# Development of Cobinamide as a Novel Treatment for Aortic Aneurysms of Marfan Syndrome:  Phase I Pharmacokinetic Studies

> **NIH NIH R43** · MESA SCIENCE ASSOCIATES, INC. · 2022 · $311,381

## Abstract

Marfan Syndrome (MFS) is a genetic disorder, with a prevalence of ~ 1 in 5,000 people. Aneurysms in the
ascending aorta are the most serious manifestation of the disease and can lead to sudden death due to
spontaneous rupture. Existing treatments are marginally effective. The aneurysms are due largely to increased
oxidative stress in aortic smooth muscle cells from abnormal production of superoxide anion and nitric oxide.
 Cobinamide is the penultimate precursor in the biosynthesis of cobalamin (vitamin B12) and is a powerful
antioxidant, serving as a superoxide dismutase and catalase mimetic and neutralizing nitric oxide and
peroxynitrite. We have found that administering cobinamide in the drinking water to mice with a fibrillin-1 mutation
analogous to a common mutation in Marfan patients abolished oxidative stress and pathological changes in the
aorta, and significantly reduced aortic dilation. Our goal is to develop cobinamide as a novel, disease-modifying
treatment that could be used in patients with MFS and other forms of aortic aneurysms associated with oxidative
stress. An international patent has been submitted for using cobinamide to treat aortic aneurysms, and Dr. Boss,
co-investigator on this application, holds patents for using cobinamide as an antidote against toxic chemicals.
 In this Phase I SBIR grant, we propose to perform pharmacokinetic (PK) studies in rats after oral
administration of cobinamide (Aim I) and to synthesize sufficient non-GMP grade cobinamide for the PK studies
(Aim II). We propose four interrelated studies in Aim I. (A) Dose Determination Studies. We will determine the
single dose administered by gavage required to achieve the plasma concentration found after administering
cobinamide continuously in drinking water to mice. (B) Formulation Selection and Mode of Administration
Studies. We will compare four different cobinamide formulations, using the dose found in Aim 1A. We will
compare the PK profile between administering the drug by gavage to direct instillation into the duodenum in
cannulated rats, since gastric acidity could affect cobinamide absorption. The goal is to find the formulation and
administration mode that yield the highest plasma concentration for the longest time. (C) Bioavailability Studies.
We will use the optimal formulation and administration mode found in Aim 1B and compare the PK profile to that
found after injecting the drug intravenously. (D) Repeated Dose Studies. Using the formulation and
administration mode found best in Aim 1B, we will determine the frequency of administration required to maintain
a steady-state, target plasma concentration.
 A subsequent Phase II SBIR grant would consist of synthesizing and formulating GMP-grade cobinamide,
and performing GLP-level PK and toxicology studies in rats and pigs. The SBIR studies would complement and
be performed simultaneously with efficacy and basic mechanistic studies supported by a five-year R01 grant
expected to start 04/01/22. Tech...

## Key facts

- **NIH application ID:** 10545967
- **Project number:** 1R43HL165981-01
- **Recipient organization:** MESA SCIENCE ASSOCIATES, INC.
- **Principal Investigator:** Kenneth Dretchen
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $311,381
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10545967

## Citation

> US National Institutes of Health, RePORTER application 10545967, Development of Cobinamide as a Novel Treatment for Aortic Aneurysms of Marfan Syndrome:  Phase I Pharmacokinetic Studies (1R43HL165981-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10545967. Licensed CC0.

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