Cyclo Therapeutics' (NASDAQ:CYTH) launch into the Alzheimer’s field began with one case study that produced the following results:
After 18 months, the patient showed neurologic and cognitive stability: this is a positive outcome given that persons with Alzheimer’s Disease dementia are generally expected to decline during an 18-month timeframe. Speech fluency also improved as documented by the treating physician’s report of a decrease latency to word-finding. In addition, mood and behavioral features of the disease improved, such as less agitation, as noted by the patient, the patient’s family, and the treating physician (source of quote).
The company will soon begin a phase 2 clinical trial for its drug candidate Trappsol Cyclo for Alzheimer’s disease. The evidence for the potential success of Trappsol Cyclo comes from multiple sources including the results from a Niemann Pick Type C disease (sometimes called childhood Alzheimer’s) trial, mechanisms of action, mice studies, and trial results from other drug candidates/natural products containing the same or similar compounds. None of these by themselves may be persuasive, but when woven together they indicate a strong potential for success.
Neurodegenerative diseases often share common features, suggesting that the same approach can potentially be used to treat more than one disease. Niemann Pick Type C disease and Alzheimer’s disease share two common features: oxidative stress and high levels of cholesterol in the brain. Trappsol Cyclo (hydroxypropyl beta-cyclodextrin: HPBCD) is an oligosaccharide that reduces cholesterol levels and reduces oxidation. For Niemann Pick Type C disease, the drug appeared to slow the progression in three patients, stabilize the disease in three other patients, one patient improved, and one worsened more than expected (trial results). Niemann Pick Type C disease affects areas such as ambulation, swallowing, cognition, speech, and fine motor coordination.
Whether a similar pattern will also be seen in patients with Alzheimer’s disease is not a given. But here is why it is a distinct possibility. First, reducing cholesterol levels shrinks the size of lipid rafts which are table setters for the onset and early progression of Alzheimer’s disease (source of chart).
Lipid rafts not only enhance amyloid oligomer toxicity, they also enhance the toxicity of many other factors (such as environmental toxins, viral, bacterial, and fungal infections, an unhealthy diet high in salt and sugar and other carbohydrates, and psychological stress) that can initially trigger Alzheimer’s disease. In theory, then, reducing cholesterol levels should reduce the risk and slow the progression of Alzheimer’s disease especially in ApoE4 carriers (since they have higher levels of cholesterol in their brain to begin with).
Peroxynitrite nitrates the phosphatidylinositol 3-kinase which ultimately reduces blood flow in the brain, prevents the regeneration of neurons, synapses, and axons, and contributes to the misfolding of tau proteins which inhibits neurotransmissions. Peroxynitrite’s oxidation of muscarinic acetylcholine, serotonin, melatonin, dopamine, and oxytocin receptors negatively affects memory, mood, sleep, alertness, and social recognition. Peroxynitrite oxidation and nitration of choline transport systems and choline acetyltransferases (which produce acetylcholine) further inhibits the ability of someone with Alzheimer’s disease to retrieve short-term memories. And finally, peroxynitrite activates caspase-3 which plays a role in amyloid formation, DNA damage, mitochondrial dysfunction, and the death of neurons.
The key to the treatment of Alzheimer’s disease then is likely the following:
The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite (source of quote).
HPBCD, which crosses the blood-brain barrier, does all three. It inhibits the formation of peroxynitrite through reduction of lipid rafts, it scavenges peroxynitrite through the donation of hydrogen atoms and electrons, and it partially reverses oxidation through the same process and contributes to denitration via water (a product of peroxynitrite scavenging). Thus, all the problems listed above, along with those shown in the diagram are at least partially reversed.
The mouse and other studies for oligosaccharides and/or polysaccharides in Trappsol Cyclo, seaweed, and panax/Korean red ginseng overlap considerably in their findings. These include reduced oxidation and inflammation, reduced tau pathology, reduced amyloid production, improvement in mitochondrial function, less neuronal cell death, increased neurogenesis, and improved memory.
Finally, there are positive trial results using oligosaccharides and polysaccharides. An oligosaccharide compound derived from brown algae (GV-971) lead to a 2.7-point improvement in ADAS-cog 12 scores at 36 weeks (trial results). Polysaccharides, saponins, and polyphenols from panax/Korean red ginseng produced an approximate 10-point improvement in ADAS-cog scores at one year that was sustained for another year (trial results).
The chances of Trappsol Cyclo producing similar results over long periods of time are quite good. It does have to be given intravenously but, if shown to be safe and effective, most caregivers and their loved ones would probably choose to take it.
Cyclo Therapeutics has somewhere between 8 and 10 million dollars cash on hand. It also has about 20 million in at the market offerings (ATM) which it may turn to after it submits its Investigational New Drug application with the FDA sometime near the end of this year.
At this point time, Cyclo Therapeutics has a high upside and investment in the company presents relatively few risks. In my opinion (which is based on nearly twenty years of studying Alzheimer’s disease), Cyclo Therapeutics is developing one of the few drugs that attacks Alzheimer’s disease at its core.
This article was written by
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