HIV Antiretrovirals in Development: An Update From ICAAC 2009
October 22, 2009
Table of Contents
The current pipeline of HIV/AIDS drugs in development is as dry as it's been in quite some time. Nearly two years have passed since the last HIV medication was approved in the U.S. (etravirine [TMC125, Intelence] got the green light in January 2008), and in the short term at least, it appears unlikely we'll see any new additions to the antiretroviral family.
However, although the drug pipeline isn't very full, there are several interesting candidates in the works. The latest findings on some of these drugs were presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009). Here is a selection of those studies.
GS-9350 may one day become the first viable "alternative" to ritonavir (RTV, Norvir) as an antiretroviral booster drug. But first, researchers need to show that it can be as effective and at least as safe as ritonavir itself. As a result, GS-9350 is working its way through various trials to directly compare how the drug stacks up against ritonavir when paired with specific antiretrovirals.
To wit, Srinivasan Ramanathan, Ph.D., and colleagues from Gilead Sciences presented data from a dose-finding study comparing how GS-9350 and ritonavir (both administered once-daily) functioned when each was administered with once-daily atazanavir (ATV, Reyataz).1
The study enrolled 42 HIV-uninfected people who each spent three successive 10-day periods (each separated by a four-day wash-out) taking 300 mg atazanavir with 100 mg ritonavir, 150 mg GS-9350 and 100 mg GS-9350 (the order varied from trial participant to trial participant). The results revealed that the 150 mg GS-9350 dose produced a bioequivalent level of atazanavir exposure to the 100 mg ritonavir dose; the 100 mg GS-9350 dose resulted in lower atazanavir exposure.
No serious adverse events were reported on any study arm and the overall rates of adverse events were similar across the study arms. Two patients discontinued atazanavir plus GS-9350 (one in the 150-mg arm, one in the 100-mg arm) after developing moderate rash, which resolved after they discontinued therapy.
This study follows data presented at CROI 2009 earlier this year suggesting that GS-9350 had a number of properties that could actually make it a more lipid-friendly option than ritonavir while exhibiting the same boosting ability -- an ability that may extend beyond protease inhibitors to include drugs from other classes, such as the experimental integrase inhibitor elvitegravir (GS 9137, JTK-303). (Elvitegravir and GS-9350 are both being developed by the same company, Gilead Sciences, Inc.)
Of course, before GS-9350 can be approved, further studies will need to explore its longer-term safety and efficacy, as well as its interaction with other commonly used medications. A phase 2 trial is currently underway comparing GS-9350 and ritonavir when each is coadministered with atazanavir and tenofovir/emtricitabine (TDF/FTC, Truvada). (A separate phase 2 trial is also underway comparing a four-drug, once-daily combination pill consisting of GS-9350, elvitegravir and tenofovir/emtricitabine to the once-daily combination pill efavirenz/tenofovir/emtricitabine [EFV/TDF/FTC, Atripla].)
More than two years after its U.S. approval, maraviroc (MVC, Selzentry, Celsentri) remains the only CCR5 antagonist on the market. However, more are in the works -- though none have travelled as far through the development process as the phase 2 drug vicriviroc (SCH 417690; SCH-D).
The most noteworthy presentation on vicriviroc from ICAAC 2009 highlighted 96-week safety and efficacy results from an ongoing extension of the VICTOR-E1 trial, a phase 2b study involving 86 treatment-experienced patients with CCR5-tropic virus.2
You can read more about the findings of this study in our interview with Lisa Dunkle, M.D., of Schering-Plough Corporation, who presented the data at ICAAC 2009. The bottom line, however, was that viral suppression remained stable from weeks 48 through 96 among patients who received vicriviroc along with an optimized background regimen.
The average CD4 count appeared to increase slightly during this period. In terms of safety, Dr. Dunkle stated that the drug's profile was "very encouraging, without any serious, medically significant adverse events -- no seizures, no hepatotoxicity." The most common adverse event in the study was upper respiratory infection (reported in 13% of study participants), which "does not constitute anything that I'd be very concerned about," Dr. Dunkle said.
Studies of vicriviroc continue, with a phase 3 trial of the drug expected to begin in early 2010 for treatment-experienced patients and a phase 2 trial currently underway in treatment-naive patients, according to Dr. Dunkle. She said Schering-Plough expects to submit the drug for U.S. Food and Drug Administration (FDA) approval in early 2010.
The experimental CCR5 antagonist PRO 140 is like no HIV drug currently on the market: PRO 140 is attempting to be the lone marathon runner in a family of sprinters.
At present, once-daily dosing is as much as we can expect from an antiretroviral. PRO 140 is aiming for something much less frequent -- perhaps on the order of one dose administered approximately every two weeks, judging by the latest study results presented at ICAAC 2009 by Jeffrey M. Jacobson, M.D., of the Drexel University College of Medicine.3 (The drug is being developed by Progenics Pharmaceuticals, Inc.)
The phase 2a study involved a single intravenous infusion of PRO 140 administered (as monotherapy) to 31 patients, all of whom had an HIV viral load above 4,999 copies/mL, a CD4+ cell count above 299 cells/mm3, CCR5-tropic virus (as determined by the original, non-enhanced Trofile assay) and no antiretroviral therapy for at least the past 12 weeks. Participants received a single injection of placebo, 5 mg/kg of PRO 140 or 10 mg/kg of PRO 140. Patients were followed for 58 days.
The findings were consistent with earlier, encouraging results on the drug. Regardless of the dose, patients receiving PRO 140 experienced a 1.8 log mean maximum reduction in HIV viral load, with antiretroviral activity appearing to peak at around the 12-day mark. From there, antiretroviral activity dropped off more quickly for patients receiving the 5 mg/kg dose than the 10 mg/kg dose.
Adverse effects appeared mild when they occurred (as they did in nearly all patients, whether they received PRO 140 or a placebo), with no single type of adverse effect being particularly common.
There is still much to learn about PRO 140 and its potential, but results thus far present an interesting possibility: Perhaps once-daily dosing is not the best we can do in terms of convenience when treating people with HIV.
Of course, intravenous infusion is not an ideal means by which to administer an antiretroviral; an earlier study of PRO 140 showed there was potential for the drug to be successfully administered subcutaneously (which could allow patients to self-administer it) and still retain its long-term activity without causing serious adverse effects.
PRO 140 has a different mechanism of action than fellow CCR5 antagonist maraviroc, and thus far appears to show limited cross-resistance.
But as PRO 140 works its way through development, it will be developed as a new option for antiretroviral-experienced patients, which is paradoxical because it requires CCR5-tropic virus in order to be effective -- and CCR5-tropic virus is far more common among antiretroviral-naive patients than it is among patients with significant drug resistance. But if all goes well with the next trials, the company will no doubt have first-line trials up and running in no time.
It also may prove to be something of an obstacle that PRO 140 must be administered via injection (particularly if it's intravenous as opposed to subcutaneous). That said, the requirement that injections only be every two weeks or so could go a long way toward ameliorating some of the concern (and the injection-site reactions) that has challenged enfuvirtide (T-20, Fuzeon) after its approval in 2003.
ICAAC 2009 also featured data on TBR-652 (formerly TAK-652), a phase 2 drug being developed by Tobira Therapeutics, Inc. In a 10-day, five-arm safety study involving 60 HIV-uninfected people, Sandra Palleja, M.D., and colleagues found that the drug appeared well-tolerated at doses of up to 200 mg taken once daily.4 Treatment-related adverse events were reported to be generally mild (there were no serious events or deaths), with constipation and headache occurring most frequently.
The researchers noted that there were two cases of elevated liver enzymes that resolved when the patients were off therapy, but felt that those cases were not directly related to TBR-652 use, since one patient had non-alcoholic fatty liver and the other had a muscle injury.
A separate in vitro study of TBR-652 in combination with several other antiretrovirals showed "additivity or weak synergy," but no antagonistic interactions, with all of them.5
The NRTI tenofovir (TDF, Viread); NNRTI etravirine; protease inhibitors lopinavir (LPV), atazanavir, and darunavir (TMC114, Prezista); and the integrase inhibitor raltegravir (RAL, Isentress) all passed muster in terms of pharmacokinetic interactions.
Tobira plans to move forward with a proof-of-concept study of TBR-652 in HIV-infected patients.
New antiretroviral classes are welcome additions to the HIV treatment pantheon in large part because of their activity against strains of HIV that have become resistant to existing classes. This is one of the great draws of raltegravir, the first approved integrase inhibitor.
But what happens when HIV-infected people develop resistance to raltegravir? Can other integrase inhibitors in the pipeline still have activity in these individuals?
In the case of an investigational family of integrase inhibitors known as quinolines, the answer may be yes. In vitro research presented by Laurent Thibaut and colleagues at BioAlliance Pharma and CNRS-ENS in France indicates that quinolines -- in particular, a quinoline candidate called QNL111 -- have a mechanism of action that differs enough from raltegravir that they are able to retain antiretroviral activity even in the face of HIV that has developed resistance to raltegravir.6 The researchers also noted that QNL111 appears to act "in synergy" with raltegravir in tests conducted on wild-type virus.
If these findings hold up to further scrutiny, they may mean that QNL111 and other quinolines have low cross-resistance with other integrase inhibitors, which bodes well for treatment-experienced patients whose raltegravir-containing regimens don't succeed in suppressing HIV.
Speaking of integrase inhibitors: A number of studies were presented at ICAAC regarding S/GSK1349572 (GSK-572), a once-daily integrase inhibitor being developed by GlaxoSmithKline and Shionogi & Co., Ltd. Arguably, these studies were just window dressing on impressive phase 2a trial results presented earlier this year at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention.
Those results indicated a roughly 2 log average viral load decline among HIV-infected patients who received the drug for 10 days. At what appeared to be the optimal (50 mg) dose of GSK-572, 70% achieved a viral load below 50 copies/mL. Mild-to-moderate diarrhea, fatigue and headache were the most frequently reported adverse effects, although these tended to be more common among patients receiving a placebo than those receiving the study drug.
At ICAAC 2009, an examination of several phase 2 studies of GSK-572 also supports the drug's satisfactory short-term safety profile. Seven studies were included in the analysis by Yu Lou and colleagues from Glaxo and Shionogi.7
A total of 183 trial participants were involved in the studies that comprised the meta-analysis, 35 of whom were HIV infected. In the studies, participants were administered varying doses of GSK-572 (generally 50 mg, but up to 100 mg) or a placebo for between one and 14 days.
Overall, an adverse event was reported for 50% of all patients who received GSK-572, the same as for placebo (though the number of patients receiving placebo was only 18). Headache, diarrhea, nausea, vomiting and dizziness were the most commonly reported adverse events among patients receiving GSK-572. The researchers noted, however, that this is typical for people who are forced to abide by the rules of such a study, which include the elimination of caffeine and other diet modifications.
Four serious (grade 3) adverse events were noted: joint pain, migraine headache, increased lipase and increased triglycerides, the last of which was believed to be unrelated to the drug.
That said, a separate pharmacokinetic study of GSK-572 by I. Song and colleagues found that the concurrent use of the drug alongside an antacid reduced GSK-572 exposure by 70%.8 The researchers recommended that the investigational drug be taken no fewer than two hours before or six hours after a patient takes any antacid that contains metal cations (such as Maalox, which was used in this study). The pharmacokinetic study also found that the use of multivitamins containing metal cations reduced GSK-572 by 30%, but the researchers felt the finding was not clinically relevant.
Additional pharmacokinetic studies examined the coadministration of GSK-572 with tenofovir,9 lopinavir/ritonavir (LPV/r, Kaletra) and darunavir plus ritonavir.10 In all cases, the researchers deemed no clinically relevant interaction, although they did note that darunavir use appeared to somewhat reduce GSK-572 concentrations.
Finally, results from a passage study of GSK-572 suggest that the drug may have a higher genetic barrier to resistance than raltegravir, according to the researchers.11
Meanwhile, a second integrase inhibitor being developed by Glaxo and Shionogi also appears promising. The drug, S/GSK1265744 (GSK-744), is regarded as a "backup" to GSK-572, but phase 1/2a study results presented at ICAAC 2009 suggest it may be just as strong as the candidate it's backing up. The double-blind, placebo-controlled, randomized study involved 48 HIV-uninfected patients and 11 HIV-infected patients who had not previously taken an integrase inhibitor.12 The HIV-uninfected patients received escalating doses of GSK-744 monotherapy or a placebo for 14 days; the HIV-infected patients received 30 mg of the drug or a placebo once daily for 10 days.
GSK-744 appeared to hold up well in terms of efficacy and safety. The HIV-infected patients experienced a median viral load drop of 2.6 log, and 88% had achieved a viral load below 50 copies/mL by the 14th day of the study. Headache was the most common side effect reported, but was about half as common in GSK-744 recipients than placebo recipients (7% versus 15%, respectively).
Despite generally promising results thus far for both GSK-572 and GSK-744, further study is required to fully flesh out the longer-term safety and efficacy of these integrase inhibitors in HIV-infected patients.
While some researchers strive to create antiretrovirals in relatively new classes, such as CCR5 antagonists and integrase inhibitors, others seek to develop entirely new classes. Such is the case for bevirimat, a maturation inhibitor, which works nearly at the opposite end of the HIV reproduction process from CCR5 and integrase inhibitors. Bevirimat's goal is to impede the "budding" process at the tail end of the viral life cycle.
The development of bevirimat has been slowed by difficulty in finding an effective formulation. The drug's ownership also changed hands in the past year, leading to its official designation switching from PA-457 (when it was being developed by Panacos Pharmaceuticals) to MPC-4326 (under the stewardship of Myriad Pharmaceuticals).
ICAAC 2009 featured the results of a pair of phase 2 monotherapy studies on bevirimat. In a 14-day monotherapy study, Mark Bloch, M.B.B.S., and colleagues administered one of two doses of the drug to 32 HIV-infected participants.13 All of the participants were male and all but one were Caucasian. The participants' mean HIV viral load was 4.48 log and mean CD4+ cell count was 407. Twenty-six of the 32 patients were antiretroviral naive. The patients were randomized to receive either twice-daily 200 mg or 300 mg doses of bevirimat (using 50 mg oral tablets) for 14 days.
Antiretroviral efficacy was modest in both groups: Patients receiving the 200 mg dose experienced a .54 log decline in viral load, while patients receiving the 300 mg dose experienced a .70 log viral load decline (the difference between the groups was not statistically significant). However, the researchers found that virologic response depended greatly on whether specific variations in the gag gene were present in a patient's strain of HIV. By predicting bevirimat's success based on the presence or absence of these variations (which were determined by genotypic testing), mean viral load decline increased to greater than 1 log specifically among patients with a "predicted response," versus a decline of just .17 log among patients who were predicted to be nonresponders.
Adverse effects were common and generally mild among patients receiving either dose of bevirimat. Gastrointestinal problems occurred most frequently by far, with 16% reporting diarrhea, 16% reporting nausea, 13% reporting constipation (one of which was a grade 3 event) and 9% reporting stomach cramps. Headache was also commonly reported, at about 22%.
Despite the lack of fireworks in these findings, phase 2 development of bevirimat will continue -- albeit with a 100 mg tablet formulation, rather than the 50 mg formulation used in this study. A pharmacokinetic and safety study presented at ICAAC 2009 found promise for the 100 mg formulation, although the same tendency toward gastrointestinal effects was noted.14
Lest you think that all of the drugs in development involve new classes of HIV medications (or classes of medications that haven't yet been approved at all), we'll close this recap on an old-school note: with an NRTI. That's right, the first class of drug ever approved to fight HIV is still being plumbed to determine if any new antiretroviral riches lie within its depths.
A study presented by Michael Parniak, Ph.D., of the University of Pittsburgh, on behalf of his colleagues highlights a next-generation NRTI in an extremely early stage of development.15 The drug was referred to as 4'-ethynyl-2-fluoro-deoxyadenosine, or EFdA for short.
In the study, EFdA monotherapy was administered to rhesus macaques infected with SIV, the simian equivalent of HIV. Data revealed a 2- to 3-log SIV viral load drop within seven days, which supports the researchers' contention that it may be one of the most potent antiretroviral nucleosides ever -- provided it continues to make its way through development. After all, EFdA has yet to be studied in humans, be they HIV-infected or uninfected.
Although these findings are exciting (as are many of the findings discussed in this review), it's important to temper hope with realism. The vast majority of drugs that enter the development pipeline never come out the other end. Of course, what keeps the research field going is the possibility that, for those antiretrovirals that do make it all the way through FDA approval, they may change the face of HIV treatment as we know it, ultimately lengthening and dramatically improving the lives of many thousands of HIV-infected patients.
This article was provided by TheBodyPRO. It is a part of the publication The 49th Interscience Conference on Antimicrobial Agents and Chemotherapy.
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