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New HIV Agents
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16th CROI 2009 Feb 8-12 Montreal
Joe Eron, MD, University of North Carolina
Antiretrovirals Get a New Boost
Ritonavir as a boosting agent for protease inhibitors has been a mainstay for antiretroviral therapy for many years. Multiple boosted PIs are among the recommend first line agents in both the DHHS and IAS USA guidelines. In treatment experienced patients RTV boosted PI are even more frequently used and are a key component of most salvage regimens. Some protease inhibitors, lopinavir and darunavir are completely dependent on RTV-boosting for activity and cannot be given without it. Other protease inhibitors, such as atazanavir and fos-amprenavir, can be given unboosted but attain substantially higher levels at reduced doses with RTV and are only useful in treatment experienced patients in the boosted form. The integrase inhibitor, elvitegravir, which is in Phase III development, is also dependent on RTV to reach adequate concentrations using a reasonable once daily milligram dose of elvitegravir. Remarkably some of the HCV protease inhibitors that are in development are also boosted by RTV though this writer does not know of any that are tying their development to RTV.
RTV, despite its substantial and relatively selective inhibition of CYP3A, has multiple real and potential drawbacks. RTV is clearly associated with lipid abnormalities and may be tied, in part, to body shape changes though this has not been clearly proven. RTV has associated GI effects and while usually well tolerated at boosting doses in some patients RTV cannot be tolerated, even in small amounts. RTV also does have "off-target" effects such as inhibition of other P450 enzymes and induction of many hepatic enzymes which lead to multiple additional drug-drug interactions.
In addition, while likely not a concern when boosting other PI there is a theoretical concern that if RTV is used to boosted a non-PI ARV like elvitegravir and there is viral load rebound, the low concentrations of RTV could select for PI resistance limiting future treatment options. Currently RTV comes only as a soft gel capsule that must be refrigerated or a barely palatable liquid. Admittedly an NDA for a Maltrex tablet formulation has been submitted to the FDA. Only one PI is co-formulated with RTV, decreasing the convenience, raising the risk of selective non-adherence and increasing insurance co-pays. Finally RTV has no competition and in a semi-competitive market place this gives the manufacturer a substantial advantage when setting price and negotiating other co-formulations.
Clearly, alternatives to RTV that are equally effective boosters would be highly desirable especially if they improved on some of the drawbacks listed above.
GS 9350
Gilead Sciences obviously has incredible motivation to develop an alternative booster to RTV. The Gilead integrase inhibitor, elvitegravir, has to be given with RTV boosting. Elvitegravir has fallen behind in development compared to raltegravir, which is already approved and there has been some reluctance to studying the elvitegravir in treatment naïve patients if it has to be given with low dose RTV. At 16th CROI Brian Kearney from Gilead presented the first human data on their pharmacologic or pharmacokinetic enhancer (PKE) GS 9350[1]. The presentation was remarkably well organized, answering one by one many of the questions one would have about an alternative non-RTV PKE and addressing some of the drawbacks to RTV listed above.
First of all the mechanism of action of GS 9350 appears to be the same as RTV with a similar inactivation constant and affinity for CYP3A. While GS 9350 also has modest inhibitory effects on some other CYP enzymes these effects, in vitro, were less than RTV for most of the other enzymes. In addition 9350 did not induce PXR, in vitro, which is the first step in the induction process for drugs like RTV and rifampicin. Importantly, in vitro studies also showed that this agent had no anti-HIV activity. In HIV negative volunteers the drug demonstrated non-linear pharmacokinetics in a multiple dose study over 14 days with 200 mg once daily having similar PK as RTV 100 mg daily. Kearney demonstrated that GS 9350 was a potent inhibitor of CYP3A in these volunteers by showing a marked decrease in midazolam clearance with GS 9350 similar to the effect seen with ritonavir. Midazolam is a standard probe drug that is metabolized specifically by CYP3A.
Because GS 9350 has good aqueous solubility it has a tablet formulation and it has already been co-formulated with elvitegravir, TDF and FTC. In HIV negative volunteers the PK of 150 mg of elvitegravir in the co-formulated FDC tablet with GS 9350 (150 mg)/TDF/FTC had very similar PK to elvitegravir 150 mg given with 100 mg of RTV. In addition we were told that the "Quad" fixed dose combination was well tolerated and GS 9350 did not significantly raise serum lipids in the 14 day dose-ranging study. Development is being rushed and studies in HIV-infected treatment naïve individuals are being designed with a head-to-head comparison of the FDC QUAD against FDC efavirenz/tenofovir/FTC (Atripla) planned.
SPI 452
Sequoia Pharmaceuticals also presented data on a non-RTV PKE[2]. This drug also does not have anti-HIV activity in vitro and is a potent preferential inhibitor of CYP3A in human liver microsomes. First in human studies demonstrated that SPI 452 had a long half life and the compound had the ability to substantially increase saquinavir concentrations with a single dose of each drug.
In a second study, single doses of the protease inhibitors darunavir or atazanavir or PI placebo were given, followed by washout and then 15 day dosing of one of 3 once daily doses of SPI 452 (50, 100, 200 mg) plus a SPI 452 placebo arm. On days 15 and 16 the protease inhibitors were dosed again. Boosting of either DRV or ATV was substantial and appeared similar to the boosting effect seen with 100 mg of RTV though no RTV control arm was included in the study. The boosting effect lasted even one day after the PKE was stopped (Day 16). SPI 452 appeared to be fairly well tolerated though there were GI side effects recorded and differences with PCB were not displayed. The changes in triglycerides and LDL cholesterol were not significant over 14 days compared to placebo. As yet his compound has not been formulated as a tablet, though formulation work is ongoing.
Both studies give hope that there will be one or more alternatives to RTV for boosting protease inhibitors and/or elvitegravir. We should remind ourselves that these are very early 14-15 day data in HIV uninfected volunteers and longer term studies in HIV infected individuals are needed with careful evaluation of lipid effects, effect on insulin sensitivity and body shape.
Several open questions remain. In the development plan should these agents be given alone to HIV infected patients for a short (7-14 days) or longer periods of time to look for anti-HIV activity in vivo (remember entecavir) and to look at toxicity in the target population isolated from other antiretroviral medications? How important are the effects of RTV on p-glycoprotein on its activity or toxicity? Will long term inhibition of CYP3A4,5 have consequences regardless of whether the inhibition is by RTV or by a non-RTV PKE?
Not so new Agents or has the pipeline slowed to a trickle?
PRO-140 subcutaneous Infusion
PRO-140 is a humanized monoclonal antibody to human CCR5 that has previously been shown with single dose IV infusions to lower HIV RNA substantially in patients who have R5 virus by the standard tropism assay.[3] The highest dose decreased plasma HIV RNA by a mean of 1.83 log10 copies/mL and was generally well tolerated. However IV infusion would be cumbersome and more feasible means of administration are being explored. At 16th CROI Melanie Thompson presented new data with PRO 140 administered for up to 3 doses by subcutaneous infusion (that's right infusion, not injection)[4]. Three dosing schemes were tried 1) 162 mg SQ weekly on day 1, 8 and 15, 2) 324 mg SQ on day 1 and 15 and 3) 324 mg SQ weekly on day 1, 8 and 15 and an arm with weekly placebo infusions. The highest dose given weekly produced a mean peak reduction in VL of 1.65 log10 and an antiretroviral effect of a mean 1 log10 decrease persisted for 2 weeks following the last infusion. Side effects were minimal with short lived infusion site reactions in a minority of patients. The investigators hope that given the long half-life of this humanized monoclonal that perhaps an initial loading dose would allow for a twice weekly infusion dosing regimen.
Realistically though PRO-140 will still have at least 2 disadvantages. Firstly it is still a CCR5 inhibitor and therefore will only be useful in about 50% of patients who are highly treatment experienced and its mode of administration might restrict its use to this group, i.e. advanced patients. Secondly the patients will still need to have an assay result to show if they indeed have R5 virus. An oral R5 inhibitor has already been approved in the US and the uptake of maraviroc has been slow. It seems somewhat unlikely that an agent requiring sub-Q infusions, even if every other week, will be used more commonly than a similarly effective pill that has a fairly extensive safety profile that will have expanded by the time PRO 140 reaches the final stages of development. SQ infusion could be useful in some situations and if an every other week regimen could be constructed I think it could be applied successfully. PRO-140 is likely to have activity against virus that remain R5 but have become resistant to maraviroc and vicriviroc. Again most individuals who do fail these oral R5 inhibitors do so with X4 using virus but there may be some that fail with an R5 virus that would benefit from PRO 140.
Where are the Maturation Inhibitors?
HIV-1 maturation inhibitors were going to be the next new agents that worked by a novel mechanism. These agents bind to the gag protein and prevent proteolytic cleavage of the gag poly-protein in a mechanism distinct from protease inhibitors. Bevirimat, which is the first agent in this class, has been in Phase IIa development (short term studies to demonstrate proof of principle and obtain initial dose ranging information)[5]. However recent data suggest that a substantial subset of subtype B variants and perhaps the majority of subtype C variants have intrinsic resistance to bevirimat based on gag polymorphisms around the bevirimat binding site[6]. Panacos stopped development of Bevirimat and this agent was picked up by Myriad Pharmaceuticals who plan to continue development. There were no new data on bevirimat at CROI but Myriad did have some preliminary data on other maturation inhibitors. Their inhibitor that is farthest along, MPC-9055, also bind to gag poly-protein at the capsid-SP1 cleavage site. This agent is active in vitro at nanomolar concentrations[7] and had activity across multiple HIV-1 sub-types including sub-type C (2 variants), which may indicate that this drug will be active against variants with gag polymorphism that reduced bevirimat activity, though such variants were not directly tested. A single point mutation at codon 364 (which is at the cleavage site) results in resistance and this mutation was selected for in vitro. This mutation also conferred resistance to bevirimat[8]. A single dose study in HIV uninfected volunteers demonstrated that it was orally bioavailable with a long half life[9]. There appeared to be some mild GI side effects with this single dose. How the concentrations achieved related to the inhibitory concentrations for the virus were not clearly defined. In summary development of maturation inhibitors continues to move forward but given development time lines it will be several years before these agents reach late stage clinical development if indeed they can pass the phase IIB hurdle of activity and safety with dosing greater than 7-14 days.
References:
1. Mathias A, Lee M, Callebaut C, Xu L, Tsai L, Murray B, Liu H, Yale K, Warren D, Kearney B. GS-9350: A Pharmaco-enhancer without Anti-HIV Activity. 16th Conference on Retroviruses and Opportunistic Infections. Montreal 2009 Abstract 40.
2. Gulnik S, Eissenstat M, Afonina E, Ludtke D, Erickson J, Dagger R, Wynne B, Guttendorf R. Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer. 16th Conference on Retroviruses and Opportunistic Infections. Montreal 2009 Abstract 41.
3. Jacobson JM, Saag MS, Thompson MA, Fischl MA, Liporace R, Reichman RC, Redfield RR, Fichtenbaum CJ, Zingman BS, Patel MC, Murga JD, Pemrick SM, D'Ambrosio P, Michael M, Kroger H, Ly H, Rotshteyn Y, Buice R, Morris SA, Stavola JJ, Maddon PJ, Kremer AB, Olson WC. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 2008,198:1345-1352.
4. Thompson M, Lalezari J, Saag M, Jacobson J, Zingman B, Stambler N, D'Ambrosio P, Maddon P, Olson W, Morris S. Weekly and Biweekly Subcutaneous PRO 140 Demonstrates Potent, Sustained Antiviral Activity. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, February 8-11 2009 Abstract 571a.
5. Martin DE, Salzwedel K, Allaway GP. Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother 2008,19:107-113.
6. Van Baelen K, Salzwedel K, Rondelez E, Van Eygen V, De Vos S, Verheyen A, Steegen K, Verlinden Y, Allaway GP, Stuyver LJ. HIV-1 Susceptibility to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag SP1. Antimicrob Agents Chemother 2009, e published.
7. Baichwal V, Austin H, Brown B, McKinnon R, Yager K, Kumar V, Gerrish D, Anderson M, Carlson R. Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055. 16th Conference on Retroviruses and Opportunistic Infections. Montreal 2009 Abstract 561.
8. Adamson CS, Ablan SD, Boeras I, Goila-Gaur R, Soheilian F, Nagashima K, Li F, Salzwedel K, Sakalian M, Wild CT, Freed EO. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J Virol 2006,80:10957-10971.
9. Beelen A, Otto J, Fidler M, Sanguinetti E, Smiley P, Balch A, Medlock M, Jackson M, Swabb E. Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of a Novel HIV-1 Maturation Inhibitor in HIV- Healthy Volunteers. 16th Conference on Retroviruses and Opportunistic Infections. Montreal 2009 Abstract 570.
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