DNA Damage

The FDA has cleared the investigational new drug (IND) application for EIS-12656, a first-in-class orally bioavailable and blood brain barrier-penetrant allosteric inhibitor of ALC1 (CHD1L), a key molecular machine in DNA repair. EIS-12656 targets homologous recombination repair deficient cancers. Its expected superior safety should facilitate novel combination therapies with and beyond PARP inhibitors in hard to treat cancers. Eisbach Bio expects to start enrolling patients in the second quarter of 2024. MARTINSRIED, Germany, May 6, 2024 /PRNewswire/ -- Eisbach Bio GmbH ("Eisbach" or the "Company"), a privately-held clinical-stage biotechnology company pioneering cancer medicines leveraging synthetic lethality, has announced United States Food and Drug Administration (FDA) clearance of its investigational new drug (IND) application for EIS-12656, a small molecule inhibiting the chromatin helicase ALC1 (CHD1L). EIS-12656 targets ALC1 through allosteric mechanisms, suppressing the cancer-relevant genome reorganization induced by DNA damage. This leads to ALC1 chromatin trapping and cancer cell killing. EIS-12656 impacts tumors deficient in DNA repair pathways. It demonstrated substantial tumor growth inhibition in preclinical models, including in combination with standard-of-care therapies. Its allosteric mechanism of action should afford selectivity compared to related synthetic lethal targets, contributing to the exceptional safety observed in all relevant preclinical models. "EIS-12656 selectively targets tumors with no apparent effects on normal tissues." said Adrian Schomburg, Ph.D., Founder and CEO of Eisbach. "Our clinical study will also explore combination therapies that were hindered by combinatorial toxicity in the past." The discovery of EIS-12656 builds on the pioneering research of Eisbach founder Prof. Andreas Ladurner, whose team discovered that PARP effects in cancer cells are reliant on chromatin remodeling by ALC1. Eisbach built upon this knowledge and designed a first-in-class, once-daily small molecule therapy, directly targeting cancer genome reorganization induced by DNA damage at its source – the PARP-activated helicase ALC1. About the Phase 1/2 Clinical Trial The open label study of EIS-12656 will evaluate its safety, tolerability and efficacy in patients with genetically-defined advanced solid tumors. Led by Principal Investigator Timothy A. Yap, M.B.B.S., Ph.D., Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, the trial includes dose escalation of EIS-12656 monotherapy, followed by dose expansion modules and evaluation in patients progressing under PARP inhibitor treatment. About Eisbach Eisbach is at the forefront of precision oncology, developing allosteric drugs that selectively disrupt molecular machines vital for tumor genome reorganization. Combining genetic vulnerabilities with its proprietary ALLOS platform, which hits the molecular vulnerability of its cancer targets, Eisbach pioneers first-in-class therapies with fewer side effects. For more information, visit and follow us on LinkedIn. Contacts: Eisbach Bio GmbH Adrian Schomburg, CEO +49 89 2153 7900 Jonathan Iorio +49 89 2153 79013 Logo - SOURCE Eisbach Bio

National TV and digital media campaign aims to motivate millions of people suffering from Erosive GERD to learn more about VOQUEZNA® (vonoprazan), the first and only FDA-approved potassium-competitive acid blocker (PCAB) A Media Snippet accompanying this announcement is available by clicking on this link. FLORHAM PARK, N.J., March 26, 2024 (GLOBE NEWSWIRE) -- Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, today announces the launch of its new broadcast ad and full-scale, Direct-to-Consumer (DTC) campaign, “VOQUEZNA Can Kick Some Acid,” to raise awareness of its powerful first-in-class treatment and encourage people to speak to their doctor about this new treatment option. VOQUEZNA (vonoprazan) is indicated for the healing and maintenance of healing of all severities of Erosive Esophagitis (EE), also referred to as Erosive GERD, and for the relief of related heartburn. VOQUEZNA represents the first major innovation to the U.S. Erosive GERD market in over 30 years.1 The multi-channel campaign delivers strong, compelling, and motivating efficacy and safety information to educate consumers about this new treatment option. It is currently live at VOQUEZNA.com and through Connected TV – streaming consumer content on popular platforms such as Prime Video, Hulu, and Peacock. The campaign will also be featured on consumer-facing platforms across Facebook, Instagram, waiting room TVs in doctor offices, and digital banner ads. Broadcast television promotion is anticipated to launch in the second quarter of 2024. By strategically utilizing a wide array of platforms, and leveraging advanced targeting, Phathom anticipates this campaign will reach the millions of Erosive GERD sufferers and motivate these patients to seek a new class of treatment that works differently than proton pump inhibitors (PPIs). “Phathom is excited to launch our first campaign directly to, and for, the people whose lives we strive to improve every day. Although Erosive GERD is a highly symptomatic condition that can have a detrimental impact on millions of patients, there has been little medical innovation in this category in decades, until now,” said Martin Gilligan, Chief Commercial Officer at Phathom Pharmaceuticals. “We believe our new DTC campaign is accessible, memorable, and informative. Our goal is to connect with people unsatisfied with their current treatment options and empower them to explore the power of VOQUEZNA with their healthcare provider.” VOQUENZA, the first and only U.S. Food and Drug Administration (FDA)-approved treatment of its kind, helps to heal and maintain healing of acid-related damage to the lining of the esophagus, in addition to helping to provide 24-hour relief of associated heartburn in most adults. Its novel mechanism of action provides rapid, potent, and durable acid suppression in a way that is distinct from other prescription and over-the-counter medications.2 VOQUEZNA offers a novel therapeutic option with strong efficacy compared to standard of care PPI lansoprazole, demonstrated across a range of clinically important endpoints, including maintaining healing of Erosive GERD for all patients through six months. VOQUEZNA 20 mg demonstrated a strong healing rate of 93% compared to 85% for lansoprazole 30 mg. And of those healed, 79% stayed healed for 6-months on VOQUEZNA 10 mg compared to 72% taking lansoprazole 15mg.1 The most common side effects of VOQUEZNA for the treatment of Erosive GERD include stomach inflammation, diarrhea, stomach bloating, stomach pain, nausea, indigestion, high blood pressure, and urinary tract infection.1 Further information on these Phase 3 results from Phathom’s pivotal clinical study is available at www.voquezna.com. Phathom is offering savings programs for eligible patients who face coverage or affordability issues, including a savings card program that allows for eligible patients with commercial insurance to pay as little as $25 for their VOQUEZNA prescription. The company has also partnered with BlinkRx, an end-to-end digital fulfillment channel that helps eligible patients find the most affordable option for filling their VOQUEZNA prescription. For more information, visit www.voquezna.com/savings. To view a video of the “VOQUEZNA Can Kick Some Acid” commercial, click here. If you are considering a new treatment option for Erosive GERD, you should speak to your healthcare provider to see if VOQUEZNA may be right for you. VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. Please visit www.voquezna.com to learn more about VOQUEZNA. INDICATION AND IMPORTANT SAFETY INFORMATION What is VOQUEZNA? VOQUEZNA® (vonoprazan) is a prescription medicine used in adults: for 8 weeks to heal acid-related damage to the lining of the esophagus (called Erosive Esophagitis) and for relief of heartburn related to Erosive Esophagitis.for up to 6 months to maintain healing of Erosive Esophagitis and for relief of heartburn related to Erosive Esophagitis. It is not known if VOQUEZNA is safe and effective in children. Do not take VOQUEZNA if you: are allergic to vonoprazan or any of the other ingredients in VOQUEZNA. Allergic reaction symptoms may include trouble breathing, rash, itching and swelling of your face, lips, tongue, or throat.are taking a medicine that contains rilpivirine (EDURANT, COMPLERA, JULUCA, ODEFSEY, CABENUVA) used to treat HIV-1 (Human Immunodeficiency Virus). Before taking VOQUEZNA, tell your healthcare provider about all your medical conditions, including if you: have low magnesium, calcium, or potassium in your blood, or you are taking a medicine to increase urine (diuretic).have kidney or liver problems.are pregnant, think you may be pregnant, or plan to become pregnant. It is not known if VOQUEZNA will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if VOQUEZNA passes into your breast milk. You and your healthcare provider should decide if you will take VOQUEZNA or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. VOQUEZNA may affect how other medicines work, and other medicines may affect how VOQUEZNA works. Especially tell your healthcare provider if you take medicine that contains rilpivirine (EDURANT, COMPLERA, JULUCA, ODEFSEY, CABENUVA). What are the possible side effects of VOQUEZNA?VOQUEZNA may cause serious side effects including: A type of kidney problem (acute tubulointerstitial nephritis): Some people who take VOQUEZNA may develop a kidney problem called acute tubulointerstitial nephritis. Call your healthcare provider right away if you have a decrease in the amount that you urinate or if you notice blood in your urine.Diarrhea caused by an infection (Clostridioides difficile) in your intestines: Call your healthcare provider right away if you have watery stools, stomach pain, and fever that does not go away.Bone fractures (hip, wrist, or spine): Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of another type of medicine that reduces acid in your stomach known as proton pump inhibitors (PPI medicines) for a long period of time (a year or longer). Tell your healthcare provider if you have a bone fracture, especially in the hip, wrist, or spine.Severe skin reactions: VOQUEZNA can cause rare, but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening: Skin rash which may have blistering, peeling, or bleeding on any part of your skin.You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. If you experience any of these symptoms, stop taking VOQUEZNA and call your healthcare provider right away. These symptoms may be the first sign of a severe skin reaction. Low vitamin B-12 levels: VOQUEZNA lowers the amount of acid in your stomach. Stomach acid is needed to absorb Vitamin B12 properly. Tell your healthcare provider if you have symptoms of low vitamin B12 levels, including irregular heartbeat, shortness of breath, lightheadedness, tingling or numbness in the arms or legs, muscle weakness, pale skin, feeling tired, or mood changes. Talk with your healthcare provider about the risk of low vitamin B12 levels if you have been on VOQUEZNA for a long time.Low magnesium levels in the body can happen in people who take VOQUEZNA. Tell your healthcare provider right away if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, or spasms of hands, feet, or voice.Stomach growths (fundic gland polyps): A certain type of stomach growth called fundic gland polyps may happen in people who take another type of medicine that reduces acid in your stomach known as proton pump inhibitors (PPI medicines) for a long time. Talk with your healthcare provider about the possibility of fundic gland polyps if you have been on VOQUEZNA for a long time. The most common side effects of VOQUEZNA for treatment of Erosive Esophagitis include: stomach inflammationdiarrheastomach bloatingstomach painnauseaindigestionhigh blood pressureurinary tract infection These are not all the possible side effects of VOQUEZNA. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. 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 Patient Information and full Prescribing Information for VOQUEZNA. About Erosive GERD (gastroesophageal reflux disease)Erosive GERD, also referred to as Erosive Esophagitis (EE), is a subtype of gastroesophageal reflux disease (GERD) characterized by erosions in the gastric mucosa caused by acidic reflux of stomach contents into the esophagus.3 There are estimated to be over 65 million individuals with GERD in the U.S., of which approximately 30% have Erosive GERD.4,5,6 In addition to experiencing troubling heartburn symptoms, patients with inadequately treated Erosive GERD may progress to more severe diseases including Barrett’s esophagus and esophageal cancer.4 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. Vonoprazan helps provide rapid, potent, and durable acid suppression.2 Phathom in-licensed the U.S., European, and Canadian 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 Erosive GERD and relief of related heartburn in adults, 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. Forward Looking StatementThis press release contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the potential success of Phathom’s DTC campaign. 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: we may not be able to successfully commercialize VOQUEZNA, VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PACK, which will depend on a number of factors including coverage and reimbursement levels from governmental authorities and health insurers as well as market acceptance by healthcare providers; 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; 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, 2023.Laine L, Sharma P, Mulford DJ, et al. Pharmacodynamics and pharmacokinetics of the potassium-competitive acid blocker vonoprazan and the proton pump inhibitor lansoprazole in US subjects. Am J Gastroenterol. 2022;117(7):1158-1161.Dickman R, Maradey-Romero C, Gingold-Belfer R, Fass R. Unmet Needs in the Treatment of Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. 2015 Jul 30;21(3):309-19. doi: 10.5056/jnm15105.Savarino E, de Bortoli N, De Cassan C, et al. The natural history of gastro-esophageal reflux disease: A comprehensive review. Dis Esophagus. 2017;30(2):1-9.Machicado J.D., Greer J.B., Yadav D. (2020) Epidemiology of Gastrointestinal Diseases. In: Pitchumoni C., Dharmarajan T. (eds) Geriatric Gastroenterology. Springer, Cham. https://doi.org/10.1007/978-3-319-90761-1_7-1.U.S. Census Bureau. U.S. and World Population Clock. Accessed May 2022. https://www.census.gov/popclock. MEDIA CONTACTNick Benedetto1-877-742-8466media@phathompharma.com INVESTOR CONTACTEric Sciorilli1-877-742-8466ir@phathompharma.com © 2024 Phathom Pharmaceuticals. All rights reserved. VOQUEZNA, VOQUEZNA TRIPLE PAK, VOQUEZNA DUAL PAK, Phathom Pharmaceuticals, and their respective logos are registered trademarks of Phathom Pharmaceuticals, Inc. 3/24 US-VPZ-24-0136

Doheny Eye Institute scientists in collaboration with UCLA Chemists show how a single gene mutation in an enzyme complex known to produce the energy required by cells causes a sudden, blinding diseasePASADENA, Calif., Jan. 29, 2024 (GLOBE NEWSWIRE) -- Doheny Eye Institute, one of the nation’s leading vision research institutions, is pleased to announce the publication of important new findings in the highly respected scientific journal Proceedings of the National Academy of Science, U.S.A. Doheny Eye Institute scientists, working with colleagues at UCLA and University of Texas, have shown how a single gene mutation in the enzyme complex that produces the energy used by cells causes a sudden, blinding disease called Leber’s Hereditary Optic Neuropathy (LHON). The mutation affects the cells’ tiny mitochondria, miniature power stations that generate the energy molecules called ‘ATP,’ that all cells of the body require to do their jobs and stay alive. The mystery of how LHON causes blindness is now illuminated: the mutation causes alterations in quantum electron tunneling. Quantum tunneling is an amazing process, totally unlike classical chemistry, that enables elementary particles, like electrons, to penetrate through energy barriers. What is now shown is that quantum tunneling is likely central to many biological reactions and may be key in explaining other human diseases. Dr. Alfredo Sadun, renowned ophthalmologist and global expert on this disease, and biophysicist Dr. Steven Barnes, both of Doheny Eye Institute and UCLA’s Department of Ophthalmology, tapped the expertise of UCLA Department of Chemistry’s Drs. Anastassia Alexandrova and Jack Fuller, to address the disease using state-of-the-art computational chemistry tools. This maternally-inherited genetic disorder typically waits for two decades before it strikes its victims, causing severe loss of vision or blindness, usually in young adult men, and to a lesser extent women, in their twenties. In a commentary published in the same journal as the study, Prof. P.J. Burke of UC Irvine praised the authors for this important step in explaining how this DNA defect causes blindness. Describing the work’s importance, Burke states that it has “broad significance as a model for dissecting the link between energy, health, and life.” Members of the team previously showed that this disease kills the eye’s retinal ganglion cells (RGCs) not by causing poor energy production, but rather by producing ‘reactive oxygen species,’ or ROS, normal cellular molecules that when over-produced seriously impair cell protein function. In LHON, these damaging ROS are an unnoticed problem that waits decades before damage suddenly exceeds a threshold, triggering the death of RGCs, neurons that transmit electrical signals coding patterns of light from the eye to the brain. In order to determine the origin of the ROS, the group examined how the single genetic mutation affects a key subsection of the cell’s mitochondria with a single amino acid swap. It is in this subsection, called Complex I, that the mobility of the energy-trafficking molecule CoQ10 is seriously impaired. CoQ10, getting into and out of a tight-fitting channel in Complex I, defines the rate of the quantum tunneling of electrons that play a central role for generating ATP. Powerful Molecular Dynamics simulations were performed using the National Supercomputer network to analyze the impact of the single amino acid swap from alanine to threonine in Complex I on the mobility of CoQ10 at different speeds via calculation of the positions and free energy of the molecules. They found that CoQ10 exits the mutated channel a billion times slower than it would in a normal channel. The continuous supply of electrons to Complex I, now having nowhere to go, produces excessive rates of electron backup and spillage that generates ROS. This conclusion supports earlier observations that neurons with models of LHON produce near normal amounts of ATP but high levels of ROS, which facilitate RGC death. Link to the full article: https://pubmed.ncbi.nlm.nih.gov/37733737/ About Doheny Eye InstituteDoheny Eye Institute is one of the nation’s leading vision research institutions with a history dating back over 75 years. Doheny scientists and clinician-scientists remain at the forefront of vision science investigating how retinal neurons function in health and in diseases, such as diabetic retinopathy, optic neuropathies, uveitis, age-related macular degeneration, and the use of artificial intelligence for improved diagnosis of ocular diseases. Since 2013, the Doheny and UCLA Stein Eye Institute affiliation combines the strength, reputation, and distinction of two of the nation’s top eye institutions to advance vision research, education, and patient care in Southern California. Together, Doheny Eye Institute and UCLA Stein Eye Institute are ranked in the Top 5 vision centers in the country by U.S. News & World Report. For more information visit www.Doheny.org. Contact:Molly Ann Woods310-717-0955mwoods@doheny.org