A Randomized Placebo-controlled Trial of Adjunctive D-Cycloserine and Accelerated Intermittent Theta Burst Stimulation for Emerging Adults With Suicidal Ideation

Background and Rationale: Suicide is the second leading cause of death in Canadian Emerging Adults (EAs; 18-24yrs). Current treatments for suicidal thoughts and behaviors are limited and novel treatments are required to save lives. Transcranial Magnetic Stimulation (TMS) is a non-invasive neurostimulation treatment for major depressive disorder, a mental health condition at high risk for suicide. It is well tolerated and effective. However, in the child and youth population, it does not appear to be superior to sham-TMS. Therefore, strategies for enhancing TMS outcomes are required.
Over time, TMS can change the function of brain regions important in depression to reduce the symptoms of depression, including suicidal ideation. The investigators believe this occurs through a process called 'synaptic plasticity', or the process by which neurons change their connectivity with other neurons in an activity-dependent manner. Using an adjunct to facilitate these changes in the EA population may improve TMS outcomes, including its effect on suicidal ideation.
The investigators' previous data indicates that, in adults, the effects of a TMS protocol called intermittent theta-burst stimulation (iTBS) can be enhanced by pairing stimulation with a medication called D-Cycloserine. This FDA-approved medication leads to enhanced synaptic plasticity with iTBS. In adults, this combination led to greater improvements in depression symptoms, with a notable rapid resolution of suicidal thoughts as well as improvements on a computerized test that is associated with future suicidal behavior.
Research Question and Objectives: To conduct a 2-week double-blind placebo-controlled randomized clinical trial where 60 participants will be randomly assigned to one of two groups: 1) accelerated iTBS+D-Cycloserine, and 2) accelerated iTBS+placebo. Participants will receive a weight-based dose of D-Cycloserine or placebo as an adjunct to iTBS (25mg/17.5kg of body weight).

Start Date11 Mar 2024

Sponsor / Collaborator

University of Calgary

[+1]

CTR20240209 / CompletedNot Applicable

随机、开放、两制剂、两序列、两周期、自身交叉对照设计，评价中国健康受试者在空腹及餐后状态下单次口服环丝氨酸胶囊后的生物等效性正式试验

[Translation] A randomized, open-label, two-dose, two-sequence, two-period, self-crossover controlled study to evaluate the bioequivalence of a single oral dose of cycloserine capsules in Chinese healthy subjects in the fasting and fed state

主要目的：以浙江百代医药科技有限公司提供的环丝氨酸胶囊为受试制剂；并以Meiji Seikaファルマ株式会社的环丝氨酸胶囊为参比制剂，进行人体相对生物利用度和生物等效性评价。

[Translation]

Main purpose: To evaluate the relative bioavailability and bioequivalence of cycloserine capsules provided by Zhejiang EMI Pharmaceutical Technology Co., Ltd. as the test preparation and cycloserine capsules produced by Meiji Seika Fluma Co., Ltd. as the reference preparation.

Start Date09 Mar 2024

Sponsor / Collaborator

Zhejiang Bio-diamond Pharmaceutical Technology Co., Ltd.

CTR20233940 / CompletedNot Applicable

环丝氨酸胶囊在健康受试者中随机、开放、两制剂、单次给药、两周期、交叉空腹和餐后状态下的生物等效性试验

[Translation] A randomized, open-label, two-dose, single-dose, two-period, crossover bioequivalence study of cycloserine capsules in healthy subjects under fasting and fed conditions

主要目的：以河北龙海药业有限公司生产的环丝氨酸胶囊（规格：250mg）为受试制剂，Meiji Seika ファルマ株式会社（日本明治）生产的环丝氨酸胶囊（规格：250mg）为参比制剂，比较中国健康受试者在空腹和餐后两种状态下单次口服环丝氨酸胶囊的体内血药浓度及主要药代动力学参数，评价两制剂的生物等效性。次要目的：评价中国健康受试者在空腹和餐后两种状态下单次口服环丝氨酸胶囊受试制剂或参比制剂后的安全性。

[Translation]

Primary objective: Using cycloserine capsules (specification: 250 mg) produced by Hebei Longhai Pharmaceutical Co., Ltd. as the test preparation and cycloserine capsules (specification: 250 mg) produced by Meiji Seika Pharma Co., Ltd. (Meiji, Japan) as the reference preparation, the plasma concentration and main pharmacokinetic parameters of cycloserine capsules in Chinese healthy subjects after a single oral administration in the fasting and postprandial states were compared to evaluate the bioequivalence of the two preparations. Secondary objective: To evaluate the safety of cycloserine capsules test preparation or reference preparation after a single oral administration in Chinese healthy subjects in the fasting and postprandial states.

Start Date11 Dec 2023

Sponsor / Collaborator

Hebei Longhai Pharmaceutical Co. Ltd.

100 Clinical Results associated with Cycloserine

100 Translational Medicine associated with Cycloserine

100 Patents (Medical) associated with Cycloserine

3,061

Literatures (Medical) associated with Cycloserine

31 Dec 2024·Systems biology in reproductive medicine

Effects of first and second division modes on euploidy acquisition in human embryo

Article

Author: Kuwatsuru, Yukari ; Moewaki, Harue ; Tokudome, Mari ; Mizobe, Yamato ; Kuroki, Yuko ; Fukumoto, Yumiko ; Iwakawa, Tokiko ; Takeuchi, Kazuhiro

The aim of this study was to non-invasively investigate euploid embryos using methods other than pre-implantation genetic testing for aneuploidy. The study focused on direct cleavage (DC) observed during early embryo development. We also investigated the relationship between the mode of early embryo division and embryo ploidy. Embryos were divided into the normal cleavage (NC) and DC groups, and the DC group was further subdivided into the DC-First (DC-F) and DC-Second (DC-S) groups, depending on whether DC was observed at the first or second cleavage, respectively. The acquisition rates of euploid embryos and embryos appropriate for transfer were compared between the groups. Our results revealed that the timing of the first division did not differ between blastocyst grades or in embryos with varying degrees of ploidy. Further, the timing of the first cleavage did not affect the acquisition rate of embryos appropriate for transfer and euploid embryo formation rate did not significantly differ between the DC and NC groups. We also noted that for embryos appropriate for transfer, euploidy acquisition rate did not differ significantly between the DC and NC groups. Further, the euploidy acquisition rate of embryos did not differ between the DC-F and DC-S groups. However, the acquisition rate of embryos appropriate for transfer, including those with low mosaicism, was significantly higher in the DC-S group than in the DC-F group. These findings indicated that the number of good-quality blastocysts formed was significantly higher in the NC group than in the DC group and the acquisition rate of embryos appropriate for transfer, including those with low mosaicism, was significantly higher in the DC-S group than in the DC-F group.

01 Nov 2024·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

A tough, strong, and fast-curing phenolic resin enabled by dopamine-grafted chitosan and polyethyleneimine-functionalized graphene

Article

Author: Zhan, Yunni ; Fang, Guigan ; Lyu, Yan ; Li, Jiongjiong

Phenolic resins are widely used for outdoor and structural wood-based panels; however, they are challenged by high curing temperatures, low curing rates, and high brittleness. Inspired by lobster epidermis hardening, a tough, strong, and fast-curing phenolic resin (named DCS/PG/PF) was proposed herein. In this approach, dopamine-grafted chitosan (DCS) and polyethyleneimine-functionalized graphene (PEI@G) were incorporated into neat phenol formaldehyde (PF) resin. The gel time and maximum curing temperature of DCS/PG/PF resin were considerably reduced from 445 s and 147.8 °C for the neat PF resin to 317 s and 127.8 °C, respectively. This was attributed to the oxidative crosslinking of catechol moieties in DCS and amino groups in PEI@G within the naturally alkaline environment of phenolic resins in addition to the high reactivity between catechol moieties and PF chains as well as between amino and PF chains. The prepared resin demonstrated a dry bonding strength of 2.56 MPa, wet bonding strength of 1.81 MPa, and debonding work of 0.714 J, exhibiting a considerable increase of 16.9 %, 52.1 %, and 95.1 %, respectively, compared with those of the PF resin. These improvements were attributed to the dense organic-inorganic hybrid crosslinking network formed in the DCS/PG/PF. Furthermore, the DCS/PG/PF resin exhibited enhanced thermal stability.

01 Oct 2024·Pharmacological Reports

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice

Article

Author: Poleszak, Ewa ; Wlaź, Piotr ; Wróbel, Andrzej ; Bogatko, Karolina ; Herbet, Mariola ; Ostrowska-Leśko, Marta ; Szopa, Aleksandra ; Serefko, Anna ; Dudka, Jarosław ; Radziwoń-Zaleska, Maria

Abstract:

Background:

The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.

Methods:

The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L–701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D–cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK–801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.

Results:

The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D–cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D–cycloserine-treated group. Adora1 expression increased with L–701,324, DPCPX + D–cycloserine, and DPCPX + CGP 37849, while D–cycloserine, CGP 37849, and MK–801 led to a decrease. Comt mRNA levels dropped with DPCPX + L–701,324, istradefylline + L–701,324/CGP 37849 but increased with D–cycloserine, MK–801, CGP 37849 and DPCPX + MK–801/ CGP 37849. Slc6a15 levels were reduced by D–cycloserine, DPCPX + L–701,324 but rose with DPCPX + CGP 37849/MK–801 and istradefylline + D–cycloserine/MK–801/CGP 37849.

Conclusion:

Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

News (Medical) associated with Cycloserine

28 Jun 2024

·www.prnewswire.com

NRx Pharmaceuticals (NASDAQ:NRXP) to Proceed with Two New Drug Applications in 2024; NRX-101 has Been Returned to the Company for Filing

New Drug Application (NDA) for Accelerated Approval planned for NRX-101 in people with bipolar depression and akathisia in 2024, based on two positive trials 1 2 and Breakthrough Therapy Designation. Potential revenue in 2025 NDA for NRX-100 (IV ketamine) in suicidal depression in advanced preparation for submission in 2024; based on four positive trials 3 4 5 6 and Fast Track Designation. Potential revenue in 2025 Gaining these approvals has the potential to yield more than $150 in revenue per NRXP share in the near term, at current share count Planning for HOPE Therapeutics share distribution progresses; audit nearing completion – critical step towards a public listing RADNOR, Pa., June 28, 2024 /PRNewswire/ -- NRx Pharmaceuticals, Inc. (Nasdaq: NRXP) ("NRx Pharmaceuticals", the "Company"), a clinical-stage biopharmaceutical company, today announced that advice from regulatory counsel, which includes former senior officials from the Food and Drug Administration, supports filing two New Drug Applications (NDAs) in 2024: an application for Accelerated Approval for NRX-101 to treat bipolar depression in patients with akathisia and an application for approval of NRX-100 (IV ketamine) for treatment of suicidal depression. Continue Reading HOPE Therapeutics, Inc. (PRNewsfoto/NRx Pharmaceuticals, Inc.) While efficacy and safety data are now in hand, filing of the above applications is dependent upon completion of 12-month stability data in manufactured lots as required by FDA regulations. As disclosed in an 8K filing, NRx will be filing the NRX-101 application without a commercial partner. The addressable market for the accelerated approval indication is such that a compact and efficient salesforce can be constructed by a small company, such as NRx, and current executives at NRx have previously held primary responsibility for launch of similar-sized pharmaceutical assets. NRx continues work to enable the distribution of shares in Hope Therapeutics. This distribution is dependent upon completion of a public audit and successful review of an SEC Form 10. "The NRx team has worked diligently since the end of the COVID pandemic to achieve these milestones for our shareholders and most importantly the patients we have always sought to help," said Dr. Jonathan Javitt, Chairman and Chief Scientist of NRx. "Given the near-term market opportunity represented by an accelerated approval process, NRx anticipates a higher potential return to NRx investors associated with an NRx-led initiative than that which would likely be achieved with a large commercial partner." NRX-101 for Bipolar Depression NRX-101 is the Company's patented (Composition of Matter), oral combination of the NMDA antagonist D-cycloserine and lurasidone for bipolar depression. Data from two active control clinical trials vs. the standard of care, lurasidone, have shown comparable antidepressant efficacy with clinically important reductions in suicidality and/or akathisia. To the Company's knowledge, no other oral agent has demonstrated such a valuable profile. Up to 15% of people treated with drugs in lurasidone's class develop akathisia7; this would constitute an estimated $3.7 billion initial market for NRX-101, with no approved medicines for akathisia. This is a population the Company can readily address without a large commercial partner, given the relatively small number of psychiatrists who treat high-risk patients. The broad bipolar market constitutes 7 million people and an opportunity greater than $20 billion per year. With a best-in-class product profile, the Company projects NRX-101 sales in excess of $2 billion. NRX-101 was awarded Breakthrough Therapy Designation, Fast Track Designation, a Biomarker Letter of Support, and a Special Protocol Agreement by the FDA for treatment of suicidal bipolar depression. NRX-100 (IV ketamine) for Suicidal Depression Intravenous ketamine is widely accepted as a standard of care for acute treatment of suicidal depression, in the absence of an FDA-labeled product; the only treatment currently approved by FDA is electroconvulsive therapy (ECT). According to the CDC, 3.5 million Americans make a plan for suicide each year.8 This represents a $3-5 billion market at expected pricing. Based on the data in the trials referenced above, the Company's regulatory counsel has encouraged the Company to file an NDA for suicidal depression for NRX-100. This application has been in development and awaits 12-month stability data for filing, which is expected in 2024. About NRx Pharmaceuticals NRx Pharmaceuticals is a clinical-stage biopharmaceutical company developing therapeutics based on its NMDA platform for the treatment of central nervous system disorders, specifically suicidal bipolar depression, chronic pain and PTSD. The Company is developing NRX-101, an FDA-designated investigational Breakthrough Therapy for suicidal treatment-resistant bipolar depression and chronic pain. NRX-101 additionally has potential to act as a non-opioid treatment for chronic pain, as well as a treatment for complicated UTI. NRx has recently announced plans to submit a New Drug Application for NRX-100 (IV ketamine) in the treatment of suicidal depression, based on results of well-controlled clinical trials conducted under the auspices of the US National Institutes of Health and newly obtained data from French health authorities, licensed under a data sharing agreements. NRx was awarded Fast Track Designation for development of ketamine (NRX-100) by the US FDA as part of a protocol to treat patients with acute suicidality. About HOPE Therapeutics, Inc. HOPE Therapeutics, Inc. () is a Specialty Pharmaceutical Company, wholly-owned by NRX Pharmaceuticals focused on development and marketing of an FDA-approved form of intravenous ketamine for the treatment of acute suicidality and depression together with a digital therapeutic-enabled platform designed to augment and preserve the clinical benefit of NMDA-targeted drug therapy. Notice Regarding Forward-Looking Statements The information contained herein includes forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended. These statements include, among others, statements regarding the proposed public offering and the timing and the use of the proceeds from the offering. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "plan," "believe," "intend," "look forward," and other similar expressions among others. These statements relate to future events or to the Company's future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause the Company's actual results to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond the Company's control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. Any forward-looking statement reflects the Company's current views with respect to future events and is subject to these and other risks, uncertainties and assumptions relating to the Company's operations, results of operations, growth strategy and liquidity. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's most recent Annual Report on Form 10-K and other filings with the Securities and Exchange Commission. Investors and security holders are urged to read these documents free of charge on the SEC's website at . Except as may be required by applicable law, The Company assumes no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, whether as a result of new information, future events or otherwise. 1 Nierenberg A, Lavin P, Javitt DC, et. al. NRX-101 vs lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior; a randomized prospective phase 2 trial. Int J Bipolar Dis 2023;11:28-38, STABIL-B 2 Nierenberg, et. al., A Randomized, Double-Blind Controlled Comparison of NRX-101 (D-cycloserine/lurasidone) to Lurasidone for Adults with Bipolar Depression and Subacute Suicidal Ideation or Behavior. Am Soc Clin Psych Annual Meeting 2024. ASCP Poster 3 Fava, M et. al., Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD) Mol Psychiatry. 2020; 25(7): 1592–1603. 4 Grunebaum, et. al., Ketamine for Rapid Reduction of Suicidal Thoughts. Am J Psychiatry. 2018 Apr 1: 175(4): 327-335 5 Abbar, et. al. Ketamine for Acute Treatment of Severe Suicidal Ideation, BMJ 2022; 376 6 Anand, et. al, Ketamine is non-inferior to ECT for non-psychotic treatment resistant depression. NEJM 2023 388(25):2315-2325 7 Chow, C, et. Al., Akathisia and Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence Pharmacotherapy 2020;40(6):565–574 8 CDC Suicide Data. SOURCE NRx Pharmaceuticals, Inc.

Fast TrackPhase 2Drug ApprovalNDABreakthrough Therapy

28 May 2024

·www.biospace.com

NRx Pharmaceuticals (Nasdaq:NRXP) Presents Landmark Trial of NRX-101 in Suicidal Bipolar Depression At the ASCP Annual Meeting: NRX-101 is the First Oral Antidepressant Demonstrated to Reduce Suicidality in Bipolar

Poster presentation of "A Randomized, Double-Blind Controlled Comparison of NRX-101 (D-cycloserine/lurasidone) to Lurasidone for Adults with Bipolar Depression and Subacute Suicidal Ideation or Behavior" NRX-101 demonstrated a similar antidepressant effect (MADRS reduction ~50%) compared to lurasidone, the Standard of Care drug NRX-101 demonstrated a 58% relative reduction in time to sustained remission from suicidality (P=.05) compared to lurasidone NRX-101 demonstrated a 76% reduction in symptoms of akathisia (p=0.03), a side effect linked to suicide, compared to lurasidone This represents the second trial of NRX-101 demonstrating reduction in suicidality and akathisia associated with NRX-101 compared to lurasidone RADNOR, Pa., May 28, 2024 /PRNewswire/ -- NRx Pharmaceuticals, Inc. (Nasdaq: NRXP) ("NRx Pharmaceuticals", "NRx", the "Company"), a clinical stage pharmaceutical company, today announced presentation of its Phase 2b/3 trial of NRX-101, entitled "A Randomized, Double-Blind Controlled Comparison of NRX-101 (D-cycloserine/lurasidone) to Lurasidone for Adults with Bipolar Depression and Subacute Suicidal Ideation or Behavior" at the American Society of Clinical Psychopharmacology (ASCP) in Miami Beach, FL. The lead author is Prof. Andrew Nierenberg, Director, Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital and Professor of Psychiatry, Harvard Medical School. "Presentation of these data at this highly respected conference is another important step toward bringing a life-saving product to patients in tremendous need," said Dr. Jonathan Javitt, Chairman and Chief Scientist of NRx. "We believe that NRX-101 may offer a paradigm changing approach to treatment of Bipolar Depression, with a product highly effective in both treating depression and reducing suicidality and associated side effects. We will continue working to bring hope to life with life-saving medications." The presentation will be held at 11:15 AM, Wednesday May 29, 2024. W89 A Randomized, Double-Blind Controlled Comparison of NRX-101 (D-cycloserine/lurasidone) to Lurasidone for Adults with Bipolar Depression and Subacute Suicidal Ideation or Behavior CONCLUSIONS of the Poster are: NRX-101 and lurasidone both demonstrated > 50% response for treating bipolar depression with no difference seen on primary efficacy endpoint (MADRS) A clinically meaningful difference was observed on both primary and secondary safety endpoints favoring NRX-101 NRX-101 was associated with 58% relative reduction in time to sustained remission from suicidality as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) when stratified by sex, mood stabilizer use, antipsychotic use, lifetime suicide event (P=0.05). NRX-101 was associated with a relative 76% reduction in symptoms of akathisia compared to lurasidone that was sustained over 42 days (Effect Size 0.37; P=0.03) on the Barnes Akathisia Rating Scale Akathisia was seen in 2% of participants treated with NRX-101 vs. 11% treated with lurasidone. NRX-101 showed superiority to lurasidone in akathisia starting at day 7 and continuing through day 42/ET. No treatment-related serious adverse event was observed in either group. No safety issues were detected except for MedDRA General disorders: NRX-101 - 18.2% vs lurasidone - 0% (p=0.002). Based on these findings, together with the earlier STABIL-B trial, the Company believes that NRX-101 has potential to become a standard of care drug for treating bipolar depression, an addressable population of 7 million patients in the US and many times that around the world. This study represents the second trial conducted under FDA Good Clinical Practices guidelines to demonstrate large and meaningful advantages of NRX-101 vs lurasidone on akathisia and suicidality and clears the path for a registration trial of NRX-101 vs. placebo to treat bipolar depression together with earlier accelerated approval for those with akathisia. An additional academic trial conducted by Chen and co-workers similarly demonstrated a statistically-significant reduction in suicidality associated with D-cycloserine, the active ingredient in NRX-101, compared to various standard of care antidepressants. To the Company's knowledge, this trial and its prior STABIL-B study represent the only clinical trials in which an oral antidepressant has been demonstrated to cause meaningful reductions in suicidality and akathisia. All currently approved antidepressant drugs carry FDA-mandated "black box" warnings on their labels indicating that they may increase the risk of suicide. Similarly, akathisia – a side effect in which patients are agitated and frequently experience involuntary movement – is a side effect that occurs in 10-15% of patients who take the lurasidone class of drugs and is closely linked to suicide. As shown in the clinical trial, those randomized to lurasidone experienced a substantial increase in akathisia from baseline, whereas those randomized to NRX-101 demonstrated a statistically-significant reduction in akathisia (see Figure). About NRx Pharmaceuticals NRx Pharmaceuticals is a clinical-stage biopharmaceutical company developing therapeutics based on its NMDA platform for the treatment of central nervous system disorders, specifically suicidal bipolar depression, chronic pain and PTSD. The Company is developing NRX-101, an FDA-designated investigational Breakthrough Therapy for suicidal treatment-resistant bipolar depression and chronic pain. NRx has partnered with Alvogen and Lotus around the development and marketing of NRX-101 for the treatment of suicidal bipolar depression. NRX-101 additionally has potential to act as a non-opioid treatment for chronic pain, as well as a treatment for complicated UTI. NRx has recently announced plans to submit a New Drug Application for HTX-100 (IV ketamine), through Hope Therapeutics, in the treatment of suicidal depression, based on results of well-controlled clinical trials conducted under the auspices of the US National Institutes of Health and newly obtained data from French health authorities, licensed under a data sharing agreement. NRx was awarded Fast Track Designation for development of ketamine (NRX-100) by the US FDA as part of a protocol to treat patients with acute suicidality. Notice Regarding Forward-Looking Statements The information contained herein includes forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended. These statements include, among others, statements regarding the proposed public offering and the timing and the use of the proceeds from the offering. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "plan," "believe," "intend," "look forward," and other similar expressions among others. These statements relate to future events or to the Company's future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause the Company's actual results to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond the Company's control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. Any forward-looking statement reflects the Company's current views with respect to future events and is subject to these and other risks, uncertainties and assumptions relating to the Company's operations, results of operations, growth strategy and liquidity. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's most recent Annual Report on Form 10-K and other filings with the Securities and Exchange Commission. Investors and security holders are urged to read these documents free of charge on the SEC's website at . Except as may be required by applicable law, The Company assumes no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, whether as a result of new information, future events or otherwise. View original content to download multimedia: SOURCE NRx Pharmaceuticals, Inc. Company Codes: NASDAQ-NMS:NRXP

Clinical ResultFast TrackBreakthrough TherapyASCO

14 May 2024

·www.prnewswire.com

NRx Pharmaceuticals (Nasdaq:NRXP) Reports First Quarter 2024 Financial Results and Provides Business Update

2024 Catalysts: Positive Clinical Data, Two Planned NDAs, Company Launch of Hope Therapeutics; FDA QIDP award in cUTI and New Schizophrenia Opportunity Executed Term Sheet from an institutional investor for an initial $7.5 million note, subject to common closing requirements, primarily to replace current debt, clearing the path to a Hope Therapeutics share distribution, with provision for funding up to $30 million to fund pipeline opportunities Positive data from a Phase 2b/3 trial of NRX-101 in Treatment Resistant Bipolar Depression (TRBD); trial demonstrated depression efficacy comparable to standard of care and significant reduction of akathisia (P=0.025). Akathisia is a potentially lethal side effect of all serotonin-targeted antidepressants and is associated with suicide. The study additionally demonstrated a 30% advantage in sustained remission from suicidality that was not statistically-significant at this sample size Above findings of reduced suicidality mirror the results of the Company's prior STABIL-B trial in acutely suicidal patients and also mirror the results of an independent published trial Company plans to file a New Drug Application (NDA) for Accelerated Approval under Breakthrough Therapy and Priority Review of NRX-101 in treatment of bipolar depression in people at risk of akathisia, based on the Phase 2b/3 and STABIL-B data Company has developed patentable pH neutral formulation for ketamine that will be suitable for both intravenous and subcutaneous administration. Ketamine efficacy data are in hand from 4 clinical trials. Three manufacturing lots are now initiated (required for NDA) and Company plans to initiate the NDA by July HOPE Therapeutics (which focuses on care delivery, not drug development) has partnered with representatives of ketamine clinic providers nationwide to construct a care platform that will include ketamine, operational support, and digital therapeutic extensions. In advance of FDA approval, HOPE is actively in the sales process to supply ketamine under 503b pharmacy licensure to meet the national ketamine shortage declared by FDA. HOPE is planned to be spun out as a separate company to be owned by NRx, current NRx shareholders, and new investors; Term Sheets received from prospective anchor investors for $60 million of new investment, once publicly listed Data expected shortly in 200-person DOD-funded trial of D-cycloserine (DCS), the key component of NRX-101, to treat chronic pain, conducted by Northwestern University. Statistical analysis plan and data unlock have been approved by Northwestern IRB NRX-101 in the treatment of Complicated Urinary Tract Infection (cUTI) granted Qualified Infectious Disease Product (QIDP), Fast Track, and Priority Review designations. Company has now demonstrated that NRX-101 does not damage the microbiome of the gut, in contrast to all other advanced antibiotics and is less likely to cause C. Difficile infection (a potentially lethal side effect of antibiotic treatment). NRx is reviewing partnership options Executed Memorandum of Understanding with Fondation FundaMental for rights to develop potential disease modifying drug for Schizophrenia. If successful, this would represent the first drug to reverse the underlying disease mechanism of schizophrenia, rather than simply treating symptoms. Management to host a conference call, May 14, 2024, at 4:30 PM ET RADNOR, Pa., May 14, 2024 /PRNewswire/ -- NRx Pharmaceuticals, Inc. (Nasdaq: NRXP) ("NRx Pharmaceuticals", the "Company"), a clinical-stage biopharmaceutical company, today announced its financial results for the quarter ended March 31, 2024, and provided a business update. Akathisia rating by study day: a consistent effect is seen commencing at first post-randomization visit and continued throughout the study (Mixed Model for Repeated Measures Regression effect size =0.037, P=0.025) STABIL-B HOPE Therapeutics, Inc. (PRNewsfoto/NRx Pharmaceuticals, Inc.)

Financial StatementFast TrackNDAClinical ResultPriority Review

100 Deals associated with Cycloserine

External Link

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D00877	Cycloserine	J04AB01	DB00260

R&D Status

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Indication	Country/Location	Organization	Date
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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02385266 (UCPPS, CTgov)	Phase 4	Chronic pelvic pain syndrome	24	D-Cycloserine (D-Cycloserine and Acetominophen)	kvbujakuxn(phlenqybfg) = osnlbulujj tpqqtixsvx (dfrmohibpx, ohyjjjgpsq - etmavhhrnj) View more	-	17 May 2023
				Placebo (for D-cycloserine) (Placebo and Acetominophen)	kvbujakuxn(phlenqybfg) = xbfdgjoptd tpqqtixsvx (dfrmohibpx, wajbbxxvhd - fowydlimhu) View more
NCT03937596 (Pubmed)	Phase 2	Depressive Disorder, Major	50	iTBS plus placebo	nvggmcoqqg(ihwydfbvxu) = jiuwhiblpq rjxfdlhzxz (hqsbgrvcyd ) View more	Positive	12 Oct 2022
				iTBS plus D-cycloserine (100 mg)	nvggmcoqqg(ihwydfbvxu) = gyjdnxkzve rjxfdlhzxz (hqsbgrvcyd ) View more
NCT00875342 (CTgov)	Not Applicable	Stress Disorders, Post-Traumatic	41	DCS (D-cycloserine)	eklxdkpahg(ngsoicysjs) = xmoiwwosis kmwwnbgvhn (iodeyuqcok, pivhzvttix - jxjdogvxul) View more	-	16 Aug 2021
				Placebo (Placebo)	eklxdkpahg(ngsoicysjs) = qljqyqwvka kmwwnbgvhn (iodeyuqcok, jdprmchvya - shxziudmut) View more
NCT01944423 (DCS/PSRT, CTgov)	Early Phase 1	Panic \| Nicotine Dependence	53	Smoking Reduction Treatment+Nicotine replacement therapy+d-cycloserine (PSRT_DCS)	vrwqirpwsl(lvderxsomf) = hqdwbksfwf trsfvbfspd (vdnpifainz, exjcknklcq - ezoggmdblr) View more	-	19 May 2021
				Pill Placebo+Nicotine replacement therapy (PSRT_PBO)	vrwqirpwsl(lvderxsomf) = ajzfjnumub trsfvbfspd (vdnpifainz, aixoypjgmf - guezqzipni) View more
NCT02066792 (CTgov)	Early Phase 1	Phobia, Social	152	Cognitive Behavioral Therapy+D-Cycloserine (Tailored Post-Session DCS)	ixsnbljgns(zraqiiyvjm) = evwkipisoj zkgypvflxg (inauqtrsvb, wezrbovdvp - leztvmmraq) View more	-	09 Jun 2020
				Cognitive Behavioral Therapy+D-Cycloserine (Pre-Session DCS)	ixsnbljgns(zraqiiyvjm) = jznwqdygfd zkgypvflxg (inauqtrsvb, uuomejxuia - dorxkcszhx) View more
NCT01680107 (d-cycloserine Augmented CBT for Panic Disorder, Pubmed \| Behav Res Ther)	Phase 3	Anxiety Disorders	33	d-cycloserine	ozgrhswfsm(jtvkcbblic) = jlahcfowbi luxrqeoykv (atgqvajfxz )	-	01 Jun 2020
				Placebo	ozgrhswfsm(jtvkcbblic) = uchgyakryn luxrqeoykv (atgqvajfxz )
NCT00674570 (VSL, CTgov)	Phase 4	Stress Disorders, Post-Traumatic	111	Hydrocortisone (Arm 1: Hydrocortisone)	rdvknazywg(zgaaeurfed) = oieavdmota cqnxxlrzya (hzrtouvily, vnbottrvoa - hhkacjikom) View more	-	30 May 2019
				D-Cycloserine (Arm 2: D-Cycloserine)	rdvknazywg(zgaaeurfed) = nsirrkfjji cqnxxlrzya (hzrtouvily, urayxsqxgl - xtrdrmuilk) View more
NCT02582515 (DCS+HRT, CTgov)	Not Applicable	Tourette Syndrome	20	D-cycloserine (D-cycloserine + Habit Reversal Training)	mtifnkghho(hfdeyqszbw) = mzqyuuqign mzkilmfnqh (fsqoisjuik, txlehinonu - rzlizlhwzg) View more	-	25 Apr 2019
				Placebo (Placebo + Habit Reversal Training)	mtifnkghho(hfdeyqszbw) = dmnqiqoieh mzkilmfnqh (fsqoisjuik, fgjsmgxjuq - ejrkyqjczu) View more
NCT00198107 (CTgov)	Phase 3	Autistic Disorder	81	Placebo (1 Placebo)	xgkuqasyht(swcnhfvrye) = krwdkhwkbk ffazamnepb (ebampxrkxu, cfbzzqnqyj - rmyhyuurzn) View more	-	29 Mar 2019
				Aripiprazole (2 Aripiprazole)	xgkuqasyht(swcnhfvrye) = rziqalpwct ffazamnepb (ebampxrkxu, xdaflfggag - hjgcbqmehu) View more
NCT00842309 (BDD/DCS, CTgov)	Early Phase 1	Body Dysmorphic Disorders	68	d-cycloserine (D-cycloserine)	pqxhpfcrjs(oxieykccbx) = hbxnkudpgr kbydofujnu (msacwqnshm, ygtlocfaze - gioeskcckz) View more	-	15 Mar 2019
				Placebo (Placebo)	pqxhpfcrjs(oxieykccbx) = uqcozrvroe kbydofujnu (msacwqnshm, xynzjzncqs - jqzqdcoymv) View more

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