CTS-1027 is a novel and proprietary oral small molecule that inhibits the activity of key members of a class of proteases, the matrix metalloproteases or MMPs. Excessive MMP activity has been demonstrated to occur in the liver in response to HCV infection. Data from our laboratory taken together with data in the literature suggest that MMP activity in HCV-infected patients could play multiple roles in shifting the balance toward sustained virus replication and away from host-mediated viral clearance. Conatus believes that HCV regulates MMP levels and activity in order to efficiently infect hepatocytes and to interfere with the host interferon response. MMP inhibitors can be effective counter-measures against HCV directly, by inhibiting new infections, and indirectly, by amplifying the antiviral effects of interferon. This intervention would impact both the clearance of HCV-infected cells and the appearance of newly infected cells that over time could lead to reduction or elimination of circulating virus and ultimately all virus-infected cells. CTS-1027 has unique potential to impact HCV survival strategies and provide significant benefit to the HCV-infected patient population.
CTS-1027 Preclinical Summary
CTS-1027 is a potent small molecule inhibitor of MMPs. It inhibits individual members of the MMP family that are believed to be important in inflammation and tissue damage. CTS-1027 was specifically designed, however, not to inhibit MMP 1, as inhibition of MMP 1 was believed to be associated with musculoskeletal side effects.
Results of studies conducted in preclinical models of hepatitis and fibrogenesis provide support for the potential usefulness of CTS-1027 in patients with chronic hepatitis C virus infection. Although there are no non-primate comprehensive models of HCV infection, various aspects of the pathogenesis in man can be studied preclinically, and CTS-1027 has effects that could lead to benefit in patients. CTS-1027 inhibits HCV infection in primary human hepatocytes when added before or after HCV infection. In the murine bile-duct ligation model of liver fibrosis, CTS-1027 significantly reduced collagen deposition, number of bile infarcts, apoptotic hepatocytes, and hepatocytes positive for activated caspases 3/7. Biomarkers of fibrogenesis and activation of stellate cells were also reduced. CTS-1027 also prevented elevations of plasma alanine aminotransferase (ALT) levels in acute hepatitis induced by tumor necrosis factor alpha (TNF-α)/D-galactosamine (Gln), activating Fas antibody, Concanavalin A (Con A), or lipopolysaccharride (LPS)/Gln.
Overall, the results of these different preclinical models of hepatitis suggest that CTS-1027 is hepatoprotective, blocks HCV replication, reduces inflammatory and fibrogenic responses associated with a variety of hepatic injuries, and may provide benefit to patients with chronic hepatitis C virus infection. The table below summarizes the preclinical experiments that have been conducted with CTS-1027 in liver disease.
Activity Profile of CTS-1027 in Liver Disease
|Hepatitis C||Active in primary human hepatocyte model of HCV infectivity/replication model:
Does not inhibit HCV protease or polymerase
Active in HCV replicon:
|Fibrosis||Orally active in bile duct model of cholestasis:
Reduces gene expression in human stellate cell line:
|Inflammation||Orally-active in 4 models of acute hepatitis: TNF-α, α-Fas, Con A, LPS/Gln:
Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse [PDF]
CTS-1027, a potent MMP inhibitor, Protects Against TNFα – and α-Fas-Induced Liver Injury. [PDF]
Oral toxicology studies have produced results that were consistent with expectations based on the pharmacology of this compound. Since the doses to be administered in human clinical trials are below the no-effect exposure level in chronic toxicology studies, clinical development of CTS-1027 is supported. Extensive metabolism, PK/ADME and toxicology studies have been completed on CTS-1027 in multiple species. In safety pharmacology studies, there were no CNS, CV, GI, renal or respiratory effects in animals given doses of CTS-1027 up to 30 mg/kg/day.
CTS-1027 Clinical Summary
More than 700 subjects (including healthy volunteers, patients with osteoarthritis and HCV patients) have been exposed to one or more doses of CTS-1027. Single dose exposures were as high as 700 mg, while multiple dose exposures have included up to 315 mg once a day for 28 days, and 150 mg once a day for 24 weeks in osteoarthritis patients.
A number of investigational trials have been conducted to test the tolerability of CTS-1027 in the hepatitis C patient population and to explore potential efficacy. Initial efficacy measures were surrogate markers presuming an anti-inflammatory and anti-fibrogenic mechanism of action. Based on additional preclinical data, antiviral endpoints are now also being explored. The therapeutic trials are summarized briefly in the table below and described in more detail in the paragraphs that follow.
Therapeutic CTS-1027 Clinical Trial Summary
|CTS-1027-01 (completed)||CTS-1027-03 (completed)||CTS-1027-04 (in progress)||CTS-1027-05 (in progress)|
|Drug(s)||CTS-1027 monotherapy||CTS-1027 +/- Ribavirin||IFN/Ribavirin + CTS-1027||IFN/Ribavirin + CTS-1027 or Placebo|
|Duration||Variable||24 Weeks||Up to 48 Weeks||Up to 48 Weeks|
|Patient Population||HCV infected patients||IFN treatment naïve||IFN/Ribavirin null responders||IFN/Ribavirin null responders|
|Population Mix||Heterogeneous, but enriched for poor IFN responders||Broadest patient group||Purest IFN refractory population||Purest IFN refractory population|
|(Expected) Outcome||Identify dose for future trials, observed some evidence of antiviral response||Significant viral load decrease coupled with decrease in ALT/AST||≥ 2 log reduction @ week 24, viral clearance @ wk 48, SVR @ wk 72||SVR @ wk 72, viral clearance @ wk 48|
CTS 1027 as Monotherapy (Trials CTS-1027-01 and CTS-1027-03)
CTS-1027 has been studied in patients with chronic hepatitis C infection, both in treatment naïve patients for whom interferon is not appropriate, and in those who previously failed to respond to SOC (treatment failures). Various doses and dosing regimens were tested initially to confirm the tolerability of twice daily dosing. It was determined that 15 mg BID (twice a day) is a well-tolerated dose for chronic administration in HCV patients. A subset of patients experienced a transient elevation in aminotransferases, followed by a transient fall in HCV-RNA. This was not a safety signal as ALT levels declined with continued exposure to drug. While these observations are anecdotal, they are consistent with CTS-1027 playing a role in overcoming immune tolerance in chronically-infected patients. Sentinel aminotransferase spikes have been reported in acutely infected HCV human patients who clear the virus spontaneously. It is also a phenomenon that precedes viral clearance in human hepatitis B infection (see figure below).
Pattern of ALT flares and HCV-RNA reductions: spontaneous clearance (adapted from Hoofnagle, Hepatology; 2002, 35, S21).
CTS-1027 with Ribavirin (Clinical Trial CTS-1027-03)
A significant proportion of HCV patients are either deemed unsuitable or decline to be treated with IFN-containing therapies. CTS-1027 was studied in this unserved patient population alone and in combination with ribavirin. Ribavirin is well established as a critical component of current and future therapies for HCV. Although understanding its mechanisms remains an area of active research, it is believed that ribavirin integrates into the HCV genome to generate mutations and reduces the overall infectivity of the virus. Ribavirin is known to stimulate IFN responsive genes in HCV patients, but has little to no effect on viral load when administered as a monotherapy. The potential stabilization and facilitation of the action of endogenously produced IFN via MMP inhibition, in concert with ribavirin driven up-regulation of interferon stimulated genes, may yield a potent antiviral response. Therefore, the clinical impact of the combined activities of CTS-1027 and ribavirin, neither of which alone significantly affects viral replication, is likely to occur during the second, slower phase of the clinical response. Trial CTS-1027-03 was designed to test whether CTS-1027 alone or in combination with ribavirin (also a second phase blocker) has an antiviral effect in interferon naïve patients with 24 weeks of treatment.
This study began in June 2009. Patients were randomized to receive 15 mg CTS-1027 BID + placebo, or 15 mg CTS-1027 BID + ribavirin for 24 weeks (30 patients per arm). While the primary endpoint was measurement of serum HCV RNA (viral load), CTS-1027, alone or in combination with ribavirin, was also evaluated for its potential anti-fibrogenic effects (normalization of aminotransferase enzymes).
Topline data from this trial show improvement in key markers for liver damage in both arms, coupled with significant reductions in HCV viral load over the course of the 24 weeks in patients treated with CTS-1027 plus ribavirin. These data support the potential use of CTS-1027 in combination with ribavirin as a long term anti-fibrotic therapy to treat liver damage in this patient population and set the stage for inclusion of CTS-1027 in future all-oral cocktails containing Direct Antiviral Agents (DAAs). Final data analysis from this trial is expected to be completed later this year.
CTS-1027 with IFN + Ribavirin (Clinical Trial CTS-1027-04)
Collective clinical experience in the treatment of patients with chronic HCV has demonstrated that patients who fail to achieve a 2 log reduction at 12 weeks have an especially low likelihood of achieving an SVR. A significant subset of treatment failure patients fall into this category. These patients, classified as “null” responders in the figure below, have few treatment options.
Graph of responses to SOC treatment with table showing success rate of retreatment of the null responder population.
The preclinical experiments in the replicon assay showing a synergistic effect of CTS-1027 with interferon, taken together with patient data from Trials CTS-1027-01 and -03, suggest that CTS-1027 might enhance the response to endogenous or exogenous interferon. In Trial CTS-1027-04, initiated in January 2010, Conatus is studying the effects of CTS-1027 in combination with SOC in patients who are null responders (patients who fail to achieve a 2 log reduction at 12 weeks) to SOC. It is a single-arm pilot study in 60 patients, using historical controls (described in the table below), and is designed to explore the interferon amplifying activity of CTS-1027. Viral load after 4, 12 and 24 weeks of dosing CTS-1027 (15 mg BID) combined with SOC will be compared to historical response to repeat SOC therapy. Patients with reductions in HCV RNA of at least 2 log units at week 24 will continue treatment for an additional 24 weeks with additional follow-up to determine SVR. IL-28B screening data will be obtained at week 24, which will allow determination of potential differences in responses to CTS-1027 + SOC due to polymorphisms at this locus.
SOC null responder retreatment (data adapted from Rustgi et al. Hepatology 2009; 50: 1719).
|SOC Historical Responses||0%||5%
HCV RNA below quantifiable limit for RVR, cEVR, CVR, EOT and SVR
HCV RNA > 2 logs reduced for EVR
Given it is likely that one or more protease or polymerase inhibitors (DAA) will become part of SOC in the near future, it is possible that Phase 3 trials in combination with this new SOC may be necessary. It is important to note that null responder patients are not necessarily good candidates for DAA therapy, as recent data from trials with telaprevir have shown that a significant proportion of these patients have viral breakthrough or relapse during triple therapy. If the CTS-1027-04 data show a significant antiviral effect of SOC plus CTS-1027 in the null responder population, CTS-1027 may be a useful addition to the soon to be approved triple therapies of SOC plus DAAs.