How does the Revenir Platform Work?

We have created a purpose-built computational drug discovery engine called Revenir that integrates computational chemistry, biophysics, and machine learning to capture protein conformer landscapes from which we can derive novel insights regarding the biophysical and thermodynamic properties of proteins – enabling us to develop a deep understanding of protein defects and to discover novel small molecules to address them.

Key capabilities of the Revenir platform

  • Modeling protein motion and functional conformational states, not just static structures
  • Identifying cryptic and allosteric binding sites inaccessible to traditional approaches
  • Virtual screening and in silico docking of billions of compounds  to identify high-value hits
  • Generative chemistry and reinforcement learning to design optimized molecules
  • Internal predictive models for binding affinity and drug-like properties

What does the Revenir Platform allow Congruence to do?

Target difficult-to-drug proteins and other historically undruggable biology.

Generate high- quality development candidates efficiently and at lower cost than industry averages.

Build a repeatable pipeline-generation engine for multiple therapeutic areas.

Pipeline

Congruence’s pipeline represents both first-in-class and best-in-class potential to address significant
unmet medical needs in a number of high value indications.

Preclinical Results Support our Expanding Pipeline

CGX-926 is a first-in-class MC4R-d corrector for the treatment of Genetic Obesity.

  • MC4R-deficiency, the most common form of genetic obesity, is associated with severe hyperphagia and obesity, affecting ~100,000 patients in the US.
  • MC4R-deficiency is caused by heterozygous and homozygous partial loss-of-function mutations in MC4R that lead to receptor misfolding and impaired trafficking to the cell surface of neurons in the paraventricular nucleus of the hypothalamus.
  • CGX-926 is an orally active, small-molecule corrector that restores proper folding, trafficking, and function of mutated MC4R, addressing the root cause of the disease.
  • CGX-926 reduces body weight and hyperphagia in a proprietary mouse MC4R-deficient model of obesity and has the potential to address the key clinical manifestations of MC4R-deficient in human patients.

What is MC4R? 
MC4R is a G-Protein Coupled Receptor (GPCR), localized primarily in the hypothalamus, involved in regulating appetite and energy balance.

What is MC4R-deficiency? 
MC4R-deficiency is the most common form of genetic obesity. MC4R partial loss of function mutations lead to MC4R deficiency (MC4R-d) due to receptor misfolding and disrupted trafficking to the cell surface.

How does Congruence’s MC4R corrector differ from MC4R agonists such as setmelanotide?
MC4R correctors are designed to penetrate the cell and bind misfolded receptors in the ER thereby improving their folding and trafficking. Once trafficked to the cell surface, the receptor can function normally and respond to endogenous signals. In contrast, MC4R agonists such as setmelanotide operate by directly activating normally functioning MC4 receptors present on the cell surface and inducing signaling. As a result, MC4R correctors, but not agonists, address the underlying cause of MC4R-deficiency disease in patients with MC4R mutations.

What drugs are approved for patients with genetic obesity due to MC4R-deficiency?
There are currently no therapies approved or in development that directly address MC4R deficiency, a distinct condition caused by mutations in the receptor itself.

Setmelanotide is not approved for genetic obesity due to MC4R-defciency. Setmelanotide is approved for obesity indications associated with impaired availability of the endogenous agonist, alpha-MSH. This includes Bardet-Biedl syndrome, acquired hypothalamic obesity and specific genetic obesity disorders that affect signaling upstream of the MC4R receptor, such as POMC, PCSK1, and LEPR deficiencies.

CGX-195 is a first-in-class corrector which has the potential to decrease the risk of liver fibrosis and lung emphysema for the treatment of alpha-1 antitrypsin deficiency.

  • Homozygous mutations (E242K) in the SERPINA1 gene, which encodes alpha-1 antitrypsin (A1AT), lead to AATD, affecting ~80,000 to 100,000 patients in the US and causing both liver and lung disease.
  • Mutant A1AT protein (Z-AAT) is misfolded and polymerizes in hepatocytes, driving liver disease, while decreased circulating Z-AAT renders the lung susceptible to elastin breakdown and causes lung disease.
  • Congruence has discovered orally active small-molecule A1AT correctors that stabilize mutant Z-AAT, prevent its polymerization in hepatocytes, and increases secretion of functional Z-AAT in plasma in cellular assays and a mouse transgenic model of AATD.
  • A1AT correctors discovered by Congruence have the potential to decrease the risk of liver fibrosis and lung emphysema in patients with AATD.

What is α1-antitrypsin (A1AT)?
α1-antitrypsin is a protein produced in the liver that protects tissues, especially the lungs, from damage caused by enzymes such as neutrophil elastase.

What is α1-antitrypsin deficiency?
A1AT deficiency is a genetic disorder where misfolded A1AT proteins accumulate in the liver and fail to reach the bloodstream, leading to lung and liver disease.

How does protein misfolding cause A1AT deficiency?
Mutations cause the A1AT protein to misfold and polymerize in liver cells, reducing its secretion and damaging the liver.

Why does A1AT deficiency affect both the liver and lungs?

  • Liver: accumulation of A1AT polymers causes liver fibrosis
  • Lungs: lack of functional A1AT to oppose the action of neutrophil elastase leads to destruction of lung tissue

How can small molecule correctors treat A1AT deficiency?
Small molecule correctors can stabilize the A1AT protein, improve its folding, prevent formation of polymers and enable proper secretion of functional A1AT into the bloodstream.

What are current treatments for A1AT deficiency?
Current treatments include augmentation therapy (protein replacement), but these do not address the underlying protein misfolding.

How is Congruence’s approach different?
Congruence aims to correct the underlying folding defect using a small orally available molecule, potentially offering a disease-modifying therapy in a convenient dosing regimen.

GCase Activators for the treatment of GBA-driven Parkinson’s Disease

  • Heterozygous mutations in the GBA1 gene, which encodes glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson’s disease, with a US prevalence of ~100,000 patients.
  • GBA1 mutations (including L444P, N370S and E326K) cause GCase misfolding and lysosomal GCase deficiency, which disrupt lipid homeostasis, leading to accumulation and aggregation of alpha-synuclein in dopaminergic neurons.
  • Congruence has discovered a series of orally active and brain-penetrant small-molecule pharmacological activators of GCase (e.g., CO-1) that activate lysosomal GCase activity in patient-derived dopaminergic neurons and in a mouse GBA-1 mutant animal model.
  • GCase activators and correctors discovered by Congruence have the potential to be disease-modifying and to slow progression of GBA-PD.

What is GCase?
GCase (glucocerebrosidase) is an enzyme that helps break down certain lipids in cells, particularly within lysosomes.

What is GBA- Parkinson’s disease?
GBA Parkinson’s disease refers to Parkinson’s disease associated with mutations in the GBA1 gene, which reduce GCase enzyme activity and contribute to neurodegeneration.

How do GBA mutations cause Parkinson’s disease?
Mutations in the GBA1 gene reduce GCase activity, leading to the accumulation of lipids and impaired lysosomal function. This contributes to the buildup of toxic proteins such as alpha-synuclein.

What is the role of lysosomal dysfunction in Parkinson’s disease?
Lysosomes are responsible for breaking down cellular waste. When they do not function properly, toxic materials accumulate, contributing to neuronal damage.

Why is GCase considered a high-value target?
GCase is genetically validated, meaning mutations are directly linked to disease risk, making it a strong target for therapeutic intervention.

What are current treatments for GBA-Parkinsons?
There are no approved treatments that specifically target GBA-Parkinson’s disease (GCase biology) today. Current care is a mix of standard Parkinson’s therapies (symptomatic) and experimental, approaches in clinical trials.

Publications