Introduction | Landscape of Current Treatment | Desired Elements of Future Therapies |
Pipeline Review | The Future of Expanded Access | Summary | References

Introduction
The antiretroviral (ARV) pipeline is important because current treatments are imperfect. In the most recent U.S. guidelines on antiretroviral treatment, there are eleven pages of tables of adverse effects and how to manage them. Some are potentially life-threatening, others chronic, cumulative, overlapping, and sometimes irreversible (DHHS 2005).

Although some current drugs are relatively benign, few combination regimens are wholly non-toxic, though some may be less so than others.

The efficacy and durability of initial highly active antiretroviral therapy (HAART) combination therapy regimens appears to have increased in the years since HAART was introduced in 1996. In the Johns Hopkins HIV Cohort, six-month viral suppression to below 400 HIV-RNA copies/mL increased from 43.8% in 1996 to 72.4% in 2001-2002; the comparable levels at twelve months were 60.1% and 79.9%, respectively (Moore 2005). Combination antiretroviral therapy (ART) doesn't cure, but the progressive introduction of new drugs and classes, simplified treatment regimens, and (in some cases) reduced toxicity and adherence burdens have led to sustained improvements in HIV-related morbidity and mortality in the U.S. and other developed countries.

Nonetheless, because of significant long-term toxicity and the growing numbers of people experiencing antiretroviral treatment failure, new drugs and drug classes continue to be urgently needed. Given stable domestic rates of HIV infection (∼40,000 new infections in the U.S. per year), rising rates worldwide (∼5 million new infections per year), and extended survival with HIV with broadening access to ART, this need will only grow in coming years.

Twenty-four new anti-HIV drugs are now in clinical trials. None of these will be a cure for AIDS. Strategically, we may be moving toward fewer pills a day, but eradication of HIV with current therapeutic approaches does not look feasible.

I. Landscape of Current Treatment
Over the past few years, the community has been repeating, to pharmaceutical companies, to FDA, and to the medical community, the information gaps characteristic of new ARVs at the time of approval and–all too often–persisting long afterwards (Camp 2004):

More data should be available on pharmacokinetics of drugs in diverse populations, including women; African-Americans and other ethnic groups; people with hepatic or renal impairment; people with HBV, HCV or TB infections; and children.

More drug-drug interaction studies should be completed at the time of approval, including studies with methadone, birth control hormones, TB drugs such as rifampin, and of course with the most commonly used antiretroviral drugs, those on the market and those still under study.

Study populations need to reflect the makeup of the epidemic by adequately representing women and people of color. New relationships need to be developed with clinics capable of enrolling more diverse groups of individuals.

After drugs have been approved, promises made by companies to continue postmarketing research should not be allowed to languish. Currently the agency has no effective way to compel completion of these Phase IV "good-faith" commitments, and Congress should pass legislation to give the FDA more authority in this area.

Better systems are urgently needed to monitor chronic and long-term side effects after drugs are approved. The current adverse events reporting system is voluntary and may miss substantial toxicity. A network of "sentinel practices" to report unusual symptoms might be a viable enhancement to the current inadequate MedWatch system. The need for a better system to detect and track side effects (such as the emergence of lipodystrophy syndrome after the approval of the protease inhibitors) has long been a major concern for the community

These "themes", in one way or another, reflect the questions that we come home with after approval of every drug, and to which we don't ever seem to get answers: What are the drug's benefits? What are its risks? How should the drug be used and managed? Who will benefit? What is still unknown?

After the recent approval hearing for tipranavir/ritonavir (TPV/R), there are more unknowns than ever before, or more agreement on accepting the unknowns than ever before. At the tipranavir hearing on 19 May 2005, the Chair of the FDA's Antiviral Drugs Advisory Committee, Dr. Janet Englund, stated, "At every meeting we have, the same issues come up again and again, like the lack of adequate numbers of women. We, the medical community, aren't comfortable with how to use the drug in women." The final vote was 11 in favor "with reservations", 3 en contra (http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1.htm).

Also, studies of future therapies need to keep in mind those pharmacokinetic (PK) issues that are constantly relegated to "we will look at that later". What is the role of pharmacokinetic data in the evaluation of dosing regimens? Are the present correlations of exposure measures enough to advise toxicity (Cmin, AUC, etc)? Which exposure measures should be considered when providing labeling information on concomitant administration of antiretrovirals? Once an alternate regimen has been identified in adults, should we expect identical PK profiles in children (ie, children and neonates as small adults)? What kinds of studies are needed to better define pharmacokinetic/ pharmacodynamic relationships for antiretroviral drugs?

II. Desired Elements of Future Therapies
Future therapies need to be affordable, offer a minimum of side effects, have no cross-resistance, and be simple to adhere to; it goes without saying that they also need to be effective, which most first-line drugs already are. In advanced and salvage settings, however, the bar for approval is much lower. FDA is now approving drugs that are 35% effective at 24 weeks in highly pretreated individuals because the drugs appear to offer some benefit. The risk that accompanies that benefit needs to be more clearly defined in the populations that will be using the drug in the real world.

Figure. Replication Cycle of HIV and Drug Targets

III. Pipeline Review
Although many drugs are in the clinical pipeline, a closer look at the chart on the following page reveals that most are far from approval. There are just a handful of drugs in phases IIb/III. Of these, four are nucleoside reverse transcriptase inhibitors (NRTIs) unlikely to offer a major step forward, while two are NNRTIs–none of which appears to be advancing quickly–while five to six are members of new classes of entry inhibitors, including the controversial CCR5 inhibitors, which appear to be moving forward rapidly. Nonetheless, after tipranavir (Boehringer Ingelheim's Aptivus®), it is unlikely that another new ARV drug will be licensed before mid-2006 in the US. Of the 32 new ARV drugs now being tested in humans, eight are not moving forward, and at least two others are doubtful (they've been sitting in their current spaces for longer than necessary–in business, this is called ‘loss of opportunity'–and there is no clear idea about whether or when they will be moving forward).

Some sponsors of early-phase drugs appear to be vexed by the simple problem of money. Estimates of the cost of bringing a new drug to market range from $200-400M (not counting the opportunity costs which double that figure); the universities and biotech firms in charge of some of these agents need to find partners, just to keep the drugs where they are.

Table. Antiretroviral Pipeline 2005

* see 2005 Antiretrovirals Pipeline Chart for current developments.

Phase I
In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (∼20-80) for the first time to evaluate its safety, determine a safe, active range of doses, and identify initial, acute side effects.

Entry Inhibitors
"Entry inhibitors" is a broad category that encompasses attachment, fusion, and the inhibition of co-receptor antagonists. Mechanically, these are separate components unlikely to induce cross-resistance.

BMS-488043, from BMS, is a small molecule that attaches to gp120, causing a conformational change that disrupts the connection to the CD4 receptor (Lin, 2005). 043 will not be moving forward, but its sister BMS-378806, also a gp120 blocker, continues to be tested.

GSK has optioned a CCR5 inhibitor (873140) from Ono that seems to be helped by a ritonavir "boost". CCR5 receptor occupancy seems both high and long, but the clinical significance of this has not been demonstrated (Sparks, Adkinson 2005). As is the case with all three CCR5 inhibitors furthest along, GSK has shown transient dual/mixed tropism switching (Kitrinos 2005).

Integrase Inhibitors
Integrase is the step in HIV's lifecycle where the HIV genome is inserted into the host's DNA, which happens after reverse transcription (see Figure). None of the integrase inhibitors now in the clinic have been reported on. Two recently got into humans, but have since been discontinued (Little 2005). There are at least seven pre-clinical integrase programs in discovery programs around the world. Merck has one–or maybe two–integrase inhibitors in humans that they will be reporting on soon, including L-870812.

Maturation Inhibitors
Maturation, like entry, is a collection of steps, but this time near the end of the replication cycle, including assembly, budding or extrusion (where the CD4 envelope opens and new immature HIV particles begin to leave the cell), and maturation (where the viral proteins are cut by protease and assume their final, infectious state). The first maturation inhibitor to enter human trials is from Panacos, PA-457. Although they claim an antiviral effect that lasts for ten days after one dose, the clinical impact of this will be determined only after further study (Martin, Li, Martin 2005).

Other Mechanisms
Preliminary studies suggest that mifepristone, a glucocorticoid antagonist, may lower viral load and raise CD4 cells; it is better known as RU-486, and is metabolized through the CYP3A4 pathway; thus, its use will need to be better defined with other medications. Although it is approved for the 6 medical termination of intrauterine pregnancy, it has not been studied with other drugs or food (Muthumani 2005). ACTG 5200 is a 48-patient randomized, placebo-controlled, phase I/II trial of the anti-HIV activity and safety of mifepristone (here called VGX-410) at three dose levels in HIV-1 infected individuals.

BioInvent has just entered human trials with a Tat inhibitor known as BI-201. It is being looked at in naïve HIV-infected patients. The primary objective is to study safety, tolerability and pharmacokinetic properties of the candidate drug.

Old Classes, New Drugs
What all new drugs in existing classes are expected to do is to offer some benefit over existing drugs in terms of tolerability, ease of use, side effects, or treatment of resistant HIV strains.

NNRTIs
KP-1212, Koronis' "covert" nucleoside, a perplexing term, has finished Phase I, and will start recruiting for a Phase Ib trial in summer 2005. No consistent toxicities were noted, the pharmacokinetics were as predicted by animal studies, and FDA has given the green light to move forward (Koronis 2005). GSK's nominee, 695634, induces the CYP3A4 pathway – that is, it speeds up the clearance of many other drugs, including HIV drugs, from the body. Rash is a reported side effect; 5/31 persons stopped the drug early in a recent 10-day trial (Persky, Kim 2004). The University of Georgia is the discoverer of another NNRTI, this one a dioxolane thymidine (DOT). DOT has shown anti-HIV activity against many nucleoside-resistant mutants, including the K65R (Chu 2005).

Tibotec has presented a 7-day phase IIA, dose-escalating, placebo-controlled proof-of-principle study, conducted in 47 male antiretroviral-naïve patients. Four doses of TMC278 once daily (in a PEG400 solution) were compared with placebo; the viral load reductions were -1.2 log₁₀ in all TMC278 treatment arms and – 0.002 log10 in the placebo group. CD4s rose a median of 55 in 7 days. There was grade 3 nausea reported, and grade 3 lowering of white blood cells and neutrophils in a small number of patients. Mild headache, fatigue, nausea and somnolence were also reported. It has a relatively high genetic barrier for an NNRTI. It is completely cross-resistant to TMC125, another Tibotec NNRTI further along in development (see below). Multinational phase II dose-finding studies are beginning now (de Bethune, Goebel 2005).

NRTIs (nukes)
Pharmasset's racivir seems to be effective against the M184V mutation (seen in 3TC failures). It has shown activity of 2 logs within a triple regimen (Pharmasset 2004). Oddly enough, Avexa's SPD-754, originally from Shire, also purportedly works in the presence of the same resistance mutation. Avexa has a trial designed to look at second line use in the presence of the 184 (Shire 2005). Both companies are also looking at head to heads trials with 3TC.

Phases II & III
In Phase II clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In Phase III studies, the study drug is given to large groups of people (500-1,000+) to confirm its effectiveness, monitor side effects, compare it to an approved standard regimen, and collect information that will allow the drug to be used safely.

Entry Inhibitors
While there is still much to learn about these new compounds, including their impact on HIV tropism switches (from the more normal, less rapidly pathogenic R5/non-syncytium inducing/NSI HIV to the more aggressive, rapidly destructive X4/SI strains), side effects, and the need for boosting with ritonavir, the rapid progress on a number of compounds which inhibit R5 HIV, X4 HIV, or block entry by other mechanisms has the potential to usher in a broad array of potent, new tools for inhibiting HIV.

PRO-542, also known as a recombinant CD4-IgG2 is the latest in the line of soluble CD4 receptors, a group of agents which showed little efficacy when tested in the years before the emergence of HAART, (AIDSMap 2004) and is probably the furthest behind developmentally. PRO-542 binds to HIV's surface at gp120 and blocks attachment and entry of virus into CD4 +cells. At 25 mg, it has a half-life of three days and lowers viral load by half a log for 4-6 weeks post-treatment. PRO-542 will be looked at in salvage patients (Jacobson 2004).

Of the CCR5 inhibitors, Schering's vicriviroc (SCH 417, SCH D) seems especially potent on a per-weight basis. It maintains good bioavailability well above the in vitro IC90 (3.9 ng/mL) even at the low doses being evaluated – between 5 and 15mg. The drug is being studied in experienced patients (clinicaltrials.gov 2004). Virus resistant to SCH 417 has recently been shown to be cross resistant to other CCR5 inhibitors (Strizki 2005). Like maraviroc and 873140, it has a long half-life and is rapidly absorbed.

Pfizer's maraviroc, formerly UK-427, is effectively doubled in the presence of lopinavir/ritonavir (Kaletra), while exposure is reduced by co-administration of efavirenz. As monotherapy, it lowered viral load in treatment-naïve people by 1.6 log10. No heart-rate (QTc) effects (a la SCH C) have been seen (Muirhead, Westby 2005). The 300 mg dose has been looked at, and an ACTG trial is looking at 150 mg administered once or twice daily (clinicaltrials.gov 2004).

Tanox licensed TNX-355, a monoclonal antibody (designed to compete with CD4-binding antibodies) from Biogen Idec. TNX-355 is a large molecule that requires intravenous infusion, but only once every week or, after eight weeks, every two weeks. TNX-355 is being studied in treatment-experienced persons who have been on at least one failing triple regimen (clinicaltrials.gov 2004).

AMD-070 is a CXCR4 inhibitor, and would seem to be a natural complement to CCR5 inhibitors, for use in treating individuals with mixed-tropic HIV populations, among those with X4 predominance and–if R5 inhibitors induce viral tropic switches–to delay or limit the emergence of X4 HIV. By itself, AMD-070 would be used in advanced individuals with a mixed or complete X4 HIV population. It has shown preliminary results versus virus with multiple resistance mutations (Schols 2005).

NRTIs
Reverset from Incyte (formerly Pharmassset) is also looking for the anti-184V prize. It is in Phase IIb, although the sponsor has only reported on 16 people so far. It seems to have strong efficacy in persons with the 184V, 41, or 210 RT mutations. Of course, besides who gets there first, price and user-friendliness will play a role if there are several simultaneous post-3TC drugs. And what about the cross resistance between them?

Elvucitabine (Achillion) was in the forefront of the anti-184 drugs (ie, those designed to treat HIV that is resistant to 3TC or FTC due to the 184V mutation in RT). Formerly known as ACH-126, elvucitabine is taken as one pill, once a week. It is being looked at in modestly detectable HIV. The doses used so far have been fairly toxic, and lower doses are being considered (Pottage, 2004).

DAPD (amdoxovir) was looked at in a double blind, placebo controlled study over an optimized background regimen that contained T-20 in all patients. The drug appeared safe but there was no appreciable difference between it and the placebo (Gripshover 2005). Lenticular opacities (eye problems) were seen in animals and Phase I studies. Gilead sold the rights back to the University of Georgia. Further progress of this agent is up to the new guardian, RSF Pharmaceuticals; an ACTG trial is moving forward.

NNRTIs
Etravirine (formerly TMC-125) is another Tibotec agent now in Phase IIb. The two Tibotec NNRTIs under development have overlapping resistance profiles. Etravirine is still in phase IIB dose-finding (400mg or 800 mg BID), while also in a first-NNRTI failure study (at 800 mg BID) (clinicaltrials.gov 2004). Etravirine will share a Phase III study with TMC-114/r, a second investigational agent, hopefully set to begin recruitment in Fall 2005.

TMC-114/r – New PI in Phase III
Tibotec has presented data from 24-week interim analyses of two phase IIB (dose-finding), randomized trials of TMC114/r in patients with 3-class experience and 1 or more primary PI mutations. These analyses showed a mean reduction in plasma HIV RNA of – 1.85 log10 in the highest dose group, 600mg/100mg twice daily. Only 11% of participants were female. People were randomized to receive optimized background regimen (OBR) plus one of four doses of TMC114/r or OBR plus investigator-selected control protease inhibitors (PIs).

The interim analysis included a total of 497 patients (Katlama 2005). After 24 weeks, the percentage of participants reaching undetectable virus levels (<50 copies/ml) ranged from 30% to 47% in the TMC114/r arms, compared with 10% in the control arm. 67% of those who were also taking T-20 went below 50. The most common adverse events were headache, nausea, diarrhea, and fatigue, although up to 90% of participants reported some sort of side effects, 25% of them grades 3 or 4. These studies will continue to 96 weeks. Based on these 24-week results, the selected dose for treatment-experienced people in phase III trials will be TMC114/r 600mg/100mg twice daily; the trials are set to begin in summer 2005.

Multi-Experimental Agent Trials (MEAT)
While drug studies for healthier patients usually utilize the very newest drugs in early development, later stage patients are often left out.

Since 1999, FDA has talked openly about how to design a good "heavily pretreated patient" study. They have let it be known that trials with multi-experimental agents are viable for registration.

As a result of the community and FDA's focusing on experienced patients, drugs such as Kaletra (lopinavir/ritonavir), Viread (tenofovir DF), Fuzeon (T-20) and tipranavir/R (Aptiva®) were all studied in pre-treated, sometimes salvage therapy populations, and these drugs were actually approved first for use in pre-treated individuals.

A combination trial can answer 'Are these two (or more) experimental agents together useful?' And it would prevent virtual monotherapy for people in salvage. Variables that need to be addressed include resistance and cross-resistance, choice of OBR, the use/availability of newer drugs not directly being studied, and drug interaction/PK studies.

Ever since the community first proposed the ARISTO [‘A RandomIzed study of Salvage Treatment Options'] study in 1999, in which three experimental agents would be evaluated together (James 1999), there has been interest in studies utilizing several experimental agents together. Feasibility of this approach has been limited by non-synchronous drug development timelines, the disinclination of sponsors to work together, and the lack of appropriate drug-drug interaction data to guide dosing regimens in such a study.

ARISTO-type studies would be able to help define the use of several new salvage therapy drugs simultaneously while avoiding the exposure of any study participants to virtual monotherapy. Important strategic answers can be achieved without sacrificing trial volunteers to multidrug resistance. Recently, the FDA clarified once again its willingness to countenance the implementation of such studies (Struble 2005).

The Future of Expanded Access
For a decade, since the introduction of HAART in 1996, sponsors have kept their expanded access programs (EAPs) small and late. In earlier years, Burroughs Wellcome provided 5,000 late-stage AIDS patients with AZT before approval in 1987. Bristol-Myers provided ddI to over 35,000 people between 1989-1991, and over 12,000 with d4T in 1992-1994. Glaxo provided 3TC to over 30,000 people in the mid-1990s. These expanded access programs reflected the very desperate state of AIDS treatment before the advent of HAART. Even then, Roche was always a grudging and late-coming provider of access to, for example, ddC for about 5,000 people and later saquinavir to an equivalent number. Sponsors claimed the complexity of protease inhibitor manufacturing processes limited their ability to distribute PIs through EAPs. Indeed, there were 10 ethically challenging programs such as lotteries for access to the first PIs. More recent EAPs for drugs such as T-20 (Roche), atazanavir (BMS), and tipranavir/R have hardly been worthy of the name.

Can expanded access be rejuvenated as a more equitable, broadly based pre-approval program which can provide access to experimental therapies for all individuals who need them but cannot access the controlled clinical trials, or are ineligible?

Summary
Of the 24 anti-HIV agents continuing in the clinical pipeline, up to twenty may likely make it through to FDA review within the next four to six years (see Table). Some companies like Anormed have announced they will not be moving forward, in this case, with their CXCR4 inhibitor AMD3100. Others companies, like BI with MIV-310, have sold the agent back to their originator. And at least two are like Advanced Life Science's Calanolide A, hovering for much too long in the same place. Even their press releases are getting old. On the other hand, if no new bad news for the entry class comes out, we may see a broadening of licensed anti-HIV therapy approaches toward the very earliest stages of the HIV life cycle– before its entry into cells–to intermediate stages such as integration and later stages such as assembly, budding, and maturation inhibition. The obstacles to a better future for people with HIV are clear, however. The great majority of the world's people living with HIV, and growing numbers even in the U.S., still lack easy access to simple, affordable, safe and effective treatments. There are many major players in the drug development process. The pharmaceutical industry is pre-eminent among them. Nonetheless, continued vigilance, activism, and informed advocacy are crucial to fostering more enlightened drug development, approval, and post-marketing access and availability processes.

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