Sodium Oligomannurarate

A Phase III study of a seaweed-derived Alzheimer’s drug, conditionally approved in China in November 2019, has been halted, five trial sites have confirmed to Endpoints News. Shanghai-based Green Valley Pharmaceuticals’ oligomannate, or GV-971, was in a late-stage Alzheimer’s study dubbed “Green Memory,” but the trial was halted due to supply chain issues, according to four of the sites. One site said it was not supply chain-related. Eric Reiman, a former scientific advisor to Green Valley, said he was informed the trial was discontinued “due to unexpected financial challenges related to the COVID-19 Pandemic in China.” “Based on the information that was shared with us, the advisors were not aware of any treatment-related safety issues,” Reiman said in an email to Endpoints. He is also executive director of Banner Alzheimer’s Institute, which is listed as one of the study’s trial sites on clinicaltrials.gov. The trial was halted at one site in early April, another about two weeks ago and others “several” and “a couple” weeks ago. One trial site said they received a calendar invite from the company for tomorrow. “Shanghai is not in a happy place,” one of the trial sites said, citing the Covid-19 lockdowns currently taking place in the city. Endpoints has reached out to multiple phone numbers and emails associated with Green Valley and will update accordingly. At the time of its IND clearance in April 2020, Green Valley said it would work with IQVIA on the trial. A spokesperson for the CRO told Endpoints in an emailed statement: “It’s our corporate policy to defer all study questions to the respective study sponsors.” The news comes after CMO Samuel Agus left his post last month, according to his LinkedIn profile. The study kicked off in October 2020 and had expected to enroll 2,046 patients with mild to moderate Alzheimer’s. At the time of the IND clearance news, Green Valley said it planned to wrap up the trial in 2024 and submit an NDA by 2025. In January, the biotech said the trial was now slated for completion by 2025 and that it had screened 949 patients and had 292 randomized, thus far. At that time, 154 clinical centers in 10 countries and regions had been activated. Green Valley has described the drug as: “Being the world’s first AD drug that targets the gut-brain axis, GV-971 reduces peripheral and central inflammation by reconditioning the gut microbiota and inhibiting the abnormal balance of gut microbiota-derived metabolites.” China’s regulators conditionally approved the drug in November 2019, sending shockwaves into the Alzheimer’s drug development world as there hadn’t been a new medicine for the memory-robbing disease in nearly two decades. But experts were “cautiously optimistic” following the nod. Related:Alzheimer's breakthrough? Not so fast — experts poke holes in data underlying China's surprise approval “The other scientific advisors and I were excited about the chance to help the company design a rigorous global Phase 3 clinical trial. We were interested in the drug’s potentially novel mechanism of action, the initial basic science and clinical trial findings from China, the chance to clarify the drug’s efficacy, and potential implications for the role of the microbiome in the development and treatment of Alzheimer’s disease,” Reiman told Endpoints. The drug was included in China’s national reimbursement drug list late last year, Green Valley said in December 2021, reducing the monthly medication cost from RMB 3,580 ($531) to RMB 1,184 ($175). The FDA also cleared an IND for a Phase II study of the drug in patients with early-stage Parkinson’s, Green Valley said in January. That trial is expected to include 300 patients at 30 centers in North America and Asia-Pacific over the course of a 36-week study. The news comes as Biogen and Eisai said Monday that they completed the submission for their second Alzheimer’s treatment, dubbed lecanemab, and as Eli Lilly works on its application for its drug donanemab. Green Valley was founded in 1997 and employs 1,500 people, according to the company’s website.

Over a decade of research and billions of dollars have been poured into Alzheimer’s disease treatment. Experts are hopeful we could finally find a cure. Alzheimer’s disease treatment is closer than ever. There may be nothing quite as gut-wrenching as sitting at the bedside of a loved one, watching helplessly as their life comes to an end. Perhaps the only thing more painful is when that loved one no longer recognizes you, slipping away not knowing who it was holding their hand. This pain is a driving force behind finding an Alzheimer’s disease treatment so that no one has to see their loved ones in pain. November is deemed “Alzheimer’s Awareness Month.” Though with the degenerative brain disease now affecting roughly 5.8 million Americans and their families today, it’s perhaps not so much an increase of awareness that’s needed, but rather a desperate need for effective treatment. Alzheimer’s is the only disease among the top 10 causes of death in America that cannot be prevented, cured or even slowed. Over a decade and billions of dollars have been spent on research to find a cure for Alzheimer’s, yet none have thus far proved real clinical benefit. If the elusive Alzheimer’s disease treatment isn’t found soon, scientists estimate that by 2050 someone in the United States will develop the disease every 33 seconds. While these statistics paint a pretty bleak picture, Cynthia Lemere, Ph.D., Associate Professor of Neurology at Brigham and Women’s Hospital and Harvard Medical School, assured BioSpace that hope is not lost. Despite the many failed drug trials, Lemere says the horizon is finally looking optimistic and expects to see multiple treatments approved within the next few years. “Any therapy developed at this point is going to be probably good for one subsection of that 5.8 million people with Alzheimer’s disease. And maybe not even that population, but maybe the population that doesn’t yet have Alzheimer’s disease but has the changes going on in their brain of Alzheimer’s, so we know that they’re on the track,” Lemere said. Current Status of Alzheimer’s Disease Treatment While no real treatment is yet approved, diagnostic capabilities have grown exponentially. When Lemere first started in the neurology field, a true diagnosis for Alzheimer’s disease treatment couldn’t be given until autopsy. The past decade has shown that the pathology of the disease starts in the brain roughly 20 years before clinical symptoms. PET scans can determine those on a trajectory to develop Alzheimer’s and with new biomarker testing working towards FDA approval, they’ll be able to predict onset of clinical symptoms. Knowing those who are most likely to develop this degenerative brain disease and when opens opportunities for clinical trials that are in the works. The majority of treatments being developed right now are targeting that window before cognitive decline. There are currently 2,050 interventional studies listed on clinicaltrials.gov around the world for the treatment of AD. One buzzworthy drug in the news is Biogen’s aducanumab. Back in March 2019, Biogen stopped two Phase III trials for the antibody drug based on an interim futility analysis that indicated a lack of efficacy. But after a full collection of their data, Biogen found there was indeed efficacy in the higher dosage group who received over 10 doses. This left them with two very different sets of trial results – EMERGE with a positive reading and ENGAGE with a negative. Lemere believes the evidence in the EMERGE trial was strong enough to show positive clinical benefits. Despite much criticism and doubts surrounding aducanumab, Biogen took it to the FDA with hopes for approval and received a harsh vote from an independent advisory committee. No word yet from the FDA. Lemere predicts the FDA will call for another, large Phase III study to confirm the positive result at the higher dose for the full study. Lemere consults with Biogen for the company’s Alzheimer’s disease treatment education program and is not involved with their drug development programs. The main breakthrough in the past year for pharmaceutical treatment of AD is that researchers finally know what the right target is - a toxic amyloid oligomer formation that is a key driver for the disease. Biogen isn’t the only one targeting it with their drug candidates. Also in the race are Alzheon with ALZ-801 , Eisai’s BAN2401 and Roche’s gantenerumab. Unlike the intravenous antibody candidates from the other three, Alzheon’s ALZ-801 is an orally administered amyloid oligomer inhibitor. Alzheon recently dosed their first patients in a Phase II biomarker study in APOE4 carriers. Patients with an APOE4 gene are at a much higher risk for developing Alzheimer’s, particularly if you were passed two of the genes. In August, the National Institute of Aging awarded Alzheon an unprecedented $47 million grant to assist with a Phase III clinical trial of ALZ-801. The trial is slated to start at the beginning of next year with a timeline of 2-3 years to complete. This Phase III will be dosing younger people with Alzheimer’s pathology to test for primary prevention, intervening before clinical symptoms appear. A Shanghai-based biotech is targeting Alzheimer’s disease treatment in a completely different way. Instead of targeting amyloid in the brain, Green Valley’s candidate is going after the gut. GV-971 is an oral capsule with its primary ingredient derived from seaweed to “therapeutically harnesses the abnormal production of amino acids, infiltration of immune cells to the brain, and in turn neuroinflammation via remodeling the gut microbiota.” Reactions to this approach range from excitement to cautious optimism to downright skepticism. Time should soon tell if there’s something to this approach as Green Valley has now identified its first patient for its Phase III trial in the US with the initial dose coming soon. Drug developers aren’t the only ones trying to stop the devastating progression of AD. A research team at MIT found that in Alzheimer’s mouse models, the right brain waves can drive microglia, scavenger cells that remove damaged neurons and infections in the central nervous system, to consume the toxic amyloid protein deposits. More research is being done in this area to explore this as a potential option for treatment in humans to reduce amyloid deposits in the brain. Lemere listed off multiple research projects in the works for Alzheimer’s disease treatment – therapies to prevent free-radical formation and reduce oxidative stress in the brain, studies into the importance of vascular health and its impact on AD, the effects of diet and exercise, and more. One study found significant results in patients using aggressive blood pressure therapy. People that had lowered their blood pressure and kept it around 120, compared to the control group hovering around 140, showed a significant slowing of the rate of visible cognitive impairment. The Alzheimer’s Association, of which Lemere is a member of the medical and scientific advisory group, is sponsoring a lifestyle intervention study in the U.S. called POINTER, that takes into account exercise, nutrition, social interactions, cognitive stimulation and management of comorbidities to protect cognitive function in healthy older adults who are at an increased risk of cognitive decline. “The big point is that probably none of these is going to work by itself,” Lemere said. Rather she sees a future in which a doctor who sees Alzheimer’s pathology brewing in a patient will recommend a multi-prong defense. “I think it’s going to be a combination of treatments. And it’s not going to be the same combination for each person,” Lemere said. “It’s going to be dependent on whatever else is going on with them. Because Alzheimer’s rarely occurs by itself. There are usually other comorbidities. So ultimately, I think it will be more personalized medicine and combination therapy.” In 2020 alone, the National Institutes of Health is expected to spend $2.8 billion on Alzheimer’s disease treatment and research. Costing the U.S. $277 billion a year, it’s the most expensive disease in America. Annual cost of care is projected to increase to $1.1 trillion by 2050. While the financial burden is exorbitantly high, for family members and caregivers it’s the emotional cost that leaves the deepest scars. Arkansas resident Linda Crafton knows firsthand the devastating effects Alzheimer’s has on a family. “To me, it’s worst disease known to mankind. I used to think the way I lost my dad, which was an instant death, was the hardest way to lose someone,” Crafton said. “I now know that was wrong. The hardest way to lose your parent is day by day, little by little, an inch at a time.” Crafton’s mother and five of her mother’s seven siblings were victims of the aggressive disease. She said she’s in a generation of cousins who now live in fear of the future, wondering which of them will be the first to show the signs, the first to receive their own diagnosis. Time magazine writer Jeffrey Kluger said, “Suffering is always hard to quantify especially when the pain is caused by as cruel a disease as Alzheimer’s. Most illnesses attack the body; Alzheimer’s destroys the mind and, in the process, annihilates the very self.” Though Alzheimer’s disease treatment has frustrated scientists for years, they’re closer now than they’ve ever been before. According to the Alzheimer’s Association, a lack of volunteers for clinical trials is one of the greatest obstacles slowing the progress of potential new treatments. If you or someone you love is on a trajectory for the development of Alzheimer’s disease, the association offers a free TrialMatch service to connect volunteers with clinical trials to advance research.