Written by Kaushal Rao, Crystal Song, and Patrick HofbauerAlzheimer’s disease (AD) is a neurodegenerative disorder that contributes to the deterioration of the cognitive abilities of afflicted patients, and is the leading cause of dementia among older adults. There have been many copiously funded research efforts over the years, but there are still a limited number of available therapies. Could the next breakthrough lie in seaweed?
In late 2019, Shanghai’s Green Valley Pharmaceuticals (GVP) developed a new drug called oligomannate, which has been conditionally approved by China’s National Medical Products Administration (NMPA) and deemed fit for treating individuals with mild to moderate forms of AD. Oligomannate is the only approved AD drug anywhere in the world since Namenda’s approval 17 years ago. According to South China Morning Post, the drug was made available everywhere throughout China by the end of 2019. Estimates vary, but experts at Alzheimer’s Disease International have suggested that as many as 50 million individuals around the world live with AD. The market for AD therapeutics is estimated to reach around $14.8 billion by 2026, according to GlobalData. Despite the financial incentive to develop effective therapies, the history of research into AD therapeutics has been filled with setbacks. Between 1998 to 2017, 146 potential medicines proved unsuccessful in clinical trials, and only four medicines received approval from the Food and Drug Administration (FDA). However, these approved medicines only manage symptoms and are unable to actually slow the disease’s progression. Progress in AD research is sluggish because of three key factors: 1) Identifying eligible patients for clinical trials is a big challenge, 2) AD is difficult to diagnose early (which ties into identifying candidates for clinical trials), and 3) The biological pathway of AD is not yet fully understood. Although these three factors will continue to play a large role in hindering AD research, modern technological advancements have helped researchers develop newer types of drugs, such as tau-based and amyloid therapeutics. Oligomannate’s approval in 2019 marked the long-awaited addition of therapy options for AD. The news brought some hope to the millions of individuals and families suffering from the disease. Many translational scientists found the news fascinating as well, especially as oligomannate was the only approved AD drug in 17 years. Over the past years, scientists have been focusing on directly attacking the beta-amyloid plaques that are thought to interfere with neural signaling in AD patients’ brains, but 99% of these therapies have failed in clinical trials. Oligomannate’s claimed successes in animal models and human trials proposed a novel strategy to treat AD through the gut microbiome, introducing a new perspective. The seaweed-derived drug is said to reduce neuroinflammation, as well as inhibit AD progression, by remodelling the patient’s gut microbiota and suppressing gut bacterial amino acid production. The mechanistic link between gut dysbiosis and AD is not yet completely proven, but several biological pathways have been proposed to explain the link. One of the more commonly accepted theories involves the accumulation of certain amino acids in the gut and the resulting proliferation of pro-inflammatory cells. These cells infiltrate the brain and contribute to AD-associated neuroinflammation. This neuroinflammation is in turn associated with the development of amyloid plaques and tau tangles, the primary physiological symptoms of the disease. By resolving this amino acid imbalance, oligomannate is hypothesized to ultimately hinder the development of plaques and tangles. At first glance, oligomannate seems like an incredible breakthrough. In its Phase III clinical trial, oligomannate had a treatment result comparable to that of the approved drug Namenda — the current standard of care drug for AD patients. However, much skepticism regarding oligomannate’s efficacy has also arisen due to the drug’s rather unusual clinical trial data. Oligomannate’s Phase IIb clinical trial was conducted in 2013 and 2014 in a cohort of 255 patients. Surprisingly, that trial was deemed a failure because the difference in cognitive function between treatment and placebo groups was not found to be statistically significant. Hence, the fact that the company continued oligomannate’s trials into Phase III was already a questionable decision. In addition, peer reviewers have been doubting the abnormal placebo data points in oligomannate’s Phase III clinical trial. As shown in the figure, the placebo group, along with the treatment group, experienced an improvement in cognitive function over the first 24 weeks of study. However, in the last 12 weeks, the placebo group’s cognitive function drastically decreased, which led to oligomannate’s “successful” clinical trial outcome. Interestingly, the company has not given any clear explanation for the bizarre trend in placebo data. As of March 2020, Green Valley Pharma has announced that they are planning to test the GV-971 compound in 200 clinical centers across Europe, North America and in certain parts of Asia. The plan is to complete these global clinical trials by 2024 and then submit GV-971 for potential approval to the FDA and EMA in 2025. However, much doubt remains regarding the true efficacy of the marine-algae-derived drug. If these trials demonstrate that GV-971 truly has therapeutic potential, then many patients will be in luck. However, given the current scientific uncertainty, it would be wise to temper any irrational exuberance with the appropriate dose of scientific skepticism. https://medium.com/@bruinmedicalentrepreneurs/too-good-to-be-true-seaweed-derived-alzheimers-therapeutic-shows-potential-ca8932fd800d
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