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Human clinical trials: Single ascending dose (SAD) and Multiple ascending dose (MAD) studies

 

How are human clinical trials conducted?

Before human trials even begin, animal trials are conducted first to evaluate safety. Once human trials begin, they move through four phases. Phase 1 is the smallest and briefest, only lasting a maximum of a few months. It usually includes healthy participants, and is used to evaluate safety and any serious side effects from the experimental treatment. Phase 2 includes only participants with the specific condition or disease being studied. It focuses on the effectiveness of the experimental treatment at improving the targeted condition. Phase 2 is an expansion of phase 1 both in duration and population size, lasting between a few months to years and including hundreds of participants. Phase 3 again increases the population size, testing hundreds to thousands of participants. It lasts multiple years, and during this time the experimental treatment is compared to existing treatments to determine if it offers any benefit to patients. After phase 3, regulatory committees can approve the treatment for use. The last phase, phase 4, occurs after approval and is an ongoing monitor of the new treatment.

 

Single ascending dose (SAD) and multiple ascending doses (MAD)

Single ascending dose (SAD) and multiple ascending dose (MAD) studies are two ways to assess drug dosing for new therapeutics. The main difference between the two is the number of treatment doses participants receive; in a SAD study, participants receive one dose of drug, whereas in a MAD study, patients receive multiple doses. They are both considered ‘ascending’ for different reasons. In SAD studies, different groups of participants will receive different doses of experimental treatment, which helps to gather information including the safe dose range for humans and the maximum tolerated dose that can be given. This is different from MAD studies, in which participants are administered multiple doses of experimental treatment over the study period, and each time they receive the drug, the dose increases.

SAD studies are usually the first in human studies, and are conducted as part of the phase 1 trial. After participants are administered treatment, there is normally a period for observation to assess how they react to the drug. Dosing in SAD studies is usually based on data from preclinical trials or animal trials.

MAD studies typically occur after SAD studies conclude, but can still be part of a phase 1 trial. MAD studies also include periods of observation, this time in between doses. Dosing for MAD studies are usually based on data gathered from the SAD study. The goal of MAD studies is to build on what was learned in the SAD study; because patients receive multiple doses, MAD studies can inform on how the body processes the experimental treatment over time.

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Potential New therapeutic for Parkinson’s disease

Recently, Gain has completed the SAD and MAD part of the Phase 1 study of GT-02287, its lead drug candidate in development for the treatment of Parkinson’s disease with or without a GBA1 mutation.The orally administered, brain-penetrant small molecule is an allosteric protein modulator that restores the function of the lysosomal protein enzyme glucocerebrosidase (GCase) which becomes misfolded and impaired due to mutations in the GBA1 gene, the most common genetic abnormality associated with PD, or other age-related stress factors. In preclinical models of PD, GT-02287 restored GCase enzymatic function, reduced aggregated α-synuclein, neuroinflammation and neuronal death, increased dopamine levels and improved motor function and cognitive performance. Additionally, GT-02287 significantly reduced plasma neurofilament light chain (NfL) levels, an emerging biomarker for neurodegeneration. 

In the Phase 1 study of GT-02287, no discontinuations or serious adverse events were reported when the study concluded. The Phase 1 study enrolled 72 healthy volunteers, males and females, up to the age of 64 years. Review of unblinded data after database lock confirmed that single and multiple doses of GT-02287 were safe and generally well tolerated up to and including the highest planned dose levels across all age groups (approximately 15% of which were over the age of 50 years). GT-02287 was present in the cerebrospinal fluid (CSF) and peripheral target engagement was demonstrated. The favorable safety and tolerability profile at oral dose levels that resulted in therapeutic plasma levels, CNS exposure, and target engagement further strengthens GT-02287’s potential to be a lead treatment for Parkinson’s disease in patients with or without a GBA1 mutation. 

 

 

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