Cabotegravir, A Paradigm Shifting HIV Drug

Since the 1980s, the AIDS epidemic has claimed more than 33 million lives as a consequence of human immunodeficiency virus (HIV) infection. With the advent of pre-, and post-exposure prophylaxis and highly active antiretroviral therapies (HAARTs), however, AIDS diagnoses have morphed from a death sentence into a chronic condition. Extensive research has enabled the development of a plethora of drugs targeting multiple aspects of HIV infection, however, poor medication adherence, drug-resistance, and long-term safety concerns converge to an unmet clinical need. Amongst recent approaches to meet this need is GlaxoSmithKline's flagship HIV-medicine Cabotegravir, which is currently in Phase-III development, trialing its
use in HIV prevention and treatment. The subject of this article is to pharmacologically characterize Cabotegravir and, particularly, to focus on identifying and exploring physicochemical, pharmacodynamic, and pharmacokinetic properties conferring the increment in therapeutic value provided by this novel drug, manifesting in improved resistance-profiles,
efficacy, treatment regimen, and safety.

Pathogenesis and therapies
HIV evokes immunopathogenesis by specific infection of CD4-positive T-Cells, dendritic cells, and macrophages culminating in the progressive failure of the immune system and compromised defense from opportunistic infections and cancers(1). The HIV-genome encodes for structural, accessory, and gene-regulatory proteins and enzymes required for virion development, such as reverse-transcriptases, ribonucleases, proteases, and integrases. These
are, inter alia, targets of standard-of-care HIV medication (Fig.1). Integrases are targeted by Cabotegravir, classifying it as an integrase strand-transfer inhibitor (INSTI). Integrases are a sensible target for antiretroviral therapy as integrase-inhibition historically displayed a more rapid decrease in viral load, and more importantly, the idiosyncratic dynamics of the HIV- lifecycle offer a longer window for effective intervention compared to other HIV chemoprophylactic agents(9,10)

Figure 1: HIV lifecycle and sites of main therapeutic intervention. CCR5 and CXCR4 inhibitors (e.g. Leronimab, Aplaviroc) inhibit viral entry of CCR5-tropic and CXCR4-tropic HIV-strains by allosteric antagonism of these cell-surface receptors (GPCRs). (2) (1). Fusion inhibitors (e.g. Enfuvirtide/T-20) prevent viral fusion by biomimicry and consequent displacement of viral fusion peptides(3) (2). Reverse transcription of viral single-stranded RNA is hindered by nucleoside reverse transcriptase inhibitors (NRTIs), synthetic analogs of deoxynucleotides (e.g. Zidovudine), that act as chain terminators effectively stopping DNA polymerization by competitive substrate inhibition(4) (3). Non-nucleotide reverse transcriptase inhibitors (e.g. rilpivirine) bind directly and non-competitively to viral reverse transcriptase, more specifically, to the
p66 subunit in the hydrophobic pocket, inducing a deactivating conformational change in the distinct but closely associated active site of the enzyme(5) (3). Integrase strand transfer inhibitors, such as Cabotegravir, inhibit the integration of viral DNA through competitive binding and chelation of metal ions in the HIV-integrase active site(6) (4). Protease inhibitors (e.g. saquinavir) prevent viral maturation by blocking the active site of the homodimeric aspartyl HIV-protease impairing the activating cleavage of virally encoded polyprotein precursors(7) (9). These medications are often co-prescribed and complemented with boosters such as CYP-inhibitors (e.g.ritonavir and cobicistat). Lastly, drugs targeting new HIV-infection processes are currently emerging such as Gilead and Merck’s Lenacapavir, a first-in-class capsid inhibitor(8). It is being evaluated as a twice-yearly injectable HIV-prophylaxis agent and may, therefore, eclipse the increment in therapeutic value provided by Cabotegravir. This figure was created with

The target
The HIV-integrase, derived from the C-terminal portion of the Pol-gene product, is a key mediator in the non-specific insertion of virally-derived DNA into the host genome, which is imperative to the orderly progression through the viral lifecycle. Following reverse- transcription of retroviral RNA to cDNA, the cDNA, viral enzymes, cellular co-factors like LEDGF/p75, viral protein-R, matrix, and the nucleocapsid associate to a nucleoprotein pre-integration complex (HIV-intasome) which mediates the integration of the viral genome into the host DNA(11,12) (Fig.2). While both 3’-processing and strand transfer are catalyzed by the HIV-integrase in a single step in the presence of divalent metal-ions (Mg2+), the final processing of the integration intermediate, such as removal of the viral 5’-overhang and ligation, is completed by cellular enzymes. By virtue of its complex structure, several further aspects of integrase activity may be manipulated pharmacologically; cDNA-binding and 3’-processing experience low-potency inhibition by INSTIs causing the integrase to disengage from the 3’-deoxyadenosine(16). Integrase oligomerization can be hindered by shifting its oligomerization equilibrium through activity-modulating ligands binding to integrases’ inactive oligomeric state(17). Protein-interactions with important cellular co-factors may be
disrupted by small molecule inhibitors of, for example LEDGF/p75-Integrase interaction, identifiable with high-throughput screening and computational design(18,19,20,21). LEDGF/p75, viral protein-R, matrix and the nucleocapsid associate to a nucleoprotein pre-integration complex (HIV-intasome) which mediates the integration of the viral genome into the host DNA(11,12) (Fig.2). While both 3’-processing and strand-transfer are catalyzed by theHIV-integrase in a single step in the presence of divalent metal-ions (Mg2+), the final processing of the integration intermediate, such as removal of the viral 5’-overhang and ligation, is completed by cellular enzymes. By virtue of its complex structure, several further aspects of integrase activity may be manipulated pharmacologically; cDNA-binding and 3’-processing experience low-potency inhibition by INSTIs causing the integrase to disengage from the 3’-deoxyadenosine(16). Integrase oligomerization can be hindered by shifting its oligomerization equilibrium through activity-modulating ligands binding to integrases’
inactive oligomeric state(17). Protein interactions with important cellular co-factors may be disrupted by small molecule inhibitors of, for example, LEDGF/p75-Integrase interaction, identifiable with high-throughput screening and computational design(18,19,20,21).

Figure 2: Mechanism of viral DNA integration. Integration of viral DNA (A) is initiated by integrase-mediated 3’-cleavage of the terminal dinucleotide in the viral DNA (referred to as 3’-processing) exposing invariant CA-3’ recessed termini (B) whose hydroxyl-group, after nuclear translocation, attack phosphodiester bonds in the target DNA (C.). Biochemical assays with chiral phosphothioates in the target DNA demonstrate that the integrase-catalyzed covalent linkage of viral and target DNA (D) is driven by an one-step isoenergetic transesterification(13). This can be concluded, as the SN2-like nucleophilic attack on the target DNA results in inversed phosphorothioate
chirality in the integration product which is characteristic to one-step mechanistic models of phosphoryl transfer reactions(14), whereas the
phosphorothioate stereo-configuration in the integration-product would be retained in two-step bond-formation through a covalent enzyme-DNA
intermediate, as seen in enzymatic DNA recombination. In this case, the resolution of the enzyme-DNA intermediate would re-invert chirality to the initial status(15). The figure is taken from source (13).

Structure-activity relationship
Atom-level resolution imaging and crystallographic studies of the HIV-integrase catalytic core revealed a metal-ion holding catalytic triad of acidic amino-acid residues (D64-D116-E152).The dependence of the catalytic activity on carboxylate-sidechain bound Mg2+ in the active site makes it an attractive target for pharmacological intervention. Therefore, developing drugs with metal-chelating scaffolds has dominated INSTI-design. The identification of several diketo-acid derivatives and quinolone-based motifs, which proved to be potent chelators of catalytically indispensable Mg2+-ions led to the development of first-generation INSTIs, such as Raltegravir (RAL) and Elvitegravir (EVG). The rapid emergence of resistance to first-generation INSTIs due to mutations in the integrase catalytic domain created the need for second-generation INSTIs, which was met by the development of Dolutegravir, Bictegravir and Cabotegravir. Cabotegravir is a structural analogue of dolutegravir and while, like first-generation INSTIs, its key inhibitory mechanism of HIV-integrase activity is based on a two-metal-chelation pharmacophore model, its chelating-scaffold is characterized by a tricyclic series of carbomoyl pyridines with an intrinsic hemiaminal ring fusion stereocenter (Fig.3). Cabotegravir’s halobenzene ring facilitates the penetration into the integrase’s hydrophobic active-site allowing a more stable interaction and, thus, low-level dissociation(26), while simultaneously, but with lower potency(27), displacing the 3’-end of the viral DNA from the
active site(28), both of which contribute to Cabotegravir’s high efficacy(29,30). Importantly, the absence of an oxadiazole-ring conferring dependency on an active-site tyrosine residue (Y143), as seen in Raltegravir, the presence of a carbonyl on the C5-carboxamide and the hydroxyl-
substitution on the tricyclic scaffold confer structural flexibility allowing cabotegravir to “react” to resistance-mutations in the active-site with subtle structural rearrangements(29).

Figure 3: 2D and 3D-representation of Cabotegravir/GSK1265744
The inhibitory mechanism arises from the interaction of the two Mg2+ ions in the core catalytic domain of the HIV-integrase and Cabotegravir’s acid moieties, which functionally sequestrate the catalytically important Mg2+ions of the integrase by permitting ion bonding through provision of lone-pairs of oxygen heteroatoms which are arranged in a coplanar fashion(22,23). Cabotegravir has a more rigid, 5-membered ring in its tricyclic chelating scaffold, whereas there are 6 carbon atoms in the last ring of Dolutegravir’s polycyclic scaffold. The
hydrophobic, enzyme-binding region, which is characterized by a difluorophenyl moiety, is identical in dolutegravir and cabotegravir but distinct from Bictegravir, another structural derivative of Dolutegravir currently in late-stage clinical trials, which has a trifluorophenyl moiety in that place and a larger molecular structure overall(24). Cabotegravir, with the chemical formula of C19H17F2N3O5, is a canonicalized compound with a molecular mass of 405.11 g/mol and topological surface area of 100.87 Å2, 2 hydrogen-bond donors, 5
hydrogen-bond acceptors, 4 rotatable bonds and a complexity rating of 814, as determined with the Bertz/Hendrickson/Ihlenfeldt formula. While cabotegravir has 2 atom stereocenters, there is no evidence of in-vivo epimerisation to one of cabotegravir’s stereoisomer during metabolism (25). These structural features, as well as the ones outlined in the main text, are the foundation of Cabotegravir’s advantageous physicochemical, pharmacodynamic and pharmacokinetic properties contributing to Cabotegravir’s therapeutic superiority. Source:
IUPHAR and with own annotation.

The high genetic barrier to mutations emanating from second-generation INSTIs’ structural features is considered one of their most significant advantage over first-generation INSTIs and other HAARTs (Fig.1)(31), as numerous HIV-strains have emerged with wide resistant profiles against NRTIs, NNRTIs, PIs and earlier INSTIs like RAL and EVG(32,33). In-vitro studies showed that Cabotegravir had the same efficacy against NNRTI-, NRTI- and PI-resistant viruses as against wild-type viruses(34). It maintained efficacy against most first-generation INSTI-resistant mutants(35) and there was no evidence of Cabotegravir-resistant viruses in clinical trials(34,36,37,38), unless participants had primary resistance against EVG or RAL in which case multimutated viruses displayed resistance to Cabotegravir and virological failure was observed(39). Compared to Dolutegravir, however, Cabotegravir maintained efficacy against a narrower range of resistance mutations, and Bictegravir had the best antiviral resistance profile of all second-generation INSTIs(40).

Treatment regimen
Another limitation of first-generation INSTIs and standard-of-care combination antiretroviral therapies (e.g.Raltegravir/Emtricitabine/Tenofovir) is the burdensome daily-dose regimen which may lead to reduced compliance and poor adherence and consequently curtail the drug’s effectiveness. Cabotegravir, however, is investigated as a daily oral tablet and long-lasting parenteral injection in monthly to quarterly intervals, both for the treatment and pre-exposure
prophylaxis of HIV infection and clinical outcomes may, thus, improve as patient do not need to adhere to a daily-dose regimen(41). This is mediated by Cabotegravir’s strikingly long half- life of up to 50 days after intramuscular/subcutaneous injection of the long-acting nanosuspension, which is due to absorption-limited flip-flop pharmacokinetics(42) and about
38.8 hours following oral dosing (43), after which absorption occurs immediately without apparent lag(44). This is almost 3-fold longer than the half-life of its analogue dolutegravir of around 13 hours(45). Studies of tail-phase pharmacokinetics of long-acting cabotegravir (ECLAIR&HPTN077-trials) showed that it remained detectable in the plasma for up to 76
weeks after treatment-termination(46). The persistence of subtherapeutic Cabotegravir-levels or up to over a year after treatment-termination underscores the necessity of adequate adherence and the need of replacement-antiretroviral treatment post-discontinuation to prevent
the emergence of Cabotegravir-resistant HIV-strains(47).

Potency, efficacy
Cabotegravir’s benefits regarding drug-regimen and resistance-barrier are complemented by superior potency and efficacy compared to standards-of-care (2NRTIs + 1PI/NNRTI/INSTI) which became apparent as preclinical evidence(48) indicated integrase-inhibition with a nanomolar to subnanomolar EC50 and proof-of-concept oral monotherapy trials (phase-I/IIa) revealed a potent suppression of HIV-RNA by, on average, 2.2 to 2.3 log10 copies/mL(44) with the maximum effect (Emax) amounting to a reduction of 2.56log10 copies/ml(49). Similar results were found for bictegravir and dolutegravir(50,51,52). Despite the 408-fold change in potency observed after adjustment for serum-protein binding, confirming that Cabotegravir is highly protein-bound, trough concentrations (Cτ) surpassing the protein-adjusted IC90 by up to 20-fold were achieved with very low oral doses (5–30mg) corroborating its highly potent viral suppression(44). This was accentuated in the HPTN083 non-inferiority trial (Phase-IIb), which was terminated three years early because interim analyses showed that the efficacy of long-acting Cabotegravir in preventing HIV-infection was 66% higher compared to established daily oral pre-exposure prophylaxis (Emtricitabine/tenofovir disoproxil)(53). Following replacement
of standard-of-care HAARTs with a combination of long-acting Cabotegravir and Rilpivirine (CAB+RPV LA), viral suppression was higher than the EMA-predefined non-inferiority margin(54). The coadministration of Cabotegravir and Rilpivirine is indicated to prevent viral growth through two independent mechanisms and to ensure that HIV-infected patients with no
detectable viral load do not experience viral breakthroughs(25). Similar results regarding efficacy were found in trials with treatment-naïve patients(55), providing empirical support for the superior efficacy of Cabotegravir for HIV-treatment. Its efficacy in a bi-monthly treatment-
regimen is currently under investigation(56).

Specificity, selectivity
The superior efficacy is accompanied by a considerable degree of selectivity as no cellular equivalent of the HIV-1 integrase is known(57) allowing INSTIs like cabotegravir to exert an effect specifically as reflected by the marginal side-effects(25). In-vitro selectivity-assays demonstrated, that Cabotegravir only significantly inhibited the melanocortin-4 receptors, however, at a concentration 100-fold higher than the maximum clinical concentration(57). This is one of INSTI’s most prominent advantages over other, more promiscuous, HAARTs such as protease-inhibitors or NNRTIs, which are notorious for off-target effects(58,59).

Advantageous selectivity and specificity are core pillars of safety and long-term tolerability. Pre-clinical toxicology assessments revealed no single-dose or repeated-dose toxicity, no genotoxicity or carcinogenicity and no embryofoetal toxicity(60). Cabotegravir stands out with
a selectivity/therapeutic index (SI) of more than 22,000 in-vitro, compared to a SI of around 4.76 of Ritonavir (Potease-inhibitor)(61), which, considering the subnanomolar-range EC50, indicates an advantageously high 50% cytotoxic concentration. This suggests a considerable therapeutic window between cytotoxic and antiviral activity, allowing Cabotegravir to exerts
its antiviral activity at concentrations well below its cytotoxic concentration. A battery of safety clinical studies confirmed long-term tolerability and safety as no clinically worrisome trends were found regarding cardiovascular parameters, vital signs and laboratory values(60). However, safety data from pooled phase-III trials of the CAB+RPV LA formulation indicated
potential adverse effects including gastrointestinal, nervous system and psychiatric disorders. The most common side effects were transient injection-site related myalgia and pyrexia as expected given the high-volume intramuscular/subcutaneous injection(60). Further risks include
hepatotoxicity, as shown by elevated liver enzymes(62), laboratory abnormalities such as elevations in bilirubin, creatinine kinase and lipases(63) and medical errors, which is why a comprehensive pharmacovigilance plan is necessary.

It is important to specifically mention metabolism as it is a key component of Cabotegravir’s therapeutic superiority and contributes to its favorable safety profile. Contrasting with earlier INSTIS (EVG, RAL), Cabotegravir does not need to be boosted with isoenzyme (CYP4503A4)-inhibitors like Cobicistat and Ritonavir(64) which may increase levels of concomitantly utilized drugs and which have been associated with negative long-term effects(65), because it is primarily metabolized by the uridine diphosphate glucuronosyltransferase-1A1, thus, not interfering with CYP-mediated metabolic pathways(66,67). This explains its low propensity for drug-drug interactions, which also applies to combination with other HAARTs, as no antagonism or enhanced toxicity was found whenco-administered(67,68). Instead, Cabotegravir is particularly synergistic with lamivudine, emtricitabine, rilpivirine and tenofovir(68,69). Importantly, none of its metabolites (glucose-conjugates, cabotegravir-glucoronide) are pharmacologically active(25). These metabolites and unchanged cabotegravir are mainly excreted with faeces, but are also detectable in the bile
suggesting enterohepatic recirculation, which is likely to contribute to Cabotegrabvir’s long half-life(66,70). While UGT1A1-polymorphisms may affect Cabotegravir exposure(71), accumulated safety-information indicates that the resulting 1.3 to 1.5-fold increase in maximum serum-concentration (Cmax) is not clinically relevant as the LATTE-trials established
Cmax-increases by up to 5.6-fold as safety-margin(25). Therefore, no dose-adjustments are required(71). Its administration, however, is contraindicated with UGT-inducers like Phenobarbital/Carbamazepine/Rifampicin as they reduce Cabotegravir bioavailability with an AUC-depression of up to 59%(72). Despite being a substrate of the P-gp and BCRP efflux-transporters, the lowest reported bioavailability was 44%(25), which, when assuming full inhibition of both transporters ( cyclosporin), relates a maximum possible increase in systemic Cabotegravir exposure of 2.3-fold, according to the Zamek-Gliszinski-relationship of drug-exposure and excretory export-function(73) which is within the safety margin(25). The moderate decrease in bioavailability may be due to Cabotegravir’s relatively high passive permeability(66,74), hence the marginal effect of efflux transporters on its intestinal absorption(67). Therefore, drug-drug interactions with P-gp/BCRP-inhibitors are not expected.

Despite its prophylactic potential and showing, overall, therapeutic superiority on the three levels of comparison; against other HAARTs, earlier INSTIs and same-generation INSTIs, Cabotegravir falls short of a panacea as, like other HAARTs, it does not eradicate the virus and
a cure, thus, remains elusive. However, it is sensible to argue that, due to its favorable pharmacological properties, Cabotegravir, particularly in combination with Rilpivirine, is a promising agent to tackle limitations of traditional standard-of-care in HIV, such as the emergence of drug-resistance, sub-optimal efficacy, long-term toxicity and burdensome drug-
regimens, which is particularly valuable for chronic conditions such as AIDS. The addition of Cabotegravir to our comprehensive anti-HIV armamentarium highlights the importance of basic research and is a testament of the link between extensive study of pathogenesis mechanisms and the resulting therapeutic opportunities.

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Fynn Comerford

Neuroscience at The University of Edinburgh | Founder of edventure | iGEM 2020 | Videographer