HTB

Incremental progress with new antiviral drugs

1 November 2003. Related: Conference reports, Antiretrovirals, .

David Margolis, NATAP.org

Despite the proliferating frequency of meetings, it was encouraging to hear reports of steady advances in the development of new antivirals. Most exciting was the progress of multiple entry inhibitor drugs, creating optimism that we are moving towards combination therapy at the point of virus entry into the T cell.

CCR5 chemokine HIV co-receptor blocker: first report of anti-HIV effect in HIV-infected people

HIV requires a second receptor in addition to CD4 to enter cells. Drugs that effectively block this interaction are hoped for to add a new and highly potent class of antivirals to our armamentarium. Of the two most-often used chemokine receptors, CCR5 is the receptor primarily used by most HIV strains dominant in HIV-infected people, both during the initial process of infection, and throughout the course of disease. This receptor is therefore a therapeutic target of great potential, particularly as some immunologically healthy humans are born with the functional absence of CCR5. Blockade of CCR5 by a drug might therefore be well tolerated.

A safety study of Pfizer’s CCR5 antagonist in HIV-negative volunteers [1] showed that steady state drug levels were reached within seven days of dosing. 100mg and 300mg BID was well tolerated over 28 days of dosing.

There were no serious adverse events reported, and all treatment related adverse events were of mild or moderate intensity. No clinically significant increases in any laboratory safety tests including haematology, clinical chemistry or lipid profiles, and no clinically significant changes in 12-lead ECGs, blood pressure, or heart rate were observed.

Pozniak and colleagues then reported on the short-term antiviral activity of UK-427,857 [2].

Twenty-four asymptomatic, untreated HIV-positive patients with CD4 counts >250 cells/mm3 and plasma viral load >5000 copies/mL were treated with UK-427,857 for 10 days. Volunteers were given 25mg once a day, 100mg twice a day or placebo for 10 days and were followed for 30 days after drug was stopped.

Prior to dosing, patients were selected for this study that had predominant circulating viral populations that used the CCR5 receptor, rather than the other major co-receptor CXCR4 (seen most often in individuals with advanced AIDS). A concern is that blockade of CCR5-using viruses may lead to the selection and outgrowth of X4-using viruses, which might result in more rapid disease progression.

UK-427,857 was well tolerated with no severe or serious adverse events. EKG abnormalities, seen with some prior chemokine blocker candidates, were not found. Although the Pfizer team hopes to develop a drug without food restrictions, plasma levels are much higher when the drug is taken in the fasted state than with a high-fat meal. A study evaluating the impact of food on viral load reduction is ongoing. In this study, drug levels were also much higher and more stable at the 100 mg bid dose, rather than the 25 mg qd dose.

However, the 100mg bid dose of UK-427,857 yielded an impressive mean decrease in viral load of 1.42 log10 in only 10 days, with a mean decrease of 0.42 log10 at the 25mg QD dose. It was discovered that one patient harboured a mixed population of X4 and R5 viruses. This subject responded poorly to UK-427,857 monotherapy, and although viral load did not increase, a semi-quantitative assay suggested that the proportion of circulating X4 virus increased roughly 10-fold.

An accompanying presentation [3] showed UK-427,857 to be a potent inhibitor of R5 HIV-1 replication in the lab, and predictably inactive against X4 or R5X4 strains.

The drug’s antiviral activity was unchanged despite increases in virus innoculum added to laboratory viral cultures, suggesting that viral load should not have a direct effect on efficacy in patients.

Recent laboratory studies suggest that R5 receptors are a limiting factor for HIV entry, and that multiple R5’s are needed for the entry of a single viral particle. In other words, one individual may have 100 R5 receptors and another person may have 90 R5 receptors, but HIV may only need 50 R5 receptors for entry. Donor-to-donor PBMC variations (variations among study subjects) in host co-receptor expression did not affect potency in the study discussed in abstract H-875, indicating that “427” should be active regardless of individual variations in CCR5 expression or function. Currently, it appears that Pfizer must define the optimal dose for UK-427,857, and whether high levels of drug that saturate available R5 receptors are necessary, or whether sub-saturating doses will be equally clinically effective. However, the initial potent antiviral effects seen in short-term monotherapy are very encouraging. An important new antiretroviral may not be too far off.

T-20 to T-1249: a sequence of fusion inhibitors?

Lalezari [4] presented further follow-up on the activity and effect of the use of the second-generation fusion inhibitor T-1249 in subjects who had failed the first generation fusion inhibitor T-20.

Data on 25 patients was initially presented at CROI in February 2003. Fifty-three patients failing T-20 and other antivirals with a median baseline HIV RNA of 4.97 log10 copies/ml received at least one dose of T-1249. These subjects had been failing T-20 for a median time of 66 weeks (range 28-165). All (52 or 53) whose virus could be amplified demonstrated T-20 resistance mutations and/or decreased susceptibility. Nevertheless, the median HIV RNA decline was 1.26 log (95% C.I. 1.40 to 1.09) after 10 days of therapy. No serious adverse events (AEs) related to T-1249 were seen, and site reactions and AEs were similar to T-20.

The authors suggested that this potent short-term response to T-1249 implied that sequencing of fusion inhibitor drugs after the development of resistance might be a viable clinical strategy. Certainly, more long-term data are needed. Alternatively, as T-1249 moves forward in development, the first use of this more potent agent may be preferable.

In a related presentation, Trottier [5] reported the 48-week response to enfuvirtide (T-20) in the TORO Trials.

As presented at CROI 2003 in February, heavily pre-treated patients (median 12 ARVs) were randomised to an optimised background (OB) regimen or to OB + enfuvirtide (ENF; 90 mg sc BID). The overall median viral load and CD4 count at baseline were 5.1 log copies/mL and 92 cells/mm3, respectively. At 48 weeks, 30.4% of patients (201/661) on ENF+OB had VL <400 copies/mL by ITT analysis. Most of these had responded by this criterion at 24 weeks, and maintained response, but a few (4.2% or 28 patients) dropped below 400 copies after 24 weeks and remained below 400 copies at 48 weeks.

These findings suggested a continuing clinical benefit of T-20 use with OB in this difficult-to-treat population. The challenges of a year of T-20 in the setting of advanced disease appear surmountable, and as with other antivirals, a clinical benefit may be reaped despite the gradual evolution of drug resistance.

Blocking the viral “handshake” with the T cell

Colonno and colleagues at Bristol first presented BMS-378806 (“806” for short) at the Resistance meeting in 2002. BMS are discontinuing 806 but pushing ahead with other candidates in their research and development programme of CD4 receptor inhibitors. The novel 806 small molecule is a specific inhibitor of HIV-1 attachment that blocks the interaction of the binding pocket of the viral envelope Gp120 with the CD4 receptor. The group presented further basic laboratory studies [6] aimed at illuminating the precise mechanism of blockade.

Their elegant work showed that 806 binding induces changes in the shape of gp120. Further, the shape-shifting forced by 806 may also affect gp120’s ability to bind the CCR5 co-receptor. Lab studies suggested a synergistic antiviral effect when 806 was combined with a CCR5 chemokine co-receptor inhibitor or gp41 fusion inhibitor. Although BMS are switching the focus of their programme, the possibilities are exciting.

Developing NNRTIs

Hazen and co-workers from GSK added to the story of this new drug class [7] as first reported at CROI 2003.

GW8248 is a benzophenone and a potent NNRTI. A prodrug form of GW8248 with increased bioavailability and solubility is also under development. Like other NNRTIs, GW8248 inhibits HIV in the low nanomolar range. It is of great interest as it is active against a wide variety of NNRTI-resistant strains, including Y181C and K103N. GW8248 exhibited additive activities with other NNRTIs (NVP, DLV and EFV), was additive or synergistic with the activity of nucleosides, and generally synergistic with the activities of PIs.

To pose a very challenging laboratory test to GW8248, Hazen and colleagues tried to evolve a GW8248-resistant virus in the laboratory, starting with a K103N NNRTI pan-resistant virus. After eight serial passages of K103N-infected cells in the presence of sub-inhibitory concentrations of GW8248, GSK scientists were able to grow out a virus encoding new mutations at V106I, P236L and E138K that was 50-fold resistant to GW8248. This is a glass half-full, as while this experiment shows that resistance can develop, the fact that eight passages and three new mutations are required is encouraging.

The activity of capravirine (CPV), a novel NNRTI, was evaluated in combination with nelfinavir and two NRTIs in a Phase 2 study in HIV-infected, NNRTI-experienced patients [8].

It is hoped that CPV will have expanded activity against NNRTI-resistant HIV. Due to animal toxicities, this study was closed prematurely, but 36 patients chose to continue on open-label CPV. Of these 16 remained virologically suppressed (VL < 400 copies/mL) after 28 to 34 months of therapy. While 80% of the patient isolates demonstrated high-level resistance (>10-fold) to one or more of the approved NNRTIs, 70% remained susceptible (<10-fold resistance) to CPV. Despite its slow development, it is hoped that we will have more promising news about CPV soon.

References:

  1. Russell D, Bakhtyari A, Jazrawi RP et al. Multiple dose study to investigate the safety of UK-427,857 (100mg or 300mg) BID for 28 days in healthy males and females. 43rd ICAAC, September, 2003; Abstract H-874
  2. Pozniak AL, Ftkenheuer G, Johnson M et al. Effect of short-term monotherapy with UK-427,857 on viral load in HIV-infected patients. 43rd ICAAC, September, 2003; Abstract H-443.
  3. Macartney MJ, Dorr PK, Smith-Burchnel C et al. In vitro antiviral profile of UK-427,857, a novel CCR5 antagonist. 43rd ICAAC, September, 2003; Abstract H-875
  4. Lalezari JP, Bellos N, Richmond G et al. Final analysis of T1249-102: T-1249 retains potent short term antiviral activity in patients who have failed a regimen containing enfuvirtide (ENF). 43rd ICAAC, September, 2003; Abstract H-444.
  5. Trottier B, Arasth K, Henry K et al. Durability of response of enfuvirtide through 48 weeks in the TORO trials. Abstract H-835.
  6. Lin P, Ho H, Fan I et al Impact of an HIV-1 attachment inhibitor on viral envelope Gp120. 43rd ICAAC, September, 2003; Abstract H-877
  7. Hazen RJ, Harvey R, Ferris R et al. Characterisation of the anti-HIV-1 activity of GW8248 in combination with other anti-retroviral drugs and in vitro selection for resistance. 43rd ICAAC, September, 2003; Abstract H-445.
  8. Hammond JL, Amantea M, Raber S et al. Long-term virologic response to capravirine in HIV-infected, NNRTI-experienced patients. 43rd ICAAC, September, 2003; Abstract H-871.

Source: NATAP.org

Links to other websites are current at date of posting but not maintained.