Research Programs
We are developing Limerick Activators both for combination therapies to reduce drug toxicity in vulnerable organs as well as monotherapies for a range of diseases. From our data, we know that activating specific ABC Transporters decrease specific end-organ drug toxicities and improve components of metabolic disease.
Here are our 2 lead programs in development:
DRUG TOXICITY PROGRAM
(Clinical Stage)
Limerick Activators as Adjunctive Therapies
The pharmaceutical armamentarium is full of drugs that play vital medical roles, but suffer from unwanted and dangerous side effects due to their uptake into vulnerable tissues and organs. High concentrations of drugs such as CNIs (e.g. tacrolimus and cyclosporin) in the kidneys and pancreas cause toxicity (e.g. nephrotoxicity and diabetes, respectively). We are tailoring our molecules to be paired with marketed or pipeline drugs in order to improve their safety profile by redistributing the drug away from organs where unwanted effects occur, and back into systemic circulation where their maximal pharmacologic activity is intended.
Adverse effects of CNIs not only impact a patient’s quality of life, but have health economic consequences as well as a negative impact on graft and host survival. Additionally, failed grafts due to CNI toxicities drain an already low organ supply. Our early animal studies have demonstrated a reduction in CNI-induced hyperglycemia and kidney toxicity when Limerick Activators are used with CNIs. Ex vivo studies demonstrated that our molecules don’t have a negative impact on the immunosuppressive effects of CNIs. Currently, our Immunosuppressant Program is in Phase 1. The study is designed to evaluate to effects of LIM-0705, an NCE adjuvant therapy, on the safety profile of tacrolimus in humans. A second compound, LIM-0723, is currently being evaluated with cyclosporin in animals.
In two proof of concept human studies, our molecules demonstrated an improvement in cognition and a decreased incidence of nausea and vomiting in patients on opioids. We continue our research in the area of pain.
In addition to CNIs and opioids, other drugs that could benefit from this novel approach include immunomodulators, selective estrogens receptor modulators, and psychotropics.
METABOLIC DISEASE PROGRAM
(Discovery Stage)
Limerick Activators as Monotherapies
Many diseases result from the improper regulation of cellular substances such as lipids (e.g. cholesterol, fatty acids, and phospholipids). Through the selective activation of ABC Transporters, we are developing molecules that enhance the clearance of these substances from vulnerable tissues and organs. Diseases that could be treated with this approach include common disorders associated with lipid accumulation including Metabolic Disease and Type 2 Diabetes (T2D).
Cellular accumulation of lipids is a harbinger of insulin resistance and hyperlipidemia. Our Activators may improve hyperglycemia and T2D by improving insulin sensitivity. Unlike many anti-diabetic agents that treat the symptoms of T2D such as hyperglycemia, early data shows that our molecules prevent the worsening of hyperglycemia or T2D by removing the cause of insulin resistance – lipid accumulation in cells. We believe our Activators can achieve this through the activation of ABC Transporters by removing excess lipids from tissues responsible for insulin resistance. Limerick Activators may provide a new disease-modifying paradigm to achieving lipid and glucose homeostasis.
In animals treated with LIM Activators as monotherapy, we have observed:
- Lowering of plasma glucose
- Lowering of HbA1c
- Improvement in response to oral glucose load
- Reduction in insulin resistance
- Protection of islet architecture
- Lowering of free fatty acid
- No difference in weight compared to vehicle
A number of Limerick Activators are being evaluated in animal models of diabetes and hyperlipidemia and other diseases related to the accumulation of endogenous materials.
