Table 5.

Clinical evidence summary: GM2 gangliosidosis—Tay–Sachs disease.

Author Year (Reference)	Enzyme	MoA (as Per Author’s Comments)	Clinical Study Type	Study Objective	Summary Outcomes
Pyrimethamine
Clarke 2011 [77]	Acid β-hexosaminidase	Depresses folate metabolism in participants receiving treatment with other folate inhibitors or agents associated with myelosuppression, including cotrimoxazole, trimethoprim, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate).	Open-label phase I/II (11 participants)	Tolerability and efficacy with escalating doses of pyrimethamine	Pyrimethamine enhances leukocyte Hex A activity in people with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects (e.g., 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed).
Osher 2015 [78]	Acid β-hexosaminidase	Depresses folate metabolism in participants receiving treatment with other folate inhibitors or agents associated with myelosuppression, including cotrimoxazole, trimethoprim, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate).	Open-label, extended pilot study (4 participants)	Tolerability and efficacy with cyclic, low-dose, long-term pyrimethamine	Hex A activity rose in all subjects, with a mean peak increase of 2.24-fold (SD ±0.52 over baseline activity, range 1.87–3). Mean treatment time required to attain this peak was 15.7 weeks (±4.8; SD). Following increased activity, Hex A gradually declined with the continued use of PMT. A second cycle of PMT treatment was then initiated, resulting again in an increase in Hex A activity. Three of the participants experienced a measurable neuropsychiatric deterioration, whereas one subject remained entirely stable.

Abbreviations: Hex A, α subunit of β-hexosaminidase enzyme; MoA, mode of action; PMT, pyrimethamine.