Respiratory Paralysis

Amylyx will spend the next eight weeks reviewing the data with the FDA and ALS community. Image credit: Shutterstock / David Herraez Calzada. Amylyx Pharmaceuticals ’s Phase III trial for amyotrophic lateral sclerosis (ALS) Relyvrio has failed to meet any of its endpoints. Following the Phase III flop, Amylyx said it will now engage with regulatory authorities and the broader ALS community, to discuss the results from the Phoenix trial over the next eight weeks and decide how to move forward. The company added this could include withdrawing Relyvrio from the market. The candidate was approved by the US Food and Drug Administration (FDA) in September 2022 based on findings from the multicentre Phase II Centaur trial that enrolled 137 ALS patients. In October 2023, the drug, which was set to be marketed as Albrioza in Europe, was rejected for approval by the European Medicines Agency (EMA). Once the market opened, the company’s stock crashed by 85.7%. The global, 48-week, randomised, placebo-controlled Phase III clinical trial of Relyvrio (AMX0035) did not meet its primary endpoint of reaching statistical significance from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. There was also no statistical significance seen in secondary endpoints. See Also: AD/PD 2024: exploring cutting-edge therapies for ALS AD/PD 2024: Vaxxinity reveals Phase I success with Parkinson’s vaccine The trial saw 664 patients randomised into two arms, Relyvrio or placebo, with both treatment groups receiving standard of care (SoC). In a statement, Amylyx co-CEOs Justin Klee and Joshua Cohen said: “We are surprised and deeply disappointed by the Phoenix results following the positive data from the Centaur trial. We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us.” Despite the disappointing efficacy results, Relyvrio was well-tolerated with no new safety signals. European participants who completed the 48-week randomised phase had the option to enrol in an open-label extension of the trial of up to two years in duration, which remains ongoing. Momna Ali, healthcare analyst at GlobalData, said: “When Relyvrio was initially approved, there was a swirl of controversy anyway. It’s a shame that the late-stage trial found no significant difference between ALS patients treated with Relyvrio and those on placebo after 48 weeks. “There are approximately 4,000 people in the US on Relyvrio and if Amylyx does pull its drug, sadly patients would only be left with three approved therapies. One, from Biogen , which targets a very small portion of the population with certain genetic mutations. The other two, called Radicava and riluzole, have shown modest therapeutic effects on both function and survival.” GlobalData is the parent company of the Clinical Trials Arena . Amylyx has two other ongoing studies with Relyvrio, a Phase III study in progressive supranuclear palsy (PSP) and a Phase II study in Wolfram syndrome. Relyvrio is a combination of sodium phenylbutyrate and taurursodiol, which cause a reduction of damage to nerve cells. ALS landscape Also known as classical motor neuron disease, ALS is a progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death. GlobalData has predicted global sales of Relyvrio to hit $1.33bn in 2029. Developing disease-modifying for ALS has proven challenging, with a high failure rate often attributed to the disease’s unclear aetiology and complex pathophysiology. Earlier this year, Sanofi and Denali Therapeutics’s SAR443820 failed to meet its primary endpoint in a Phase II trial and Ferrer Internacional’s FAB122 failed to meet its primary endpoint in a Phase III study.

- PHOENIX Study Did Not Meet Prespecified Primary or Secondary Endpoints - Data From 664-Participant Study Reinforce That AMX0035 is Generally Safe and Well-Tolerated - Within the Next Eight Weeks, Amylyx Will Continue to Engage With Regulatory Authorities and the ALS Community to Share Topline Data; Amylyx Will Share Plans for RELYVRIO/ALBRIOZA in ALS Which May Include Voluntarily Withdrawing RELYVRIO/ALBRIOZA From the Market - At This Time, RELYVRIO/ALBRIOZA Will Continue to be Available for People Living With ALS; Amylyx Has Voluntarily Decided to Pause Promotion; Related Patient Support Services Will Remain in Place - Studies With AMX0035 in Wolfram Syndrome (WS) and Progressive Supranuclear Palsy (PSP) to Continue Based on Data Supporting its Potential in These Diseases - Amylyx to Host Investor Conference Call Today, March 8, at 8:00 a.m. ET CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced topline results from PHOENIX, a global, 48-week, randomized, placebo-controlled Phase 3 clinical trial of AMX0035 (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; RELYVRIO® in the U.S., ALBRIOZA™ in Canada) in people living with amyotrophic lateral sclerosis (ALS). PHOENIX did not meet its primary endpoint of reaching statistical significance (p=0.667) as measured by change from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at Week 48, nor was there statistical significance seen in secondary endpoints. Amylyx plans to present the data from PHOENIX at an upcoming medical meeting and will publish the results in a medical journal later this year. Amylyx will continue to engage with regulatory authorities and the broader ALS community, including ALS specialists and other multidisciplinary experts, people living with ALS, and advocates, to discuss the results from PHOENIX within the next eight weeks and make informed decisions. Amylyx intends to share plans for RELYVRIO/ALBRIOZA in ALS, which may include voluntarily withdrawing RELYVRIO/ALBRIOZA from the market. At this time, RELYVRIO/ALBRIOZA and its related patient support program will continue to be available for people living with ALS. Amylyx has voluntarily decided to pause promotion of the medication during this time. “We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial. Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX. We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us. On behalf of the entire Amylyx team, we are grateful to the ALS community and for the dedication of trial participants, investigators, and study site teams. With data collected from 664 participants in PHOENIX, we are certain there will be important learnings that will help inform future ALS research. We are steadfast in our commitment to the ALS community and our mission, including with AMX0035 where it has shown potential in neurodegenerative diseases such as Wolfram syndrome and progressive supranuclear palsy, and with AMX0114, our investigational antisense oligonucleotide targeting calpain-2, in ALS,” said Justin Klee and Joshua Cohen, Co-CEOs of Amylyx. PHOENIX Study Results: The Phase 3 PHOENIX study enrolled 664 adults living with ALS. Participants were randomized three-to-two to receive either AMX0035 or placebo, with both treatment groups receiving standard-of-care. Continuation of a stable dosing regimen of riluzole and/or edaravone was permitted. PHOENIX did not meet the primary endpoint: There was no significant difference observed between participants treated with AMX0035 and placebo in ALSFRS-R total score change from baseline at Week 48 (p=0.667). No significant difference was observed in the subset of participants who met the CENTAUR trial criteria. There were also no significant differences observed across secondary endpoints. Consistent safety and tolerability profile: AMX0035 was well-tolerated in PHOENIX. There were no new safety signals, reinforcing the favorable and manageable safety pro with AMX0035 to date. European participants who completed the 48-week randomized phase had the option to enroll in an open label extension of the trial of up to two years in duration, which remains ongoing. Science of AMX0035: AMX0035, a specially formulated oral fixed-dose combination of PB and TURSO, has been shown in numerous preclinical studies to have a robust, synergistic effect in targeting two different destructive neurodegenerative disease pathways by mitigating endoplasmic reticulum stress and the associated unfolded protein response and mitochondrial dysfunction thereby reducing neuronal cell death. Additionally, AMX0035 has been shown to also reduce markers associated with neurodegenerative diseases in clinical trials, including a reduction of tau, a key protein aggregate shared across several neurodegenerative diseases, and YKL-40, a marker of neuroinflammation. Update on Ongoing AMX0035 Studies: The global, randomized, double-blind, placebo-controlled Phase 3 ORION clinical study of AMX0035 in PSP remains ongoing. The first participant was dosed in December 2023, and the Company is planning for an interim analysis. Topline results continue to be anticipated in 2025 or 2026. Data from the ongoing 12-participant, single site, open-label Phase 2 HELIOS clinical study are demonstrating evidence of clinical activity of AMX0035 in Wolfram syndrome. This study is fully recruited, and the Company plans to present preliminary data in the second quarter of 2024. Investor Conference Call Information Amylyx’ management team will host a live conference call and webcast today, March 8, 2024, at 8:00 a.m. ET to discuss the results of the PHOENIX trial. To participate in the conference call, please dial +1 (877) 870-4263 (U.S.), +1 (855) 669-9657 (Canada), or +1 (412) 317-0790 (International) at least 10 minutes prior to the start time and ask to be joined into the Amylyx Pharmaceuticals call. All interested parties are invited to access a live broadcast of the call via a webcast, which will be available on the “Events and Presentations” page in the “Investors” section of the Company’s website at investors.amylyx.com/news-events/events. An archived webcast will be available on the Company's website approximately two hours after the conference call and will be available for replay for 90 days following the call. About the PHOENIX Trial PHOENIX was a 48-week, randomized, placebo-controlled, global Phase 3 clinical trial further evaluating the safety and efficacy of AMX0035 (sodium phenylbutyrate and taurursodiol) for the treatment of ALS. The primary efficacy outcome of the trial was change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks. Secondary endpoints include quality of life patient-reported outcome assessments, overall survival, and respiratory function as measured by slow vital capacity (SVC). Safety and tolerability were also assessed. European participants who completed the 48-week trial had the option to enroll in an open-label extension (OLE) phase. During this phase, all participants receive AMX0035, and continued safety and efficacy measures will be assessed. About the CENTAUR Trial CENTAUR was a multicenter Phase 2 clinical trial in 137 participants with ALS encompassing a 6-month randomized, placebo-controlled phase and an open-label long-term follow-up phase. The trial met its primary efficacy endpoint of reducing functional decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Overall, reported rates of adverse events and discontinuations were similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group. Detailed data from CENTAUR is published in the New England Journal of Medicine (NEJM) and Muscle & Nerve. The CENTAUR trial was funded, in part, by the ALS ACT grant and the ALS Ice Bucket Challenge, and was supported by The ALS Association, ALS Finding a Cure (a program of The Leandro P. Rizzuto Foundation), the Northeast ALS Consortium, and the Sean M. Healey & AMG Center for ALS at Mass General. About AMX0114 AMX0114 is an antisense oligonucleotide designed to target the gene encoding calpain-2, a key contributor to the axonal (Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 has been implicated in the pathogenesis of ALS based on findings of elevated levels of calpain-2 and its cleavage products in postmortem ALS tissue, therapeutic benefit of calpain-2 modulation in animal models of ALS, and the role of calpain-2 in cleaving neurofilament, a broadly researched biomarker in ALS. Preclinical studies completed to date have shown that AMX0114 achieves potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in iPSC-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. About ALS Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) is a relentlessly progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death. More than 90% of people with ALS have sporadic disease, showing no clear family history. ALS affects around 30,000 people in the U.S., and more than 30,000 people are estimated to be living with ALS in Europe (European Union and United Kingdom). People living with ALS have a median survival of approximately two years from diagnosis. About HELIOS The HELIOS trial (NCT05676034) is a 12-participant, open-label proof of biology, Phase 2 trial designed to study the effect of AMX0035 on safety and tolerability, and various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome (WS). About Wolfram Syndrome Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of WS include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. Genetic and experimental evidence suggest that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of WS. The prognosis of WS is poor, and many people with the disease die prematurely with severe neurological disabilities. About the ORION Trial The Phase 3 ORION trial (NCT06122662) is a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with progressive supranuclear palsy (PSP). The ORION Phase 3 trial was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations. About PSP Progressive supranuclear palsy (PSP) is a sporadic, rare and adult-onset neurodegenerative disorder that affects walking and balance, eye movement, swallowing, and speech. People living with PSP have a life expectancy of six to eight years after initial diagnosis, and its epidemiology is similar to that of amyotrophic lateral sclerosis (ALS). PSP typically begins in late-middle age and rapidly progresses over time. The disease affects approximately seven in 100,000 people worldwide, and there are currently no disease-modifying therapies approved for the treatment of PSP. PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy. Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial with several genetic and environmental factors likely contributing to tau dysfunction and aggregation. Multiple pathways, including genetic mutations, endoplasmic reticulum (ER) stress and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation. About AMX0035 / RELYVRIO® / ALBRIOZA™ AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol (known as ursodoxicoltaurine outside of the U.S.). It is approved as RELYVRIO® to treat amyotrophic lateral sclerosis (ALS) in adults in the U.S. and approved with conditions as ALBRIOZA™ for the treatment of ALS in Canada. AMX0035 is being studied for the potential treatment of other neurodegenerative diseases, and Amylyx is exploring its treatment in other populations and regions. The formulation of RELYVRIO, ALBRIOZA, and AMX0035 is identical. RELYVRIO® (sodium phenylbutyrate and taurursodiol) Safety Information for United States WARNINGS AND PRECAUTIONS Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders RELYVRIO contains taurursodiol, which is a bile acid. In patients with disorders that interfere with bile acid circulation, there may be an increased risk for worsening diarrhea, and patients should be monitored appropriately for this adverse reaction. Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases that may alter the concentration of bile acids may also lead to decreased absorption of either of the components of RELYVRIO. Because different enterohepatic circulation, pancreatic, and intestinal disorders have varying degrees of severity, consider consulting with a specialist. Patients with disorders of enterohepatic circulation (e.g., biliary infection, active cholecystitis), severe pancreatic disorders (e.g., pancreatitis), and intestinal disorders that may alter concentrations of bile acids (e.g., ileal resection, regional ileitis) were excluded from the study; therefore, there is no clinical experience in these conditions. Use in Patients Sensitive to High Sodium Intake RELYVRIO has a high salt content. Each initial daily dosage of 1 packet contains 464 mg of sodium; each maintenance dosage of 2 packets daily contains 928 mg of sodium. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of RELYVRIO and monitor appropriately. ADVERSE REACTIONS The most common adverse reactions (at least 15% and at least 5% greater than placebo) with RELYVRIO were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal-related adverse reactions occurred throughout the study but were more frequent during the first 3 weeks of treatment. Please click here for RELYVRIO Full U.S. Prescribing Information. About Amylyx Pharmaceuticals Amylyx Pharmaceuticals, Inc. is committed to supporting and creating more moments for the neurodegenerative disease community through the discovery and development of innovative new treatments. Amylyx is headquartered in Cambridge, Massachusetts and has operations in Canada, EMEA, and Japan. For more information, visit amylyx.com and follow us on LinkedIn and X, (formerly Twitter). For investors, please visit investors.amylyx.com. Forward-Looking Statements Statements contained in this press release and related comments in our earnings conference call regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, Amylyx’ expectations regarding: interactions with regulatory authorities; the continued availability of RELYVRIO/ALBRIOZA for people living with ALS while such interactions are ongoing; the pausing of promotion of RELYVRIO/ALBRIOZA; pathways for continued access for patients if RELYVRIO/ALBRIOZA are withdrawn from the market; the possibility for Amylyx to voluntarily withdraw RELYVRIO/ALBRIOZA from the market; the continued evaluation of AMX0035 in other neurodegenerative diseases, including the timing for expected data readouts in the ORION and HELIOS studies; and the evidence of biological activity of AMX0035 in Wolfram syndrome. Any forward-looking statements in this press release and related comments in the Company's conference call are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include the risks and uncertainties set forth in Amylyx’ United States Securities and Exchange Commission (SEC) filings, including Amylyx’ Annual Report on Form 10-K for the year ended December 31, 2023, and subsequent filings with the SEC. All forward-looking statements contained in this press release and related comments in our conference call speak only as of the date on which they were made. Amylyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Final results from inspIRE study demonstrate 80% freedom from atrial arrhythmia recurrence at 12 months in patients with optimal Pulsed Field Ablation applications First look results from admIRE study suggests similar outcomes IRVINE, Calif., Feb. 2, 2024 /PRNewswire/ -- Biosense Webster, Inc., a global leader in cardiac arrhythmia treatment and part of Johnson & Johnson MedTechi, announced 12-month results from the company-sponsored inspIRE study, "Predictors of Success for Pulmonary Vein Isolation with Pulsed Field Ablation (PFA) Using a Variable Loop Catheter with 3D Mapping Integration: Complete 12-month outcomes from inspIRE," presented as a late-breaking presentation at the 29th Annual International AF Symposium.1 Interim results from the company-sponsored admIRE study, titled "PFA Using a Variable Loop Circular Catheter with 3D Mapping Integration: Early Outcomes of the admIRE Study," were also shared in a late-breaking presentation.2 Both the inspIRE and admIRE studies were conducted using the Biosense Webster VARIPULSE™ Platform, consisting of the VARIPULSE™ Catheter – a fully integrated variable-loop multielectrode catheter; the TRUPULSE™ Generator – a multichannel PFA generator; and the CARTO™ 3 System VARIPULSE™ Service Pack Software, which provides full integration with the world's leading 3D cardiac mapping system. The CARTO™ System enables an intuitive and reproducible workflow with real-time visualization and feedback mechanisms. "Biosense Webster is committed to bringing forward a versatile, differentiated portfolio of PFA solutions designed to help electrophysiologists deliver safe, effective, and efficient cardiac ablation procedures," said Jasmina Brooks, President, Biosense Webster, Inc. "The encouraging outcomes from clinical trials with VARIPULSE™ fuel our excitement as we continue to deliver innovations to meet the diverse needs and ablation strategies required to successfully treat atrial fibrillation." Data from inspIRE Demonstrate 80% of Patients Achieved Freedom from Recurrence with Zero Primary Adverse Events The inspIRE study evaluated the safety and effectiveness of the VARIPULSE™ Platform for the treatment of drug-refractory paroxysmal AFib in Europe and Canada.1 In the study, the primary effectiveness endpoint of acute pulmonary vein isolation and 12-month freedom from atrial arrhythmia recurrence (AFib, Atrial Tachycardia, or Atrial Flutter) was 75.6%. Among participants receiving optimal PFA applications, 80% achieved the primary effectiveness endpoint.1 The study reported a low fluoroscopy time of 7.8 minutes, partly attributed to the integration of the VARIPULSE™ Platform to the CARTO™ 3 System. The safety results demonstrated a primary adverse event rate of 0.0%ii.1 "High efficacy of 80% freedom from atrial recurrence at 12 months and a strong safety profile are promising evidence of the capabilities of the VARIPULSE™ Platform," said Vivek Y. Reddy, M.D., Director of Electrophysiology at the Mount Sinai Fuster Heart Hospital and The Helmsley Trust Professor of Cardiac Electrophysiology at the Icahn School of Medicine at Mount Sinai, corresponding author for the inspIRE study publication.iii "As the VARIPULSE™ Platform was designed to integrate seamlessly with the CARTO™ 3 Mapping System, this technology should be able to effectively treat patients with atrial fibrillation with low radiation exposure to patients and lab staff alike." admIRE Pilot Results Show All Pilot Phase Patients Achieved Acute Success and 80% Remained Free from Atrial Arrhythmia Recurrence After One Year Twelve-month outcomes data from the pilot phase of the admIRE study, which assessed the safety and efficacy of the VARIPULSE™ Platform among U.S. patients, were presented as a late-breaker at the AF Symposium.2 Among 20 patients who completed the 12-month follow-up visit, 100% achieved acute success from ablation procedures and 80% remained free from atrial arrhythmia recurrence at one year.2 No procedure or device-related primary adverse events were reported in the pilot phase of the study.2 For patients who had received ablation, median procedure and fluoroscopy times were 90.0 and 3.5 minutes, respectively, as a result of the CARTO™ integration.2 "The results observed in the pilot phase of the admIRE study point to the promise of the VARIPULSE™ Platform in treating patients with paroxysmal AFib," said David Newton, M.D., Clinical Cardiac Electrophysiologist, Memorial Health University Medical Center, Savannah, Georgia.iv "These initial results are encouraging and demonstrate the potential for the VARIPULSE™ Platform to become a key component of the suite of tools electrophysiologists have at their disposal to perform catheter ablations." AFib is the most common type of cardiac arrhythmia and affects more than 6 million people in the United States and nearly 38 million people worldwide.3,4 Approximately 1 in 4 adults over the age of 40 are at risk for developing AFib.5 Despite these projections, many people are unfamiliar with AFib symptoms, available treatment options, and the importance of early treatment to avoid disease progression.6 Catheter ablation is a safe and effective procedure when drugs don't work to help restore the heart's incorrect electrical signals, which cause an abnormal heart rhythm.7 About inspIRE The inspIRE study (Study for Treatment of Paroxysmal Atrial Fibrillation [PAF] by PFA System With Irreversible Electroporation [IRE]) (NCT04524364) was a prospective, multi-center, single-arm study of drug-refractory PAF, conducted at 13 institutions in Canada and Europe, from March 2021 to May 2022. In the study, PVI was performed with the VARIPULSE™ Platform. Follow up with 24-hour Holter monitoring was performed at three, six, and 12 months. Remote rhythm monitoring was performed weekly from three to five months; monthly, from six to 12 months; and for symptoms. The primary effectiveness endpoint (PEE) was acute PVI plus freedom from all atrial arrhythmia (AFib, Atrial Tachycardia, or Atrial Flutter), at 12 months. This final analysis of the study focused on the pivotal phase (Wave II) per-protocol population of 186 patients with 12 months of follow up. About admIRE The admIRE study (Assessment of Safety and Effectiveness in Treatment Management of Atrial Fibrillation With the Biosense Webster IRE Ablation System) (NCT05293639) is a prospective, multi-center, single-arm study to demonstrate the safety and long-term effectiveness of the VARIPULSE™ Platform when used for isolation of pulmonary veins in treatment of patients in the United States with symptomatic drug refractory paroxysmal AFib. Pulmonary vein isolation (PVI) was achieved using the VARIPULSE™ Platform. The study consisted of a pilot phase, which assessed initial device safety and effectiveness, and a pivotal phase, which assessed these against pre-specified performance goals. The primary safety endpoint was incidence of early onset (within seven days) primary adverse events; atrio-esophageal fistula (within 90 days); cardiac tamponade or perforation (within 30 days); and PV stenosis (within 12 months). Acute procedure success (defined as confirmed entrance block at the end of procedure) and freedom from documented atrial arrhythmia recurrence at 12 months were also assessed. About the VARIPULSE™ Platform The VARIPULSE™ Platform is Biosense Webster's Irreversible Electroporation ablation system. The fully integrated platform includes the VARIPULSE™ Catheter, TRUPULSE™ Generator, and CARTO™ 3 Mapping System VARIPULSE™ Service Pack Software. In January 2024, Biosense Webster announced that the VARIPULSE™ Platform received its first regulatory approval from the Japan Ministry of Health, Labour and Welfare for the treatment of symptomatic drug refractory recurrent paroxysmal AFib using PFA. In the U.S., the VARIPULSE™ Catheter and TRUPULSE™ Generator are currently investigational and are not approved by regulatory authorities. In Europe, the TRUPULSE™ generator received CE mark in late 2023 and VARIPULSE™ Catheter is pending CE mark. About Biosense Webster Biosense Webster, Inc. is the global market leader in the science and technology behind the diagnosis and treatment of cardiac arrhythmias. Part of Johnson & Johnson MedTech, the specialized medical-technology company is headquartered in Irvine, California, and works across the world to advance the tools and solutions that help electrophysiologists identify, treat, and deliver care. Learn more at biosensewebster.com and connect on LinkedIn and X, formerly Twitter. About Johnson & Johnson MedTechii At Johnson & Johnson MedTech,i we unleash diverse healthcare expertise, purposeful technology, and a passion for people to transform the future of medical intervention and empower everyone to live their best life possible. For more than a century, we have driven breakthrough scientific innovation to address unmet needs and reimagine health. In surgery, orthopaedics, vision, and interventional solutions, we continue to help save lives and create a future where healthcare solutions are smarter, less invasive, and more personalized. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding the VARIPULSE™ Platform clinical trials. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Biosense Webster, Inc., and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: uncertainty of regulatory approvals; uncertainty of commercial success; challenges to patents; competition, including technological advances, new products and patents attained by competitors; product efficacy or safety concerns resulting in product recalls or regulatory action; changes to applicable laws and regulations, including global health care reforms; changes in behavior and spending patterns of purchasers of healthcare products and services; and trends toward healthcare cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at sec.gov, jnj.com or on request from Johnson & Johnson. None of Biosense Webster, Inc. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. © Johnson & Johnson Biosense Webster, Inc. 2024. All rights reserved. US_BWI_THER_303927.1 i Johnson & Johnson MedTech comprises the surgery, orthopedics, vision, and interventional solutions businesses within Johnson & Johnson's MedTech segment. ii Primary adverse events were defined as myocardial infarction, thromboembolism, transient ischemic attack, diaphragmatic paralysis, pneumothorax, heart block, pulmonary edema, vagal nerve injury, pericarditis, major vascular access complication or bleeding, death, stroke, or any other cerebrovascular accident. Atrioesophageal fistula and PV stenosis occurring >7 days post ablation along with cardiac tamponade or perforations occurring within 30 days of the ablation procedure were also considered primary adverse events. iii Nemocnice na Homolce entered into a clinical trial agreement with Johnson & Johnson Medical NV/SA for their participation in the inspIRE Study. Dr. Reddy served as a study coinvestigator. Dr. Reddy was compensated for consultancy purposes for his Multielectrode IRE Catheter Program Study Advisory Committee membership. Dr. Reddy was not compensated for this authorship contributions. iv Memorial HCA Savannah entered into a clinical trial agreement with Biosense Webster, Inc. for their participation in the admIRE Study. Dr. Newton served as a study coinvestigator. Dr. Newton serves as a consultant for BWI. Dr. Newton was not compensated for this authorship contributions. 1 Reddy V, Grimaldi M, Duytschaever M, Anic A. Predictors of Success for Pulmonary Vein Isolation with Pulsed Field Ablation Using a Variable Loop Catheter with 3D Mapping Integration: Complete 12-month outcomes from inspIRE [abstract]. In: AF Symposium.; February 2-4; Boston. 2 Newton D, Natale A, Mansour M, Nair D, Senn T. Pulsed Field Ablation Using a Variable Loop Circular Catheter with 3D Mapping Integration: Early Outcomes of the admIRE Study [abstract]. In: AF Symposium.; February 2-4; Boston. 3 Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. Int J Stroke. 2021 Feb;16(2):217-221. doi: 10.1177/1747493019897870. Epub 2020 Jan 19. Erratum in: Int J Stroke. 2020 Jan 28;1747493020905964. PMID: 31955707. 4 Kornej J, Börschel CS, Emelia J. Benjamin EJ, Schnabel RB. Epidemiology of Atrial Fibrillation in the 21st Century. Circulation Research. 2020 June;127(1):4-20. doi: 10.1161/CIRCRESAHA.120.316340 5 Staerk, et al. 2018 Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study. BMJ 2018;361:k1453 doi: 10.1136/bmj.k1453 6 Kuck KH, Lebedev DS, Mikhaylov EN, et al. Catheter ablation or medical therapy to delay progression of atrial fibrillation: the randomized controlled atrial fibrillation progression trial (ATTEST). Europace 2021;23(3)362-369. doi: 10.1093/europace/euaa298. 7 Natale, A. Reddy VY, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. Journal of the American College of Cardiology, 2014;64(7),647–656. doi: 10.1016/j.jacc.2014.04.072 SOURCE Biosense Webster