NeuroSense Therapeut...
NasdaqCM:NRSN
$
0,70
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$-0,03 (-4,11%)
0,70
$
$-0,03 (-4,11%)
End-of-day quote: 04/10/2026
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NeuroSense Therapeutics Company Info
EPS Growth 5Y
23,05%
Market Cap
$0,03 B
Long-Term Debt
$0,00 B
Quarterly earnings
04/24/2026
Dividend
$0,00
Dividend Yield
0,00%
Founded
2017
Industry
Country
Website
ISIN Number
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Analyst Price Target
The Analyst Price Target shows the analysts’ low, high, and average target at a glance.
$8,25
1078.57%
Last Update: 04/11/2026
Analysts: 4
Highest Price Target $14,00
Average Price Target $8,25
Lowest Price Target $3,00
In the last five quarters, NeuroSense Therapeutics’s Price Target has risen from $3,29 to $5,25 - a 59,57% increase. One analysts predict that NeuroSense Therapeutics’s share price will increase in the coming year, reaching $8,25. This would represent an increase of 1078,57%.
Top growth stocks in the health care sector (5Y.)
What does NeuroSense Therapeutics do?
NeuroSense Therapeutics Ltd. is a clinical-stage biotechnology company.
The company is focused on discovering and developing treatments for people living with neurodegenerative diseases, including ALS AD and PD. Due to the complexity of neurodegenerative diseases, the company’s strategy is utilizing a combined therapeutic approach to target multiple disease-related pathways.
The company’s lead therapeutic candidate, PrimeC, is a novel extended-release oral formulation, fixed-dose combination o...
NeuroSense Therapeutics Ltd. is a clinical-stage biotechnology company.
The company is focused on discovering and developing treatments for people living with neurodegenerative diseases, including ALS AD and PD. Due to the complexity of neurodegenerative diseases, the company’s strategy is utilizing a combined therapeutic approach to target multiple disease-related pathways.
The company’s lead therapeutic candidate, PrimeC, is a novel extended-release oral formulation, fixed-dose combination of two FDA-approved drugs, ciprofloxacin and celecoxib. PrimeC is designed to treat ALS by modulating microRNA synthesis, iron accumulation, and neuroinflammation, all of which are hallmarks of ALS pathology. The U.S. Food and Drug Administration, or the FDA and the European Medicines Agency, or the EMA have granted PrimeC orphan drug designation for the treatment of ALS. In addition, the EMA has granted PrimeC the Small and Medium-Sized Enterprise, or SME, status, which offers significant potential benefits leading up to and following drug regulatory approval. PrimeC’s multifunctional mechanism of action has the potential to significantly prolong lifespan and improve ALS patients’ quality of life, thereby reducing the burden of this debilitating disease on both patients and healthcare systems.
PrimeC was evaluated in PARADIGM, a Phase 2b randomized, multi-center, multinational, prospective, double-blind, placebo-controlled study, to evaluate safety, tolerability, and efficacy of PrimeC in 68 people living with ALS. Participants were being administered PrimeC or placebo at a 2:1 ratio, respectively, for the six-month double-blind part. Study participants were allowed to continue standard of care treatment of approved products. The primary endpoints of the study are an evaluation of ALS-biomarkers, as well as safety and tolerability assessment. Secondary and exploratory endpoints are the evaluation of clinical efficacy (ALS Functional Rating Scale — Revised, or ALSFRS-R, and slow vital capacity), survival, and improvement in quality of life. All subjects who completed the six-month double-blind, placebo-controlled dosing period had the opportunity to be transferred to the PrimeC active arm for a 12-month open label extension. The study completed enrollment in May 2023, enrolling 69 participants, in which 68 are living with ALS and one participant who was misdiagnosed for ALS and was excluded from the evaluations. Four ALS clinical centers participated in the study in three territories: Israel, Italy, and Canada. In December 2023, the company reported that the company met the primary safety and tolerability endpoints and achieved secondary clinical efficacy endpoints in the top-line results of the company’s 6-month double-blind phase of PARADIGM.
In May 2024, the company announced new positive data analysis from PARADIGM clinical trial demonstrating statistically significant slowing of disease progression in high-risk ALS patients. In July 2024, the company announced results from the 12-month analysis of the PARADIGM clinical trial which showed a significant improvement in the rate of decline of ALS Functional Rating Scale-Revised (ALSFRS-R) scores and survival rates for subjects who received PrimeC from the start of the trial compared to those who started on placebo. In August 2024, the company announced positive 12-month biomarker data from the PARADIGM clinical trial, which showed a significant decrease in ferritin levels and a corresponding increase in transferrin levels, both indicating alleviation of the pathology. In October 2024, the company completed the full 18-month dosing in PARADIGM, and in December 2024, the company announced results from the 18-month analysis of the PARADIGM clinical trial which showed statistically significant positive results from the 18-month data analysis of the PARADIGM study, evaluating the efficacy of PrimeC in the treatment of ALS. In February 2025, the company announced additional findings from an 18-month analysis of the PARADIGM clinical trial showing improvements in two additional endpoints, complication-free survival (analysis which includes death from any cause or respiratory insufficiency or hospitalization due to ALS-related complications) and Slow Vital Capacity (SVC), measuring respiratory function.
Following the FDA’s recommendation for additional non-clinical data to support long term use of Ciprofloxacin (as PrimeC is intended for long-term administration in treating ALS) a long-term tox study was initiated.
In September 2024, the company announced the successful completion of the in-life phase of the study, as the company move towards the initiation of a Phase 3 study in the U.S.
In December 2024, the company concluded a productive Type C meeting with the FDA. The purpose of the meeting was to discuss the design of a proposed Phase 3 clinical study and the plan for submission of an eventual 505(b)(2) marketing application. In light of the FDA’s feedback, the company plans to submit a final protocol to the FDA during the first half of 2025 and approach the EMA, with the aim of commencing enrollment of the pivotal Phase 3 study in the second half of 2025, which would include approximately 300 patients divided by a ratio of 2:1, PrimeC to placebo. The Phase 3 study is expected to be a randomized, multi-center, multinational, prospective, double-blind, placebo-controlled study, with an open label extension (OLE), to evaluate the efficacy and safety of PrimeC in people living with ALS. Following 12 months of treatment, it is expected that all participants will transition to PrimeC for a 12-month open label extension.
In December 2024, the company entered into a binding term sheet with a leading global pharmaceutical company to advance the development and commercialization of PrimeC, in certain key territories. The company retains full rights to PrimeC in other key territories.
PrimeC was previously evaluated in a Phase 2a clinical trial, or NST002, in 15 people living with ALS, conducted at the Tel Aviv Sourasky Medical Center, Israel. The primary endpoint of the NST002 trial, which was safety and tolerability, was met. In this trial, the safety profile observed was consistent with known safety profiles of ciprofloxacin and celecoxib. Side effects were mild and transient in nature. There were no new or unexpected safety signals detected during the trial.
Additionally, the company observed positive clinical signals in comparison to virtual controls, and a serum biomarker analysis showed significant changes following treatment, indicating biological activity of the drug in comparison to untreated matched ALS patients. All 12 patients who completed the NST002 trial elected to continue into an extension study with PrimeC, that was conducted as an Investigator Initiated Study. As of December 31, 2024, the company was still supporting the drug supply for a few of the participants in this study, which is over than 40 months since NST002 was initiated.
The company completed three additional studies in 2022 as part of the company’s drug development program to further support the company’s future regulatory submissions. In April 2022, the company initiated a pharmacokinetic, or PK, study, or NCT05232461, of PrimeC. The PK open-label, randomized, single-dose, three-treatment, three-period crossover study evaluated the effect of food on the bioavailability of PrimeC as compared to the bioavailability of co-administered ciprofloxacin tablets and celecoxib capsules in adult subjects in the U.S. under an FDA cleared IND protocol.
In August 2022, the company completed enrollment and dosing of all subjects in a multi-dose PK study, or NCT05436678. On September 28, 2022, the company released the results of the NCT05436678 study. Based on results, the PK profile of PrimeC supports the formulation’s extended-release properties, as the concentrations of the active components have been synchronized, aiming to potentially maximize the synergism between the two compounds. In June 2022, the company reported the successful completion of the ‘in-life’ phase of its 90-day GLP toxicology study. In this study, the components of PrimeC, celecoxib and ciprofloxacin, were administered to rodents at doses 4x the maximal clinical dose. All animals appeared normal, with no significant findings observed. The company intends to present the data from these studies to the FDA as part of PrimeC’s drug development plan.
The company has a strong patent estate, including patents on method of use, combination, and formulation. The company has secured U.S. Patent 10,980,780 relating to methods for the treatment of ALS using ciprofloxacin and celecoxib, the components of PrimeC, which expires in 2038. Equivalent patents also have been issued in the European Patent Office, Canada, Australia, Israel and Japan. The patent estate also includes US Patent 12,097,185, which relates to Prime C formulations. This patent will expire in December 2042. Equivalent applications are pending in many jurisdictions worldwide. The company also expects to take advantage of orphan drug exclusivity for PrimeC, if approved, for seven years in the United States and ten years in the European Union. In addition, U.S. patent application 16/623,467, which relates to methods of treatment of neurodegenerative disease using combinations of ciprofloxacin and celecoxib, is pending. This patent application, once granted, is expected to expire on June 20, 2038.
In addition to PrimeC, the company extended its pipeline and conducted research and development efforts for AD and PD, with a similar strategy of combined products.
Current ALS Treatment Options and Drugs in Development
Until recently, the only approved drug used for slowing disease progression in ALS was Rilutek (riluzole). It was the first drug to be approved by the FDA for the treatment of ALS over 25 years ago. In May 2017, the FDA approved Radicava (edaravone), which is administered through chronic cycles of ten days of intravenous infusions followed by a two-week treatment-free period. In recent years, the FDA has also approved two new formulations of riluzole that address the need for an improved route of administration in patients who suffer from swallowing complications. In September 2018, the FDA approved Tiglutik, the oral suspension of riluzole administered via syringe, and in November 2019, the FDA approved Exservan, a new soluble oral formulation of riluzole which dissolves on the tongue. In Europe, edaravone is not approved, and therefore the only approved drug for ALS is riluzole.
In April 2023, the FDA approved Qalsody (tofersen) to treat patients with ALS associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS). Qalsody is an antisense oligonucleotide that targets SOD1 mRNA to reduce the synthesis of SOD1 protein. The approval was based on a correlation between clinical outcome and reduction in plasma neurofilament light chain (NfL), a blood-based biomarker of axonal (nerve) injury and neurodegeneration.
As both approved drugs, riluzole and edaravone, have been shown to have minimal effect on prolonging patient lifespans or improving their quality of life and independence, and Qalsody is aimed for patients with SOD1 mutation, which represents approximately 2% of the overall ALS population, there is still a significant need for new treatments for patients with ALS in order to improve the disease course and to further extend survival.
Other treatments for ALS that the company is aware are under development include:
Novartis is developing VHB937, an anti-human TREM2 mAb, being tested in a Phase 2 clinical trial.
Brainstorm Cell Therapeutics is developing NurOwn, an adult stem cell therapy, which has completed a pivotal Phase 3 trial and did not achieve the primary endpoint. NurOwn is expected to be reevaluated in a Phase 3b trial.
Clene is developing CNM-Au8, an investigational gold nanocrystal suspension, completed a Phase 3 clinical trial. CNM-Au8 did not meet its primary endpoint of change in ALSFRSR, However, it showed that the drug was able to reduce the risk of death in patients with ALS.
Prilenia, is developing Pridopidine, which was originally developed for Huntington’s disease. The drug did not reach statistical significance in Phase 2 primary and key secondary endpoints; nevertheless, based on additional analysis, the drug is in preparations for a Phase 3 trial for ALS.
Eledon is developing Tegoprubart, an anti-CD40L antibody, which completed a Phase 2a open-label study, and is now seeking non-equity dilutive financing to move into a Phase 3 study.
QurAlis is developing a pipeline of RNA-based therapies for ALS, now in Phase 1 clinical trials.
The company’s Solution — PrimeC for ALS
The company’s lead product candidate, PrimeC, is designed to treat ALS by targeting multiple pathways involved in ALS, including regulating miRNA synthesis, influencing iron accumulation, and reducing neuroinflammation.
miRNA are small non-coding RNAs which play a critical role in regulating gene expression. Studies show that miRNA are dysregulated in motor neurons of autopsy tissues from patients with ALS, and that reduction in miRNA is sufficient to cause spinal motor neuron degeneration in-vivo. Consequently, dysregulation of miRNA levels due to inefficient activity of Dicer enzyme which plays a key role in their generation, is common in multiple forms of ALS. Dysregulated miRNAs are found in multiple ALS models and patient-based microglia cells, motor neurons and skeletal muscles controlling multiple targets, such as neuroinflammation, synaptic formation, neuronal activity and differentiation.
Iron accumulation has been shown to be present in many neurodegenerative diseases, including ALS. As such, iron chelation therapies have been shown to have a positive effect in pre-clinical models of neurodegeneration.
Finally, chronic neuroinflammation is increasingly recognized as a major factor that promotes ALS disease progression and amplifies the motor neuron death-inducing processes. Neuroinflammation is characterized by extensive astrogliosis, microglial activation, and infiltration of peripheral immune cells at sites of neurodegeneration.
PrimeC is a novel formulation of a fixed dose combination of two generic FDA-approved drugs, ciprofloxacin and celecoxib, combined at a specific ratio, aiming to target multiple ALS-related pathways simultaneously.
Ciprofloxacin is a fluoroquinolone antibiotic often used to treat bacterial infections, which has been safely used for many years in large and diverse patient populations. Ciprofloxacin is approved for use in gram-negative bacterial infections such as lower respiratory tract infections, chronic sinusitis, genital tract infections and infections of the skin and soft tissues. Additionally, ciprofloxacin is approved for chronic ear infections, urinary tract infections, gastro-intestinal and intra-abdominal infections, malignant external otitis, infections of the bones and joints, prophylaxis of invasive infections due to Neisseria meningitidis, inhalation anthrax, and broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa. Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.
Studies have shown that besides its antibiotic mechanisms, ciprofloxacin is also able to upregulate the expression of miRNAs by inducing dicer activity and is a moderate iron chelator.
Celecoxib is a prescription nonsteroidal anti-inflammatory drug, or NSAID, used to treat pain through the inhibition of cyclooxygenase-2, or COX-2, and the reduction of inflammatory processes, thereby affecting glutamate excitotoxicity and oxidative stress, among others. Celecoxib is approved for use for the management of the signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis in patients two years and older, and ankylosing spondylitis. Additionally, celecoxib is approved for the management of acute pain in adults, and for the management of primary dysmenorrhea. Although not shown to be beneficial in ALS when given at high doses as a single agent, low doses of celecoxib were shown to be effective in pain management and played a synergistic role with ciprofloxacin in pre-clinical models of ALS zebrafish (SOD1 and TDP-43).
Through the analysis of blood samples from healthy subjects and patients with ALS, the company observed the relevance of PrimeC’s mechanism of action using a novel method involving neuron-derived exosomes. In the recently competed interim analysis of NST-003 Phase 2b study conducted in ALS patients with PrimeC, the primary endpoint of safety and tolerability was successfully met. Furthermore, the clinical parameters measured and the quality of life questionnaires demonstrated a clinically significant benefit to ALS patients treated with PrimeC compared to placebo. Additionally, the primary endpoint of safety and tolerability was met in the company’s NST002 trial in ALS patients, which was completed in February 2021. Through analysis of blood samples from this study using the same exosomal method, the company observed significant changes in ALS-related biomarkers, indicating biological activity of PrimeC.
Product Candidates
PrimeC
The company’s lead product candidate, PrimeC, is a novel ER oral formulation composed of a novel fixed dose combination of two generic FDA-approved drugs, ciprofloxacin and celecoxib, combined in a specific ratio. PrimeC is designed to treat ALS by regulating miRNA synthesis, influencing iron accumulation and reducing neuroinflammation.
PrimeC was evaluated in PARADIGM, a Phase 2b randomized, multi-center, multinational, prospective, double-blind, placebo-controlled study, with an open label extension, to evaluate safety, tolerability, and efficacy of PrimeC in 69 people living with ALS in a 2:1 ratio to receive PrimeC or placebo, respectively, which the company refers to as NST003. Study participants were allowed to continue standard of care (SOC) treatment of approved products. Primary endpoints of the study included an evaluation of ALS-biomarkers, as well as safety and tolerability assessment. Secondary and exploratory endpoints are the evaluation of clinical efficacy (ALSFRS-R, SVC), survival, and improvement in quality of life. All subjects who complete the six-month double-blind, placebo-controlled dosing period switched to the PrimeC active arm for a 12-month open label extension. The study commenced recruitment of patients in Israel in May 2022 and in Italy and Canada in March 2023.
In May 2023, the company completed enrollment for the PARADIGM trial. In November 2023, the company concluded a successful Type D meeting with the FDA for PrimeC in the treatment of ALS where the company discussed PrimeC’s CMC development plans in advance of an expected Phase 3 pivotal study and potential subsequent marketing approval. The FDA agreed with the company’s proposed CMC development plan.
In December 2023, the company reported that the company met the primary safety and tolerability endpoints and achieved secondary clinical efficacy endpoints in the top-line results of the company’s Phase 2b trial.
In May 2024, the company announced new positive data analysis from PARADIGM clinical trial demonstrating statistically significant slowing of disease progression in high-risk ALS patients. In July 2024, the company announced results from the 12-month analysis of the PARADIGM clinical trial which showed a significant improvement in the rate of decline of ALS Functional Rating Scale-Revised (ALSFRS-R) scores and survival rates for subjects who received PrimeC from the start of the trial compared to those who started on placebo. In August 2024, the company announced positive 12-month biomarker data from the PARADIGM clinical trial, which showed a significant decrease in ferritin levels and a corresponding increase in transferrin levels, both indicating alleviation of the pathology. In February 2025, the company announced additional findings from an 18-month analysis of the PARADIGM clinical trial showing improvements in two additional endpoints, complication-free survival and Slow Vital Capacity (SVC).
In October 2024, the company provided a further update on the company’s plans to file for early commercialization approval for PrimeC under Health Canada’s Notice of Compliance with Conditions (NOC/c) policy. This decision follows the recommendations of Canadian regulatory experts and recent clinical findings.
In December 2024, the company concluded a Type C meeting with the FDA. The purpose of the meeting was to discuss the design of a proposed Phase 3 clinical study and the plan for submission of an eventual 505(b)(2) marketing application. The company had a productive discussion with the FDA regarding the design of the planned Phase 3 pivotal study with PrimeC, including efficacy and safety measurements. In light of the FDA’s feedback, the company plans to submit a final protocol to the FDA during the first half of 2025 with the aim of commencing enrollment of the pivotal Phase 3 study in mid-2025, which would include approximately 300 patients divided by a ratio of 2:1, PrimeC to placebo. The Phase 3 study is expected to be a randomized, multi-center, multinational, prospective, double-blind, placebo-controlled study, with an open label extension (OLE), to evaluate the efficacy and safety of PrimeC in people living with ALS. Following 12 months of treatment, it is expected that all participants will transition to PrimeC for a 12-month open label extension.
Clinical Results
NST003 Phase 2b Trial in ALS
In December 2023, the company announced topline clinical efficacy results in the company’s Phase 2b PARADIGM (NST003) trial of PrimeC for the treatment of ALS, reporting that the company met the primary safety and tolerability endpoints and achieved secondary clinical efficacy endpoints.
The PARADIGM study was a randomized, multi-center, multinational, prospective, double-blind, placebo-controlled study, to evaluate safety, tolerability, and efficacy of PrimeC in 68 people living with ALS. Participants were administered PrimeC or placebo at a 2:1 ratio, respectively. After completion of the 6-month double-blind segment, participants had the option to enroll in a 12-month OLE, during which they all received treatment with PrimeC. Study participants were allowed to continue standard of care treatment of approved products.
The primary endpoints of the study included an evaluation of ALS-biomarkers, as well as safety and tolerability assessment. Secondary and exploratory endpoints included the evaluation of clinical efficacy (ALSFRS-R and slow vital capacity), survival, and improvement in quality of life. The study completed enrollment in May 2023, enrolling 68 participants living with ALS in Israel, Italy, and Canada.
A primary endpoint of the PARADIGM study pertained to the evaluation of PrimeC’s safety and tolerability profile in ALS. Noteworthy findings indicate that the incidence of adverse events under PrimeC treatment were similar to that observed in the placebo arm, thereby underscoring the favorable safety profile of PrimeC. Additionally, assessments of electrocardiographic parameters and laboratory indices, encompassing QTc interval, hepatic enzymes, and renal function, revealed no significant aberrations attributable to PrimeC.
Top-line results in the PARADIGM trial revealed a statistically significant slowing of disease progression in ALS patients, compared to the placebo. The study demonstrated a 37.4% (p=0.03) difference in the FDA-approved ALSFRS-R compared to placebo, and a 17% difference in favor of PrimeC in slow vital capacity (p=0.39) in the Per Protocol population, and a strong safety profile. Over the course of 6 months, patients treated with PrimeC experienced a slowing of disease progression, including preserved daily function. The clinical efficacy results showed a 29% difference in favor of PrimeC in ALSFRS-R (p=0.12), and a 13% difference in favor of PrimeC in slow vital capacity (p=0.5) in the Intent To Treat (ITT) population based on data from 68 out of 69 participants, due to one misdiagnosed participant. These data include 45 patients randomized to the PrimeC arm and 23 patients randomized to the placebo arm, from the 6-month double-blind segment. The safety and tolerability profile of PrimeC was well comparable to the placebo. Nearly all participants, 96%, who completed the 6-month double-blind portion of the trial chose to receive treatment with PrimeC through the 12-month open label extension.
In tandem with objective clinical assessments, PrimeC exerted favorable influences on diverse dimensions of patients’ quality of life. Comprehensive evaluations encompassing mental health domains, as exemplified by the mental health subscale of the PROMIS-10 questionnaire, showed improvements attributable to active treatment (PrimeC). Moreover, analyses pertaining to survival outcomes underscored the implications of PrimeC intervention in mitigating disease progression. Across diverse analytical frameworks, including hazard ratios derived from ALS complication free survival, MiTOS and King’s Advanced Staging system, PrimeC consistently exhibited numerical advantage over placebo, signaling tangible gains in extending survival and delaying disease progression milestones. MiTOS and King’s Advanced Stage-free Survival in ALS are two prognostic staging systems for ALS, assessing progression and complication free survival. ALS complication free survival is defined as time to death from any cause or respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for at least 22 hours per day for at least 10 consecutive days) or hospitalization due to ALS.
These data highlight a novel approach to treating ALS, with potential implications in other neurodegenerative conditions. PrimeC is a unique fixed-dose combination of ciprofloxacin and celecoxib, which may utilize complementary and synergistic mechanisms to preserve motor neuron health in ALS.
Additionally, in a preliminary analysis conducted following six months of double-blind, placebo-controlled treatment in the PARADIGM Phase 2b study, patients who received PrimeC demonstrated a trend towards decreased Neurofilaments-light chain (NfL) levels compared to placebo, with this trend being more pronounced in an earlier stage of the disease. The analysis was conducted by ALS biostatistician experts. The company is preparing for a follow-up analysis of NfL levels after a 12-month dosing period.
In May 2024, the company announced new positive data analysis from PARADIGM clinical trial demonstrating statistically significant slowing of disease progression in high-risk ALS patients. In July 2024, the company announced results from the 12-month analysis of the PARADIGM clinical trial which showed a significant improvement in the rate of decline of ALS Functional Rating Scale-Revised (ALSFRS-R) scores and survival rates for subjects who received PrimeC from the start of the trial compared to those who started on placebo. In August 2024, the company announced positive 12-month biomarker data from the PARADIGM clinical trial, which showed a significant decrease in ferritin levels and a corresponding increase in transferrin levels, both indicating alleviation of the pathology. In December 2024, the company announced positive 18-month clinical data from the PARADIGM clinical trial, which showed a significant difference in ALSFRS-R when comparing participants that were treated with PrimeC for 18 months versus those initially on placebo, indicating a disease-modifying effect. In February 2025, the company announced additional findings from an 18-month analysis of the PARADIGM clinical trial showing improvements in two additional endpoints, complication-free survival and Slow Vital Capacity (SVC).
NST002 Phase 2a Trial in ALS
In February 2021, the company completed its Phase 2a NST002 trial of PrimeC for the treatment of ALS. NST002 was an open label study that was designed to assess the safety and tolerability of an intermediate immediate-release formulation of PrimeC (PrimeC-IR), as well as routine disease progression measures. Fifteen patients with familial or sporadic ALS received a fixed dose of PrimeC-IR three times per day for 12 months. Patients were then evaluated by phone every 1.5 months and at a clinical site visit every three months.
The primary endpoint of the trial was PrimeC-IR’s safety and tolerability, which was measured by the number of patients with one or more treatment-emergent adverse events, the number of patients who discontinued treatment prematurely, the number of patients who discontinued treatment prematurely due to adverse events and the number of patients with significant abnormal laboratory values. The primary endpoint was met, with PrimeC-IR showing a safety profile that was consistent with known safety profiles of ciprofloxacin and celecoxib, and was mild and transient in nature. There were no new or unexpected safety signals detected during the trial.
Specifically, of the 15 patients in the safety population, ten patients (67%) experienced at least one treatment emergent adverse event, or TEAE. While most of the TEAEs were assessed by the investigator as unrelated to study drug, four patients (27%) experienced a TEAE that was assessed by the investigator as related to the study drug. Of TEAEs that were assessed as related to study drug, 11 were gastrointestinal disorders (flatulence was reported four times, nausea three times, dyspepsia twice, and abdominal pain and constipation once each), as well as dizziness and insomnia being reported once each. None of the TEAEs related to the study drug were serious.
The TEAEs in descending order of frequency were gastrointestinal disorders (38.4%), infections (15.4%), injury (12.8%), general disorders, psychiatric disorders, and nervous system disorders (7.7% each), and investigative, musculoskeletal, skin, and surgical procedures (2.6% each).
Most of the TEAEs (67%) were mild or moderate in intensity. Six patients (40%) experienced at least one severe TEAE. No clinically meaningful treatment-emergent changes were noted for any patient in the laboratory safety parameters, vital signs, or electrocardiograms. Two male patients died at home during the trial, and these events were considered by the investigator to be unrelated to the study drug.
All 12 patients who completed the NST002 trial elected to continue into an extension study with PrimeC-IR. The primary endpoint of the extension study is safety, and the company may use this additional data in communications with the FDA when presenting on long-term safety of the combined use of ciprofloxacin and celecoxib.
Investigators also measured PrimeC-IR’s potential efficacy using two accepted ALS clinical endpoints: the ALSFRS-R and forced vital capacity, or FVC. The ALSFRS-R is a validated rating scale for monitoring the progression of disability in patients with ALS. Patients are scored within the range of 0-48 points (with 48 indicating full function and zero indicating no function). ALSFRS-R scores correlate significantly with quality of life as measured by the Sickness Impact Profile, a behaviorally-based measure of health status, indicating that the quality of function is a strong determinant of quality of life in ALS patients. Historical data indicates that the average deterioration of ALS patients is one point per month in the ALFRS-R. FVC is a standard measure of pulmonary function that measures the amount of air that can be exhaled forcefully and quickly after a deep inhalation.
To better understand the ALSFRS-R and FVC data, the company compared the open-label results to two prediction models and virtual patient arms. The first was a virtual placebo generated by Origent Data Sciences, which projected an individual patient’s deterioration and survival for 12 months. This comparison indicated another aspect of safety, as it showed that the PrimeC-IR treated patients exceeded their projected survival and did not deteriorate more than predicted. This was strengthened by the use of the ENCALS survival prediction model, which also indicated that treated patients exceeded their projected survival.
Additionally, PrimeC-IR treated patients were compared to a historical placebo by matching patients in the trial with similar patients in the PRO-ACT database, one of the largest publicly available repositories of merged ALS clinical trials data. Patients were matched using a propensity score matching method, which is a statistical method that seeks to approximate a random experiment by matching each patient in the trial with a patient from the PRO-ACT database.
At 12 months, the average ALSFRS-R total score declined only by -0.84 points per month for patients treated with PrimeC, whereas the ALSFRS-R total score deteriorated -1.02 for the PRO-ACT group, a difference of 18%. Additionally, when breaking down the ALSFRS-R into the sub-domains of the four categories (bulbar, fine motor, gross motor and respiratory functions), PRO-ACT patients showed higher deterioration in gross motor functions and respiratory functions compared to the PrimeC cohort.
Respiratory function was further assessed by FVC. The FVC of PRO-ACT patients deteriorated by 2.99% of the predicted value, and PrimeC patients deteriorated by 2.09% of the predicted value, or a difference of 30%, matching the results from the ALSFRS-R respiratory function section.
Despite the p-values not showing statistical significance (i.e., p-value < 0.05), the study results indicate a clinical trend of slowing disease progression, achieved with an intermediate formulation of PrimeC. Based on the trend the company observed, that in a study with a larger sample size and with the optimal PrimeC dosage and formulation, there is much higher potential to achieve statistically significant clinical benefit with PrimeC.
Mechanism of Action Evaluation — Healthy vs ALS blood sample analysis
Neuronal derived exosomes (NDEs) have been shown to cross the blood-brain-barrier and enter blood circulation, enabling their isolation from patients’ blood using minimally invasive procedures. NDEs carry neuronal molecular signatures echoing the content of the cells from which they originated, providing potentially valuable information of disease pathogenesis. As a result, neuron-derived exosomes can serve as sources of potential biomarkers in neurodegenerative disorders, including ALS.
In parallel to the company’s NST002 trial, the company explored the relevance of PrimeC’s mechanism of action in ALS by examination of the changes in expression or activation of several disease biomarkers and key drug target biomarkers. The measurements were performed in neuronal extracellular vesicles, extracted from the blood serum of patients diagnosed with ALS and then compared to corresponding healthy volunteers, in collaboration with Mass General Hospital (MGH) in Boston.
The company examined and further validated key enzymes known the be affected in ALS in the same manner. It is well established that TDP-43 levels are increased in ALS patients, leading to a toxic accumulation. Additionally, a growing body of evidence shows decreased expression of LC3, a marker for autophagy in a number of ALS models, suggesting reduced basal levels and a decreased overall capacity for autophagy. Lastly, Cathepsin D (CatD) is a regularly expressed lysosomal protease that is involved in proteolytic degradation, cell invasion, and apoptosis. Growing evidence suggests that endolysosomal and autophagic defects are key pathogenic processes in various neurodegenerative disorders such as ALS. In examining these three biomarkers, the company observed a significant difference between ALS and healthy subjects (TDP-43 p-value = 0.002, LC3 p-value < 0.001, CatD p-value < 0.001).
Furthermore, since PrimeC aims to target miRNA dysregulation, iron accumulation, and neuroinflammation, the target engagement markers the company explored were EIF2C2 (Ago2), a component of the Dicer complex, which is essential to the regulation of miRNA and is affected in ALS, as well as Ferroportin-1, an iron pump serving as a marker of iron accumulation, and PGJ2, an endogenous product of inflammation, which induces neuronal death and the accumulation of proteins into aggregates. It has been previously demonstrated that PGJ2 was accumulated in the spinal cord of sporadic ALS patients. In this evaluation the company observed clear differences between ALS and healthy subjects in these three key PrimeC targets (EIF2C2 p-value = 0.007, PGJ2 p-value > 0.05, Ferroportin p-value = 0.005).
These biomarker evaluation results support the potential relevance of PrimeC’s mechanism of action for the treatment of ALS.
NST002 Biomarker Analysis — Assessing the Effect of PrimeC on Key Biomarkers
In order to assess the natural course of the observed ALS-related markers over time, longitudinal matched samples were tested over 12 months. This study was performed to obtain an indirect placebo control. Results showed no significant changes over time in most of the tested markers. Interestingly, a significant decrease was detected in LC3, a marker for autophagy, suggesting down regulation of the process.
Based on the parameters validated in the comparison of healthy vs ALS patient samples and the indirect placebo group, generated from non-PrimeC samples, the company examined the effect of PrimeC on these biomarkers. To that end, the company used its previously established NDE paradigm to examine the levels of the biomarkers in NDEs extracted from longitudinal blood samples obtained from the participants in the company’s NST002 clinical trial. These samples were collected at three time points throughout the study, namely, prior to initiation of PrimeC treatment, during their interim visit between the 3-6 month point and at the 12-month end of study visit.
Statistically significant changes were observed in the levels of TDP-43, following PrimeC treatment. TDP-43 is a protein highly associated with ALS pathology, and in a recent publication neuron-derived exosomal TDP-43 was shown to increase in longitudinal serum samples of patients with ALS. TDP-43 in PrimeC treated patients were observed to have a statistically significant decrease throughout the study (p-value = 0.002), indicating positive biological signs of the treatment. Analysis of additional ALS-associated pathological markers also showed significant positive changes, including LC3, a central protein in the autophagy pathway. Among PrimeC treated patients, LC3 levels were observed to elevate and stabilize (p-value = 0.054), suggesting that such treatment has positive effects on autophagy. Another ALS biomarker the company examined was CatD, which remained in a stable state before showing a decrease (p-value = 0.015), indicating a potential benefit for lysosomal activity. Lastly, the company assessed the change in PGJ2, downstream of COX-2, representing neuroinflammation. Levels of PGJ2 were observed to significantly decrease during PrimeC treatment (p-value<0.001), indicating a reduction in neuroinflammatory processes.
These results indicate positive biological activity of PrimeC, in a manner that attenuates disease-related pathologies, as well as indicating target engagement.
Clinical Results — NST001 Phase 1 Trial in ALS
The company has completed its Phase 1 NST001 trial of PrimeC for the treatment of ALS. NST001 was an open label, IND-exempt study designed to assess the safety and tolerability of an intermediate immediate-release formulation of PrimeC, at slightly different doses than NST002. The study was conducted at the Barrow Neurological Institute (BNI) in Phoenix, Arizona. Six patients with familial or sporadic ALS received a fixed dose of PrimeC-IR twice daily for 12 months. Patients were evaluated by phone every three months.
The primary endpoint of the trial was PrimeC-IR’s safety and tolerability, measured in the same manner as in NST002: number of patients with one or more treatment-emergent adverse events, number of patients who discontinued treatment prematurely, number of patients who discontinued treatment prematurely due to adverse events and number of patients with significant abnormal laboratory values.
NST001 and NST002 began simultaneously since both these studies were designed with the goal of assessing the safety and tolerability of two different doses and regimens of PrimeC-IR and were therefore considered independent of each other. Since no safety issues were expected due to the well-understood nature of both generic drugs comprising PrimeC, the company determined that there was not a need to wait for the completion of NST001 in order to begin NST002. Moreover, while NST001 was an IND-exempt clinical trial, NST002 was conducted in Israel, according to Israeli regulations, and did not require FDA input. Nonetheless, in January 2021, the company participated in a pre-IND meeting with the FDA to discuss the company’s past and future development plans.
Pre-clinical Results
In pre-clinical studies of two models of ALS zebrafish, SOD1 and TDP-43, PrimeC was observed to improve locomotor and cellular deficits, indicating a potential neuroprotective effect. In the SOD1 studies, treatment with PrimeC was observed to improve motor performance of the mutant larvae by 84%, and elicited recovery of motor neuron morphology and neuromuscular junction structure (NMJ), as well as preserving ramified morphology of microglia cells.
mSOD1 larvae exhibited a substantial recovery of motor neuron morphology and NMJ structure, suggesting a potential neuroprotective role for PrimeC treatment. As shown in the graphic titled ‘Neuromuscular Junction Structures’ below, following treatment with PrimeC, the company observed a higher number of intact organized synapses (yellow), with reduced proportion of orphaned pre-(red) and post-synaptic (green) puncta, resembling WT zebrafish. A second study, conducted in TDP-43 mutant zebrafish, substantiated these results and showed a significant improvement in their swimming abilities with an increase of 110% in distance and 43.8% in maximum swim velocity.
Elucidating The Synergistic Effect of PrimeC Combination for ALS utilizing in-vivo and in-vitro models
PrimeC novel formulation composed of unique doses of ciprofloxacin and celecoxib is aimed to synergistically inhibit the progression of ALS by addressing key elements of its pathophysiology. As described below, the effectiveness of PrimeC was compared to each of the individual active substances comprising it, celecoxib and ciprofloxacin, and PrimeC’s ability to improve drug pharmacokinetics and mode of action were assessed.
Pharmacokinetic (PK) studies in rodents showed that the combination of celecoxib and ciprofloxacin had a synergistic effect, as the addition of celecoxib increased the concentration of ciprofloxacin in the brain tissue and serum of rodents. These findings were confirmed by assessing the efficacy of PrimeC combination in an induced pluripotent stem cell (iPSC) model. Results showed that neurons treated with PrimeC combination had higher survival rates than those treated with individual compounds. The efficacy of PrimeC was also demonstrated in a Synaptoneurosome (SN) model, showing a beneficial effect on PrimeC related mechanisms.
In summary, data from the PK studies suggests that PrimeC’s combination therapy can be a beneficial approach for treating ALS.
The toxicology studies that the company performed with celecoxib and ciprofloxacin combination included a 90-day oral repeat-dose combination toxicity and toxicokinetic study in rats, 21-day oral dose range-finding (DRF) repeat-dose combination toxicity and toxicokinetic study in rats, a 56 day non-GLP DRF oral repeat-dose toxicity and toxicokinetic study of ciprofloxacin in beagle dogs and a 270 day GLP repeat-dose oral Ciprofloxacin toxicity and toxicokinetics study in beagle dogs with a 28-day recovery period.
In the 90-day oral repeat-dose combination toxicity and toxicokinetic study in rats, no effects were observed at combination doses up to 50 mg/kg/day celecoxib and 600 mg/kg/day ciprofloxacin (NOAEL). These doses convert to human equivalent doses of 483 mg/day for celecoxib and 5806 mg/day for ciprofloxacin, respectively (based on body surface area conversion for a 60 kg individual), which are 3.6 times greater and 4.3 times greater, respectively, than the maximal celecoxib and ciprofloxacin proposed daily doses in the PrimeC extended-release formulation (1360 mg ciprofloxacin and 136 mg celecoxib).
In the 21-day oral DRF repeat-dose combination toxicity and toxicokinetic study in rats, no adverse or combination-related effects were observed at combination doses up to 50 mg/kg/day celecoxib and 400 mg/kg/day ciprofloxacin.
In the 56 day non-GLP DRF oral repeat-dose toxicity and toxicokinetic study of ciprofloxacin in beagle dogs, dogs aged 8-10 months old were dosed twice daily 8 hours apart for a period of 56 consecutive days with ciprofloxacin at 150 mg/kg/day or 300 mg/kg/day (3/sex/group) or with the vehicle (2/sex/group). No adverse effects were observed at ciprofloxacin doses up to 300 mg/kg/day, and this dose was determined as the NOAEL.
The 270 day GLP repeat-dose oral Ciprofloxacin toxicity and toxicokinetics study in beagle dogs with a 28-day recovery period was completed. The NOAEL was set to 200 mg/kg/day.
In addition, the Phase 2a and Phase 2b clinical studies results, in which a total 57 ALS subjects (15 subjects from Phase 2a and 45 subjects from Phase 2b) were treated with PrimeC, demonstrated that PrimeC is safe and well-tolerated, with the safety profile that is consistent with the known safety profile of celecoxib and ciprofloxacin. No new or unexpected safety signals were detected. PrimeC did not result in any drug-related fatal SAEs. This safety profile has also been demonstrated in 32 healthy volunteers in PK studies conducted by the company.
Collaboration Agreement with Biogen
In May 2023, the company entered into a Collaborative Evaluation Agreement with Biogen under which Biogen agreed to evaluate the impact of PrimeC on neurofilament levels in the plasma of participants in PARADIGM. Biogen agreed to fund the neurofilament biomarker study and conduct the analysis. Biogen also received a right of first refusal for a definitive licensing agreement to co-develop and/or commercialize PrimeC for the treatment of ALS. In March 2024, Biogen and NeuroSense agreed not to continue the Collaborative Evaluation Agreement.
Collaboration Agreement with Lonza
In April 2024, the company announced a collaboration with Lonza to evaluate biological changes occurring in people with neurodegenerative diseases, including ALS. This agreement provides the company with access to Lonza’s unparalleled, state-of-the-art extracellular vesicles expertise and capabilities quickly and on an ‘on-demand’ basis, without further commitments. The company will leverage Lonza’s extensive experience in biomarker utilization in neurodegenerative diseases. Lonza will provide the development, optimization, and qualification of a method measuring biomarkers from NDEs, which will be integrated into the development of PrimeC.
Additional Studies
In May 2023, the company announced positive preliminary results from a novel biomarker study conducted to evaluate the potential of PrimeC for the treatment of PD.
In October 2023, the company announced the results of a non-sponsored in vitro study of PrimeC in ALS, which demonstrated that PrimeC has a positive effect ion ALS survival in an innovative induced pluripotent stem cell model.
AD Program
In the fourth quarter of 2023, the company initiated a randomized, prospective double-blind, single-center, placebo-controlled Phase 2 study to assess the safety, tolerability, target engagement, and efficacy of PrimeC (an intermediate formulation of CogniC) in patients with mild to moderate Alzheimer’s Disease (AD). The study is being conducted at the Rambam Medical Center site in Israel and aims to enroll 20 patients (10 participants per study arm). The study incorporates a comprehensive panel of biomarkers utilizing both cerebrospinal fluid (CSF) and blood to evaluate PrimeC’s biological activity and target engagement. Additionally, blood samples collected from each participant will be used to generate induced pluripotent stem cells (iPSCs), allowing for the study of disease mechanisms and drug response at the cellular level. This approach enables a deeper understanding of individual variability and may aid in predicting patient response to PrimeC.
The current study builds upon a proof-of-concept biomarker-driven cross-sectional study conducted in plasma samples from individuals with Alzheimer’s disease. This study aimed to assess the relevance of PrimeC’s proposed mode of action for addressing AD pathology. To this extent, a discovery biomarkers study was conducted utilizing neuronal-derived exosomes (NDEs) extracted from the plasma of 31 people living with AD vs. 19 neurologically healthy controls. To reinforce the study findings, the study was conducted in two cohorts to assure the robustness of the results. The obtained results from the discovery biomarkers study, as expected, showed higher levels of known proteins implicated in AD, i.e., Aß42 (p<0.05) and pTau (p<0.01) (Figure 4A). Moreover, the company found higher levels of TDP-43 (p<0.05) in AD samples (Figure 5B). Other markers related to the recycling process, such as cathepsin D (CatD), and inflammatory response, such as prostaglandin J2 (PgJ2), is altered in AD samples in comparison to control (Figure 2C). Specifically, CatD levels were lower (p<0.0001) in NDEs isolated from AD samples compared to control, and PgJ2 levels were higher (p<0.001) in AD samples. TDP-43 has been known to colocalize with senile plaques and neurofibrillary tangles, suggesting a direct interaction between TDP-43 and amyloid-ß (Aß) or tau, which are known to be hallmark biomarkers in AD. TDP-43 has been found in up to 57% of AD cases and aggregates of TDP-43 have been shown to be cytotoxic both in vitro and in vivo. Neuroinflammation plays a key role in the pathophysiology of the disease.
In view of the shared pathophysiology of these two neurodegenerative diseases, as well as the preliminary biomarker data, that there is a reasonable basis to hypothesize that ciprofloxacin and celecoxib combination can be an effective treatment for people living with AD.
Pre-clinical Pipeline
The company’s preclinical pipeline includes one additional product candidate, StabiliC, for the treatment of PD. The company is conducting pre-clinical studies related to PD. It is likely that the company will choose to consult with the FDA with regards to the company’s findings prior to the initiation of an advanced clinical studies, if and once relevant, and in order to obtain their advice and consent for the study design and clinical plan forward for each of the indications.
Many pathological pathways involve neuroinflammation, protein aggregation, mitophagy, excitotoxicity, oxidative stress, iron accumulation, and dysregulation of miRNAs between neurodegenerative diseases, leading to the hypothesis that an effective drug for one neurodegenerative disease can lay the foundations for other diseases-modifying drugs. Therefore, the company aimed to evaluate the putative neuroprotective effects of celecoxib and ciprofloxacin in a zebrafish pharmacological neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced, or ‘MPTP’-induced, PD model. The objective of this study was to determine if celecoxib and ciprofloxacin were able to prevent and/or rescue MPTP-induced altered behavior. Locomotor activity was assessed through a ‘tapping’ assay.
Results indicated that the symptomatic MPTP model is not relevant for StabiliC, suggesting that a different model with underlying PD pathologies may be required. The company therefore plans to further explore StabiliC’s mode of action and to assess its ability to effect or alter key PD-related hallmarks by utilizing both the in-vitro patients’ derived cells method and the in-vivo rodent adeno-associated-virus alpha synuclein, or AAV-SYN, model. StabiliC is planned to be a combination of ciprofloxacin and celecoxib, and/or another molecule to be determined during ongoing pre-clinical development. These assays will focus on the ability of StabiliC to reduce AAV-SYN aggregation and to improve morphological and functional markers.
Competition
Below is a description of competition surrounding each of the company’s disease targets and other technologies in development in the neurodegenerative field:
ALS. Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies and academic institutions, including Biogen, Novartis, AB Science, Prilenia Therapeutics, Brainstorm Cell Therapeutics, Clene, QurAlis, Eledon, among others, in various stages of clinical trials.
Alzheimer’s Disease. Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Biogen, Eli Lilly, Eisai, Roche (including Genentech, its wholly owned subsidiary) and Alector in various stages of clinical trials.
Parkinson’s Disease. Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Prothena, Roche (including Genentech, its wholly owned subsidiary), Prevail/Eli Lilly, AstraZeneca, and Takeda in various stages of clinical trials.
Intellectual Property
Patents
The company’s patent portfolio includes U.S. Patent 10,980,780, which relates to methods for the treatment of ALS using ciprofloxacin and celecoxib, and which expires in 2038. This patent also been issued in the European Patent Office, Japan, Canada, Australia, and Israel. In addition, U.S. patent application 16/623,467, which relates to methods of treatment of neurodegenerative disease using combinations of ciprofloxacin and celecoxib, is pending. The patent based on this application is expected to expire on June 20, 2038.
In addition, the company has developed a pharmaceutical composition comprising, as active ingredients, ciprofloxacin and celecoxib, and have been granted US Patent 12,097,185 and have filed international PCT application PCT/IL2022/051096 relating to the compositions. This patent and patent applications relate to pharmaceutical formulations. The U.S. patent will expire in December 2042 and the national patent applications based on the PCT application are expected to expire in October 2042.
Government Regulation
Depending upon the timing, duration and specifics of the company’s product candidates, some of the company’s U.S. patents claiming a new drug product may be eligible for limited patent term extension under the Hatch-Waxman Amendments, which permit a patent term restoration of up to five years for the patent term lost during product development and the FDA regulatory review process.
The company’s operations are subject to regulation by various federal, state, and local authorities in addition to the FDA, including but not limited to the Centers for Medicare & Medicaid Services, or CMS, the Department of Health and Human Services, or HHS, (including the Office of Inspector General, Office for Civil Rights and the Health Resources and Services Administration), the DOJ and individual U.S. Attorney offices within the DOJ, and state and local governments.
Research and Development
The company’s research and development expenses were $5,698 thousand for the year ended December 31, 2024.
History
NeuroSense Therapeutics Ltd. was founded in 2017. The company was incorporated in 2017 and was registered as a private company limited by shares under the laws of the state of Israel.
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