Mechanism of Action

ANG-3070 is a highly selective, oral small molecule tyrosine kinase receptor inhibitor developed internally as a potential treatment for chronic fibrotic diseases, particularly in the kidney and lung.

In September of 2021, we held an R&D Day focused on the ANG-3070 program. You can view a recording of the event on our Events & Presentations page.

ANG-3070 is an investigational product and is not approved by any regulatory authority.

ANG-3070 for the treatment of fibrosis

To date, we have focused our research efforts on the key fibrotic pathways impacted by tyrosine kinases, the intersecting nodes between these pathways, and the correlation of genomic and proteomic signatures for different types of fibrosis within these known pathways. This approach enabled us to design ANG-3070 with high specificity and receptor-binding affinity to deliver activity in fibrotic pathways while limiting off-target inhibition. In preclinical models and IND-enabling toxicology studies, ANG-3070 was well tolerated.

ANG-3070 has been studied in multiple models of kidney fibrosis, including models of primary proteinuric kidney diseases like IgAN, FSGS, and membraneous nephropathy.

In the passive Heymann’s nephritis model of membraneous nephropathy (MN), ANG-3070 reduced proteinuria compared with vehicle control and was also associated with reduced kidney fibrosis upon histopathalogical examination.

In a model of focal segmented glomerulosclerosis (FSGS), ANG-3070 significantly reduce proteinuria compared to vehicle and was associated with significantly reduced kidney inflammation and scarring upon histopathological examination.

ANG-3070 has also been studied in multiple models of lung fibrosis, including one of the most widely used models of lung fibrosis using endotracheal administration of bleomycin, a chemotherapeutic agent, to induce fibrosis, replicating many elements of IPF. We evaluated pulmonary fibrosis using picosirius red staining, and levels of TGF-β (a pro-fibrotic cytokine) to assess ANG-3070’s effects on markers of lung fibrosis. On both measures, ANG-3070 showed significant reductions relative to vehicle.

ANG-3070 Reduced Proteinuria in Membraneous Nephropathy and FSGS Models

ANG-3070 Improved Markers of Lung Injury Relative to Placebo

Phase 1 Healthy Volunteer Trial

In August 2021, we reported positive topline data from our Phase 1 Healthy Volunteer study of ANG-3070.  97 healthy adult volunteers were enrolled in the study with 72 receiving ANG-3070 and 25 receiving placebo to assess the safety, tolerability, pharmacokinetics, and food effect of ANG-3070. Overall, data from the study surpassed our expectations.

Key findings from the Phase 1 study included:

  • ANG-3070 achieved drug exposures in humans exceeding exposures in which activity was demonstrated in animal models of proteinuric kidney diseases
  • Encouraging safety and tolerability profile, particularly given the well-recognized incidence and severity of gastrointestinal side effects in approved TKIs
  • Pharmacokinetic data supportive of potential once-daily oral dosing for ANG-3070

There were no Serious Adverse Events reported at any dose schedule or level in the preliminary safety reports. The reported (non-serious) Adverse Events (AEs) were mostly seen at higher doses, 600 mg administered once daily and 500 mg administered twice daily. These AEs included nausea, abdominal cramps, and diarrhea. Overall, ANG-3070 demonstrated an encouraging safety and tolerability profile, especially given the well-recognized incidence and severity of gastrointestinal side effects in approved TKIs.

A key finding in the Phase 1 study was ANG-3070 exposure levels in humans exceeded the exposure levels necessary to demonstrate activity in our pre-clinical models.

For example, 15mg/kg dose in rats provides the same approximate exposure as 3mg/kg in humans and a 50mg/kg dose in rats is comparable to 6mg/kg (400mg once daily) dose in humans.

A human dose of 4mg/kg (equivalent to 250mg) twice daily provides an AUC of 1,850. This compares to the NOAEL* exposure dose in non-human primates of an AUC of 10,510, corresponding to a human dose of about 80mg/kg, or about 4,800mg for a 60kg human.

(*NOAEL = No Observed Adverse Effect Level, denoting the level of drug exposure at which there is no biologically or statistically significant increase in the frequency or severity of adverse events.)

Human Exposure of ANG-370 in Phase 1 Healthy Volunteer Trial Exceeded Active Exposure Levels in Membraneous Nephropathy Model

Clinical Trials

Primary Proteinuric Kidney Disease: We have initiated JUNIPER, a randomized, double-blind, and placebo-controlled global Phase 2 dose-finding study of ANG-3070 in approximately 100 patients with primary proteinuric kidney diseases, including IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). The trial will compare three different dose levels of ANG-3070 (200mg orally 1x/day, 400mg orally 1x/day, and 300mg orally 2x/day) to placebo over 12 weeks of dosing.

Idiopathic Pulmonary Fibrosis (IPF): We have received U.S. Food and Drug Administration acceptance of an Investigational New Drug (IND) application supporting the clinical development of ANG-3070 in IPF and clearance to begin a Phase 1b study of ANG-3070 in patients with IPF. We expect this trial to begin enrolling patients in 2022 with data expected in the second half of 2022.