Atazanavir Sulfate

FLORHAM PARK, N.J., Oct. 27, 2024 (GLOBE NEWSWIRE) -- Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, today announced that the company will present data from multiple investigational studies for its first-in-class treatment VOQUEZNA® (vonoprazan) tablets at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting, being held October 25-30 in Philadelphia, PA. VOQUEZNA is approved for the relief of heartburn associated with Non-Erosive Gastroesophageal Reflux Disease (Non-Erosive GERD), for the treatment of all severities of Erosive Esophagitis, commonly referred to as Erosive GERD, and relief of related heartburn, and in combination with antibiotics for the eradication of Helicobacter pylori (H. pylori) infection.1 VOQUEZNA is the first and only U.S. Food and Drug Administration (FDA)-approved potassium-competitive acid blocker (PCAB).2 Evaluating On-Demand VOQUEZNA Treatment from the PHALCON-NERD-201 Trial3In an oral presentation being presented Monday, October 28 at ACG, Ronnie Fass, M.D., director of the Division of Gastroenterology and Hepatology and medical director of the Digestive Health Center at MetroHealth in Cleveland, Ohio, and lead investigator of the PHALCON-NERD-201 trial, will provide results from a post-hoc analysis of the Phase 2 study. This research, recognized with the ACG Outstanding Research Award in the ‘Esophagus’ category, evaluated the efficacy of As Needed (On-Demand) dosing of VOQUEZNA, compared to placebo, for relief of episodic heartburn in participants with Non-Erosive GERD following a 4-week VOQUEZNA daily dosing “run-in” period. As previously reported, the primary analysis of the study demonstrated that all three VOQUEZNA doses tested (10 mg, 20 mg and 40 mg) had higher percentages of heartburn completely relieved within three hours of dosing and sustained for 24 hours, with significant differences reported as early as one hour. Use of As Needed dosing in this population is investigational as VOQUEZNA has been neither evaluated nor approved by the FDA as an As Needed treatment for Non-Erosive GERD. To understand the practical application of As Needed dosing for VOQUEZNA, the new analysis examined daily heartburn symptom burden at baseline, during daily VOQUEZNA treatment, and upon switching to As Needed treatment after achieving symptom control during the run-in period. It also further evaluated the rate of symptom improvement upon treating new onset heartburn episodes during the As Needed dosing period.3 “As a healthcare provider, the concept of a novel As Needed dosing option for Non-Erosive GERD is highly compelling. I am pleased that ACG has recognized this data as a recipient of the ACG Outstanding Research Award, further reinforcing its importance to the GI community,” said Ronnie Fass, M.D. “The low frequency of heartburn after discontinuing daily VOQUEZNA treatment, coupled with the rapid onset of improvement following As Needed dosing, suggests that transitioning from daily dosing to As Needed treatment is a viable option for patients who previously respond well to daily therapy of VOQUEZNA. These promising results warrant further investigation in a larger and extended As Needed study period.” The double-blind, placebo-controlled PHALCON-NERD Phase 2 study randomized 207 patients who were eligible for On-Demand (“As Needed”) treatment following a 4-week daily dosing run-in period in which patients received VOQUEZNA 20 mg once-daily. Patients without heartburn in the last seven days of the run-in period were evenly randomized to receive 10 mg, 20 mg or 40 mg of VOQUEZNA, or placebo, for six weeks. Results of the study were published in Alimentary Pharmacology & Therapeutics in September 2023.4 Results:3 Patients eligible for the On-Demand period (n=207) were highly symptomatic with a reported mean of 16.1% [95% CI: (13.5%, 18.7%)] heartburn-free days during screening. Heartburn-free days increased during the run-in period to a mean of 82.9% [95% CI: (80.4%, 85.4%)] and remained well above pre-treatment levels (means 71% to 75%) throughout the six-week On-Demand period.The difference in the improvement of treated heartburn episodes between the active and placebo groups became evident within the first hour of dosing (10 mg [75.5%, p<0.0001], 20 mg [69.1%, p = 0.0010], 40 mg [75.5%, p<0.0001], placebo [57.0%]).Over 90% of heartburn episodes treated with VOQUEZNA improved within two hours. Non-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. An estimated 45 million U.S. adults are living with Non-Erosive GERD, and approximately 15 million are treated with a prescription medicine annually. Despite longstanding treatment options, many patients continue to suffer from heartburn symptoms. As Needed dosing is a unique and differentiated dosing regimen for which proton pump inhibitors (PPIs), a mainstay of GERD treatment, are not approved in the U.S.5 In July 2024, VOQUEZNA was approved by the FDA as a daily dosing treatment for the relief of heartburn associated with Non-Erosive GERD in adults.1 Nocturnal GERD Symptoms in Non-Erosive GERD6 In a poster presentation on Monday, October 28 at ACG, which has received ACG’s Presidential Poster Award, Dr. Catiele Antunes, M.D., Yale New Haven Hospital, will present data looking at the common, yet infrequently evaluated, nocturnal symptoms among patients with Non-Erosive GERD. The study included an exploratory analysis of a validated patient-reported outcomes scale, the Nocturnal Gastro-esophageal reflux disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to determine the severity, morning impact, and concern about nocturnal GERD. “We are very pleased to continue to add to the body of clinical research evaluating the potential benefits of VOQUEZNA for GERD patients,” said Eckhard Leifke, M.D., Chief Medical Officer at Phathom. “In our study, patients who experienced nocturnal GERD symptoms prior to VOQUEZNA treatment found effective and meaningful relief with daily dosing, reinforcing its potent and durable acid suppression profile in helping to address both daytime and nighttime heartburn. While these findings are exploratory, they show promise for the many individuals suffering from nocturnal GERD symptoms.” Results:6 Among 772 subjects, the mean percentage of heartburn-free nights during the screening period was 29.6%, 25.8% and 31.1%, for patients randomized to placebo, VOQUEZNA 10 mg and 20 mg, respectively.After 4 weeks, the least-square (LS) mean percentage of heartburn-free nights was significantly better with 59.9% for VOQUEZNA 10 mg (LS mean difference=16.5%, p<0.0001 vs. placebo), and 56.4% for VOQUEZNA 20 mg (LS mean difference=13.1%, p<0.0001 vs. placebo), compared to 43.3% for placebo. The median percentage of heartburn-free nights was 70.4% for VOQUEZNA 10 mg and 71.0% for VOQUEZNA 20 mg, compared to 45.5% for placebo.N-GSSIQ scores showed significant improvement with VOQUEZNA compared to placebo in total score (LS mean difference vs. placebo of -2.9 and -1.8 for VOQUEZNA 10 mg and 20 mg, respectively; p<0.005 for both comparisons), nocturnal symptom severity (LS mean difference vs. placebo of -5.4 and -3.5 for VOQUEZNA 10 mg and 20 mg; p<0.001 for both comparisons), and concern about nocturnal GERD (LS mean difference vs. placebo of -2.0 for both VOQUEZNA 10 mg and 20 mg; p<0.0001). In addition to these data presentations, Phathom will sponsor a product theater highlighting VOQUEZNA as an approved treatment for GERD and will also have a presence on the exhibit floor at booth #757 throughout the conference. Following the conclusion of ACG 2024, the abstracts will be posted to the publications and scientific section of the Phathom company website. VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. and is currently available via prescription. Please visit voqueznapro.com to learn more about VOQUEZNA. About Non-Erosive Gastroesophageal Reflux DiseaseNon-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. There are over 65 million U.S. patients living with GERD, and it is estimated that approximately 70% of this population have Non-Erosive GERD. Symptoms of Non-Erosive GERD may impact overall quality of life and can include episodic heartburn, especially at night, regurgitation, problems swallowing, and chest pain.7,8 About VOQUEZNA®VOQUEZNA® (vonoprazan) tablets contain vonoprazan, an oral small molecule potassium-competitive acid blocker (PCAB). PCABs are a novel class of medicines that block acid secretion in the stomach. VOQUEZNA is approved in the U.S. for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD, the relief of heartburn associated with Erosive GERD, the relief of heartburn associated with Non-Erosive GERD, and for the treatment of H. pylori infection in combination with either amoxicillin or amoxicillin and clarithromycin. Phathom in-licensed the U.S. rights to vonoprazan from Takeda, which markets the product in Japan and numerous other countries in Asia and Latin America. About Phathom Pharmaceuticals, Inc.Phathom Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases. Phathom has in-licensed the exclusive rights to vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB) that is currently marketed in the United States as VOQUEZNA® (vonoprazan) tablets for the treatment of heartburn associated with Non-Erosive GERD in adults, the healing and maintenance of healing of Erosive GERD in adults and associated heartburn, in addition to VOQUEZNA® TRIPLE PAK® (vonoprazan tablets, amoxicillin capsules, clarithromycin tablets) and VOQUEZNA® DUAL PAK® (vonoprazan tablets, amoxicillin capsules) for the treatment of H. pylori infection in adults. For more information about Phathom, visit the company’s website at www.phathompharma.com and follow on LinkedIn and X. INDICATIONS AND USAGE VOQUEZNA® (vonoprazan) is a potassium-competitive acid blocker (PCAB) indicated in adults: for the healing of all grades of Erosive Esophagitis (Erosive Gastroesophageal Reflux Disease or Erosive GERD) and relief of heartburn associated with Erosive GERD.to maintain healing of all grades of Erosive GERD and relief of heartburn associated with Erosive GERD.for the relief of heartburn associated with Non-Erosive GERD.in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection.in combination with amoxicillin for the treatment of H. pylori infection. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VOQUEZNA is contraindicated in patients with a known hypersensitivity to vonoprazan or any component of VOQUEZNA, or in patients receiving rilpivirine-containing products. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with VOQUEZNA, refer to the Contraindications section of the corresponding prescribing information. WARNINGS AND PRECAUTIONS Presence of Gastric Malignancy: In adults, symptomatic response to therapy with VOQUEZNA does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in patients who have a suboptimal response or an early symptomatic relapse after completing treatment with VOQUEZNA. In older patients, also consider endoscopy. Acute Tubulointerstitial Nephritis: Acute tubulointerstitial nephritis (TIN) has been reported with VOQUEZNA. If suspected, discontinue VOQUEZNA and evaluate patients with suspected acute TIN. Clostridioides difficile-Associated Diarrhea: Published observational studies suggest that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridioides difficile-associated diarrhea (CDAD), especially in hospitalized patients. VOQUEZNA may also increase the risk of CDAD. Consider CDAD in patients with diarrhea that does not improve. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with VOQUEZNA, refer to Warnings and Precautions section of the corresponding prescribing information. Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine, especially in patients receiving high dose (multiple daily doses) and long-term therapy (a year or longer). Bone fracture, including osteoporosis-related fracture, has also been reported with vonoprazan. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. Severe Cutaneous Adverse Reactions (SCAR): Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with VOQUEZNA. Discontinue VOQUEZNA at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. Vitamin B12 (Cobalamin) Deficiency: Long-term use of acid-suppressing drugs can lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Vitamin B12 deficiency has been reported postmarketing with vonoprazan. If clinical symptoms consistent with vitamin B12 deficiency are observed in patients treated with VOQUEZNA, consider further workup. Hypomagnesemia and Mineral Metabolism: Hypomagnesemia has been reported postmarketing with vonoprazan. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. Consider monitoring magnesium levels prior to initiation of VOQUEZNA and periodically in patients expected to be on prolonged treatment, in patients taking drugs that may have increased toxicity in the presence of hypomagnesemia or drugs that may cause hypomagnesemia. Treatment of hypomagnesemia may require magnesium replacement and discontinuation of VOQUEZNA. Consider monitoring magnesium and calcium levels prior to initiation of VOQUEZNA and periodically while on treatment in patients with a preexisting risk of hypocalcemia. Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing VOQUEZNA. Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Temporarily discontinue VOQUEZNA treatment at least 4 weeks before assessing CgA levels and consider repeating the test if initial CgA levels are high. Fundic Gland Polyps: Use of VOQUEZNA is associated with a risk of fundic gland polyps that increases with long-term use, especially beyond one year. Fundic gland polyps have been reported with vonoprazan in clinical trials and during postmarketing use with PPIs. Most patients who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. ADVERSE REACTIONS: Healing of Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include gastritis (3%), diarrhea (2%), abdominal distention (2%), abdominal pain (2%), and nausea (2%). Maintenance of Healed Erosive GERD: The most common adverse reactions (≥3% of patients in the VOQUEZNA arm) include gastritis (6%), abdominal pain (4%), dyspepsia (4%), hypertension (3%), and urinary tract infection (3%). Relief of Heartburn Associated with Non-Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include abdominal pain (2%), constipation (2%), diarrhea (2%), nausea (2%), and urinary tract infection (2%). Treatment of H. Pylori Infection (VOQUEZNA and Amoxicillin): The most common adverse reactions (≥2% in any treatment arm) include diarrhea (5%), abdominal pain (3%), vulvovaginal candidiasis (2%), nasopharyngitis (2%), dysgeusia (1%), headache (1%), and hypertension (1%). Treatment of H. Pylori Infection (VOQUEZNA, Amoxicillin and Clarithromycin): The most common adverse reactions (≥2% in any treatment arm) include dysgeusia (5%), diarrhea (4%), vulvovaginal candidiasis (3%), headache (3%), abdominal pain (2%), hypertension (2%), and nasopharyngitis (<1%). For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the corresponding prescribing information. DRUG INTERACTIONS VOQUEZNA has the potential for clinically important drug interactions, including interactions with drugs dependent on gastric pH for absorption, drugs that are substrates for certain CYP enzymes, and some diagnostic tests. Avoid concomitant use of VOQUEZNA with atazanavir or nelfinavir. See full Prescribing Information for more details about important drug interactions. Consult the labeling of concomitantly used drugs to obtain further information about interactions with vonoprazan. For information about drug interactions, contraindications, and warnings and precautions of antibacterial agents (amoxicillin or clarithromycin) indicated in combination with VOQUEZNA, refer to their corresponding prescribing information. USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended during treatment. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, advise patients not to breastfeed during treatment with VOQUEZNA. Renal Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with severe renal impairment (eGFR < 30 mL/min). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with severe renal impairment. Hepatic Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with moderate to severe hepatic impairment. You are encouraged to report suspected adverse reactions by contacting Phathom Pharmaceuticals at 1-888-775-PHAT (7428) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see full Prescribing Information for VOQUEZNA. Forward-Looking StatementsThis press release contains forward-looking statements. Words such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or continue” and similar expressions, are intended to identify forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the ability of vonoprazan to relieve symptoms of GERD following As Needed dosing and to suppress nocturnal symptoms among patients with Non-Erosive GERD. The inclusion of forward-looking statements should not be regarded as a representation by Phathom that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Phathom’s business, including, without limitation: additional data related to vonoprazan to relieve symptoms of GERD following As Needed dosing may be inconsistent with the data produced as of the date hereof, and further analysis of existing data and analysis of new data may lead to conclusions different from those established as of the date hereof; the inherent risks of clinical development of vonoprazan; Phathom’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of vonoprazan that may limit its development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Phathom’s ability to obtain and maintain intellectual property protection and non-patent regulatory exclusivity for vonoprazan; Phathom’s estimates regarding patient population and commercial coverage could prove to be inaccurate; and other risks described in the Company’s prior press releases and the Company’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Phathom undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. References VOQUEZNA. Prescribing Information. Phathom Pharmaceuticals; 2024.Data on file. Phathom Pharmaceuticals, Inc. Florham Park, NJFass R, et al. Heartburn Frequency and Symptom Improvement Rates of Treated Episodes when Switching From Daily to On-Demand Vonoprazan Treatment for Non-Erosive Reflux Disease; American College of Gastroenterology (ACG) 2024 abstract; October 25-30, Philadelphia, PA.Fass R, Vaezi M, Sharma P, et al. Randomised clinical trial: Efficacy and safety of on-demand vonoprazan versus placebo for non-erosive reflux disease. Accessed September 17, 2024. Available at: https://doi.org/10.1111/apt.17728Antunes C, Aleem A, Curtis SA. Gastroesophageal reflux disease. NCBI Bookshelf. Accessed January 21, 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441938/?report=printableAntunes C, et al. Vonoprazan Improves Nocturnal Gastroesophageal Reflux Symptoms in Non-Erosive Reflux Disease; American College of Gastroenterology (ACG) 2024 abstract; October 25-30, Philadelphia, PA.Machiacado JD, Greer JB, Yadav D. (2021) Epidemiology of Gastrointestinal Diseases. In: Pitchumoni CS, Dharmarajan T, (eds). Geriatric Gastroenterology. Springer, Cham. https://doi.org/10.1007/978-3-030-30192-7_7Antunes C, Aleem A, Curtis SA. Gastroesophageal reflux disease. NCBI Bookshelf. Accessed January 21, 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441938/?report=printable MEDIA CONTACTNick Benedetto1-877-742-8466media@phathompharma.com INVESTOR CONTACTEric Sciorilli1-877-742-8466ir@phathompharma.com © 2024 Phathom Pharmaceuticals. All rights reserved.VOQUEZNA, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, Phathom Pharmaceuticals, and their respective logos are registered trademarks of Phathom Pharmaceuticals, Inc. 10/24US-VPZ-24-0557

SOUTH SAN FRANCISCO, Calif., Aug. 01, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases, today reported financial results for the second quarter ended June 30, 2024, and provided business highlights. "In the second quarter, our Enzyme Transport Vehicle franchise gained additional momentum with continued engagement with the FDA on an accelerated approval pathway for tividenofusp alfa (DNL310, ETV:IDS) in MPS II and the FDA's selection of DNL126 (ETV:SGSH) in MPS IIIA for the START program," said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics. “Today, we are also pleased to share that we have regained the rights to our TfR-based ATV:Abeta program from Biogen, thereby expanding our opportunities for addressing Alzheimer's disease with a potential best-in-class approach. We look forward to continuing to make significant progress as leaders in the promising and growing field of BBB-crossing therapeutics." Second Quarter 2024 and Recent Program Updates Late-stage and mid-stage clinical programs Tividenofusp alfa (DNL310): Enzyme Transport Vehicle (ETV)-enabled, iduronate-2-sulfatase (IDS) replacement therapy in development for MPS II (Hunter syndrome) In April, completed enrollment of 47 participants with MPS II in the Phase 1/2 open-label study.COMPASS, the global Phase 2/3 study, is expected to complete enrollment in 2024.In July, Molecular Genetics and Metabolism published a review co-authored by Denali's Chief Medical Officer, Carole Ho, M.D., titled, "Community consensus for heparan sulfate as a biomarker to support accelerated approval in neuronopathic mucopolysaccharidoses", which summarizes many of the presentations at the Reagan-Udall Foundation workshop held in February 2024 and provides a perspective on the path forward for neuronopathic MPS disorders.Following the Reagan-Udall Foundation workshop, Denali received written communication from the Center for Drug Evaluation and Research (CDER) division of the FDA indicating openness to discussing an accelerated approval pathway for tividenofusp alfa in MPS II with cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate biomarker. Denali looks forward to continued engagement with CDER regarding Denali’s intention to file for approval of tividenofusp alfa using the accelerated approval pathway. Denali will provide an update in 2H 2024. DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS) In May, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS) announced that enrollment is complete in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial. SAR443820/DNL788: CNS-penetrant RIPK1 inhibitor in development for the treatment of multiple sclerosis (MS) Sanofi is evaluating SAR443820/DNL788 in a Phase 2 study in participants with MS, which is fully enrolled. BIIB122/DNL151: LRRK2 inhibitor in development for the treatment of Parkinson’s disease (PD) Biogen is conducting the ongoing global Phase 2b LUMA study of BIIB122 in participants with early-stage Parkinson’s disease.Denali plans to initiate a global Phase 2a study in 2024 to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This study is being funded under the Collaboration and Development Funding Agreement with a third party. Eclitasertib (SAR443122/DNL758): Peripheral RIPK1 inhibitor in development for the treatment of ulcerative colitis (UC) Sanofi is conducting the ongoing Phase 2 study of SAR443122/DNL758 in participants with UC. Early-stage clinical and preclinical programs DNL126: ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy in development for the treatment of MPS IIIA (Sanfilippo syndrome Type A) In June, Denali announced that the CDER selected DNL126 for participation in the FDA's Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program to further accelerate the development of novel drug and biological products for rare diseases. Participation in START is expected to facilitate and accelerate development of DNL126.Phase 1/2 biomarker and safety data are expected by the end of 2024. TAK-594/DNL593: Protein Transport Vehicle (PTV)-enabled progranulin (PGRN) replacement therapy in development for the treatment of frontotemporal dementia-granulin (FTD-GRN) Denali has finalized the protocol amendment for the Phase 1/2 study and prescreening of participants for Cohort B2 is ongoing. Oligonucleotide Transport Vehicle (OTV) platform Denali is advancing OTV:MAPT, targeting tau for Alzheimer’s disease, and OTV:SNCA, targeting alpha-synuclein for Parkinson’s disease, in the investigational new drug (IND)-enabling stage of development. Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program Today, Denali also announced that Biogen terminated its license to the ATV:Abeta program enabled by Denali’s TfR-targeting technology against amyloid beta for the potential treatment of Alzheimer's disease and granted Denali rights to data generated during the collaboration. As a result of the termination, all rights to develop, manufacture, perform medical affairs activities, and commercialize new TfR-targeting ATV:Abeta therapeutics reverted to Denali. Biogen licensed Denali's TfR-targeting ATV:Abeta program in April 2023 having exercised an option that was part of the 2020 collaboration agreement between the two companies. Biogen’s decision was not related to any efficacy or safety concerns with the Transport Vehicle platform.Denali is working to develop the next generation of anti-amyloid beta therapeutics with ATV:Abeta, which is designed to increase exposure of the therapeutic antibody and achieve broad biodistribution in the brain with the potential for improved efficacy and safety. Preclinical data demonstrated potential for a wider therapeutic window compared to a standard antibody, with superior plaque decoration and reduction and very low rates of amyloid related imaging abnormalities (ARIA). These data are included in a recent manuscript posted on bioRxiv.Denali plans to advance a TfR-targeting ATV:Abeta molecule as well as a CD98hc-targeting ATV:Abeta molecule into development for Alzheimer's disease. Discovery programs Denali applies its deep scientific expertise in neurodegeneration biology and the BBB to discover and develop medicines and platforms with the focus on programs enabled by the TV technology and targeting neurodegenerative disease, including Alzheimer’s and Parkinson’s, and lysosomal storage diseases. In July, Denali posted the manuscript titled, "Fc-engineered large molecules targeting the blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution compared to standard antibodies" on bioRxiv. Using comprehensive and unbiased approaches, Denali scientists reveal distinct biodistribution of the TfR and CD98hc transport vehicle delivery platforms from the brain single-cell level all the way to the whole body. Participation in Upcoming Investor Conferences BTIG Virtual Biotechnology Conference, August 5-62024 Wedbush PacGrow Healthcare Conference, August 13-14Morgan Stanley 22nd Annual Global Healthcare Conference, September 4-6H.C. Wainwright 26th Annual Global Investment Conference, September 9-112024 Cantor Global Healthcare Conference, September 17-19 Second Quarter 2024 Financial Results Net loss was $99.0 million for the quarter ended June 30, 2024, compared to net income of $183.4 million for the quarter ended June 30, 2023. There was no collaboration revenue for the quarter ended June 30, 2024, compared to $294.1 million for the quarter ended June 30, 2023. The decrease in collaboration revenue was primarily due to $293.9 million of revenue recognized in the quarter ended June 30, 2023 as a result of Biogen exercising their option to license our ATV:Abeta program. Total research and development expenses were $91.4 million for the quarter ended June 30, 2024, compared to $97.5 million for the quarter ended June 30, 2023. The decrease of approximately $6.1 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel and external expenses associated with the divestiture of the Company's preclinical small molecule programs. There were also decreases in external expenses associated with the ATV:TREM2 and PTV:PGRN programs due to the discontinuation of clinical development of TAK-920/DNL919 (ATV:TREM2) in Alzheimer’s disease and voluntary pause of Part B in the TAK-594/DNL593 (PTV:PGRN) Phase 1/2 study, respectively. Additionally, the Company commenced recognition of research funding for the LRRK2 program from the Collaboration and Development Funding Agreement executed in January 2024. These decreases were partially offset by increases in costs in various clinical stage programs, including eIF2B, ETV:SGSH and ETV:IDS reflecting the continued progress of these programs in clinical trials. General and administrative expenses were $25.2 million for the quarter ended June 30, 2024, compared to $26.1 million for the quarter ended June 30, 2023. The decrease of $0.9 million for the quarter ended June 30, 2024 was primarily attributable to a decrease in personnel-related expenses consisting of employee compensation and stock-based compensation expense, partially offset by combined increases of $0.2 million in professional services, facilities and other corporate costs. Cash, cash equivalents, and marketable securities were approximately $1.35 billion as of June 30, 2024. About Denali Therapeutics Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding expectations regarding Denali’s TV technology platform; statements made by Denali’s Chief Executive Officer; plans, timelines, and expectations regarding DNL310 and the ongoing Phase 2/3 COMPASS and Phase 1/2 studies, the timing and likelihood of accelerated approval, and the timing and availability of program updates; plans and timelines regarding DNL343, including in Regimen G of the Phase 2/3 HEALEY ALS Platform Trial; plans, timelines, and expectations of both Denali and Sanofi regarding DNL788, including the Phase 2 study in MS; plans, timelines, and expectations regarding DNL151, including with respect to the ongoing LUMA study as well as enrollment and timing of the proposed Phase 2a study in PD patients with LRRK2 mutations; expectations regarding DNL758, including the ongoing Phase 2 study in patients with UC; plans, timelines, and expectations related to DNL126, including the timing and availability of data in the ongoing Phase 1/2 study and the impact on development of participation in START; plans, timelines, and expectations of both Denali and Takeda regarding DNL593 and the ongoing Phase 1/2 study; plans, timelines, and expectations regarding the advancement of OTV:MAPT and OTV:SNCA towards clinical development; plans, timelines, and expectations regarding the ATV:Abeta program, including its therapeutic potential and the clinical advancement of ATV:Abeta molecules; plans and expectations for Denali's preclinical programs; Denali's future operating expenses and anticipated cash runway; Denali's PIPE financing and its anticipated proceeds; and Denali's participation in upcoming investor conferences. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: any and all risks to Denali’s business and operations caused by adverse economic conditions; risk of the occurrence of any event, change, or other circumstance that could give rise to the termination of Denali’s agreements with Sanofi, Takeda, or Biogen, or any of Denali’s other collaboration agreements; Denali’s transition to a late-stage clinical drug development company; Denali’s and its collaborators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; Denali’s dependence on successful development of its blood-brain barrier platform technology and its programs and product candidates; Denali’s and its collaborators' ability to conduct or complete clinical trials on expected timelines; the risk that preclinical profiles of Denali’s product candidates may not translate in clinical trials; the potential for clinical trials to differ from preclinical, early clinical, preliminary or expected results; the risk of significant adverse events, toxicities or other undesirable side effects; the uncertainty that product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create a pipeline of product candidates or develop commercially successful products; developments relating to Denali's competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; implementation of Denali’s strategic plans for its business, product candidates, and blood-brain barrier platform technology; Denali's ability to obtain additional capital to finance its operations, as needed; Denali's ability to accurately forecast future financial results in the current environment; and other risks and uncertainties, including those described in Denali's most recent Annual and Quarterly Reports on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 28, 2024 and May 7, 2024, respectively, and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results, or to make changes in Denali’s expectations, except as required by law. Denali Therapeutics Inc.Condensed Consolidated Statements of Operations(Unaudited)(In thousands, except share and per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023Collaboration revenue: Collaboration revenue from customers(1)$— $294,123 $— $329,264 Total collaboration revenue — 294,123 — 329,264 Operating expenses: Research and development(2) 91,399 97,520 198,415 226,336 General and administrative 25,194 26,120 50,430 53,260 Total operating expenses 116,593 123,640 248,845 279,596 Gain from divestiture of small molecule programs — — 14,537 — Income (loss) from operations (116,593) 170,483 (234,308) 49,668 Interest and other income, net 17,567 12,900 33,480 23,934 Net income (loss)$(99,026) $183,383 $(200,828) $73,602 Net income (loss) per share: Net income (loss) per share, basic$(0.59) $1.34 $(1.26) $0.54 Net income (loss) per share, diluted$(0.59) $1.30 $(1.26) $0.52 Weighted-average shares used in calculating: Net income (loss) per share, diluted 168,831,329 137,047,227 159,117,759 136,787,321 Weighted average number of shares outstanding, basic and diluted 168,831,329 140,930,625 159,117,759 140,550,226 __________________________________________________(1) Includes related-party collaboration revenue from customers of $294.1 million and $294.3 million for the three and six months ended June 30, 2023, respectively.(2) Includes expenses for cost sharing payments due to a related party of $7.0 million and $11.1 million for the three and six months ended June 30, 2023, respectively. Denali Therapeutics Inc.Condensed Consolidated Balance Sheets(Unaudited)(In thousands) June 30, 2024 December 31, 2023Assets Current assets: Cash and cash equivalents$74,679 $127,106 Short-term marketable securities 821,365 907,405 Prepaid expenses and other current assets 32,339 29,626 Total current assets 928,383 1,064,137 Long-term marketable securities 450,994 — Property and equipment, net 48,077 45,589 Operating lease right-of-use asset 24,533 26,048 Other non-current assets 50,578 18,143 Total assets$1,502,565 $1,153,917 Liabilities and stockholders' equity Current liabilities: Accounts payable$13,936 $9,483 Accrued clinical and other research & development costs 19,915 19,035 Accrued manufacturing costs 7,111 15,462 Other accrued costs and current liabilities 6,013 5,152 Accrued compensation 9,555 21,590 Operating lease liability, current 7,771 7,260 Deferred research funding liability 10,232 — Total current liabilities 74,533 77,982 Operating lease liability, less current portion 40,981 44,981 Total liabilities 115,514 122,963 Total stockholders' equity 1,387,051 1,030,954 Total liabilities and stockholders’ equity$1,502,565 $1,153,917 Investor and Media Contact: Laura Hansen, Ph.D.Vice President, Investor Relations(650) 452-2747hansen@dnli.com