Treatment Issues: Newsletter of Current Issues in HIV/AIDS
Volume 18, Number 7 & 8 - July / August 2004
Bob Huff

A Canadian company, Anormed Inc., is carving out a specialty niche for itself as a developer of drugs that bind to chemokine receptors, such as CCR5 and CXCR4. They were the first to put an X4 blocking drug into people with HIV and proved that the concept was viable. Unfortunately, the company's first X4 drug candidate, AMD3100, produced heart rhythm abnormalities in several patients during Phase I testing and only demonstrated limited efficacy at achievable concentrations. Undaunted, Anormed has come back with a new, structurally different candidate, called AMD070, an orally available drug that has now been tested in healthy subjects and was shown to be available in the blood at concentrations thought sufficient to suppress HIV.

In Bangkok, results were presented from a Phase I dose escalation study of AMD070 in uninfected adult men conducted by the federal AIDS Clinical Trials Group (ACTG). Single 50mg doses were initially given to three individuals then escalated to 100, 200 then 400mg in subsequent groups of three. Next, multiple (7) doses were given at 100mg every 12 hours to a cohort of six individuals, then escalated to 200mg in a subsequent cohort. A group of six men also received single 400mg doses with and without food to evaluate bioavailability in a fed state.

In the single dose studies, the maximum concentration of drug (C_max), the total exposure to the drug over time (AUC), and the rate the drug was cleared from the body (half life) each tended to be proportional to the dose, although there was a great deal of variability between the subjects within the dose groups for each of these parameters. The half life was estimated as 6 to 10 hours. The single 400mg dose produced blood concentrations at 12 hours that were above the EC₉₀, a value derived from laboratory studies as the drug concentration required to achieve 90% of its maximum antiviral response. Multiple dosing doubled the concentrations seen with single dosing at 12 and 24 hours. However, multiple dosing at 100mg could only sustain concentrations above the EC90 for 4 hours. Taking the drug with food tended to lift blood levels, but not significantly. The only adverse events reported were several headaches.

The next step for this drug will probably be a proof-of-concept study in people with R5/X4 or X4 HIV to see if it can actually produce an antiviral effect in people at these concentrations. If that pans out, then the drug will move forward in the development process of setting a dose and enrolling larger trials. Anormed should plan to continue performing pharmacokinetic studies similar to those reported here, but in more diverse populations, including women and people with liver disease. All too often we have seen a dose selected after study in very homogenous populations that proves to be either too toxic or have too little activity in certain segments of the patient population. In particular, the interpatient variability seen in this early study suggests that one size may not fit all — let's just hope that AMD070 doesn't need ritonavir boosting. (Stone, B4475)

Bangkok also offered preclinical reports on two other X4 drug candidates. A group of researchers from Okinawa gave a late breaker report on KRH-2731-5HCl, an orally available CXCR4 blocker that suppressed X4 and R5/X4 replication in a cell line at very low concentrations. They describe the potency of the drug as 10-fold greater than AMD070. Addressing worries that X4 blockers might disrupt important natural immune functions, the paper reports that the drug did not inhibit immune responses in mice with human-like immune systems. (Murakami, LBOrA01)

Finally, Swiss researchers reported on a peptide mimetic compound called POL2438 that they said suppressed R4 HIV in a cell line at very low concentrations with no toxicity. (Klimkait, A1307)

The Big Dogs Bark
While the X4 blockers are likely to be crucial in the clinic, all of big money is riding on getting an R5 drug to market, probably because the toxicity issues were expected to be much less problematic. Pfizer, Glaxo Smith-Kline, and Schering are the big players here (Anormed has its own CCR5 blocker in preclinical development; lab-based studies showed synergy when used in a combo with their X4 drug). Schering was first into people with its SCH-C compound, but cardiac abnormalities at high doses forced them to switch to a fallback candidate, SCH-D, a structurally different drug with improved potency and no worrisome side effects so far.

At Bangkok, Pfizer presented five posters on its CCR5 blocker, UK-427,857, including results from a 10-day proof-of-concept study. Patients with CD4 counts above 250 cells/mm³ (currently off treatment or treatment-naïve) were randomized to a series of escalating doses or to placebo. Dosing began at 25mg once-a-day (QD) and increased to 300mg twice-a-day (BID), including one arm at 150mg BID taken with food. Monitoring continued for 30 days after treatment was stopped at day 10.

All doses from 100mg QD onward produced mean viral load reductions better than -1.0 log copies/mL. At the 150mg BID dose, food reduced the peak concentration and total exposure (AUC) to the drug by about half, although there was no difference in viral load reduction at that dose whether taken with food or not. This may be because blood concentrations of CCR5 blockers are not as important as how many R5 receptors become occupied by drug molecules and how long they stay. It seems that these drugs tend to stick to their targets and not let go, a quality that could extend the effective potency of a dose by several days. In this study, high levels of receptor saturation were achieved at every dose except 25mg QD.

All persons enrolled were assayed for HIV co-receptor usage phenotype and were required to have an exclusively R5-using strain at time of enrollment. Of the 66 patients exposed to the drug, 2 experienced an emergence of a dual R5/X4 strain by day 11 of the study. One of these individuals reverted to R5 phenotype by day 40, but the other's dual phenotype HIV persisted throughout the first 6 months of follow-up. Because the assay can not pick up sequestered or very small populations of X4-using HIV, the risk of forcing a population shift is evident in this small, initial study. However, in the person whose X4 phenotype persisted, no evidence of accelerated immunological or clinical deterioration has yet been reported. A more detailed presentation of this individual's case is anticipated at an upcoming conference. Adverse events were mild to moderate and included headache and dizziness. A separate report found no impact on QT interval, the cardiac rhythmic parameter that was perturbed by Schering's first R5 blocker. (Fatkenheuer, B4489)

Glaxo Smith-Kline (GSK) has licensed GW 873140, an orally available CCR5 inhibitor from ONO Pharmaceuticals in Japan, and has already performed multiple-dose testing in uninfected persons that demonstrated safety and favorable pharmacokinetics. At Bangkok, GSK reported on the compound's in vitro anti-viral activity in a range of patient-derived cells infected with various laboratory HIV strains and clinical isolates, including non-B subtypes. The drug had consistent activity at very low concentrations with most R5 isolates and cell lines tested. Screening for activity in HIV strains and subtypes that exist outside of the most lucrative markets is an important test of a drug's ultimate relevance. In the future we would like to see every new drug candidate broadly challenged as GSK has done with GW 873140. (Demarest, A1231)

Progenics Pharmaceuticals showed results in modified SCID mice for their anti-CCR5 monoclonal antibody, PRO 140. In this bit of good news for mice with HIV, PRO 140 was able to reduce viral load to undetectable levels within 8 days; viral suppression persisted for 6 to 12 days after the last dose. They also report that pharmacokinetics in a mouse model were favorable. (Franti, A1230)

Being first to market with an oral entry inhibitor is a high stakes race for Pfizer, and they are sprinting to make it happen. The company is said to be planning an innovative development track that takes a Phase II dose finding study and rolls it straight into a Phase III efficacy trial once the dose is set. This is a bit of a gamble because they will have to start investing in Phase III preparations before much of the key information about the drug (like the dose) is in hand. The payoff, though, is that they can shave six months or more off of the time it takes to get to market. After Schering had to switch to its fallback candidate SCH D, and with GSK's late entry into the entry inhibitor sweepstakes, Pfizer sees itself poised to dominate the next big thing in HIV therapy. If the Phase II trials get going soon, and if Pfizer maintains its aggressive course, the drug could possibly become available through expanded access programs in 2006 and be on pharmacy shelves by 2007. Now, who's going to step in and help tiny Anormed pick up the pace on AMD070?

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