# Oral PCSK9/LDLR antagonist direction to the clinic

> **NIH NIH R44** · SHIFA BIOMEDICAL CORPORATION · 2021 · $945,393

## Abstract

Project Summary/Abstract
Heart disease has been the leading cause of death in the United States and the world for more than a century,
ever since the early 1900s. About 610,000 people die of heart disease in the United States every year–that's 1
in every 4 deaths. The epidemic burden is enormous; in 2016, cardiovascular disease (CVD) cost $555 billion
in the US alone, and by 2035, the cost will skyrocket to $1.1 trillion. A high cholesterol level is well-known risk
factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of
which statins are the leading drugs, more than 7M patients have high LDL-cholesterol and not responsive to
statin, and an additional 4M statin intolerance and 1.3M are familial hypercholesteremic (FH). These and other
patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of
this work is to develop novel orally bioavailable drugs for cholesterol lowering. Our therapeutic target is the
protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the
LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as
a precursor protein that undergoes processing. Secreted PCSK9 binds to the LDL-receptor (LDLR) and
chaperones it to the degradation pathway. To achieve our goal, we identified a nanomolar orally active small
molecule PCSK9/LDLR antagonist (P-21) that showed outstanding potency in mice fed high-fat diet. The LDL-
cholesterol lowering effect of P-21 is as potent as the marketed monoclonal antibodies. As part of this Phase-II
SBIR proposal, our goal is to advance the development of our lead compound (P-21) to Phase-I clinical trial.
Our studies will focus on ensuring that P-21 adheres to the set of established criteria as a pre-clinical
candidate and on undertaking the work required to obtain the safety and toxicology studies in two mammalian
species required for a GLP-IND enabling study application submission.

## Key facts

- **NIH application ID:** 10150084
- **Project number:** 5R44HL150923-02
- **Recipient organization:** SHIFA BIOMEDICAL CORPORATION
- **Principal Investigator:** Nabil A Elshourbagy
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $945,393
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150084

## Citation

> US National Institutes of Health, RePORTER application 10150084, Oral PCSK9/LDLR antagonist direction to the clinic (5R44HL150923-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10150084. Licensed CC0.

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