NASH: Building a Platform Therapy for an Emerging Pandemic
NASH is emerging as the next major epidemic to threaten the health of people around the globe. Diet and other factors lead to excess fat in the liver driving further lipid production, inflammation and fibrosis. Left untreated, the damaged liver functions poorly, becoming cirrhotic and even cancerous with time. The damage can also exacerbate a spectrum of other health problems including cardiovascular diseases.
We used both cell-based and murine models to demonstrate the potential of a FASN inhibitor to treat NASH and restore liver health by reducing liver fat, inflammation and fibrosis.
A Phase 1 study has been conducted with experts at the University of Missouri to determine the dose of TVB-2640 that inhibits liver fat synthesis in humans (NCT02948569). Liver fat synthesis was measured in 12 healthy adults who had characteristics of metabolic syndrome, including a high body mass index. TVB-2640 reduced liver fat synthesis in a meaningful and dose-dependent manner. These data support further development of TVB-2640 in patients with NASH.
Oncology: An Opportunity for Targeted Therapy
FASN over-expression is associated with aggressive disease in multiple tumor types (including breast, ovarian and K-Ras mutated non-small cell lung cancer) and provides an opportunity to identify patients most likely to respond to therapy. We designed our proprietary FASN inhibitors specifically to target FASN and minimize off-target effects. In preclinical studies, our FASN inhibitors have demonstrated potent activity against a number of tumor types, potential synergy with approved cytotoxic agents, and excellent tolerability.
A Phase 1 study with our lead FASN inhibitor TVB-2640 has been conducted in patients with solid tumors (NCT02223247). Clinical activity was observed in defined patient populations including breast, ovarian and non-small cell lung cancer with a K-Ras mutation.
TVB-2640: First-In-Class, Once Daily, Oral Inhibitor of FASN
In a Phase 1 trial of TVB-2640 in patients with solid tumors we have established:
- The safety profile supporting further development
- Pharmacokinetic profile enabling once daily dosing
- The maximally tolerated dose
- FASN inhibition in patients
- Clinical activity in defined patient populations including breast, ovarian and non-small cell lung cancer with a K-Ras mutation
Additional details of our Phase 1 trial can be found on our Posters/Publications page, and at https://clinicaltrials.gov/ct2/show/NCT02223247.
In a Phase 1 trial of TVB-2640 in men with high body mass index and characteristics of metabolic syndrome we have established:
- Dose-dependent reduction of liver fat synthesis – proof of mechanism
- Strong pharmacokinetic/pharmacodynamics (PK/PD) relationship
- Trend of reduced liver enzyme levels
Additional details of our Phase 1 Proof of Mechanism trial can be found on our Posters/Publications page and at https://clinicaltrials.gov/ct2/show/NCT02948569