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Long-term, non-clinical toxicology for advancing CMS121 to Phase 2 trials for AD

Award Number: U01AG084549
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Long-term, non-clinical toxicology for advancing CMS121 to Phase 2 trials for AD - Abstract CMS121 is an orally delivered small molecule that has shown efficacy in multiple mouse models of Alzheimer's Disease (AD) and offers a novel therapeutic approach for treatment of AD in humans. A Phase 1 clinical trial has been completed where CMS121 showed excellent safety and tolerability with no serious adverse effects detected. The goal now is to advance CMS121 to a Phase 2 clinical trial. Before proceeding to the longer duration Phase 2 trials, a long-term toxicology study in animals is required by the FDA to provide critical safety information. The studies proposed in the parent application are a 6-month rat and a 9-month dog toxicology study in which dosing will be administered daily over those periods. The results will guide the dosing and testing design of the Phase 2 human trial. The parent grant for which this supplement is requested has two aims. Aim 1: The manufacture of a multi-kg quantity of CMS121-M, the maleate salt of CMS121 needed for the 6- month daily dosing of rats and 9-month daily dosing of dogs. The synthesis of CMS121-M utilizes a straightforward, 3-step process which was used previously to make 4 kg quantities of GLP-grade CMS121 for the earlier 14- and 28-day non-clinical toxicology studies and the GMP-grade material for the Phase 1 trial. A large scale, 12 kg synthesis of GLP-grade CMS121-M was to be produced for the proposed long-term, non- clinical toxicology studies. Aim 2: The conduct of the long-term animal toxicology studies and the associated methods development and validations for the detection of CMS121 in rat and dog plasma will follow upon the manufacture of sufficient product. A key goal (Aim 1) of the parent grant was to develop the large-scale synthesis of CMS121 in order to facilitate the long-term animal toxicology studies as well as to provide the basis for future large-scale synthesis that will be needed to support the next clinical trials. The manufacturing process that produced excellent yields of CMS121 at laboratory scale for the earlier 13-week animal toxicology studies unexpectedly produced 35% less product than anticipated when the process was performed in the large-scale facility. The lower yield was primarily due to unanticipated loss at a particularly slow filtration step at the large scale. That filtration step, which took many days at large-scale instead of the one to two days expected from the laboratory-scale synthesis, is also expensive since that step ties up the equipment far longer than expected. Adjustments to solvent ratios and crystallization parameters were also identified as potential contributors to the poor yield using the large-scale equipment and so need to be tested as additional factors that can be modified to improve yield at large-scale. Supplemental funds are requested to investigate process improvements to address the unexpected loss of yield that occurred during the large-scale manufacturing of CMS121. These studies should then allow the efficient large-scale synthesis of GMP-grade CMS121 that will be needed for future clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,539,464 )
2026	2026	VIROGENICS, INC.	4050 SORRENTO VALLEY BLVD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	3	8/12/2026	NON-COMPETING CONTINUATION	$1,345,792
2026	2026	VIROGENICS, INC.	4050 SORRENTO VALLEY BLVD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	001	3	9/10/2026	SUPPLEMENT FOR EXPANSION	$193,672
														Subtotal = $1,539,464

Issue Date FY: 2025 ( Subtotal = $1,562,187 )
2025	2025	VIROGENICS, INC.	4050 SORRENTO VALLEY BLVD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	001	2	8/12/2025	NON-COMPETING CONTINUATION	$1,562,187
2025	2024	VIROGENICS, INC.	4050 SORRENTO VALLEY BLVD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	1	12/19/2024	NEW	$0
														Subtotal = $1,562,187

Issue Date FY: 2024 ( Subtotal = $1,594,649 )
2024	2024	VIROGENICS, INC.	4050 SORRENTO VALLEY BLVD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	1	9/23/2024	NEW	$1,594,649
														Subtotal = $1,594,649

Grand Total All Awards = $4,696,300

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Long-term, non-clinical toxicology for advancing CMS121 to Phase 2 trials for AD

Award Number: U01AG084549

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/24/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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