Since the advent of integrase inhibitors, bringing about our latest highly effective combination therapy, with viral suppression rates approaching 97%+, many clinicians have questioned a place for new antiretrovirals. How do we get much better? Will there be any compelling reasons to switch our patients to newer agents? In addition, studies such as SWORD have shown simplification strategies can be highly effective, using exisiting drugs, without the need for a third agent. Studies examining cabotegravir, a long-acting integrate inhibitor which can be given as a depot injection, have now entered phase 3 clinical trials, which may possibly negate the need for daily oral treatment. So what does this mean for future drugs? How will they find their niche in what is becoming a rather crowded market? I think given the aforementioned advances, new drugs will need to be highly effective, have high genetic barriers to resistance, thus possibly lending themselves to either dual or monotherapy. Additionally, long-acting drugs which may be able to be given less frequently (through depot or implant), may have an important role in the future of ART. Finally, drugs with novels modes of action, may have a continued role in treatment experienced patients with resistant virus.
This presentation from Gilead Sciences (abstract below) introduced a novel first-in-class capsid inhibitor which leads to a defective HIV-1 virion through interference in the capsid core assembly. In-vitro assays have revealed CS-CA1 to be a highly potent drug with no measurable toxicity in target and non-target cells. The drug binds to a largely conserved region on the capsid protein. In addition, the drug appears to have activity blocking some of the post-entry capsid functions. Pharmacokinetic studies in rats have demonstrated sustained plasma concentrations and the drugs limited aqueous solubility make a drug possibly well suited to long-acting depot administration.
I feel that this novel drug offers exciting promise, especially if the in-vitro activity translates to highly effective antiviral activity in-vivo - possibly leading to a long-acting drug lending itself to simplified depot administration.
DISCOVERY OF NOVEL POTENT HIV CAPSID INHIBITORS WITH LONG-ACTING POTENTIAL
Winston C Tse, John O. Link, Andrew Mulato, Anita Niedziela-Majka, William Rowe, John R. Somoza, Armando G. Villasenor, Stephen R. Yant, Jennifer R. Zhang, Jim Zheng
Gilead Scis, Inc, Foster City, CA, USA
Background: While HIV capsid (CA) plays an essential role in multiple stages of the viral life cycle, it remains an unexplored target for antiretroviral (ARV) therapy. Here, we report the discovery of a novel class of exquisitely potent and metabolically stable HIV capsid inhibitors (CAIs) that exhibit pharmacokinetic (PK) profiles suitable for slow-release parenteral administration.
Methods: In vitro CA binding and assembly assays, together with X-ray co-crystal structures of CAIs with cross-linked CA hexamers, were used to optimize compounds for
high binding affinity to CA. Medicinal chemistry approaches were employed to optimize the antiretroviral activity and drug-like properties using a cytopathic antiviral assay in conjunction with extensive metabolism and pharmacokinetic profiling. CAI resistance-associated mutations were identified by in vitro resistance selections. CAI mode-of-action was defined by inhibitor time-of-addition, virion electron microscopy and viral DNA quantification.
Results: GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in T cell lines (EC50 = 0.24 nM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades in human PBMCs. Identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a CA hexamer and accelerate CA assembly in vitro. The identified CAIs maintain full activity against HIV-1 mutants resistant to licensed ARVs and select for HIV CA variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry CA functions. GS-CA1 shows high in vitro metabolic stability and favorable PK profiles in multiple preclinical species with low systemic drug clearances (0.08–0.33 L/ hr/kg) and long half-lives (7.2–18.7 hr). Low aqueous solubility provides for an extended-release preclinical PK profile following subcutaneous administration of a solid depot formulation.
Conclusion: We have identified novel HIV-1 capsid inhibitors with uniquely potent antiviral activity and a favorable resistance profile orthogonal to existing ARVs. The high metabolic stability and low aqueous solubility of this new inhibitor class should enable the development of an extended-release parenteral formulation with the potential to be used as a novel long-acting antiretroviral treatment.