This is a multi-national, multi-center, randomized, double-blind, placebo-controlled study to evaluate the effects of etripamil NS in patients with atrial fibrillation (AF). This study includes Screening Visit, Randomization Visit, a Treatment Period with scheduled Follow-up Visits (Monthly Follow-up and Post-treatment Follow-up Visits), a Final Study Visit, and an End of Study Telephone Follow up Visit.
Each patient will be randomized 1:1 to receive placebo or 70 mg Etripamil NS regimens. Patients will self-administer study drug for a perceived episode of AF with RVR with an initial dose of placebo or 70 mg etripamil NS, followed by an optional second dose of the same study drug 10 minutes after the first dose if the patient continues to experience symptoms. Patients may treat up to a maximum of 4 episodes in the study.
Informed consent will be obtained prior to any study procedures.

Start Date01 Mar 2025

Sponsor / Collaborator

Milestone Pharmaceuticals, Inc.

NCT05763953 / RecruitingPhase 2

The NODE-202 Study Multi-Center, Multi-National, Open-Label, Efficacy and Safety Study of Etripamil Nasal Spray in Pediatric Patients With Paroxysmal Supraventricular Tachycardia

NODE-202 is a Phase 2, multicenter, multinational, single dose, open-label, 2-part, sequential design study in pediatric patients with an established diagnosis of paroxysmal supraventricular tachycardia (PSVT) presenting with a symptomatic episode of PSVT.
In Part 1, at least 30 patients aged 12 to <18 years will be enrolled and treated with etripamil nasal spray (NS). Efficacy, safety, tolerability and PK (for at least 12 patients) will be assessed after administration of 70 mg etripamil NS (Part 1A). At least 18 subsequent patients will be enrolled and treated with the etripamil NS with the dose determined by the Pharmacokinetic (PK) analysis and will undergo efficacy and safety/tolerability assessments (Part 1B).
In Part 2, at least 30 patients aged 6 to <12 years will be enrolled and treated with etripamil NS at a dose selected based on appropriate body size-based modeling, as well as efficacy, safety/tolerability, and PK data collected in Part 1. Efficacy, safety, tolerability and PK (for at least 12 patients) will be assessed after administration of etripamil NS (Part 2A). At least 18 subsequent patients will be enrolled and treated with the etripamil NS with the dose determined by the PK analysis and will undergo efficacy and safety/tolerability assessments (Part 2B).
The study will include the following visits: A Screening Visit, A Treatment Visit, , and A Follow-Up/End of Study Visit.

Start Date11 Dec 2023

Sponsor / Collaborator

Milestone Pharmaceuticals, Inc.

CTR20221959 / CompletedPhase 1

一项在中国健康受试者中评价Etripamil药代动力学、药效学、安全性和耐受性的单中心、随机、双盲、安慰剂对照1期临床研究

[Translation] A single-center, randomized, double-blind, placebo-controlled phase 1 clinical study to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of Etripamil in healthy Chinese subjects

主要目的： · 在中国健康成年受试者中评价Etripamil的药代动力学（PK）次要目的： · 在中国健康成年受试者中评价Etripamil的药效学（PD） · 在中国健康成年受试者中评价Etripamil的安全性和耐受性探索性目的： · 在中国健康成年受试者中评价Etripamil的PK（暴露）-PD（效应）关系

[Translation]

Primary objective: · To evaluate the pharmacokinetics (PK) of Etripamil in healthy Chinese adult subjects Secondary objective: · To evaluate the pharmacodynamics (PD) of Etripamil in healthy Chinese adult subjects · To evaluate the safety and tolerability of Etripamil in healthy Chinese adult subjects Exploratory objective: · To evaluate the PK (exposure)-PD (effect) relationship of Etripamil in healthy Chinese adult subjects

Start Date07 Mar 2023

Sponsor / Collaborator

Milestone Pharmaceuticals, Inc.

[+2]

100 Clinical Results associated with Etripamil

100 Translational Medicine associated with Etripamil

100 Patents (Medical) associated with Etripamil

Literatures (Medical) associated with Etripamil

01 Oct 2024·INTERNATIONAL JOURNAL OF TOXICOLOGY

Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia

Article

Author: Lopez Mendez, Carlos ; Pion, Johanne ; Boulanger, Veronique ; Wight, Douglas ; Moreau, Jean-Pierre

Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.

01 May 2024·Journal of the American College of Cardiology

Etripamil Nasal Spray for Recurrent Paroxysmal Supraventricular Tachycardia Conversion

Article

Author: Singh, Narendra ; Camm, A John ; Noseworthy, Peter A ; Parody, Maria L ; Sears, Samuel F ; Coutu, Benoit ; Rafii, Farhad ; Ip, James E ; Bharucha, David B ; Stambler, Bruce S

This study aimed to evaluate the efficacy and safety of etripamil, a nondihydropyridine calcium-channel blocker, in the treatment of atrioventricular (AV)-nodal-dependent paroxysmal supraventricular tachycardia (PSVT) using a self-administered nasal spray in a real-world outpatient setting.NODE-303, an open-label study conducted from June 2019 to Feb. 2023, involved 1,116 patients across 148 sites in the United States, Canada, and South America. Patients with perceived PSVT episodes, including those with a history of atrial fibrillation/flutter, self-administered etripamil 70 mg as needed.The study protocol, approved by ethics committees, allowed for up to 4 episodes per patient and did not require prior test-dosing.Data on efficacy and safety were collected, including electrocardiog. monitoring.A total of 1,054 episodes were treated with etripamil, with 727 providing interpretable electrocardiog. data.Of these, 552 (75.9%) were adjudicated as AV-nodal-dependent PSVT.Conversion to sinus rhythm within 60 min was achieved in 69.9% of episodes, with a median time-to-conversion of 17.0 min.Conversion rates varied from 57.7% to 77.8% across the first to fourth episodes, with median times ranging from 14.0 to 19.1 min.Safety data indicated that 59.8% of patients experienced at least one treatment-emergent adverse event (TEAE), mostly mild and localized to the nasal administration site, such as nasal discomfort and congestion.Serious adverse events were rare and not related to the drug.There was a noted decrease in TEAE frequency with successive episodes.Etripamil demonstrates effective and rapid conversion of PSVT to sinus rhythm in a real-world, unsupervised setting, with a favorable safety profile.The study supports the potential of etripamil as a valuable self-administered treatment option for patients with PSVT, showing consistent efficacy across multiple episodes and good tolerability with decreasing adverse event frequency over successive uses.

01 Apr 2024·American heart journal

Rationale and design of the NODE-303 study: evaluating the safety of symptom-prompted, self-administered etripamil for paroxysmal supraventricular tachycardia episodes in real-world settings

Article

Author: Stambler, Bruce ; Uribe, Juan Agudelo ; Vyselaar, John ; Camm, A John ; Sears, Samuel F ; Shardonofsky, Silvia ; Omodele, Sarah ; Noseworthy, Peter A ; Bharucha, David B ; Bui, Hanh ; Ip, James E ; Coutu, Benoit ; Parody, Maria Leonor ; Singh, Narendra

BACKGROUND:

Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a nonmedical supervised setting.

METHODS:

This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the nonhealthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil.

RESULTS:

Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 minutes after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 minutes. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey.

CONCLUSIONS:

Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT.

News (Medical) associated with Etripamil

12 Nov 2024

·www.globenewswire.com

Milestone Pharmaceuticals Reports Third Quarter 2024 Financial Results and Provides Regulatory and Corporate Update

NDA for CARDAMYST™ in PSVT under review by FDA; PDUFA March 27, 2025MONTREAL and CHARLOTTE, N.C., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Milestone® Pharmaceuticals Inc. (Nasdaq: MIST) today reported financial results for the third quarter ended September 30, 2024 and provided a corporate update. “Our primary focus at Milestone is preparing for potential FDA approval of CARDAMYST (etripamil) nasal spray for the management of PSVT,” said Joseph Oliveto, President and Chief Executive Officer of Milestone Pharmaceuticals. “We believe that CARDAMYST has the potential to improve how PSVT is managed and positions Milestone to deliver meaningful value to patients, providers, and payors. Complementing our efforts in PSVT, we are very encouraged by clinician interest in the etripamil Phase 3 study in AFib-RVR which we are working toward commencing in the first half of 2025.” Third Quarter and Recent Program Updates CARDAMYST for patients with paroxysmal supraventricular tachycardia (PSVT) New Drug Application (NDA) for CARDAMYST for PSVT under review by U.S. FDA. The FDA accepted the NDA for CARDAMYST in May 2024 and has set a Prescription Drug User Fee Act (PDUFA) target date for March 27, 2025. Preparations for a commercial launch in 2025 are underway.Milestone’s partner, Corxel (formerly Ji Xing Pharmaceuticals Ltd), announced positive top line results from a Phase 3 trial of etripamil conducted in China. In September, Corxel announced positive results from the multi-center, randomized, double-blind, placebo-controlled trial which expands the etripamil global development program to more than 2,000 unique patients treated with etripamil. The trial (JX02002) successfully met its primary endpoint, with a Kaplan Meier analysis showing a statistically significantly greater proportion of patients who self-administered etripamil converted from PSVT to sinus rhythm within 30 minutes compared to placebo (40.5% vs. 15.9%, respectively; hazard ratio [HR] = 3.00; p<0.001). Statistically significant (p<0.05) results were also achieved for the secondary efficacy endpoints for percent of patients’ PSVT converting to sinus rhythm by 10, 15, 45, and 60 minutes after self-administration of study drug. The safety and tolerability data from the trial were consistent with previous clinical studies. Milestone entered into an agreement with Ji Xing in 2021, granting it an exclusive license to develop and, if approved, commercialize etripamil in PSVT in Greater China. Milestone hosted a KOL webinar entitled “Learnings from the Field: Managing PSVT and Studying AFib-RVR in the Community Setting.” The event, which is the second of a series of planned webinars learning from community-based health care providers, featured Aamer H. Jamali, MD, FACC and Farhad Rafii, MD, FACC, both from Interventional Cardiology Medical Group in West Hills, CA. The physicians discussed how they manage patients with PSVT and atrial fibrillation with rapid ventricular rate (AFib-RVR) and highlighted clinical trial experience in PSVT as well as upcoming trials in AFib-RVR with the potential to impact the current standard of care. A replay of the webinar is available on the Milestone corporate website here. Patient Reported Outcomes (PRO) data from PSVT patients receiving etripamil were presented at the annual meeting of the European Society of Cardiology (ESC Congress) in London. On August 30, 2024 Professor John Camm of St. George’s University of London, UK, presented PRO data from the NODE-303 Phase 3 trial of etripamil in PSVT in a moderated poster presentation. The poster presentation is available here. Etripamil for patients with AFib-RVR Milestone is on track to initiate a Phase 3 trial evaluating etripamil in AFib-RVR in H1 2025. The Company has been in communication with the FDA regarding Phase 3 study design and is planning a trial that will be conducted in the at-home setting, comprising approximately 150 events from patients with a history of symptomatic episodes and using a repeat-dose regimen of 70 mg per dose (the same as the self-administration dosing regimen approach that was studied in the RAPID trial in PSVT). Corporate Updates In September, Joseph Papa was appointed to the board of directors. Mr. Papa brings more than 35 years of experience, having previously served as Chairman and CEO of Bausch + Lomb, Bausch Health and Perrigo and as a director of SparingVision and Candel Therapeutics. He has broad commercial experience and proven capabilities of advancing innovative products aimed at significantly enhancing patients’ lives. Third Quarter 2024 Financial Results As of September 30, 2024, Milestone had cash, cash equivalents, and short-term investments of $76.4 million, compared to $66.0 million as of December 31, 2023.Research and development expense, net of tax credits for the third quarter of 2024 was $4.0 million, compared with $6.7 million for the same period in 2023. For the nine months ended September 30, 2024, research and development expense, net of tax credits was $10.4 million compared with $25.6 million for the same period in 2023. This decrease in research and development expenses was driven by lower clinical development costs and clinical personnel-related costs driven by completion of phase 3 studies, as well as a decrease in drug manufacturing and regulatory costs.General and administrative expense for the third quarter of 2024 was $3.7 million, compared with the $4.2 million reported for the same period in 2023. For the nine months ended September 30, 2024, general and administrative expense was $12.7 million, compared with the with $12.6 million for the prior year period. The decrease between the third quarter periods is primarily due to a decrease in personnel costs, partially offset by an increase in outside service costs.Commercial expense for the third quarter of 2024 was $1.9 million, compared with $4.4 million for the same period in 2023. For the nine months ended September 30, 2024, commercial expense was $6.6 million compared with $10.1 million for the prior year period. The decreases are a result of decreases in personnel costs, professional costs and other operational expenses related to commercialization.For the third quarter of 2024, net loss was $9.4 million, compared to $15.1 million for the prior year period. For the nine months ended September 30, 2024, Milestone's net loss was $29.2 million, compared to $46.1 million in the prior year period. For further details on the Company’s financials, refer to the quarterly report on Form 10-Q for the quarter ended September 30, 2024, filed with the SEC on November 12, 2024. About Etripamil Etripamil is Milestone's lead investigational product. It is a novel calcium channel blocker nasal spray under clinical development for frequent and often highly symptomatic episodes of PSVT and AFib-RVR. It is designed as a self-administered rapid response therapy for patients thereby bypassing the need for immediate medical oversight. If approved, etripamil is intended to provide health care providers with a new treatment option to enable on-demand care and patient self-management. This portable, self-administered treatment may provide patients with active management and a greater sense of control over their condition. CARDAMYST™ (etripamil) nasal spray, the conditionally approved brand name for etripamil nasal spray, is well studied with a robust clinical trial program that includes a completed Phase 3 clinical-stage program for the treatment of PSVT and Phase 2 trial for the treatment of patients with AFib-RVR. About Milestone Pharmaceuticals Milestone Pharmaceuticals Inc. (Nasdaq: MIST) is a biopharmaceutical company developing and commercializing innovative cardiovascular solutions to improve the lives of people living with complex and life-altering heart conditions. The Company’s focus on understanding unmet patient needs and improving the patient experience has led us to develop new treatment approaches that provide patients with an active role in self-managing their care. Milestone's lead investigational product is etripamil, a novel calcium channel blocker nasal spray that is being studied for patients to self-administer without medical supervision to treat symptomatic episodic attacks associated with PSVT and AFib-RVR. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “believe,” “continue,” “could,” “demonstrate,” “designed,” “develop,” “estimate,” “expect,” “may,” “pending,” “plan,” “potential,” “progress,” “will”, “intend” and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Milestone’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding: the timing and outcomes of future interactions with U.S. and foreign regulatory bodies, including the FDA, including the timing of the FDA’s review of the NDA; the ability of CARDAMYST to improve how PSVT is managed and position Milestone to deliver meaningful value to patients and providers; the timing of the commercial launch of etripamil for PSVT; and the timing, design and outcomes of our clinical trials, including our Phase 3 study in AFib-RVR. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, whether our future interactions with the FDA will have satisfactory outcomes; whether and when, if at all, our NDA for etripamil will be approved by the FDA; whether the FDA will require additional trials or data which may significantly delay and put at risk our efforts to obtain approval and may not be successful, the risks inherent in biopharmaceutical product development and clinical trials, including the lengthy and uncertain regulatory approval process; uncertainties related to the timing of initiation, enrollment, completion, evaluation and results of our clinical trials; risks and uncertainty related to the complexity inherent in cleaning, verifying and analyzing trial data; and whether the clinical trials will validate the safety and efficacy of etripamil for PSVT or other indications, among others, general economic, political, and market conditions, including deteriorating market conditions due to investor concerns regarding inflation, Russian hostilities in Ukraine and ongoing disputes in Israel and Gaza and overall fluctuations in the financial markets in the United States and abroad, risks related to pandemics and public health emergencies, and risks related the sufficiency of Milestone’s capital resources and its ability to raise additional capital in the current economic climate. These and other risks are set forth in Milestone’s filings with the U.S. Securities and Exchange Commission (SEC), including in its annual report on Form 10-K for the year ended December 31, 2023 and its quarterly report on Form 10-Q for the quarter ended September 30, 2024, under the caption “Risk Factors,” as such discussion may be updated from time to time by subsequent filings Milestone may make with the SEC. Except as required by law, Milestone assumes no obligation to update any forward looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contact: Kim Fox, Vice President, Communications, kfox@milestonepharma.com Investor Relations Chris Calabrese, ccalabrese@lifesciadvisors.com Kevin Gardner, kgardner@lifesciadvisors.com Milestone Pharmaceuticals Inc.Condensed Consolidated Statements of Loss (Unaudited)(in thousands of US dollars, except share and per share data) Three months ended September 30, Nine months ended September 30, 2024 2023 2024 2023 Revenue$— $— $— $1,000 Operating expenses Research and development, net of tax credits 3,963 6,721 10,417 25,600 General and administrative 3,742 4,227 12,741 12,561 Commercial 1,911 4,412 6,596 10,137 Loss from operations (9,616) (15,360) (29,754) (47,298) Interest income 1,080 1,120 3,260 2,921 Interest expense (903) (841) (2,662) (1,697) Net loss and comprehensive loss$(9,439) $(15,081) $(29,156) $(46,074) Weighted average number of shares and pre-funded warrants outstanding, basic and diluted 66,190,302 42,973,160 60,856,495 42,920,620 Net loss per share, basic and diluted$(0.14) $(0.35) $(0.48) $(1.07) Milestone Pharmaceuticals Inc.Condensed Consolidated Balance Sheets (Unaudited)(in thousands of US dollars, except share data) September 30, 2024 December 31, 2023Assets Current assets Cash and cash equivalents$12,799 $13,760 Short-term investments 63,620 52,243 Research and development tax credits receivable 837 643 Prepaid expenses 2,523 3,178 Other receivables 1,211 3,208 Total current assets 80,990 73,032 Operating lease right-of-use assets 1,515 1,917 Property and equipment 201 277 Total assets$82,706 $75,226 Liabilities, and Shareholders' Equity Current liabilities Accounts payable and accrued liabilities$4,676 $6,680 Operating lease liabilities 582 546 Total current liabilities 5,258 7,226 Operating lease liabilities, net of current portion 1,002 1,457 Senior secured convertible notes 52,434 49,772 Total liabilities 58,694 58,455 Shareholders’ Equity Common shares, no par value, unlimited shares authorized 53,327,908 shares issued and outstanding as of September 30, 2024, 33,483,111 shares issued and outstanding as of December 31, 2023 288,006 260,504 Pre-funded warrants - 12,910,590 issued and outstanding as of September 30, 2024 and 9,577,257 as of December 31, 2023 53,076 48,459 Additional paid-in capital 38,112 33,834 Accumulated deficit (355,182) (326,026) Total shareholders’ equity 24,012 16,771 Total liabilities and shareholders’ equity $82,706 $75,226

Phase 3Financial StatementLicense out/inClinical ResultNDA

28 Oct 2024

·www.globenewswire.com

CORXEL and LENZ Therapeutics Announce Positive Topline Data from China Phase 3 Presbyopia Trial of LNZ100

Primary endpoint was met with 74% of participants dosed with LNZ100 achieving three-lines or greater improvement at 3 hours post treatment，and maintaining their optimal distance visual acuity (i.e., not losing 5 or more letters). The difference in efficacy was statistically significant in the LNZ100 treatment group compared to the vehicle group (p<0.0001) Rapid onset and long duration shown with 69% of participants achieving three-lines or greater improvement at 30 minutes and 30% at 10 hours 91% of participants indicated they noticed an improvement in their near vision LNZ100 could potentially be the best-in-class non-invasive treatment for presbyopia SHANGHAI, China and SAN DIEGO, Oct. 27, 2024 (GLOBE NEWSWIRE) -- Corxel Pharmaceuticals (CORXEL) and LENZ Therapeutics (Nasdaq: LENZ) today announced positive topline data from the Phase 3 JX07001 clinical trial of LNZ100 in patients with presbyopia in China. CORXEL is a leading biotech company committed to bringing innovative science and medicines to underserved patients with serious and life-threatening diseases. LENZ Therapeutics is a pre-commercial biopharmaceutical company focused on developing the first and only aceclidine-based eye drop to improve near vision in people with presbyopia. In this China Phase 3 safety and efficacy trial, LNZ100 (1.75% aceclidine HCl) achieved the primary endpoint and key secondary endpoints, with statistically significant three-lines or greater improvement in Best Corrected Distance Visual Acuity (BCDVA) at near, and maintaining their optimal distance visual acuity (i.e., not losing 5 or more letters). More results showed (all p<0.0001): Rapid onset: 84% and 69% achieved two-lines and three-lines or greater improvement at 30 minutes respectively.3 hours post treatment: 88% and 74% achieved two-lines and three-lines or greater improvement at 3 hours respectively，and maintained their optimal distance visual acuity (i.e., not losing 5 or more letters).Long duration: 61% and 30% achieved two-lines and three-lines or greater improvement at 10 hours respectively. LNZ100 was well-tolerated with no serious treatment-related adverse events observed in the trial. The study was a Phase 3, multicenter, randomized, double-blind, vehicle-controlled study, including a 4-week efficacy study followed by a 5-month extension safety study, designed to evaluate the efficacy and safety of LNZ100 (an aceclidine-based ophthalmic solution) in participants with presbyopia. The objectives were to assess the potential of LNZ100 to improve near vision among Chinese presbyopia patients and to evaluate the efficacy and safety profiles.  The trial has enrolled 300 participants, with a broad enrollment criteria of between 45 and 75 years of age with a refractive range of -4.0D SE to +1.0D SE, including those who had undergone laser-assisted cornea refractive surgery/monofocal IOL implantation. Professor Jia Qu, Principal Investigator and Co-Principal Investigator，Vice Chairman of Ophthalmology Branch, Chinese Medical Association, Director of optometry department, Wenzhou Medical University said: “we are very pleased with the results of the LNZ100 trial, particularly the significant efficacy and favorable safety profile of LNZ100 in patients with presbyopia, demonstrating an important advance in the field of presbyopia treatment in China. Currently, patients mainly rely on wearing eyeglasses as treatment for presbyopia. There is a large unmet need for non-invasive and reversible treatments. We expect that LNZ100 will fill this vacuum and become an innovative force in the treatment of presbyopia in China, providing more patients with the hope of clear vision." Professor Fan Lyu, Principal Investigator and Co-Principal Investigator，Head of optometry working-group under Ophthalmology Branch, Chinese Medical Association, Director of National Clinical Medical Research Centre for Eye Diseases said: "The main active ingredient of LNZ100, aceclidine, causes temporary pupil constriction, resulting in an optical effect that significantly extends the depth of focus and improves the quality of vision. The statistically significant data and clinically meaningful outcomes observed in the trials provide strong support for the efficacy and safety of LNZ100. We anticipate that LNZ100 will be a practical treatment option for a wide spectrum of patients and will have a favorable impact on paradigm shift of helping improve near-vision in the Chinese presbyopia population. “We are especially grateful to all the hard-working and dedicated researchers, partner organizations and all the volunteers who participated in the study,” Sandy Mou, Board Executive Director and Chief Executive Officer of CORXEL, said. “The common goal is to benefit hundreds of millions of people around the world, to set an international leading research benchmark, and to introduce novel treatment concepts and potentially optimal products to China first, providing a safe and convenient treatment option for the vast number of presbyopia patients. Looking ahead, we will actively communicate and cooperate with drug regulatory authorities to expedite the submission and approval of LNZ100. We believe that LNZ100 will not only significantly improve patients' vision and quality of life, but will also have a profound impact on the field of presbyopia treatment and research in China.” “We would like to first congratulate the team at CORXEL for their effort in their Phase 3 clinical study in China. We are pleased with the impressive and consistent performance demonstrated by LNZ100 in our collective studies, further validating the vision of targeting an ‘all eyes, all day’ solution,” said Eef Schimmelpennink, President and Chief Executive Officer of LENZ Therapeutics. “With this data, we believe LNZ100 has further enhanced its potential as a global therapy and is further on its path towards providing access to the estimated 400 million people with presbyopia in China. This data signifies a tremendous joint effort between the CORXEL and LENZ teams and comes in rapid succession to the recent FDA acceptance of our New Drug Application for LNZ100 in the United States.” About PresbyopiaPresbyopia is a physiological phenomenon associated with aging that results in a progressively worsening ability to see nearby objects clearly. It is caused by the gradual hardening of the lens. This results in a decline of the eye's adjustment function, and the inability to focus the image of nearby objects on the retina, leading to a decline in near vision. Studies have shown that the onset of presbyopia typically occurs around the age of 38, reaching a prevalence rate of nearly 100 percent at the age of 52 in China. It is estimated that more than 400 million people in China suffer from presbyopia.  Currently, the treatment options for presbyopia are very limited. Wearing glasses requires frequent removal and insertion, causing many inconveniences in work and life. Surgery, as an irreversible invasive operation, has a very limited acceptance. There are no approved drugs for the treatment of presbyopia in China and the medical need for non-invasive, safe, efficient and reversible treatments for presbyopia remains unsolved.  About LNZ100LNZ100 (aceclidine) eye drops are being developed by LENZ Therapeutics and CORXEL acquired the Greater China rights for the development and commercialization in April 2022. LNZ100 is formulated with aceclidine, a miotic, and designed to achieve optimal pupil diameter without impacting distance vision, a key limitation of other miotics. Miotics are compounds that cause pupil constriction, or miosis, creating a pinhole effect that enables better focus of incoming light from near objects onto the retina. Research has shown that a pupil diameter below two millimeters (2 mm) is optimal for presbyopia treatment and results in clinically meaningful improvement in near vision. Unlike other miotics such as pilocarpine and carbachol, aceclidine’s mechanism of action is pupil-selective, meaning it can activate the iris sphincter muscle and cause miosis of the pupil to a diameter below 2 mm without overstimulating the ciliary muscles that can cause a myopic shift and impair distance vision. As a result, aceclidine does not require any remaining accommodation to improve near vision, broadening its benefits to older presbyopes whose lens has lost this capacity. Therefore, we expect that users may be able to benefit from treatment even as they age from mid-40s to well into their mid-70s and across a broad range of refractive errors, as demonstrated in clinical testing to date. About CORXELCORXEL, formerly named Ji Xing Pharmaceuticals, is a leading biotech company headquartered in US and China committed to bringing innovative science and medicines to underserved patients with serious and life-threatening cardiometabolic diseases. Backed by RTW Investments, CORXEL was founded in 2019 to develop and commercialize novel, innovative therapeutics to treat unmet medical needs in diseases. With a strong and further developing asset pipeline, industry leading talent, and patient-centric focus, CORXEL is dedicated to deliver a meaningful and lasting impact on patients. The full portfolio of CORXEL consists of 2 assets with global rights and 4 assets with Greater China rights in late-stage clinical development. The portfolio with global rights are JX09 for hypertension and JX10 for acute ischemic stroke (AIS), while the portfolio with Greater China rights include aficamten, etripamil, varenicline solution nasal spray/US brand name TYRVAYA®, and LNZ100. For further information about CORXEL, please visit www.corxelbio.com.   About LENZ TherapeuticsLENZ Therapeutics is a pre-commercial biopharmaceutical company focused on the development and commercialization of the first and only aceclidine-based eye drop to improve near vision in patients with presbyopia. LENZ’s product candidate, LNZ100 is a preservative-free, single-use, once-daily eye drop containing aceclidine. LNZ100 was evaluated in the registration-enabling Phase 3 CLARITY study as a potential therapy for the treatment of presbyopia, a condition impacting an estimated 1.8 billion people globally and 128 million people in the United States. The U.S. Food and Drug Administration (FDA) has assigned a Prescription Drug User Fee Act (PDUFA) target action date of August 8, 2025 for LNZ100. LENZ is committed to commercializing an ideal pharmaceutical presbyopia solution that enhances vision for “all eyes, all day”. LENZ is headquartered in San Diego, California. For more information, visit: LENZ-Tx.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of United States federal securities laws. You can identify forward-looking statements by words such as “may,” “will,” “could,” “can,” “would,” “should,” “expect,” “intend,” “plan,” “anticipate,” “believe,” “estimate,” “predict,” “project,” “potential,” “poised,” “continue,” “ongoing” or the negative of these terms or other comparable terminology, but not all forward-looking statements will contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding the potential of LNZ100 to have best-in-class performance and LNZ100 as a global therapy; the size of the addressable population for LNZ100; expectations regarding the commercial opportunity and beneficial characteristics of LNZ100; and plans and expectations regarding commercialization of LNZ100, if approved. These statements are based on numerous assumptions concerning the development of LENZ’s products and target markets and involve substantial risks, uncertainties and other factors that may cause actual results, levels of activity, performance or achievement to be materially different from the information expressed or implied by these forward-looking statements, including those risk factors described in the section titled “Risk Factors” in LENZ’s Quarterly Report on Form 10-Q filed for the quarter ended June 30, 2024 and in LENZ’s subsequent filings with the SEC. LENZ cannot assure you that the forward-looking statements in this press release or the assumptions upon which they are based will prove to be accurate. The forward-looking statements in this press release are as of the date of this press release. Except as otherwise required by applicable law, LENZ disclaims any duty to update any forward-looking statements. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this press release. LENZ Therapeutics Contact: Dan Chevallard IR@LENZ-Tx.com

Phase 3Clinical Result

24 Sep 2024

·www.globenewswire.com

Milestone Pharmaceuticals to Host Investor KOL Event

Learnings from the Field: Managing PSVT and Studying AFib-RVR in the Community Setting Hosted 10 am ET, Tuesday, October 8, 2024 MONTREAL and CHARLOTTE, N.C., Sept. 24, 2024 (GLOBE NEWSWIRE) -- Milestone® Pharmaceuticals Inc. (Nasdaq: MIST), a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines, today announced it will host Part 2 of its virtual investor education series on Tuesday, October 8, 2024 from 10:00 AM ET to 11:30 AM ET. To register for “Learnings from the Field: Expert Perspectives on Managing PSVT and Studying AFib-RVR in the Community Setting”, click here. The event will feature Aamer H. Jamali MD, FACC and Farhad Rafii, MD, FACC from Interventional Cardiology Medical Group in West Hills, CA, who will discuss the burden of paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation (AFib) on patients and how these conditions are managed in their practice. It will also highlight clinical trial experience in PSVT and upcoming trials in atrial fibrillation with rapid ventricular rate (AFib-RVR) with the potential to impact the current standard of care. A live question and answer session will follow the formal presentation. About Aamer H. Jamali, MD, FACC Aamer H. Jamali, MD, FACC, a cardiologist at Interventional Cardiology Medical Group, holds an appointment as an Assistant Clinical Professor of Medicine at UCLA School of Medicine, and is affiliated with the Smidt Heart Institute at Cedars-Sinai. Dr. Jamali has been practicing medicine in the San Fernando Valley for over 16 years. He launched the first structural heart program in the valley, offering cutting edge procedures such as PFO/ASD closure, watchman, and minimally invasive aortic valve surgery to the local community. He has also served as Chief of Medicine and as Chief of Staff at West Hills Hospital. Additionally, Dr. Jamali serves as the Secretary of SBMAA, an international non-profit organization devoted to healthcare equality. Dr. Jamali graduated with highest honors from the University of California, Berkeley, attended the UCLA School of Medicine and chose Stanford University for his post-graduate training in Internal Medicine. He completed fellowships in General and Interventional Cardiology at Cedars-Sinai Medical Center, where he also served as Chief Fellow. Dr. Jamali has published in multiple scientific journals, written textbook chapters, and presented at international cardiology conferences. About Farhad Rafii, MD, FACC Farhad Rafii, MD, FACC, a cardiologist at Interventional Cardiology Medical Group, is Clinical Assistant Professor of Medicine, Keck School of Medicine of the University of Southern California, Volunteer Faculty, and Clinical Assistant Professor of Internal Medicine, Western University of Health Sciences/College of Osteopathic Medicine of the Pacific. Dr. Rafii joined Interventional Cardiology Medical Group in August 2013. He holds five board certifications and is a Diplomate of the American Board of Internal Medicine, Board of Cardiovascular Diseases, the National Board of Echocardiography, International Board of Heart Rhythm Examiners, and the Certification Board of Nuclear Cardiology. He graduated Keck School of Medicine of the University of Southern California class of 2007, completed his internal medicine residency at UCLA – Kaiser Permanente Los Angeles Medical Center, and subspecialty training at UCSF – Fresno Cardiology Fellowship program. He has been elected a Fellow of the American College of Cardiology. Dr. Rafii has co-authored and published multiple manuscripts and original research articles in major cardiovascular journals. His clinical interests include prevention and treatment of coronary artery disease and heart attacks, heart failure, disorders of heart valves and heart rhythm, cholesterol abnormalities, hypertension, and heart disease in women. About Interventional Cardiology Medical Group (ICMG) Founded nearly 40 years ago, ICMG’s community-based cardiology team of physicians, nurse practitioners, sonographers, radiation technologists, research staff and patient care coordinators have distinguished itself as the preeminent cardiology practice in the West Valley area (suburban Los Angeles, CA). About Paroxysmal Supraventricular Tachycardia An estimated two million people in the United States are currently diagnosed with PSVT which is a type of arrhythmia or abnormal heart rhythm. PSVT is characterized by episodes of sudden onset rapid heartbeats often exceeding 150 to 200 beats per minute. The heart rate spike is unpredictable and may last several hours. The rapid heart rate often causes disabling severe palpitations, shortness of breath, chest discomfort, dizziness or lightheadedness, and distress, forcing patients to limit their daily activities. The uncertainty of when an episode of PSVT will strike or how long it will persist can provoke anxiety in patients and negatively impact their day-to-day life between episodes. The impact and morbidity from an attack can be especially detrimental in patients with underlying cardiovascular or medical conditions, such as heart failure, obstructive coronary disease, or dehydration. Many health care providers are dissatisfied with the lack of effective treatment options with patients often requiring prolonged, burdensome, and costly trips to the emergency department or even invasive cardiac ablation procedures. About Atrial Fibrillation with Rapid Ventricular Rate An estimated five million Americans suffer from atrial fibrillation (AFib), a common arrhythmia marked by an irregular, disruptive and often rapid heartbeat. The incidence of AFib is expected to grow to approximately 10 million by 2025 and up to about 12 million by 2030. A subset of patients with AFib experience episodes of abnormally high heart rate most often accompanied by palpitations, shortness of breath, dizziness, and weakness. While these episodes, known as AFib-RVR, may be treated by oral calcium channel blockers and/or beta blockers, patients frequently seek acute care in the emergency department to address symptoms. In 2016, nearly 800,000 patients were admitted to the emergency department due to AFib symptoms where treatment includes medically supervised intravenous administration of calcium channel blockers or beta blockers, or electrical cardioversion. With little available data for AFib-RVR, Milestone's initial market research indicates that 30 to 40% of patients with AFib experience one or more symptomatic episodes of RVR per year that require treatment, suggesting a target addressable market of approximately three to four million patients in 2030 for etripamil in patients with AFib-RVR. About Etripamil Etripamil is Milestone's lead investigational product. It is a novel calcium channel blocker nasal spray under clinical development for frequent and often highly symptomatic episodes of PSVT and atrial fibrillation with rapid ventricular rate (AFib-RVR). It is designed as a self-administered rapid response therapy for patients thereby bypassing the need for immediate medical oversight. If approved, etripamil is intended to provide health care providers with a new treatment option to enable on-demand care and patient self-management. This portable, self-administered treatment may provide patients with active management and a greater sense of control over their condition. CARDAMYST™ (etripamil) nasal spray, the conditionally approved brand name for etripamil nasal spray, is well studied with a robust clinical trial program that includes a completed Phase 3 clinical-stage program for the treatment of PSVT and Phase 2 trial for the treatment of patients with AFib-RVR. About Milestone Pharmaceuticals Milestone Pharmaceuticals Inc. (Nasdaq: MIST) is a biopharmaceutical company developing and commercializing innovative cardiovascular solutions to improve the lives of people living with complex and life-altering heart conditions. The Company’s focus on understanding unmet patient needs and improving the patient experience has led us to develop new treatment approaches that provide patients with an active role in self-managing their care. Milestone’s lead investigational product is etripamil, a novel calcium channel blocker nasal spray that is being studied for patients to self-administer without medical supervision to treat symptomatic episodic attacks associated with PSVT and AFib-RVR. Contact:Kim Fox, Vice President, Communications,kfox@milestonepharma.com Investor RelationsChris Calabrese,ccalabrese@lifesciadvisors.com Kevin Gardner,kgardner@lifesciadvisors.com Source: Milestone Pharmaceuticals Inc.

Phase 3Executive ChangeAHA

100 Deals associated with Etripamil

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D10932	-	-	DB12605

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Paroxysmal supraventricular tachycardia	NDA/BLA	US	Milestone Pharmaceuticals, Inc.	26 Feb 2024
Atrial Fibrillation	Phase 3	-	Milestone Pharmaceuticals, Inc.	01 Mar 2025
Tachycardia, Supraventricular	Phase 3	CN	Ji Xing Pharmaceuticals Co., Ltd.	30 Jun 2022
Tachycardia, Supraventricular	Phase 3	CN	Milestone Pharmaceuticals, Inc.	30 Jun 2022

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04467905 (ReVeRA-201, CTgov)	Phase 2	Atrial Fibrillation	69	Placebo (Placebo)	ngwswmzqjo(btpzqtzarr) = fvfxdsrynz mmcvcqzrhv (qzfhycncvt, oddnwcigza - diyegraurd) View more	-	19 Sep 2024
				Etripamil (Etripamil)	ngwswmzqjo(btpzqtzarr) = vkqhaxgwah mmcvcqzrhv (qzfhycncvt, utwsiywolp - tnwcsuuilp) View more
NCT05410860 (JX02002, GlobeNewswire) Manual	Phase 3	Paroxysmal supraventricular tachycardia	500	etripamil	dsowbqyaqp(skxbttajgj) = zzuqgaajjm cpknyntmfr (ryitvzzzil ) Met	Positive	06 Sep 2024
				Placebo	dsowbqyaqp(skxbttajgj) = vntqccdmqi cpknyntmfr (ryitvzzzil ) Met
NCT03464019 (NODE-301 \| RAPID, CTgov)	Phase 3	Paroxysmal supraventricular tachycardia	1,097	Placebo (Part 1 - Placebo Single Dose)	rkyykhhkws(oiykzljpvn) = uitfcqglvg zmdupskrbz (yziuvhhkex, vwrychujzc - evddsldebm) View more	-	12 Jul 2024
				Etripamil (Part 1 - Etripamil 70 mg)	rkyykhhkws(oiykzljpvn) = pmsdkotvmg zmdupskrbz (yziuvhhkex, kuifihmrmm - hpfjzzjzfw) View more
NCT04072835 (NODE-303, CTgov)	Phase 3	Paroxysmal supraventricular tachycardia	1,116	etripamil NS	rveldebpwg(wgxwewekbl) = ohjfsoewau yjimhbayzm (jslxjwqden, cxxzxptvzm - nemyiuwrxo) View more	-	23 May 2024
NCT04467905 (ReVeRA-201, Pubmed \| Circ Arrhythm Electrophysiol)	Phase 2	Atrial Fibrillation	-	Etripamil nasal spray 70 mg	gkecwdvuex(vqrkavujlt) = 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hypervagotonia wtdnnbdgst (jdichqyvuk ) View more	Positive	01 Dec 2023
NCT03464019 (RAPID, Pubmed \| Lancet)	Phase 3	Tachycardia, Atrioventricular Nodal Reentry	692	Etripamil 70 mg nasal spray	oetmyuqhxi(cvcpknryeb) = Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%) axdsoubclc (zkdudchcwv ) View more	Positive	15 Jun 2023
				Placebo
NCT03635996 (CTgov)	Phase 3	Paroxysmal supraventricular tachycardia	169	Aptar Pharma Nasal Spray Bidose System+Etripamil NS 70 mg	poddqarabc(egjscjaxne) = pwygamyqek jcmxpzclzx (tejfbuglji, nqmzcbznkj - vqqyescgup) View more	-	24 Apr 2023
NCT03464019 (NODE-301, Pubmed) Manual	Phase 3	Paroxysmal supraventricular tachycardia	156	Etripamil	mrnqtkythk(dmdmxctlbg): HR = 1.086 (95% CI, 0.726 - 1.623), P-Value = 0.12	Negative	28 Nov 2022
				Placebo
NCT03464019 (RAPID, Corporate Publications) Manual	Phase 3	Paroxysmal supraventricular tachycardia	706	Etripamil	tzomldqqyq(emgqctmveo) = emqxsdklnp nxulumpsty (fvtysrsvnm ) View more	Positive	17 Oct 2022
				Placebo	tzomldqqyq(emgqctmveo) = xgydftrrsd nxulumpsty (fvtysrsvnm ) View more
NCT02296190 (NODE-1, CTgov)	Phase 2	Paroxysmal supraventricular tachycardia	199	Placebo	ynozuexlsc(vbruazugbi) = dpddnaubxv shgihjjfio (diakzpydpp, mxtwbrhgpw - zkwzswostd) View more	-	30 Dec 2020

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