the earlier RELIEF study stands in contrast to the missed primary endpoint in RALLY,” said Dr. Gregory Sullivan, M.D., Chief Medical Officer of Tonix. “We believe the difference between these study results may be driven in large part by a 79% increase in adverse event-related participant discontinuations in the drug treatment group in RALLY as compared to RELIEF. Similarly, a 77% increase of adverse event-related participant discontinuations was observed in the placebo group in RALLY as compared to RELIEF.” (Table 1)

Table 1. Increases in AE-Related Discontinuations in RALLY Compared with RELIEF in Both Placebo and TNX-102 SL Groups
	RALLY (F306)		RELIEF (F304)		RALLY (F306)		RELIEF (F304)
	Placebo				TNX-102 SL
Patients with at least one TEAE leading to early discontinuation	6.2	%	3.5	%	15.2	%	8.5	%
Ratio of patients with at least one TEAE leading to early discontinuation in F306 to F304 (F306/F304)	1.77				1.79

TEAE = treatment-emergent adverse event

The missing data for the primary and secondary endpoints were imputed by a method called ‘multiple imputation’ (MI), and discontinuations due to adverse events can negatively impact the statistical outcome when using this approach. Since 2010, The U.S. Food and Drug Administration (FDA) has generally required MI be used to account for missing data in efficacy analyses. Table 2 illustrates how the higher discontinuation rates due to adverse events attenuate the p-values of RALLY using the MI approach.

Table 2: Comparisons of Analytic Methods on Primary and Secondary Endpoints at Week 14 Between the RALLY and RELIEF Phase 3 Studies of TNX-102 SL 5.6 mg in Fibromyalgia

	RALLY (F306)
	MMRM+MI*		MMRM**
Endpoints	LSMD (SE)	p-value	LSMD (SE)	p-value
Pain by Diary	-0.2 (0.16)	0.115#	-0.4 (0.16)	0.014
FIQR Symptom domain	-1.9 (1.52)	0.216	-3.4 (1.55)	0.030
FIQR Function domain	-0.4 (1.46)	0.797	-1.6 (1.48)	0.266
PROMIS Sleep Disturbance	-2.3 (0.80)	0.004	-3.3 (0.73)	<0.001
PROMIS Fatigue	-1.2 (0.74)	0.101	-2.0 (0.73)	0.007
Sleep Quality by Diary	-0.3 (0.16)	0.094	-0.4 (0.16)	0.008
	RELIEF (F304)
	MMRM+MI*		MMRM**
Endpoints	LSMD (SE)	p-value	LSMD (SE)	p-value
Pain by Diary	-0.4 (0.16)	0.010#	-0.5 (0.16)	0.004
FIQR Symptom domain	-4.3 (1.60)	0.007	-5.6 (1.60)	<0.001
FIQR Function domain	-4.4 (1.69)	0.009	-5.2 (1.63)	0.001
PROMIS Sleep Disturbance	-2.9 (0.82)	<0.001	-3.3 (0.82)	<0.001
PROMIS Fatigue	-1.8 (0.76)	0.018	-2.1 (0.79)	0.007
Sleep Quality by Diary	-0.6 (0.17)	<0.001	-0.7 (0.17)	<0.001

FIQR = Fibromyalgia Impact Questionnaire-Revised; LSMD = least squares mean difference
(between TNX-102 SL and placebo); MMRM = mixed model repeated measures; MI = multiple imputation;
PROMIS = Patient-Reported Outcomes Measurement Information System; SE = standard error
* MMRM with MI was the pre-specified primary analysis
**MMRM without MI was a pre-specified analysis
^# Primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale scores

Dr. Sullivan continued, “When the data are analyzed without MI, the results of RALLY appear consistent with the previous RELIEF study. The mixed model repeated measures (MMRM) results without MI method are presented to illustrate the impact of the increased discontinuations on the results when using MI as the primary analytic approach. At this time, the anticipated analytic approach for the upcoming Phase 3 RESILIENT study is MMRM with MI.”

“Without knowing the precise reasons, we postulate the increased rate of adverse event-related discontinuations may be related to conducting the study during the peak phase of the COVID-19 pandemic in the U.S., during which time vaccines were being rolled out,” said Dr. Seth Lederman, M.D., Chief Executive Officer of Tonix. “Since the pandemic phase of COVID-19 appears to be transitioning to an endemic phase, we believe that starting the new RESILIENT Phase 3 study imminently is justified based on the expectation that rates of adverse event-related discontinuations will return toward the levels of RELIEF and our PTSD studies. We are grateful to the individuals who participated in the RALLY study, and to their families, particularly because of the many challenges presented by different phases of the COVID-19 pandemic.”

“Tonix remains dedicated to improving the lives of the millions suffering from fibromyalgia,” Dr. Lederman continued. “FM is a complex syndrome, and while TNX-102 SL at 5.6 mg missed the primary endpoint in RALLY, it continued to show strong activity on sleep disturbance (p=0.004) and on the Patient Global Impression of Change (PGIC; p=0.038), which is a patient-reported assessment of overall improvement during the trial. These findings and our general understanding of TNX-102 SL tolerability encourage us to move forward with our plans to initiate our new F307 RESILIENT Phase 3 study for fibromyalgia in the first half of 2022.”

¹TNX-102 SL is an investigational new drug and has not been approved for any indication.

²Sarmento, CVM, et al. “Opioid prescription patterns among patients with fibromyalgia.” J Opioid Manag.  2019;15(6):469-477.  doi: 10.5055/jom.2019.0537. PMID: 31850508; https://pubmed.ncbi.nlm.nih.gov/31850508/

EFFICACY RESULTS OF THE PHASE 3 RALLY STUDY

The RALLY study missed statistical significance on the primary efficacy endpoint: change from baseline to Week 14 in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.6 [0.11] units) versus placebo (-1.3 [0.11] units), analyzed by mixed model repeated measures with multiple imputation (MMRM+MI) (LS mean difference [SE]: -0.2 [0.16] units, p=0.115, Table 2).

Key secondary endpoint results
The responder analysis of PGIC was nominally significant (Pearson’s Chi-square test; difference in proportions [95% CI]: 8.0% [0.5%, 15.5%]; p=0.038), with a greater proportion of responders (rating of “very much improved” or “much improved” at Week 14) receiving TNX-102 SL (29.7%) compared to placebo (21.7%).

Consistent with the proposed mechanism that TNX-102 SL acts in FM through improving sleep quality, TNX-102 SL achieved nominal significance on the PROMIS Sleep Disturbance measure (LS mean difference [SE]: -2.3 [0.80] units; p=0.004). As shown in Table 2, other key secondary endpoints did not achieve nominal significance, including the Fibromyalgia Impact Questionnaire–Revised (FIQR) Symptom and Function domains, the PROMIS Fatigue instrument, and the daily sleep quality diary.

SAFETY RESULTS OF THE PHASE 3 RALLY STUDY

In the RALLY study, TNX-102 SL 5.6 mg was well tolerated. There were no new safety signals observed. Among participants randomized to the drug treatment and placebo groups, 73.8% and 81.4%, respectively, completed the 14-week dosing period. As expected, based on prior TNX-102 SL studies, oral administration site reactions were higher in the drug treatment group, including rates of tongue/mouth numbness, pain/discomfort of tongue/mouth, and product taste abnormal (typically a transient bitter aftertaste) (Table 3). Tongue/mouth numbness or tingling and product aftertaste were local effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most occurrences. Adverse events resulted in premature study discontinuation in 15.2% of those who received TNX-102 SL compared with 6.2% of placebo recipients. Approximately 95% of adverse events in both the drug treatment and placebo groups were rated as mild or moderate. There were a total of six serious adverse events (SAEs) in the drug treatment group, none of which were deemed related to investigational product.

Table 3. Treatment-Emergent Adverse Events at Rate of 3% or Greater in TNX-102 SL Group in RALLY

Oral Cavity or Systemic Adverse Events	TNX-102 SL (N=256)	Placebo (N=258)
Preferred Term
Oral Cavity Adverse Events
Hypoaesthesia oral	72 (28.1%)	2 (0.8%)
Product taste abnormal	26 (10.2%)	2 (0.8%)
Oral discomfort	23 (9.0%)	2 (0.8%)
Tongue discomfort	16 (6.3%)	2 (0.8%)
Paraesthesia oral	11 (4.3%)	0 (0.0%)
Dry mouth	10 (3.9%)	6 (2.3%)
Oral pain	8 (3.1%)	0 (0.0%)
Systemic Adverse Events
Headache	12 (4.7%)	11 (4.3%)
Somnolence	12 (4.7%)	2 (0.8%)
Sedation	10 (3.9%)	2 (0.8%)
Fatigue	8 (3.1%)	1 (0.4%)
COVID-19	8 (3.1%)	7 (2.7%)

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 6-12 million adults in the U.S., approximately 90% 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 serotonin-2A, alpha-1 adrenergic, histamine-H1, and muscarinic-M1 receptors, TNX-102 SL is in development as a daily bedtime treatment for fibromyalgia, PTSD, Long COVID (PASC), alcohol use disorder and agitation in Alzheimer’s disease. 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.

About the Phase 3 RALLY Study

The RALLY study was a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets). The two-arm trial enrolled 514 participants across 36 U.S. sites. For the first two weeks of treatment, there was a run-in period in which participants started on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all participants had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was 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. An interim analysis by an Independent Data Monitoring Committee was conducted on the primary endpoint based on the first 50% of enrolled participants.

The first interim cohort of the study was enrolled between September 2020 and March 2021, which included the periods of the second and third waves of the COVID-19 pandemic in US. The post-interim cohort was enrolled between third week of March and last week of July 2021. At the time of the interim analysis in July 2021, there were 125 participants still active in the study, who all completed their participation by 1 November 2021.

About Tonix Pharmaceuticals Holding Corp.

Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics and diagnostics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of immunology, central nervous system (CNS) and infectious disease product candidates. The Company’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL², (cyclobenzaprine HCl sublingual tablets), is a small molecule drug in mid-Phase 3 development for the management of fibromyalgia, with a new Phase 3 study expected to start in the first half of 2022. TNX-102 SL is also being developed to treat Long COVID, a chronic post-COVID-19 condition. Tonix expects to initiate a Phase 2 study in Long COVID in the first half of 2022. TNX-1300³ is a biologic designed to treat cocaine intoxication that is expected to start a Phase 2 trial in the first half of 2022. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer. Tonix’s lead immunology candidate, TNX-1500¹, is a humanized monoclonal antibody targeting CD40 ligand being developed for the prevention of allograft rejection and the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to start in the second half of 2022. Tonix’s infectious disease pipeline includes a vaccine in development to prevent smallpox, next-generation vaccines to prevent COVID-19 and an antiviral to treat COVID-19. Tonix’s lead vaccine program is TNX-801 (live horsepox virus for percutaneous administration) for preventing smallpox and monkeypox⁴. Horsepox is also the basis for Tonix’s recombinant pox vaccine (RPV) platform. Tonix’s lead vaccine candidates for COVID-19, TNX-1840 and TNX-1850⁵, are live virus vaccines in development based on the RPV platform. Finally, TNX-3500⁶ (sangivamycin, i.v. solution) is a small molecule antiviral drug to treat acute COVID-19 and is in the pre-IND stage of development.

¹TNX-1500 is an investigational new biologic at the pre-IND stage of development and has not been approved for any indication.

²TNX-102 SL is an investigational new drug and has not been approved for any indication.

³TNX-1300 is an investigational new biologic and has not been approved for any indication.

⁴TNX-801 is an investigational new biologic at the pre-IND stage of development and has not been approved for any indication.

⁵TNX-1840 and TNX-1850 are investigational new biologics at the pre-IND stage of development and have not been approved for any indication. TNX-1840 and TNX-1850 are designed to express the spike protein of SARS-CoV-2 from omicron and BA.2 variants, respectively, based on the experience from TNX-1800, which expresses the spike protein from the ancestral Wuhan strain.

⁶TNX-3500 is an investigational new drug at the pre-IND stage of development and has not been approved for any indication.

This press release and further information about Tonix can be found at www.tonixpharma.com.

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 development of TNX-102 SL; the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; delays and uncertainties caused by the global COVID-19 pandemic; 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, 2021, as filed with the Securities and Exchange Commission (the “SEC”) on March 14, 2022, 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.

Contacts

Jessica Morris (corporate)
Tonix Pharmaceuticals
investor.relations@tonixpharma.com
(862) 799-8599

Olipriya Das, Ph.D. (media)
Russo Partners
olipriya.das@russopartnersllc.com
(646) 942-5588

Peter Vozzo (investors)
ICR Westwicke
peter.vozzo@westwicke.com
(443) 213-0505

Source: Tonix Pharmaceuticals Holding Corp.

  Image: Aurolean Adoue (Flickr)

AI Maps Psychedelic ‘Trip’ experiences to Regions of the Brain – Opening New Route to Psychiatric Treatments

 

For the past several decades, psychedelics have been widely stigmatized as dangerous illegal drugs. But a recent surge of academic research into their use to treat psychiatric conditions is spurring a recent shift in public opinion.

Psychedelics are psychotropic drugs: substances that affect your mental state. Other types of psychotropics include antidepressants and anti-anxiety medications. Psychedelics and other types of hallucinogens, however, are unique in their ability to temporarily induce intense hallucinations, emotions and disruptions of self-awareness.

Researchers looking into the therapeutic potential of these effects have found that psychedelics can dramatically reduce symptoms of depression and anxiety, PTSD, substance abuse and other psychiatric conditions. The intense experiences, or “trips,” that psychedelics induce are thought to create a temporary window of cognitive flexibility that allows patients to gain access to elusive parts of their psyches and forge better coping skills and thought patterns.

Precisely how psychedelics create these effects, however, is still unclear. So as researchers in psychiatry and machine learning, we were interested in figuring out how these drugs affect the brain. With artificial intelligence, we were able to map people’s subjective experiences while using psychedelics to specific regions of the brain, down to the molecular level.

Psilocybin, a psychoactive compound found in some mushrooms, has been the focus of many studies for its potential therapeutic qualities. 24K-Production/iStock via Getty Images

 

Mapping ‘Trips’ in the Brain

Every psychedelic functions differently in the body, and each of the subjective experiences these drugs create have different therapeutic effects. Mystical type experiences, or feelings of unity and oneness with the world, for example, are associated with decreases in depression and anxiety. Knowing how each psychedelic creates these specific effects in the body can help clinicians optimize their therapeutic use.

To better understand how these subjective effects manifest in the brain, we analyzed over 6,000 written testimonials of hallucinogenic experiences from Erowid Center, an organization that collects and provides information about psychoactive substances. We transformed these testimonials into what’s called a bag-of-words model, which breaks down a given text into individual words and counts how many times each word appears. We then paired the most commonly used words linked to each psychedelic with receptors in the brain that are known to bind to each drug. After using an algorithm to extract the most common subjective experiences associated with these word-receptor pairs, we mapped these experiences onto different brain regions by matching them to the types of receptors present in each area.

We found both new links and patterns that confirm what’s known in the research literature. For example, changes in sensory perception were associated with a serotonin receptor in the visual cortex of the brain, which binds to a molecule that helps regulate mood and memory. Feelings of transcendence were connected to dopamine and opioid receptors in the salience network, a collection of brain regions involved in managing sensory and emotional input. Auditory hallucinations were linked to a number of receptors spread throughout the auditory cortex.

Our findings also align with the leading hypothesis that psychedelics temporarily reduce top-down executive function, or cognitive processes involved in inhibition, attention and memory, among others, while amplifying brain regions involved in sensory experience.

 

Why it Matters

The U.S. is going through a profound mental health crisis that has been exacerbated by the COVID-19 pandemic. Yet there have been no truly new psychiatric drug treatments since Prozac and other selective serotonin reuptake inhibitors, the most common type of antidepressants, of the 1980s.

Our study shows that it’s possible to map the diverse and wildly subjective psychedelic experiences to specific regions in the brain. These insights may lead to new ways to combine existing or yet to be discovered compounds to produce desired treatment effects for a range of psychiatric conditions.

Pychiatrist Stanislav Grof famously proposed, “[P]sychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is to the study of biology and medicine or the telescope for astronomy.” As psychedelics and other hallucinogens become more commonly used clinically and culturally, we believe more research will further illuminate the biological basis of the experiences they invoke and help realize their potential.

 

This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of Galen Ballentine, Resident in Psychiatry, SUNY Downstate Health Sciences University and Sam Friedman, Machine Learning Scientist at the Broad Institute of MIT &, Harvard University.

 

Suggested Reading

Prominent Study Suggests Magic Mushroom Ingredient on Depression has Long-Term Benefit

Stem Cell Science and The New Age of Therapeutic Discovery

Immune Response to Gene Therapy and How CRISPR Works to Combat It

A Quick Look at 8 Small Caps in the Growing Psychedelics Space

 

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Lineage Announces Pipeline Expansion To Include Auditory Neuronal Cell Therapy For Treatment Of Hearing Loss

Research, News, and Market Data on Lineage Cell Therapeutics

 

• Expansion of Pipeline Into a Third Neuronal Cell Type Builds on Existing Capabilities
• Intellectual Property Has Been Filed Covering Composition and Methods for Generating Auditory Neuronal Progenitors
• Hearing Loss Afflicts More Than 5% of the Population; More Than 430 Million People

CARLSBAD, Calif.–(BUSINESS WIRE)–Mar. 21, 2022– 

Lineage Cell Therapeutics, Inc.
 (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, today announced that the Company is expanding its novel cell therapy pipeline to include a new investigational product candidate, an auditory neuronal cell transplant for the treatment of hearing loss, with an initial focus on the treatment of auditory neuropathy spectrum disorders. To support this new therapeutic effort, Lineage has filed for intellectual property covering the composition and methods for generating auditory neuronal progenitors which may be capable of functioning as sensory neurons and the connecting neuronal ganglion cells of the ear, and to methods of treatment that employ these cells for the potential treatment of auditory neuropathy. According to the 
World Health Organization, hearing loss currently afflicts over 5% of the world’s population, or more than 430 million people, and by 2050 it is estimated that one in every ten people, or more than 700 million people, will have disabling hearing loss.

“Hearing loss is a major sensory deficit which affects an enormous number of individuals worldwide, yet current approaches leave much room for improvement. I am pleased to be advising Lineage and providing insights and experience in the launch of this new endeavor and working toward developing cell-based solutions for this condition,” stated 
Stefan Heller, Ph.D., Edward C. and  Amy H. Sewall Professor, 
Stanford University School of Medicine, 
Department of Otolaryngology – Head & 
Neck Surgery and Institute for Stem Cell Biology and Regenerative Medicine ISCBRM.

“We are excited to announce this new, internally-developed initiative for Lineage, and to do it so quickly following the partnership we announced with Roche and 
Genentech for our lead program, OpRegen^®, in a deal worth up to 
$670M USD,” added  Brian Culley, Lineage CEO. “Many patients with sensorineural hearing loss are poorly addressed, cannot benefit from cochlear implants, and/or have no FDA-approved treatment options. Similar to OpRegen, which has demonstrated to be able to replace and restore retinal pigment epithelium cells in patients with vision loss, and OPC1, which similarly replaces oligodendrocytes for the treatment of spinal cord injury, replacing auditory neurons or augmenting an existing but damaged auditory neuron population may provide a benefit beyond the reach of alternate approaches such as prostheses. We believe auditory neuronal transplants represent a unique opportunity to leverage our knowhow and capabilities in cellular differentiation into a fourth indication with a large unmet need. In addition to the speed with which the team created this new program from our internal technology, we have done so with a modest investment of capital so far, because we were able to take advantage of our established manufacturing infrastructure and broad knowhow in the expansion and differentiation of pluripotent cells. This is another example of the efficiency and versatility of our technology platform, which is gaining broader awareness, and which offers us a favorable competitive position in the emerging fields of regenerative medicine and anti-aging technologies.”

Auditory neuropathy is a hearing disorder in which the inner ear successfully detects sound but has a problem with sending signals from the ear to the brain. Current state of the art medical knowledge suggests that auditory neuropathies play a substantial role in hearing impairments and deafness. Hearing depends on a series of complex steps that change sound waves in the air into electrical signals. The auditory nerve then carries these signals to the brain. Outer hair cells help amplify sound vibrations entering the inner ear from the middle ear. When hearing is working normally, the inner hair cells convert these vibrations into electrical signals that travel as nerve impulses to the brain, where the brain interprets the impulses as sound. Auditory neuropathy can be caused by a number of factors including: (i) damage to the auditory neurons that transmit sound information from the inner hair cells – specialized sensory cells in the inner ear – to the brain; (ii) damage to the inner hair cells themselves; (iii) inherited genes with mutations or suffering damage to the auditory system, either of which may result in faulty connections between the inner hair cells and the auditory nerve, which leads from the inner ear to the brain; or (iv) damage to the auditory nerve itself. Researchers are still seeking effective treatments for those affected with auditory neuropathy.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineage’s programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineage’s clinical programs are in markets with billion dollar opportunities and include four allogeneic (“off-the-shelf”) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, which is now being developed under a worldwide collaboration with Roche and 
Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineage’s VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer and (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy. For more information, please visit www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as “believe,” “aim,” “may,” “will,” “estimate,” “continue,” “anticipate,” “design,” “intend,” “expect,” “could,” “can,” “plan,” “potential,” “predict,” “seek,” “should,” “would,” “contemplate,” “project,” “target,” “tend to,” or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the collaboration and license agreement with Roche and 
Genentech and activities expected to occur thereunder, the upfront, milestone and royalty consideration payable to Lineage and Lineage’s planned use of proceeds therefrom; the potential benefits of treatment with OpRegen, the potential success of other existing partnerships and collaborations, the broad potential for Lineage’s regenerative medicine platform and Lineage’s ability to expand the same; Lineage’s plans to advance its spinal cord injury, oncology and auditory neuron programs and announce new disease settings where it plans to deploy its technology; the projected timing of milestones of future studies, including their initiation and completion, the projected timing of interactions with the FDA to discuss product designation, manufacturing plans and improvements, and later-stage clinical development; the potential opportunities for the establishment or expansion of strategic partnerships and collaborations and the timing thereof, and the potential for Lineage’s investigational allogeneic cell therapies to generate clinical outcomes beyond the reach of traditional methods and provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineage’s actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, but not limited to, the risk that competing alternative therapies may adversely impact the commercial potential of OpRegen, which could materially adversely affect the milestone and royalty payments payable to Lineage under the collaboration and license agreement, the risk that Roche and 
Genentech may not be successful in completing further clinical trials for OpRegen and/or obtaining regulatory approval for OpRegen in any particular jurisdiction, the risk that Lineage might not succeed in developing products and technologies that are useful in medicine and demonstrate the requisite safety and efficacy to achieve regulatory approval in accordance with its projected timing, or at all; the risk that Lineage may not be able to manufacture sufficient clinical and, if approved, commercial quantities of its product candidates in accordance with current good manufacturing practice; the risks related to Lineage’s dependence on other third parties, and Lineage’s ability to establish and maintain its collaborations with these third parties; the risk that government-imposed bans or restrictions and religious, moral, and ethical concerns about the use of hES cells could prevent Lineage or its partners from developing and successfully marketing its stem cell product candidates; the risk that Lineage’s intellectual property may be insufficient to protect its products; the risk that the COVID-19 pandemic or geopolitical events may directly or indirectly cause significant delays in and substantially increase the cost of development of Lineage’s product candidates, as well as heighten other risks and uncertainties related to Lineage’s business and operations; risks and uncertainties inherent in Lineage’s business and other risks discussed in Lineage’s filings with the 
Securities and Exchange Commission (SEC). Lineage’s forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading “Risk Factors” in Lineage’s periodic reports with the 
SEC, including Lineage’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the 
SEC and its other reports, which are available from the SEC’s website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Lineage Cell Therapeutics, Inc. IR
Ioana C. Hone
(ir@lineagecell.com)
(442) 287-8963

Solebury Trout IR
Mike Biega
(Mbiega@soleburytrout.com)
(617) 221-9660

Russo Partners – Media Relations
Nic Johnson or  David Schull
Nic.johnson@russopartnersllc.com
David.schull@russopartnersllc.com
(212) 845-4242

Source: 
Lineage Cell Therapeutics, Inc.

Tonix Pharmaceuticals Announces Phase 3 RALLY Study Results for TNX-102 SL 5.6 mg for the Management of Fibromyalgia

Research, News, and Market Data on Tonix Pharmaceuticals

 

As Expected Based on Interim Analysis Results Reported in July 2021, TNX-102 SL Did Not Achieve Statistical Significance Over Placebo on the Primary Endpoint of Reduction in Daily Pain in RALLY Study

Relative to the Previous Positive Phase 3 Study (RELIEF), RALLY had an Unexpected Increase in Study Participant Adverse Event-Related Discontinuations in both Drug and Placebo Groups

TNX-102 SL Generally Well Tolerated with Overall Adverse Event Profile Comparable to Prior Studies; No New Safety Signals Observed

Confirmatory Phase 3 Study RESILIENT for the Management of Fibromyalgia Planning to Enroll Participants Imminently

CHATHAM, N.J., March 21, 2022 (GLOBE NEWSWIRE) — Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced that, as expected based on previously reported pre-specified interim analysis results, TNX-102 SL (cyclobenzaprine HCl sublingual tablets)¹ did not achieve statistical significance on the primary endpoint of reducing fibromyalgia (FM) daily pain at Week 14 compared to placebo (p=0.115) in the Phase 3 RALLY study. RALLY was a 14-week randomized, double-blind, placebo-controlled trial of TNX-102 SL 5.6 mg, in which 514 participants with FM were randomized in a 1:1 ratio across 36 U.S. sites. All participants received TNX-102 SL 2.8 mg or placebo for the first two weeks, which was increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. Tonix reported interim analysis results of RALLY in July 2021 at which time the Independent Data Monitoring Committee recommended stopping the study as it was unlikely to succeed on the primary endpoint for the planned full sample. The Company therefore stopped enrollment of new participants while continuing those enrolled at that time to completion.

TNX-102 SL is in mid-Phase 3 development for the management of fibromyalgia. In December 2020, Tonix reported positive results from the Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of FM (primary endpoint, p=0.010). FM is a pain disorder characterized by chronic widespread pain, non-restorative sleep, fatigue, and impaired cognition. Approximately one-fourth of FM patients resort to prescription opioids for analgesia². TNX-102 SL is a centrally acting analgesic that has the potential to be a new non-addictive, non-opioid bedtime medication for the management of FM. Cyclobenzaprine, the active ingredient of TNX-102 SL, has no recognized potential for addiction.

“The positive outcome of the earlier RELIEF study stands in contrast to the missed primary endpoint in RALLY,” said Dr. Gregory Sullivan, M.D., Chief Medical Officer of Tonix. “We believe the difference between these study results may be driven in large part by a 79% increase in adverse event-related participant discontinuations in the drug treatment group in RALLY as compared to RELIEF. Similarly, a 77% increase of adverse event-related participant discontinuations was observed in the placebo group in RALLY as compared to RELIEF.” (Table 1)

Table 1. Increases in AE-Related Discontinuations in RALLY Compared with RELIEF in Both Placebo and TNX-102 SL Groups
	RALLY (F306)		RELIEF (F304)		RALLY (F306)		RELIEF (F304)
	Placebo				TNX-102 SL
Patients with at least one TEAE leading to early discontinuation	6.2	%	3.5	%	15.2	%	8.5	%
Ratio of patients with at least one TEAE leading to early discontinuation in F306 to F304 (F306/F304)	1.77				1.79

TEAE = treatment-emergent adverse event

The missing data for the primary and secondary endpoints were imputed by a method called ‘multiple imputation’ (MI), and discontinuations due to adverse events can negatively impact the statistical outcome when using this approach. Since 2010, The U.S. Food and Drug Administration (FDA) has generally required MI be used to account for missing data in efficacy analyses. Table 2 illustrates how the higher discontinuation rates due to adverse events attenuate the p-values of RALLY using the MI approach.

Table 2: Comparisons of Analytic Methods on Primary and Secondary Endpoints at Week 14 Between the RALLY and RELIEF Phase 3 Studies of TNX-102 SL 5.6 mg in Fibromyalgia

	RALLY (F306)
	MMRM+MI*		MMRM**
Endpoints	LSMD (SE)	p-value	LSMD (SE)	p-value
Pain by Diary	-0.2 (0.16)	0.115#	-0.4 (0.16)	0.014
FIQR Symptom domain	-1.9 (1.52)	0.216	-3.4 (1.55)	0.030
FIQR Function domain	-0.4 (1.46)	0.797	-1.6 (1.48)	0.266
PROMIS Sleep Disturbance	-2.3 (0.80)	0.004	-3.3 (0.73)	<0.001
PROMIS Fatigue	-1.2 (0.74)	0.101	-2.0 (0.73)	0.007
Sleep Quality by Diary	-0.3 (0.16)	0.094	-0.4 (0.16)	0.008
	RELIEF (F304)
	MMRM+MI*		MMRM**
Endpoints	LSMD (SE)	p-value	LSMD (SE)	p-value
Pain by Diary	-0.4 (0.16)	0.010#	-0.5 (0.16)	0.004
FIQR Symptom domain	-4.3 (1.60)	0.007	-5.6 (1.60)	<0.001
FIQR Function domain	-4.4 (1.69)	0.009	-5.2 (1.63)	0.001
PROMIS Sleep Disturbance	-2.9 (0.82)	<0.001	-3.3 (0.82)	<0.001
PROMIS Fatigue	-1.8 (0.76)	0.018	-2.1 (0.79)	0.007
Sleep Quality by Diary	-0.6 (0.17)	<0.001	-0.7 (0.17)	<0.001

FIQR = Fibromyalgia Impact Questionnaire-Revised; LSMD = least squares mean difference
(between TNX-102 SL and placebo); MMRM = mixed model repeated measures; MI = multiple imputation;
PROMIS = Patient-Reported Outcomes Measurement Information System; SE = standard error
* MMRM with MI was the pre-specified primary analysis
**MMRM without MI was a pre-specified analysis
^# Primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale scores

Dr. Sullivan continued, “When the data are analyzed without MI, the results of RALLY appear consistent with the previous RELIEF study. The mixed model repeated measures (MMRM) results without MI method are presented to illustrate the impact of the increased discontinuations on the results when using MI as the primary analytic approach. At this time, the anticipated analytic approach for the upcoming Phase 3 RESILIENT study is MMRM with MI.”

“Without knowing the precise reasons, we postulate the increased rate of adverse event-related discontinuations may be related to conducting the study during the peak phase of the COVID-19 pandemic in the U.S., during which time vaccines were being rolled out,” said Dr. Seth Lederman, M.D., Chief Executive Officer of Tonix. “Since the pandemic phase of COVID-19 appears to be transitioning to an endemic phase, we believe that starting the new RESILIENT Phase 3 study imminently is justified based on the expectation that rates of adverse event-related discontinuations will return toward the levels of RELIEF and our PTSD studies. We are grateful to the individuals who participated in the RALLY study, and to their families, particularly because of the many challenges presented by different phases of the COVID-19 pandemic.”

“Tonix remains dedicated to improving the lives of the millions suffering from fibromyalgia,” Dr. Lederman continued. “FM is a complex syndrome, and while TNX-102 SL at 5.6 mg missed the primary endpoint in RALLY, it continued to show strong activity on sleep disturbance (p=0.004) and on the Patient Global Impression of Change (PGIC; p=0.038), which is a patient-reported assessment of overall improvement during the trial. These findings and our general understanding of TNX-102 SL tolerability encourage us to move forward with our plans to initiate our new F307 RESILIENT Phase 3 study for fibromyalgia in the first half of 2022.”

¹TNX-102 SL is an investigational new drug and has not been approved for any indication.

²Sarmento, CVM, et al. “Opioid prescription patterns among patients with fibromyalgia.” J Opioid Manag.  2019;15(6):469-477.  doi: 10.5055/jom.2019.0537. PMID: 31850508; https://pubmed.ncbi.nlm.nih.gov/31850508/

EFFICACY RESULTS OF THE PHASE 3 RALLY STUDY

The RALLY study missed statistical significance on the primary efficacy endpoint: change from baseline to Week 14 in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.6 [0.11] units) versus placebo (-1.3 [0.11] units), analyzed by mixed model repeated measures with multiple imputation (MMRM+MI) (LS mean difference [SE]: -0.2 [0.16] units, p=0.115, Table 2).

Key secondary endpoint results
The responder analysis of PGIC was nominally significant (Pearson’s Chi-square test; difference in proportions [95% CI]: 8.0% [0.5%, 15.5%]; p=0.038), with a greater proportion of responders (rating of “very much improved” or “much improved” at Week 14) receiving TNX-102 SL (29.7%) compared to placebo (21.7%).

Consistent with the proposed mechanism that TNX-102 SL acts in FM through improving sleep quality, TNX-102 SL achieved nominal significance on the PROMIS Sleep Disturbance measure (LS mean difference [SE]: -2.3 [0.80] units; p=0.004). As shown in Table 2, other key secondary endpoints did not achieve nominal significance, including the Fibromyalgia Impact Questionnaire–Revised (FIQR) Symptom and Function domains, the PROMIS Fatigue instrument, and the daily sleep quality diary.

SAFETY RESULTS OF THE PHASE 3 RALLY STUDY

In the RALLY study, TNX-102 SL 5.6 mg was well tolerated. There were no new safety signals observed. Among participants randomized to the drug treatment and placebo groups, 73.8% and 81.4%, respectively, completed the 14-week dosing period. As expected, based on prior TNX-102 SL studies, oral administration site reactions were higher in the drug treatment group, including rates of tongue/mouth numbness, pain/discomfort of tongue/mouth, and product taste abnormal (typically a transient bitter aftertaste) (Table 3). Tongue/mouth numbness or tingling and product aftertaste were local effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most occurrences. Adverse events resulted in premature study discontinuation in 15.2% of those who received TNX-102 SL compared with 6.2% of placebo recipients. Approximately 95% of adverse events in both the drug treatment and placebo groups were rated as mild or moderate. There were a total of six serious adverse events (SAEs) in the drug treatment group, none of which were deemed related to investigational product.

Table 3. Treatment-Emergent Adverse Events at Rate of 3% or Greater in TNX-102 SL Group in RALLY

Oral Cavity or Systemic Adverse Events	TNX-102 SL (N=256)	Placebo (N=258)
Preferred Term
Oral Cavity Adverse Events
Hypoaesthesia oral	72 (28.1%)	2 (0.8%)
Product taste abnormal	26 (10.2%)	2 (0.8%)
Oral discomfort	23 (9.0%)	2 (0.8%)
Tongue discomfort	16 (6.3%)	2 (0.8%)
Paraesthesia oral	11 (4.3%)	0 (0.0%)
Dry mouth	10 (3.9%)	6 (2.3%)
Oral pain	8 (3.1%)	0 (0.0%)
Systemic Adverse Events
Headache	12 (4.7%)	11 (4.3%)
Somnolence	12 (4.7%)	2 (0.8%)
Sedation	10 (3.9%)	2 (0.8%)
Fatigue	8 (3.1%)	1 (0.4%)
COVID-19	8 (3.1%)	7 (2.7%)

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 6-12 million adults in the U.S., approximately 90% 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 serotonin-2A, alpha-1 adrenergic, histamine-H1, and muscarinic-M1 receptors, TNX-102 SL is in development as a daily bedtime treatment for fibromyalgia, PTSD, Long COVID (PASC), alcohol use disorder and agitation in Alzheimer’s disease. 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.

About the Phase 3 RALLY Study

The RALLY study was a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets). The two-arm trial enrolled 514 participants across 36 U.S. sites. For the first two weeks of treatment, there was a run-in period in which participants started on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all participants had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was 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. An interim analysis by an Independent Data Monitoring Committee was conducted on the primary endpoint based on the first 50% of enrolled participants.

The first interim cohort of the study was enrolled between September 2020 and March 2021, which included the periods of the second and third waves of the COVID-19 pandemic in US. The post-interim cohort was enrolled between third week of March and last week of July 2021. At the time of the interim analysis in July 2021, there were 125 participants still active in the study, who all completed their participation by 1 November 2021.

About Tonix Pharmaceuticals Holding Corp.

Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics and diagnostics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of immunology, central nervous system (CNS) and infectious disease product candidates. The Company’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL², (cyclobenzaprine HCl sublingual tablets), is a small molecule drug in mid-Phase 3 development for the management of fibromyalgia, with a new Phase 3 study expected to start in the first half of 2022. TNX-102 SL is also being developed to treat Long COVID, a chronic post-COVID-19 condition. Tonix expects to initiate a Phase 2 study in Long COVID in the first half of 2022. TNX-1300³ is a biologic designed to treat cocaine intoxication that is expected to start a Phase 2 trial in the first half of 2022. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer. Tonix’s lead immunology candidate, TNX-1500¹, is a humanized monoclonal antibody targeting CD40 ligand being developed for the prevention of allograft rejection and the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to start in the second half of 2022. Tonix’s infectious disease pipeline includes a vaccine in development to prevent smallpox, next-generation vaccines to prevent COVID-19 and an antiviral to treat COVID-19. Tonix’s lead vaccine program is TNX-801 (live horsepox virus for percutaneous administration) for preventing smallpox and monkeypox⁴. Horsepox is also the basis for Tonix’s recombinant pox vaccine (RPV) platform. Tonix’s lead vaccine candidates for COVID-19, TNX-1840 and TNX-1850⁵, are live virus vaccines in development based on the RPV platform. Finally, TNX-3500⁶ (sangivamycin, i.v. solution) is a small molecule antiviral drug to treat acute COVID-19 and is in the pre-IND stage of development.

¹TNX-1500 is an investigational new biologic at the pre-IND stage of development and has not been approved for any indication.

²TNX-102 SL is an investigational new drug and has not been approved for any indication.

³TNX-1300 is an investigational new biologic and has not been approved for any indication.

⁴TNX-801 is an investigational new biologic at the pre-IND stage of development and has not been approved for any indication.

⁵TNX-1840 and TNX-1850 are investigational new biologics at the pre-IND stage of development and have not been approved for any indication. TNX-1840 and TNX-1850 are designed to express the spike protein of SARS-CoV-2 from omicron and BA.2 variants, respectively, based on the experience from TNX-1800, which expresses the spike protein from the ancestral Wuhan strain.

⁶TNX-3500 is an investigational new drug at the pre-IND stage of development and has not been approved for any indication.

This press release and further information about Tonix can be found at www.tonixpharma.com.

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 development of TNX-102 SL; the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; delays and uncertainties caused by the global COVID-19 pandemic; 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, 2021, as filed with the Securities and Exchange Commission (the “SEC”) on March 14, 2022, 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.

Contacts

Jessica Morris (corporate)
Tonix Pharmaceuticals
investor.relations@tonixpharma.com
(862) 799-8599

Olipriya Das, Ph.D. (media)
Russo Partners
olipriya.das@russopartnersllc.com
(646) 942-5588

Peter Vozzo (investors)
ICR Westwicke
peter.vozzo@westwicke.com
(443) 213-0505

Source: Tonix Pharmaceuticals Holding Corp.

Monday, March 21, 2022

Onconova Therapeutics (ONTX)
Full-Year Financial Report Included Strong Pipeline Progress

Onconova Therapeutics Inc is a clinical-stage biopharmaceutical company operating in the US. It focuses on discovering and developing novel small molecule product candidates primarily to treat cancer. The company has created a library of targeted agents designed to work against cellular pathways important to cancer cells. Its product candidates are Single-agent IV rigosertib, Oral rigosertib + azacitidine, IV Briciclib, Recilisib, and ON 123300. The key product candidate Rigosertib is a small molecule which blocks cellular signaling by targeting RAS effector pathways.

Robert LeBoyer, Vice President, Research Analyst, Life Sciences, Noble Capital Markets, Inc.

Refer to the full report for the price target, fundamental analysis, and rating.

Onconova Reported FY2021 and Updated Its Clinical Trials In Progress.  Onconova reported a loss of $16.2 million or $(0.96) per share for FY2021. Importantly, the company reiterated its development schedule for the announcement of clinical data and the start of new clinical trials. Cash on hand on December 31, 2021 was $55.1 million or $2.64 per share.

Narazaciclib Continues Patient Treatment In Its Dose Escalation Trials.  Narazaciclib is currently in two trials testing increasing doses and different administration schedules. The US trial is enrolling patients in its fourth cohort dosed at 160 mg once daily. The China trial is testing its fifth cohort at 200mg in cycles of daily dosing for three weeks followed by one week off. Data from these …

This Company Sponsored Research is provided by Noble Capital Markets, Inc., a FINRA and S.E.C. registered broker-dealer (B/D).

*Analyst certification and important disclosures included in the full report. NOTE: investment decisions should not be based upon the content of this research summary. Proper due diligence is required before making any investment decision.