Contravir Pharmaceuticals
Overview
Contravir Pharmaceuticals (CTRV) is a biopharmaceutical company focused on the development of antiviral drugs with a primary emphasis on the treatment of Hepatitis B virus (HBV) infections. Contravir is developing two compounds to treat HBV infection, TXL and CRV431. TXL is a highly potent oral lipid prodrug of tenofovir. Prodrugs are designed to improve the characteristics of drugs, such as better efficacy, lower pill burden, improved safety, etc. Another prodrug of tenofovir, Viread®, is approved for the treatment of HIV and HBV infections. CRV431 is a novel drug candidate also designed for the treatment of HBV infection that the company acquired through its merger with Ciclofilin Pharmaceuticals Inc. CRV431 has been designed to target enzymes (cyclophilins) that play a key role in the HBV viral life cycle. Contravir is also developing an antiviral asset known as VALNIVUDINE, VALNIVUDINE is an orally available, small molecule compound being developed for the prevention of post-herpetic neuralgia (PHN) and treatment of herpes zoster infection and acute zoster-associated pain. Herpes zoster, otherwise known as shingles, is an infection caused by the reactivation of varicella zoster virus or VZV, the cause of Chickenpox.1
TXL
TXL is a novel lipid acyclic nucleoside phosphonate that delivers high intracellular concentrations of the active antiviral agent tenofovir diphosphate. TXL's novel structure results in decreased circulating levels of tenofovir (TFV), lowering systemic exposure and thereby reducing the potential for renal side effects. It has completed a Phase 1 clinical trial in healthy volunteers, demonstrating a favorable safety, tolerability and drug distribution profile. Contravir is developing TXL for Hepatitis B (HBV).
Contravir licensed TXL from Chimerix in exchange for an upfront payment of 120,000 shares of its preferred stock, valued at $1.2 million (time of the deal). Contravir intend to develop TXL for the treatment of chronic HBV infection. A recently issued composition of matter patent for TXL provides intellectual property protection to at least 2031.
Contravir completed a Phase 1b safety and pharmacokinetic study in 2016. Data from the Phase 1b study demonstrate that TXL was safe and well tolerated by healthy volunteers in all dosing groups the company also completed a Phase 2a multiple ascending dose proof of concept clinical trial. The study enrolled 62 treatment-naïve patients with chronic HBV infection and compared TXL to the standard dose of TDF. Data from the Phase 2a study demonstrated that TXL was safe and well tolerated by patients with chronic HBV infection in all dosing groups
The data in the phase 2a atudy demonstrated that doses of TXL from 25-mg to 100-mg resulted in comparable mean HBV viral load reductions to the 300-mg dose of TDF after 28 days of treatment. The reduction in viral load persisted for up to one month after cessation of treatment. The data demonstrated that TXL, at all doses tested, resulted in substantially lower systemic circulating levels of tenofovir in the blood compared to TDF. These results demonstrate the potential for TXL to reduce the risk of bone- and kidney-related toxicities associated with TDF.
Contravir submitted an Investigational New Drug application (IND) to the U.S. Food and Drug Admnistration (FDA) to support initiation of its HBV clinical development program in the United States and received a notice of approval in September 2017. The company plan to initiate a safety study in patients with severe renal impairment will be intiated during the fourth quarter of 2017. Data from this study are expected to further support the strong safety profile of TXL in patients with comorbidities. Additionally, Contravir received approval for its Clinical Trial Application (CTA) in the United Kingdom.
The decision to develop TXL for Hepatitis B has been taken because the company do not see a large opportunity to grow the HIV market with new compounds, even though CMX157 is 200 times more potent than tenofovir in vitro. Contravir believe the Hepatitis B market is poised for exceptional growth. TXL is 4.5 times more potent than PDFtenofovir in vitro and thus potentially allows for a lower dose to achieve similar results in future head to head clinical studies. The lower dose may also allow for a better safety profile than TDF. The strategy for TXL is to develop the compound to serve as a critical backbone therapy in future HBV combination therapies. Contravir will be seeking to submit an Investigational New Drug application (IND) to support an initiation of its HBV clinical development program at the end of 2015.
CRV 431
CRV431 is a novel drug candidate designed to target a class of proteins called cyclophilins, of which there are many types. Cyclophilins play a role in health and in the pathogenesis of certain diseases, and are known as peptidyl prolyl isomerases. The isomerase activity plays an important role in a number of biological processes including, for example, folding of proteins to confer certain 3-dimensional configurations. And, specific host cyclophilins (e.g., cyclophilin A, B, C, D) play a role in the life cycle of certain viruses, including for example, HBV, HIV, and hepatitis C virus (HCV) infections. CRV431 has been developed to inhibit the role of host cyclophilins and therefore interfere in the propagation of these viruses. CRV431 does not directly target the virus and, as such, should be less susceptible to drug resistance, borne from viral mutations.
Thus far, in vitro testing of CRV431 has been conducted in-house and in collaboration with external groups including for example, the Scripps Research Institute (Scripps). Data in various cell lines of either transfected or infected HBV demonstrates nanomolar efficacy (EC50 values) and micromolar toxicity (CC50 values). The selective index (SI), therefore, is wide and suggests that CRV431 presents a viable clinical drug candidate for the treatment of viral infections, including HBV. Additional testing in a transgenic mouse model of HBV indicated that CRV431 reduced HBV DNA in the liver. In a non-alcoholic steatohepatitis (NASH) mouse model, CRV431 demonstrated anti-fibrotic potential, thus addressing an important concern of the downstream effects of chronic HBV infection and liver disease. Both animal models confirmed that CRV431 is orally active and appeared to be well tolerated.
VALNIVUDINE
VALNIVUDINE is an orally available, small molecule, nucleoside analogue pro-drug of CF-1743 that Contravir is developing for the treatment of herpes zoster, which is an infection caused by the reactivation of varicella zoster virus or VZV. VZV is responsible for producing the infectious disease known as chicken pox in individuals upon initial exposure to the virus. After the initial infection, the virus can remain dormant in nerve endings for many years and if reactivated, causes a painful rash called shingles. VALNIVUDINE is being developed specifically for the treatment of shingles. Nucleoside analogs are capable of disrupting replication of the virus. VALNIVUDINE is a pro-drug of CF-1743, which enables it to take advantage of VALNIVUDINE's more readily absorbed properties compared to CF-1743 when given orally. VALNIVUDINE is then broken down to the active moiety, CF-1743, upon entry into the blood stream. Published preclinical studies demonstrate that VALNIVUDINE is significantly more potent against VZV than currently marketed compounds acyclovir, valacyclovir, and famciclovir, the FDA-approved drugs used for the treatment of shingles. Contravir conducted an extensive review of the clinical data from the completed Phase 2 trial, including performing post-hoc analyses. Contravir performed additional market research (including unmet medical need), reimbursement, pricing, and competitive landscape analyses, etc. Contravir also evaluated a number of clinical, regulatory and commercial pathways for the potential future development of VALNIVUDINE. Based upon the analyses of the completed Phase 2 study coupled with the additional market research, the company approached the FDA to discuss its clinical development program and requested an End of Phase 2 (EoP2) meeting. The meeting was granted and the result was a streamlined development plan for VALNIVUDINE that allowed it to proceed directly into a Phase 3 trial without the need to conduct any additional Phase 2 studies. Contravir had satisfied these criteria and initiated Protocol 007 during 2Q/2015.
In parallel to the Phase 3 initiation, Study 008, a drug-drug interaction trial was conducted during January-March, 2015. The study's objective was to highlight potential drug interactions with compounds which are metabolized using the CYP450 pathway. This is a very common trial in virology and in drug development overall.
