In most therapeutic areas, it would be difficult to replicate the advances made in the treatment of chronic hepatitis C (CHC) over the last 10 years. Response rate increases have outpaced most stock market returns as overall sustained viral response (SVR) rates have increased from 5%-10% for standard interferon monotherapy to 50%-55% for pegylated interferon and ribavirin combination regimens.1 However, a clearer understanding of the mechanisms of hepatitis C virus (HCV) replication, technical advances in in vitro replication assays and targeted “designer drug” production all offer the hope of even more significant increases in response rates over the next decade. Solid translational research in this area has resulted in current drug development programs for several exciting molecular entities for the treatment of CHC. These entities generally target enzymes involved in HCV replication, for example, HCV polymerase or protease inhibitors, or are immunomodulators aimed at stimulating preferential HCV immune responses. All of these new molecular entities appear to be based on strong scientific platforms built with robust preclinical investigations.2 In this issue of HEPATOLOGY, McHutchinson and colleagues report on one such new molecular entity, CPG 10101 (Actilon) from Coley Pharmaceutical Group Inc., Wellesley, MA, the first of a new class of immunomodulatory drugs arising as a result of expanding scientific knowledge of the importance of B cell and plasmacytoid dendritic cell (pDC) Toll-like receptor 9 (TLR9) stimulation as a mechanism of HCV antiviral effect.3 The sound scientific rationale for CPG 10101, a “naked DNA” synthetic oligodeoxynucleotide, is that TLR9 stimulation on B cells and pDCs results in activated antiviral cytokine production, including alpha interferon, in addition to selected T cell activation favoring an adaptive immune response.3
In the reported placebo-controlled phase 1b study, patients with CHC, both naïve and treatment experienced, were treated with placebo or 1 of 7 varying dose or dosing frequency regimens of CPG 10101 for 4 weeks. As expected, dose-dependent cytokine induction was observed in the subjects receiving CPG 10101, including significant increases in interferon alpha levels. Fortunately, the investigators also observed a clinically significant ≥1 log10 dose-dependent decrease in HCV-RNA in 22 of 40 subjects receiving ≥ 1 mg of CPG 10101; the overall HCV-RNA response for CPG 10101 appeared to be similar for that previously reported for pegylated interferon monotherapy. CPG 10101 was well tolerated, and the observed adverse event profile comported with the predicted mechanism of action for TLR9 stimulation and the profile observed with interferon alpha therapy. The authors conclude their Abstract of the study by suggesting “the data support further clinical studies of CPG 10101 for treating chronic HCV infection”. However, in the last paragraph of the Discussion, we are told that further development of CPG 10101 has been temporarily suspended. Although the unusual diversity regarding prior therapy of the subjects (running the gamut from treatment naïve, relapsers, nonresponders, or previous treatment intolerant patients) and the mixed HCV genotypes enrolled might raise some concerns with the clinical trial purists among us, these minor details do not seem sufficient to make us pause. Good results with acceptable tolerability, both predicted by strong science, and no further development; what gives? Good science in HCV antiviral drug development seems necessary but clearly not sufficient. Accordingly, we must turn to look at factors other than translational science involved in shaping decisions to undertake further drug development.
CPG 10101 is the not the only new molecular entity for HCV treatment to see its development suspended. Another toll-like receptor agonist drug was withdrawn from further development after the start of clinical trials when ongoing preclinical toxicology studies raised safety concerns.4 More recently, 2 other exciting and initially promising compounds were withdrawn or suspended from further study; for both these entities, however, it was a result of early clinical safety signals and modest antiviral effects suggesting that the risk versus benefits for the treatment of CHC were unacceptable. NM283, an HCV polymerase inhibitor, was noted to be associated with unacceptable gastrointestinal side-effects when used at higher doses.5 More worrisome, administration of HCV-796, another initially promising NS5B polymerase inhibitor, was noted to be associated with possible hepatic toxicity.6 In both these cases, it appears that there were no safety signals identified in preclinical and very early clinical investigations, reminding us that even good (or excellent) science has very real limitations when it comes to drug safety. Even today's excellent science cannot totally overcome the inherent unpredictability of the human response to new molecular entities.
In the absence of a reported early safety signal, such as appears to be the case for CPG 10101, what other factors could influence a decision to suspend, either permanently or temporarily, further drug development? Certainly, the current regulatory environment for HCV drug development is one consideration. Spurred by an overall philosophy of heightened vigilance for safety during the drug development process and the increasing number of molecular or biological entities being developed for the treatment of HCV—more than 30 by a conservative count—the U.S. Food and Drug Administration (FDA) convened a special meeting of the Antiviral Drug Advisory Committee in fall 2006 to provide guidance to sponsors developing therapies for CHC.7 Although several aspects of HCV drug development were discussed, the agency was clear in suggesting that it favored an add-on approach where pivotal drug registration trials for initial approval of an agent should be designed to demonstrate that adding your agent to current standard of care (SOC) with pegylated interferon and ribavirin is associated with increased SVR and an acceptable adverse event profile where benefit exceeds risk. If your agent is meant from the beginning to be a substitute for one of the components of SOC, regulatory agencies would probably allow noninferiority studies with a SOC comparison design. Is this where CPG 10101 would fit in? Would it be best to develop the drug as a substitute for pegylated interferon (which the underlying science would seem to dictate) or as additive therapy to SOC? The regulatory implications of this decision are clear and major. With the increased SVR associated with current SOC therapy approaching 50% overall, these paradigms of HCV drug development considerably increase the complexity (and costs) of even early trial design whether you have add-on or SOC component substitution therapy. The result has been increasingly complicated multiarm trial designs almost exclusively focusing on genotype 1 patients with high viral loads. Add in (or on) the likelihood that at least one small-molecule viral enzyme inhibitor will be approved for add-on therapy to SOC during the CPG 10101 approval process, and the clear indication that the HCV therapeutic area is heading to multidrug therapy regimens similar to current HIV therapy, it is easy to appreciate a decision to temporarily suspend drug development for an entity like CPG 10101 as a rational one.
Beyond regulatory considerations, basic pharmaceutical economics influence development decisions for HCV antiviral drugs, as is the case for other drugs and biologics. These are in part related to regulatory factors. In the case of HCV drug development, these include the costs of doing the complex multiarm studies noted above and studies requiring 48-week treatment periods with 24 weeks of follow-up as a result of drug approval agencies rejecting, perhaps appropriately, drug approvals based on markers of on-treatment early viral response or shortened periods of posttreatment follow-up to determine SVR. Decisions made at various stages along the development pathway, some of which are at so-called “full development decision points”, require decisions which could cost the sponsor $200 million to $400 million of irretrievable development costs. The costs of fully developing an HCV drug today through the approval and launch process is estimated to be approximately $800 million to $1 billion (Fig. 1).8 Considering manufacturing costs, intellectual property analyses of patent life, patent protection, and generics threats, marketing costs, the competitive landscape, and the entire life-cycle of a new molecular entity, most sponsors must develop models of return on investment that justify drug development. For HCV drug development, the competitive landscape is increasingly becoming crowded, and whereas “HIV-like” multidrug regimens will allow room in the market for multiple agents, product sponsors must consider the costs and challenges of competing against similar products if differentiation based on efficacy and tolerability is absent. If CPG 10101 was developed as an interferon substitute, in the absence of increased efficacy or improved tolerability (the latter an attribute very difficult to demonstrate in registration trials and hence promote), it would come undifferentiated into a competitive environment against the now firmly entrenched pegylated interferon products or other interferon agents, such as albuferon, well ahead in the development process.9 The study reported by McHutchinson and colleagues does not suggest an increased efficacy of CPG 10101 sufficient to allay these competition concerns. Unless a sponsor is unencumbered by a need to show a return on investment, using either dollars or goodwill, in the current scheme of pharmaceutical economics, even excellent science cannot overcome adverse basic market forces.
When safety, efficacy, regulatory, and economic considerations are rolled up into the HCV drug development decision-making process and the dust settles on the underlying translational scientific platform, it is estimated that less than 1 of 5 drugs reaching a successful phase 2 development point will progress to full development with approval and launch This estimate is based on the historical perspective for HIV drug development and overall industry trends.8 Although the majority of development failures appear to be largely related to efficacy failure and safety concerns, these concerns are intimately entwined with regulatory and economic considerations. The CPG 10101 saga is an example of even when there are apparently no safety or efficacy concerns, further drug development may be sidelined by other considerations. CPG 10101 is the not the first and certainly will not be the last promising new agent for HCV therapy withdrawn from development despite strong scientific evidence and rationale supporting further clinical studies. It appears that perhaps particularly for HCV drug development, good science is necessary to get you on the team and in the stadium, but it is not sufficient to guarantee you'll be in the game. To paraphrase the Bard, CPG 10101, we hardly knew ye.