Candidate: CRV431

Type: Cyclophilin inhibitor designed to block the participation of cyclophilins in disease processes such as cell death, fibrosis, and cancer cell growth and metastasis. CRV431 is Hepion’s lead drug candidate and is also in development for for nonalcoholic steatohepatitis (NASH) and viral hepatitis-induced liver disease.

Status: Hepion said December 22 that the FDA has accepted its IND application for CRV431 for COVID-19. As part of the IND filing, Hepion provided data from previously completed Phase I studies of CRV431

Daren Ure, PhD, Hepion’s Chief Scientific Officer, noted the identification in December of a mutational variant of SARS-CoV-2 in the U.K. that was potentially more infectious than previous strains in asserting that: “CRV431 is likely less prone to treatment resistance that may be seen when viral mutations occur,” since the drug, a cyclophilin inhibitor, interrupts the ability of the virus to use these human cyclophilins and thereby reduces viral propagation.

“Although Hepion’s focus and lead indication remain squarely on the treatment of NASH, this IND may allow us opportunities to seek collaboration partnerships to support the initiation of Phase II studies of CRV431 for COVID-19, and to explore sources of non-dilutive external funding for our COVID-19 program,” Ure added.

Hepion said September 17 that a study of CRV431 conducted by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) showed positive antiviral activity against SARS-CoV-2.

Using preclinical services and funding from NIAID, Hepion carried out an in vitro study testing CRV431 at concentrations of 0.0032 to 10 µM and a positive control compound, a protease inhibitor, at 0.032 to 100 µg/ml in Caco-2 cells infected with SARS-CoV-2. CRV431 was found to inhibit production of infectious virus in these cells with almost five-times greater potency than the positive control compound, Hepion said. The concentration of CRV431 required to inhibit virus production by 90% (IC90) was 1.5 µM, versus 7.3 µM for the control.

Separate experiments assessing cellular toxicities independent of virus infection showed no significant CRV431 cellular toxicity, Hepion added, indicating that CRV431 antiviral activity was due to specific effects on the virus.

“Our intention, at present, is to continue to work with external collaborators to bring peer review to our science so that we may work towards filing a submission to move to clinical trials in the near future,” said Hepion CEO Robert Foster, PharmD, PhD.

In July, Hepion said CRV431 showed effectiveness in two distinct preclinical research models related to COVID-19 disease. CRV431 demonstrated strong anti-inflammatory responses in a non-viral, acute lung injury mouse model, decreasing total inflammatory cell counts by 62% and neutrophil counts by 66%. CRV431 outperformed dexamethasone—the anti-inflammatory corticosteroid that generated successful results in the University of Oxford’s Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial—which decreased total cell and neutrophil counts by only 3% and 8%, Hepion said.

CRV431 also lowered three inflammatory cytokines in bronchial alveolar lavage (BAL) fluid, reducing IL-1β, TNFα, and IL-6 concentrations in mice intranasally administered with the microbial toxin lipopolysaccharide (LPS) by 62%-69%; dexamethasone decreased all three cytokines by 69%-91%. However, CRV431 attenuated the increase in protein in BAL fluid reflective of lung damage by 70%, vs. 76% for dexamethasone.

Hepion also cited cell culture experiments which showed CRV431 decreased one or both markers of SARS-CoV-2—measurement of viral RNA and secretion of infectious virus from the cells—in all cell types and experiments. The extent of SARS-CoV-2 reduction was dependent on CRV431 concentration, cell type, and type of measurement, but exceeded 90% in some experiments.

The results, according to Hepion, indicate the potential of CRV431 to address two key objectives in the development of a COVID-19 therapeutic by treating both viral infection and lung inflammation. Investors sent Hepion stock price surging 43% on July 7, to $4.12, before it fell 10% to $3.69 a day later.

“We will endeavor to pull together the necessary resources and/or seek collaborations to create an opportunity for CRV431 in COVID-19, while maintaining our focus on advancing CRV431 for NASH in the clinic,” stated Hepion CEO Robert Foster, PharmD, PhD.

COVID-19: 200 Candidates and Counting

To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types: