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Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1

Award Number: R01DK112955
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/23/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1 - Project Summary/Abstract This proposal requests funding for continuation and extension of a phase IIa clinical trial of rifampin, an FDA- approved antibiotic, for safety and efficacy as a treatment for idiopathic infantile hypercalcemia (IIH) due to mutations in the gene encoding CYP24A1 gene. IIH is an uncommon metabolic condition characterized by elevated plasma levels of the activated form of vitamin D, calcitriol, and consequently increased intestinal absorption of calcium and increased bone resorption that together cause hypercalcemia and hypercalciuria. Although IIH typically presents in infancy, patients manifest a life-long defect in vitamin D metabolism that results in hypercalciuria, nephrolithiasis, and renal insufficiency. CYP24A1 encodes the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, and biallelic mutations cause the most common and severe form of IIH. Loss of this pathway allows plasma levels of calcitriol to rise excessively and overcomes feedback mechanisms that should downregulate production of calcitriol. Patients who carry only one defective CYP24A1 allele have a less severe phenotype. There is at present no specific long-term treatment for patients with CYP24A1 mutations and conventional care consists of minimizing sunlight exposure, a low calcium diet, and avoidance of vitamin D-rich foods and vitamin D supplements. This approach does not reduce the risk of renal calcification and renal insufficiency, however, and may lead to low bone density. Thus, there is a significant unmet medical need for safe and effective treatments for this disorder. We have compelling data supporting a therapeutic approach in which the antibiotic rifampin is repurposed to induce expression of CYP3A4, an enzyme that is expressed in the liver and intestine, to provide an alternative pathway for inactivation of vitamin D metabolites. The long-term goal of this project is to develop novel strategies for medical treatment of patients with IIH and other forms of hypercalciuria and nephrolithiasis that are associated with elevated plasma levels of calcitriol. The objective in this application is to determine the optimal safe and effective dose of rifampin that normalizes serum and urine levels of calcium and reduces intestinal absorption of calcium (primary outcomes). Our two complementary goals are to evaluate the extent to which these primary outcomes are related to plasma levels of rifampin, induction of CYP3A4, polymorphisms in the CYP3A4 gene and other genes that influence mineral metabolism, and changes in plasma levels of vitamin D metabolites and to determine the effect of CYP24A1 mutations on bone health. Our central hypothesis is that induction of CYP3A4 by rifampin will reduce levels of calcitriol and thereby decrease intestinal absorption of calcium and we expect that benefits will be related to the extent of CYP3A4 induction. We have access to the necessary study subjects and the expertise and resources to pursue these studies. Our approach is innovative because it proposes to repurpose a well-characterized and safe medication to a new role as a primary therapy for a disorder that currently lacks an effective treatment.


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 = $710,595 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	12/3/2025	NON-COMPETING CONTINUATION	$710,595
														Subtotal = $710,595

Issue Date FY: 2025 ( Subtotal = $657,228 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	11/20/2024	NON-COMPETING CONTINUATION	$657,228
2025	2021	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	1/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $657,228

Issue Date FY: 2024 ( Subtotal = $701,043 )
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	11/22/2023	NON-COMPETING CONTINUATION	$657,228
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	5/7/2024	NON-COMPETING CONTINUATION	$43,815
														Subtotal = $701,043

Issue Date FY: 2023 ( Subtotal = $631,840 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/22/2022	COMPETING CONTINUATION	$631,840
2023	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $631,840

Issue Date FY: 2021 ( Subtotal = $452,039 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/3/2021	NON-COMPETING CONTINUATION	$452,039
														Subtotal = $452,039

Issue Date FY: 2020 ( Subtotal = $497,467 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/22/2020	NON-COMPETING CONTINUATION	$497,467
														Subtotal = $497,467

Issue Date FY: 2019 ( Subtotal = $497,467 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/18/2019	NON-COMPETING CONTINUATION	$497,467
														Subtotal = $497,467

Issue Date FY: 2018 ( Subtotal = $497,467 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/29/2018	NON-COMPETING CONTINUATION	$497,467
														Subtotal = $497,467

Issue Date FY: 2017 ( Subtotal = $497,467 )
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/21/2017	NEW	$497,467
														Subtotal = $497,467

Grand Total All Awards = $5,142,613

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Repurposing rifampin to reduce elevated levels of blood and urine calcium in patients with inactivating mutations of CYP24A1

Award Number: R01DK112955

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/23/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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