Cyclo Therapeutics, Inc., a clinical stage biotechnology company developing cyclodextrin-based products for the treatment of Niemann-Pick Disease Type C and Alzheimer’s disease, announced the presentation of favorable data from its clinical and drug development program for its lead candidate, Trappsol® Cyclo™. These data are being presented at the 17th Annual WORLDSymposium 2021, a leading medical and scientific conference for professionals working to advance understanding and treatments for lysosomal storage diseases, including Niemann-Pick Disease Type C (“NPC”), being held virtually February 8–12, 2021.
Trappsol® Cyclo™, Cyclo Therapeutics’ proprietary formulation of hydroxypropyl beta cyclodextrin, used intravenously (IV), is currently in development for the treatment of NPC1, a rare genetic disorder causing cholesterol accumulation in lysosomes of cells, organ dysfunction and premature death. Functioning like the NPC1 protein, Trappsol® Cyclo™ has been shown to transport cholesterol out of cells, normalizing cholesterol metabolism. Following review of the Phase 1 and Phase 1/2 data, coupled with preclinical compassionate use data, regulatory authorities acknowledged that IV hydroxypropyl beta cyclodextrin has the potential to treat systemic and neurologic manifestations of NPC, and has the capacity when given intravenously to be a preventative treatment. The Company has confirmation that the pivotal Phase 3 study may begin enrollment.
Ongoing Phase 1/2 Safety and Efficacy Results
The Phase 1/2 trial of Trappsol® Cyclo ™, evaluates 3 dose groups (1500, 2000, 2500 mg/kg) administered intravenously (IV) in NPC patients aged 2-plus bi-weekly over 48 weeks. Enrollment of 12 patients was completed in February 2020. Last patient last visit for the study is expected in February 2021. An interim unblinded analysis occurred in May 2020. To-date, individual and cumulative safety data show the drug to be well tolerated with a favorable safety profile for all dose groups.
Previously reported data show effects of IV drug administration on markers of cholesterol synthesis and metabolism. Pharmacokinetic data show the drug in cerebrospinal fluid during and even after the end of IV infusion, at all dose levels. Lysosphingomyelin-509 in plasma demonstrates a clear downward trend over the 48-week study, with no apparent dose-relationship, further supporting the drug’s ability to clear lipids from lysosomes. Tau, a biomarker of neurodegeneration, is reduced in cerebrospinal fluid of patients who opted for lumbar punctures at 24 and 48 weeks, suggesting a neuroprotective effect of the drug. For the 7 patients who completed the trial as of September 2020, 6 (86%) met the first efficacy criterion of the study related to improvement in 2 domains of the 17-domain Severity Scale. For the second efficacy outcome measure, change from baseline in global impression of disease, 5 of 7 patients improved per the Clinicians Global Impression of Improvement scale and 2 were stabilized.
Completed Phase 1 Study Results and the Effects of Dosing Upon Biomarkers of NPC Disease
The Phase 1 study of Trappsol® Cyclo ™ in NPC1 patients was randomized, double-blinded, with no control group (NCT02939547). Patients 18 years-plus received either 1500 or 2500 mg/kg of drug intravenously (IV) over 8-9 hours bi-weekly for 7 doses. Individual and cumulative safety data show both dose levels to have a favorable safety profile, although the 2500 mg/kg group included 3 serious adverse events related to transient hearing loss. Pharmacokinetic findings show Tmax of 6-8 hours with T ½ of 2 hours. The drug is detectable in cerebrospinal fluid (CSF) at 4 hours after start of infusion and persists up to 4 hours post-infusion. IV treatment impacts cholesterol homeostasis as evidenced by transient increases in total cholesterol levels; serum markers of cholesterol synthesis and metabolism; and liver biopsy data showing significant cholesterol clearance for both doses. Lysosphingomyelin-509 decreases significantly in most patients with successive infusions. Plasma biomarkers of inflammation, including lysozyme, show a general decrease. Effects within the CNS are shown by the CSF biomarker tau which is reduced in 6 of 10 patients as compared to baseline, suggesting a neuroprotective effect, and a serum increase of a CNS-derived metabolite of cholesterol, 24S-hydroxycholesterol. Three patients improved in Swallow and 1 worsened in Cognition as measured by the 17-domain NPC Severity Scale.
After individual doses and at trial end some patients reported feeling more focused, more engaged in social interactions; more likely to initiate conversations or activities; word finding ability reaching back into the past; improvements in ability to swallow without coughing; and improvements in stance and gait.
All 8 eligible patients (U.S. residents) enrolled in the Extension Protocol, receiving infusions in the home setting. Initial efficacy evaluation in September 2020 showed disease stabilization with notable clinical improvements in some patients.
These findings confirm target engagement with a positive impact on cholesterol metabolism and liver cholesterol clearance in patients with NPC1 supporting continued evaluation of Trappsol® Cyclo™ as a therapeutic for NPC1.
The oral poster presentations are now available on the Company’s website in the Presentations section.