# Executing the IND-Enabling Studies for Oral PCSK9/LDLR antagonist

> **NIH NIH R44** · SHIFA BIOMEDICAL CORPORATION · 2024 · $1,267,886

## 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 697,000 people die of heart disease in the United States every year (CDC,
2022) and 17.9M death worldwide (WHO 2021). 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 (CDC, 2023)
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, in the US, more than 7M patients who
have high LDL-cholesterol are not sufficiently responsive to statin, and an additional 4M patients are statin
intolerance and 1.3M are familial hypercholesteremic (FH). These and other patients will substantially benefit
from a different mechanism for 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 and safety profile in animal in vivo. The LDL-cholesterol lowering effect
of P-21 is as potent as the marketed monoclonal antibodies. Currently, we have completed bulk of the IND-
enabling studies, including the rats GLP toxicology. As part of this direct SBIR Phase II proposal, our goal is to
obtain funds that are urgently needed to support the dogs DRF, GLP toxicology, safety pharmacology and FDA
Regulatory Services which are crucial to successfully complete the IND-enabling study to initiate Phase-I clinical
trial.

## Key facts

- **NIH application ID:** 11005271
- **Project number:** 1R44HL174192-01A1
- **Recipient organization:** SHIFA BIOMEDICAL CORPORATION
- **Principal Investigator:** Nabil A Elshourbagy
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,267,886
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005271

## Citation

> US National Institutes of Health, RePORTER application 11005271, Executing the IND-Enabling Studies for Oral PCSK9/LDLR antagonist (1R44HL174192-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11005271. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*