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Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts

Award Number: R43EY031609
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts - Project Summary Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery. However, surgery is associated with significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the Medicare vision care expense by 50%. Our preliminary data supports the hypothesis that an FDA approved small-molecule drug, tafamidis (CAP4349) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. However, tafamids and its salts exhibit extremely poor aqueous solubility, limiting its potential as an ophthalmic drug. Therefore, the basic goal of our proposal is: optimization of tafamids to improve its solubility by using prodrug concept and demonstrate its potential as a promising topical anti-cataract agent using the following specific aims. Aim 1a. Design and synthesis of prodrugs of CAP4349. Aim 1b. Enzymatic evaluation of conversion of prodrugs into active metabolite. Aim 2a. Formulation of prodrugs for topical route of delivery to achieve enhanced corneal permeation and metabolic conversion. Aim 2b. Evaluation of compounds for corneal permeation and metabolic conversion using 3D human organotypic corneal tissue model. Aim 3a. Seven day repeat topical dose acute toxicity and safety in New Zealand white rabbits. Aim 3b. In-vivo ocular pharmacokinetics. Project milestone: Successful completion of these aims will identify a minimum of two optimized tafamids prodrugs with acceptable in-vivo efficacy and acceptable ocular PK to be advanced into non-GLP preclinical development and GLP enabling IND studies (Phase II).


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: 2024 ( Subtotal = $0 )
2024	2021	PLEX PHARMACEUTICALS INC	1770 CORPORATE CIR	PETALUMA	CA	94954	SONOMA	USA	Vision Research	000	2	4/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	PLEX PHARMACEUTICALS, INC.	6330 NANCY RIDGE DR STE 105	SAN DIEGO	CA	92121	SAN DIEGO	USA	Vision Research	000	2	2/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	PLEX PHARMACEUTICALS, INC.	6330 NANCY RIDGE DR STE 105	SAN DIEGO	CA	92121	SAN DIEGO	USA	Vision Research	000	2	11/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $149,295 )
2021	2021	PLEX PHARMACEUTICALS, INC.	6330 NANCY RIDGE DR STE 105	SAN DIEGO	CA	92121	SAN DIEGO	USA	Vision Research	000	2	7/13/2021	NON-COMPETING CONTINUATION	$149,295
														Subtotal = $149,295

Issue Date FY: 2020 ( Subtotal = $149,295 )
2020	2020	PLEX PHARMACEUTICALS, INC.	6330 NANCY RIDGE DR STE 105	SAN DIEGO	CA	92121	SAN DIEGO	USA	Vision Research	000	1	6/25/2020	NEW	$149,295
														Subtotal = $149,295

Grand Total All Awards = $298,590

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Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts

Award Number: R43EY031609

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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