bioworld article.
Stress is often a factor that contributes to many conditions ranging from psoriasis to irritable bowel syndrome, but it also has an effect on the brain, and recent evidence has shown that stress may be involved in accelerating the onset of Alzheimer's disease as well as worsening the course of the disease.Actinogen Medical Ltd.'s lead compound, Xanamem, is designed to inhibit excess cortisol in the brain, with the aim of reducing cognitive impairment to treat the symptoms of Alzheimer's disease. The candidate is in phase II trials, with results expected to read out in May or June, CEO Bill Ketelbey told BioWorld Asia.The company licensed a family of compounds from Edinburgh University about four years ago. The program evolved from the premise that chronically raised cortisol in elderly people was associated with cognitive decline and Alzheimer's disease. Xanamem is a small-molecule inhibitor of the 11beta-HSD1 enzyme in the brain that activates cortisol intracellularly in the neurons."It's recognized that many chronic diseases are associated by raised cortisol, and it's not as benign as previously perceived," Ketelbey explained, noting that diabetes, depression, epilepsy, schizophrenia and Parkinson's disease are all associated with raised cortisol."That elevated cortisol in the elderly population may be pathological and may lead to cognitive decline. It really is toxic to the brain," he said.Cortisol is expressed in the liver and adipose tissue, but particularly in the hippocampus and frontal cortex, which are areas in the brain that impact Alzheimer's disease early on, he said.A recent study published in Neurology reported that higher levels of cortisol were associated with memory impairment and smaller brain volumes in young and middle-aged adults. The findings come from a large study of 2,231 men and women who were free of dementia. Their blood cortisol levels were measured, and then cognitive functions were evaluated, including memory, abstract reasoning, visual perception, attention and executive function.Brain MRI imaging was also carried out, and total brain volume, brain volumes of different brain regions, and structural changes in the brain were assessed. According to the study, those people with the highest cortisol levels also had reduced volume in the frontal and occipital lobes of the brain as well as changes to the white matter in the brain."Cortisol is a normal hormone in relation to stress, but excess cortisol needs to be brought down to normal physiological levels so people have a normal stress response and normal circadian levels," Ketelbey said."The most appropriate approach seems to be to inhibit the cortisol production at the cellular level by inhibiting the 11beta-HSD1 enzyme that is expressed throughout the body."A physician by trade, Ketelbey also held senior roles at Pfizer Inc., where he was involved with the development of Aricept (donepezil) nearly 25 years ago. Aricept was the first Alzheimer's disease treatment to come to market and is still the market leader."It's not that it's a particularly spectacular drug; it's just that it's the best there is for now," he said.Elusive searches for a curePharma companies have taken different approaches to treating the symptoms of Alzheimer's disease, most of which focused on reducing the build-up of beta-amyloid."Of these hundred other compounds in development [for Alzheimer's disease], none of these are direct competitors because they are approaching the disease through different targets," Ketelbey said. "In the foreseeable future, the treatment of Alzheimer's disease will be combination therapies targeting the disease from different directions."In the future there will be cholinesterase inhibitors, there will be amyloid compounds, there will be tau compounds, there will be other neurotransmitters, and there will be cortisol inhibitors like Xanamem used in combination to try to manage the disease."Although some companies, such as Astellas Pharma Inc. and Abbvie Inc. are doing some work in the cortisol inhibition area, Ketelbey said that Actinogen is "way ahead of the pack.""We absolutely will have the first-mover advantage by some way," he said.Results from the phase II XanADu trial are expected in the second quarter of 2019. The trial is a double-blinded, 12-week, placebo-controlled study in patients with mild dementia due to Alzheimer's disease. Patients are receiving a 10-mg dose daily of Xanamem vs. placebo. It is fully enrolled with 186 patients from 25 sites across Australia, the U.K. and the U.S."Results won't be binary," Ketelbey said, "as there will be a range of outcomes that will inform the next stage of development.""So far, the drug has behaved exactly as predicted from all animal modeling and phase I data, so there have been no surprises after four years of work," he said, noting that the molecule is brain-penetrating and orally active."Early Alzheimer's disease patients present with problems of memory, behavior and personality, and that's where the enzyme we're targeting is particularly concentrated, so we're hoping that by inhibiting cortisol in those areas of the brain we'll produce a clinical benefit," he said."The 12-week treatment period replicates the rapid response we saw in animal data whereby cortisol inhibition produces a very rapid cognitive response within four to six weeks."The phase II trial will measure two primary endpoints and a number of secondary endpoints. Primary endpoints include the Alzheimer's Disease Assessment Scales - Cognitive Subscale Score (ADAS-COG14) and composite data derived from ADAS-COG-14.Nine additional studies have also been initiated that include target occupancy, a higher dose study as well as toxicology studies, which will all read out in May or June.Actinogen completed two phase I trials, one of which involved a single ascending dose and the other a multiple ascending-dose study. Xanamem was well-tolerated with no serious adverse events in both studies. The trials showed substantial inhibition of 11B-HSD1 for at least 24 hours after a single dose.Two additional substudies included a fed-fasted study to confirm the effect of food on the absorption of Xanamem. A CNS pharmacokinetic study confirmed Xanamem crosses the blood-brain barrier in concentrations that would adequately inhibit the excess production of cortisol in the brain."We're getting better at diagnosing and refining the patient population thanks to biomarkers, but it's going to take time," Ketelbey said. "The next drug to show a benefit is going to do amazingly well."Other potential indications for Xanamem include diabetes, depression, schizophrenia, Parkinson's disease and Down syndrome.Actinogen backdoor-listed on Australia's Securities Exchange (ASX:ACW) in 2014. Edinburgh University took an equity stake in the company and is one of the lead shareholders. Other major shareholders include Biotechnology Value Fund (BVF) Partners in the U.S., Australia's Platinum Assets Management and Australian Ethical Investors.The company raised AU$11 million (US$7.9 million) in 2015. It completed another capital raise of AU$5.3 million in December 2017, and it raised AU$16 million in May 2018, which is enough to fund all of its studies.The CEO said Actinogen is currently in discussions with big pharma.Actinogen has a market cap of AU$60 million; its shares were trading at AU5 cents on market close Monday.
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