Vitamin B 12 Deficiency

The algae P. antarctica has two forms of the enzyme that makes the amino acid methionine, one needing B12, and one that is slower, but doesn't need it. This means it has the ability to adapt and survive with low B12 availability. The presence of the MetE gene in P. antarctica gives the algae the ability to adapt to lower vitamin B12 availability, giving it a potential advantage to bloom in the early austral spring when bacterial production is low. P. antarctica takes in the CO2 and releases oxygen through photosynthesis. Understanding its ability to grow in environments with low vitamin B12 availability can help climate modelers make more accurate predictions. Vitamin B12 deficiency in people can cause a slew of health problems and even become fatal. Until now, the same deficiencies were thought to impact certain types of algae, as well. A new study examined the algae Phaeocystis antarctica's (P. antarctica) exposure to a matrix of iron and vitamin B12 conditions. Results show that this algae has the ability to survive without B12, something that computer analysis of genome sequences had incorrectly indicated. The alga, native to the Southern Ocean, starts as a single-cell that can transform into millimeter scale colonies. The research published in PNAS, "Flexible B12 ecophysiology of Phaeocystis antarctica due to a fusion B12-independent methionine synthase with widespread homologues," conducted by MIT, WHOI, J.C. Venter Institute, and Scripps Institution of Oceanography (UCSD), found that unlike other keystone polar phytoplankton, P. antarctica can survive with or without vitamin B12. "Vitamin B12 is really important to the algae's metabolism and because it allows them to make a key amino acid more efficiently," said Makoto Saito, one of the study's co-authors and senior scientist at the Woods Hole Oceanographic Institution (WHOI). "When you can't get vitamin B12, life has ways to make those amino acids more slowly, causing them to grow slower as well. In this case, there's two forms of the enzyme that makes the amino acid methionine, one needing B12, and one that is much slower, but doesn't need B12. This means P. antarctica has the ability to adapt and survive with low B12 availability." Researchers came to their conclusion by studying P. antarctica's proteins in a lab culture, and also searching for key proteins in field samples. During their observation, they found the algae to have a B12-independent methionine synthase fusion protein (MetE). The MetE gene isn't new, but was previously believed not to have been possessed by P. antarctica. MetE gives the algae the flexibility to adapt to low vitamin B12 availability. "This study suggests that the reality is more complex. For most algae, maintaining a flexible metabolism for B12 is beneficial, given how scarce the vitamin's supply is in seawater," said Deepa Rao, lead researcher of the study and former MIT postdoc." Having this flexibility enables them to make essential amino acids, even when they can't obtain enough of the vitamin from the environment. Implying that the classification of algae as B12-requiring or not might be too simplistic" Antarctica, which lives at the base of the food web, has been thought to be entirely controlled by iron nutrition. The discovery of the MetE gene also indicates vitamin B12 likely plays a factor. Because of its presence in P. antarctica, the adaptability of the algae gives it a potential advantage to bloom in the early austral spring when the bacteria that produce B12, are scarcer. This discovery also has implications for climate change. The Southern Ocean, where P. antarctica is found, plays a significant role in the Earth's carbon cycle. P. antarctica takes in the CO2 and releases oxygen through photosynthesis. "As our global climate warms, there's increasing amounts of iron entering the coastal Southern Ocean from melting glaciers," Saito said. "Predicting what the next limiting thing after iron is important, and B12 appears to be one of them. Climate modelers want to know how much algae is growing in the ocean in order to get predictions right and they've parameterized iron, but haven't included B12 in those models yet." "We are particularly interested in knowing more about the extent of strain level diversity. It will be interesting to see if B12 independent strains have a competitive advantage in a warmer Southern Ocean," said co-author of the study Andy Allen, a joint professor at the J. Craig Venter Institute and the Scripps Institution of Oceanography at the University of California, San Diego. "Since there is a cost to B12 independence in terms of metabolic efficiency, an important question is whether or not strains that require B12 might become reliant on B12 producing bacteria." The discovery that P. antarctica has the ability to adapt to minimal vitamin B12 availability turns out to be true for many other species of algae that were also assumed to be strict B12 users previously. The findings from this study will pave the way for future research related to the carbon cycle and how different types of algae survive in the Southern Ocean's cold and harsh environment.

New drug application (NDA) seeks U.S. Food and Drug Administration (FDA) approval for VOQUEZNA® as a daily treatment for heartburn associated with Non-Erosive GERD, the largest subcategory of GERD July 19, 2024 PDUFA target action date assigned by the FDA FLORHAM PARK, N.J., Dec. 06, 2023 (GLOBE NEWSWIRE) -- Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal diseases, announced today the FDA has accepted for review the company’s NDA for VOQUEZNA (vonoprazan) as a daily treatment of heartburn associated with Non-Erosive gastroesophageal reflux disease (GERD) in adults. The FDA has assigned the application a standard 10-month review with a Prescription Drug User Fee Act (PDUFA) target action date of July 19, 2024. "Today marks an important step forward for Phathom Pharmaceuticals as we announce the FDA's acceptance for filing of our New Drug Application for VOQUEZNA as a daily treatment of heartburn for patients with Non-Erosive GERD,” said Azmi Nabulsi, M.D., Chief Operating Officer at Phathom. “Non-Erosive GERD represents a substantial segment of the U.S. GERD population, affecting millions of individuals and impacting their quality of life. The supportive data in our regulatory application include the positive Phase 3 results from the investigational PHALCON-NERD-301 trial, along with a safety pro with prior studies. We look forward to working closely with the FDA throughout the review process and if approved, expect to launch VOQUEZNA for this new indication in the third quarter of 2024.” Non-Erosive GERD is the largest subcategory of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. There are an estimated 38 million U.S. adults living with Non-Erosive GERD, of these approximately 15 million are diagnosed and treated with a prescription medicine annually. Symptoms impact overall quality of life and can include episodic heartburn, especially at night, regurgitation, problems swallowing, and chest pain. Phathom is also finalizing its plans to initiate an additional Phase 3 study in 2024 evaluating VOQUEZNA as an investigational As Needed treatment for episodic heartburn relief in adults with Non-Erosive GERD, a novel dosing treatment regimen for which proton pump inhibitors (PPIs) are not approved in the U.S. INDICATIONS AND USAGE VOQUEZNA® (vonoprazan) is a potassium-competitive acid blocker (PCAB) indicated: for the healing of all grades of Erosive Esophagitis (Erosive Gastroesophageal Reflux Disease or Erosive GERD) and relief of heartburn associated with Erosive GERD in adults. for the maintenance of healing of all grades of Erosive GERD and relief of heartburn associated with Erosive GERD in adults. 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. 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. 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 14 days 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%). 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. 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). 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). 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 . Please see full Prescribing Information for VOQUEZNA. About PHALCON-NERD-301 PHALCON-NERD-301 was a randomized, placebo-controlled, double-blind, multicenter Phase 3 study that enrolled 772 adult patients with symptomatic Non-Erosive GERD in the U.S. The trial evaluated the efficacy of VOQUEZNA 10 mg and 20 mg as a daily dosing (QD) treatment, as compared to placebo (QD), in the relief of heartburn over four weeks in participants with symptomatic Non-Erosive GERD. The trial also included a 20-week blinded long-term extension period to further evaluate the safety and efficacy of both doses of VOQUEZNA after six months of continuous use. About VOQUEZNA® VOQUEZNA® (vonoprazan) tablets contain vonoprazan, an oral small molecule potassium-competitive acid blocker (PCAB), approved in the U.S. for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD, and the relief of heartburn associated with Erosive GERD. PCABs are a novel class of medicines that block acid secretion in the stomach. 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 in the U.S., Europe, and Canada to vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB). For more information about Phathom, visit the Company’s website at and follow the Company on LinkedIn and X (formerly Twitter). Forward-Looking Statement This press release contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the timing of regulatory approval and launch of VOQUEZNA for the treatment of heartburn associated with Non-Erosive GERD, initiation of a Phase 3 trial evaluating VOQUEZNA as an As Needed treatment of heartburn associated with Non-Erosive GERD, and the size of the Non-Erosive GERD patient population. 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 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; future data generated from our stability program may be different from the data submitted to the FDA to date and may not demonstrate that our mitigation efforts will continue to maintain the level of the nitrosamine impurity below the acceptable intake (AI) level throughout the shelf life of products containing vonoprazan, which could result in market action or shelf life reduction; risks associated with product manufacturing or formulation changes required to be made in connection with achieving the AI; 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 access additional capital under its term loan facility and royalty interest finance agreements is subject to certain conditions; Phathom’s ability to obtain and maintain intellectual property protection for vonoprazan; Phathom’s ability to comply with its license agreement with Takeda; 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 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. MEDIA CONTACT Nick Benedetto 1-877-742-8466 media@phathompharma.com INVESTOR CONTACT Eric Sciorilli 1-877-742-8466 ir@phathompharma.com © 2023 Phathom Pharmaceuticals. All rights reserved. VOQUEZNA, Phathom Pharmaceuticals, and their respective logos are registered trademarks or trademarks of Phathom Pharmaceuticals, Inc.

Though blood tests for Alzheimer’s are likely to become common in the years ahead, the Alzheimer’s Association said it’s premature to offer a test of this kind directly to consumers. For the first time, people worried about their risk of Alzheimer’s disease can go online, order a blood test, and receive results in the privacy of their homes. This might seem appealing on the surface, but the development has Alzheimer’s researchers and clinicians up in arms. The Quest Diagnostics blood test, AD-Detect, measures elevated levels of amyloid-beta proteins, a signature characteristic of Alzheimer’s. Introduced in late July, the test is targeted primarily at people 50 and older who suspect their memory and thinking might be impaired and people with a family history of Alzheimer’s or genetic risks for the condition. Given Alzheimer’s is among the most feared of all medical conditions, along with cancer, this could be a sizable market, indeed. Nearly 7 million older adults in the U.S. have Alzheimer’s, and that number is expected to double by 2060 if medical breakthroughs don’t occur. But Alzheimer’s researchers and clinicians aren’t convinced the Quest test is backed by sound scientific research. The possibility of false-positive results is high, as is the likelihood that older adults won’t understand the significance of their results, they say. The test should be taken only under a physician’s supervision if at all, they advise. And, priced originally at $399 (recently discounted to $299) and not covered by insurance, it isn’t cheap. Though blood tests for Alzheimer’s are likely to become common in the years ahead, the Alzheimer’s Association said it’s premature to offer a test of this kind directly to consumers. For its part, Quest, which also sells direct-to-consumer tests for sexually transmitted diseases and various other conditions, suggests older adults can be trusted to respond responsibly to AD-Detect results. The test is not meant to diagnose Alzheimer’s, the company stressed; instead, it’s meant to help assess an individual’s risk of developing the condition. But under a new, proposed biological definition of Alzheimer’s, excess amyloid could automatically trigger a diagnosis of “preclinical” Alzheimer’s. Michael Racke, Quest’s medical director of neurology, said individuals who test positive might be inspired to talk to their physicians about cognitive symptoms and seek comprehensive evaluations from dementia specialists. Others may just want to adopt behaviors associated with brain health, such as exercising more and maintaining healthy blood pressure, blood sugar, and cholesterol levels. “People who do consumer-initiated testing are often very motivated to figure out what they can do to help reduce the risk of disease,” he said. To get the test, a person first needs to go to the AD-Detect test’s website and report that they’re experiencing mild cognitive decline and have at least one other risk factor. (Self-reported complaints of this kind are often unreliable, experts note.) The order then goes automatically to a doctor paid by Quest, who will order a blood test to be drawn at a Quest laboratory. Results classifying a person as low, medium, or high risk will be provided on a secure patient portal. Post-test counseling isn’t mandatory, but individuals can speak to a physician paid by Quest, if they like. (There is a separate $13 “physician service fee.”) A new poll from the University of Michigan confirms that older adults will take results seriously: Ninety-seven percent of seniors said they would take steps to improve brain health upon receiving a positive result from a blood test, while 77% said they would consider changes to financial or end-of-life plans. But research scientists and clinicians worry that Quest hasn’t published any peer-reviewed studies documenting the test’s validity. The company’s preliminary data released at the 2022 Alzheimer’s Association International Conference in San Diego suggests there’s a relatively high chance of false-positive results, said Suzanne Schindler, an associate professor of neurology at Washington University School of Medicine in St. Louis. That’s a significant problem because telling someone they have biological changes associated with Alzheimer’s disease is a “big deal and you want to be as accurate as possible,” Schindler noted. Racke said at least three scientific studies giving more details about the AD-Detect test have been submitted to medical journals and might be published by the end of this year. Experts also question the usefulness of the test since a positive result (indicating abnormal levels of amyloid in the blood) doesn’t mean an individual will definitely develop Alzheimer’s disease. Amyloid in the brain accumulates slowly over the course of decades, typically beginning in middle age, and becomes more common as people age. “This test gives you a fuzzy answer. We don’t know whether you’re going to get dementia, or when symptoms might begin, or, really, how high the risk is for any individual,” said Meera Sheffrin, medical director of the Senior Care clinic at Stanford Healthcare. Also, cognitive symptoms that prompt someone to take the test might be due to a wide variety of other causes, including mini-strokes, sleep apnea, thyroid problems, vitamin B12 deficiency, or medication interactions. If an older adult becomes anxious, depressed, or hopeless upon learning they’re at risk for Alzheimer’s—another source of concern—“they may not go for further evaluation and seek appropriate care,” said Rebecca Edelmayer, senior director of scientific engagement at the Alzheimer’s Association. The University of Michigan poll confirms the potential for misunderstanding. Upon receiving a positive result from a blood test, 74% of seniors said they would believe they were likely to develop Alzheimer’s and 64% said they would be likely to experience significant distress. Because the science behind blood tests for Alzheimer’s is still developing and because “patients may not really understand the uncertainty of test results,” Edelmayer said, the Alzheimer’s Association “does not endorse the use of the AD-Detect test by consumers.” Quest’s blood test is one of several developments altering the landscape of Alzheimer’s care in the United States. In early July, the FDA granted full approval to Leqembi, an anti-amyloid therapy that slightly slows cognitive decline in people with mild cognitive impairment and early-stage Alzheimer’s. Early detection of cognitive symptoms and diagnosis of cognitive dysfunction have assumed greater importance now that this disease-modifying drug is available. Also in July, a workgroup convened by the National Institute on Aging and the Alzheimer’s Association proposed a new definition of Alzheimer’s disease to be used in clinical practice. Previously, Alzheimer’s could be diagnosed only when there was evidence of underlying brain pathology (amyloid plaques and tau tangles) as well as cognitive symptoms (memory loss, poor judgment, disorientation, among others) and accompanying impairments (difficulty with managing finances, wandering, problems with self-care, and more). Under the new definition, Alzheimer’s would be defined purely on a biological basis, as a “continuum that is first evident with the appearance of brain pathologic changes” including amyloid accumulation, according to a draft of the work group’s report. That would mean “you can get a positive result from the Quest test and be diagnosed with Alzheimer’s disease if these guidelines are adopted, even if you’re cognitively normal,” cautioned Eric Widera, a professor of medicine at the University of California-San Francisco. Demand for follow-up evaluations by dementia specialists is likely to be high and contribute to already-long waits for care, he suggested. Additional concerns about the test relate to safeguarding privacy and the potential for discrimination. No federal laws protect people who receive Alzheimer’s biomarker results from discriminatory practices, such as employment discrimination or the denial of life, disability, or long-term care insurance. (The Genetic Information Nondiscrimination Act applies only to genetic tests.) And “laws that normally protect the privacy of health information do not apply in this space,” said Emily Largent, an assistant professor of medical ethics and health policy at the University of Pennsylvania’s Perelman School of Medicine. Notably, HIPAA, the Health Insurance Portability and Accountability Act, doesn’t extend to laboratory tests marketed directly to consumers. The bottom line: Before taking a test, “older adults need to ask themselves, ‘Why do I want to know this? What will I do with the information? How will I react? What would I change in the future?’” said C. Munro Cullum, a neuropsychologist and distinguished professor of clinical psychology at the University of Texas Southwestern Medical Center. “This test needs to be used very cautiously and with great forethought.” KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.