Recent regulatory and scientific developments suggest a novel oral formulation (CoM pat. pend.) of HP‐alpha‐cyclodextrin as a safe (not ototoxic) and convenient (oral) drug against Alzheimer's disease

Background There are no disease‐modifying treatments (DMTs) for Alzheimer's disease (AD). HP‐beta‐cyclodextrin (HPβCD) was effective in AD models and, in Feb 2021, clinical results were presented at a conference: a phase 1/2 trial of IV HPβCD qow for >8 h had shown reduction of CSF tau protein after 12 wk. HPβCD is known for its risk of cholesterol‐related ototoxicity, but hearing loss was only transient (Fig. 1) and the FDA accepted INDs for overnight IV HPβCD as a drug against NPC1 (phase 3) and AD (phase 2). Method To test whether one could avoid ototoxicity and chaining patients to the bed overnight, we conducted a human PK/PD study of a novel (non‐covalent) clathrate of HPαCD and a milk/coconut oil medium‐chain fatty acid. HPαCD alone, co‐administered with, and as a clathrate with decanoate (both 2:1 molar) were administered orally before bedtime. HPαCD and phospholipids (PLs) were measured by FPLC in morning urine. We also conducted animal studies in breast cancer and movement disorders, where high levels of endocytosis are known to “derail” the endocytosis‐lysosome‐autophagy (ELA) axis. Result In the absence of dietary milkfat, no HPαCD was excreted into urine. With C10 added, some HPαCD and small increases in PLs were seen, but twice as much with the clathrate (Fig. 2). Animal studies showed IP HPαCD as more effective than HPβCD in breast cancer (reducing endocytosis and inflammation, Fig. 3) and also effective in movement disorders (not shown). Conclusion Intermittent fasting (IF) and the IF mimetic HPαCD (too small to fit cholesterol) were previously shown to be more effective than HPβCD in lysosomal storage diseases and in cancer, where endocytosis is also involved, albeit with manifestations in destinations different from AD (Fig. 4). With the new results showing that (a) the HPαCD clathrate ASD‐005 is intestinally absorbed, safe, and has systemic effects in other ELA axis diseases, including cancer (Ancidoni 2021, Alzheimers Res Ther 13:96), and (b) HP‐CDs are active across the blood‐brain barrier, two barriers against a more convenient, safer, and potentially more effective DMT for AD, as well as regulatory hurdles against cyclodextrins accepted as drugs were overcome in Feb 2021.