Presentations

Clinical directions with novel targets

Abstract

As previously discussed by Dr Lange, several new targets are under development for antiretroviral therapy in HIV disease. Three of these targets � initial binding of virus, co-receptor interactions and fusion events � relate to HIV entry into host cells. It is not inconceivable, given the number of different ways in which cellular infection can be blocked, that in the future entire regimens focusing on HIV entry may be possible, just as viral reverse transcription is currently targeted by triple nucleoside and NRTI/NNRTI regimens. While there is obviously much work to be done before this possibility is realised, progress is being made with the introduction of entry inhibitor drugs � in particular the experimental agent T-20, currently in clinical trials. This drug is a 36 amino-acid peptide inhibiting gp41-mediated fusion. It acts by adhering to the N terminal of gp41, preventing the C terminal folding back in an
anti-parallel fashion, thereby preventing subsequent viral-cell fusion (see figure 1).

Figure 1

T-20 has demonstrated activity in T-cell lines at nanomolar concentrations. In vitro it is active against NSI and SI viruses and is synergistic with other experimental entry inhibitors as well as with RTIs and PIs. Due to the size of the molecule and the fact that this drug is a peptide, oral administration is not possible hence T-20 is administered by twice-daily subcutaneous injections. It is currently entering Phase III clinical trials.

Trials of T-20 started with a small Phase I, proof-of-concept trial, moving on to dosage and formulation studies. Ongoing, Phase II development has involved a paediatric study, chronic safety study, dose comparison study and a formulation improvements study. Collectively, these trials have provided a strong body of evidence that T-20 is active and generally well tolerated.

The initial Phase I, proof-of-concept trial involved four doses (3 mg, 10 mg, 30 mg and 100 mg) of IV monotherapy T-20, given bid over an 18-day period. Significant decreases in viral load were observed with the 100 mg dose group, achieving a median decrease of 1.96 log 10 copies/ml [1] (see figure 2).

Figure 2

Given these very promising data, study TRI-003 was established. This was a multicentre, randomized, Phase II, dose-ranging trial in heavily pre-treated patients. Seventy eight patients were randomised to one of six different regimens:

• Continuous subcutaneous infusion (CSI) daily
  � 12.5 mg
  � 25 mg
  � 50 mg
  � 100 mg

• bid subcutaneous injection (SC)
  � 50 mg
  � 100 mg

Treatment was administered for 28 days against a background of stable antiretroviral therapy or no therapy. Median baseline HIV RNA was 100,000 copies/ml and median CD4 count was 96 cells/mm3. The greatest decreases in HIV RNA levels were seen in patients receiving the bid subcutaneous injections rather than the continuous infusion. In this group, those receiving 50 mg bid SC achieved decreases of approximately 1.2 log 10 copies/ml from baseline, while those receiving 100 mg bid SC achieved decreases of 1.5 log 10 copies/ml (median nadir over 28-day study period). These results are particularly significant when one considers that these patients were heavily antiretroviral-experienced and did not initiate T-20 therapy with a new background regimen. Intent-to-treat analysis also showed significant decreases in viral load over the 28-day study period, with the greatest decreases observed in the 100 mg bid SC group.

Following these results, the T20-205 safety study was initiated. This multicentre, open-label, single-arm, 48-week study involved a rollover protocol from prior short-term T-20 studies. The study allowed for individualized therapy based on drug history and genotype. A dose of 50 mg bid SC was selected for the study. At baseline, mean HIV RNA levels were 5.0 log 10 copies/ml and median CD4 count was 90 cells/mm 3 . 97% of patients were PI-experienced while 79% were NRTI-, NNRTI- and PI-experienced. The median number of prior antiretrovirals was nine and the median number of concomitant therapies in the study was five [2,3].

At 16 weeks, intent-to-treat analysis revealed that approximately 54% of patients (60% by an on-treatment analysis) had achieved plasma viral loads <400 copies/ml or had at least a one log reduction in viral load. The data also highlighted two important facts:

• 60% of patients who had been exposed to all three classes of approved ARVs (NRTIs, NNRTIs
  and PIs), achieved overall viral loads <400 copies/ml or had at least a one log reduction in viral load
• 53% of patients, resistant at baseline to drugs in all three drug classes, responded to therapy while 30% achieved plasma viral loads <400 copies/ml

At week 48, using an intent-to-treat analysis, 33% of these extensively pre-treated individuals (56% by an on-treatment analysis) had achieved plasma viral loads <400 copies/ml or experienced more than a tenfold reduction in viral load from baseline levels.

These results were particularly encouraging as they demonstrate that T-20 containing combination regimens are effective in patients who are heavily pre-treated and harbour multi-drug resistant viral strains.

As previously discussed, due to the size of the T-20 molecule, it cannot be administered orally, hence parenteral administration is necessary. Given the potential impact of this on long-term patient acceptance, a T20-205 Activities of Daily Living (ADL) survey was conducted, which required patients to complete written questionnaires at baseline and at week 48 of the 205 study. Measures included activities of daily living and assessment of the ease of T-20 preparation, storage and disposal.

Fifty four of 71 surveys were received and results clearly indicated that the majority of patients (64%) did not consider that T-20 injections limited their daily activities. Perhaps, unsurprisingly, the activity most negatively affected by daily T-20 injections was 'travel', however, this view was held by only 53% of patients. Furthermore, 87% of patients indicated that ease of injection was �not bad, easy or very easy�. A similarly positive response was recorded for patient experience with preparation, storage and disposal. On a scale of one to five, where one is very difficult and five is very easy, patients indicated that disposal was easy (4.4), refrigeration was easy (3.8) and dissolving was not bad (3.4).

A randomized, controlled, open-label, dose comparison study, T20-206, has also been initiated to evaluate the addition of T-20 to a background antiretroviral regimen compared to background therapy alone. Three doses of T-20 are being evaluated (50 mg, 75 mg and 100 mg bid) and background therapy includes abacavir, amprenavir, ritonavir and efavirenz.

Preliminary analysis of study T20-208 data has revealed comparable PK profiles between a single injection formulation (100 mg T-20) and that of the original drug regimen comprising 2x50 mg injections. It is hoped that this more convenient regimen will benefit the patient since the number of daily injections has been reduced from four to two.

As a final point, it is pertinent to balance the positive results seen to date with T-20 against the challenges that face the future development of this drug. The most obvious challenge is that of patient acceptance of parenteral administration, but early survey results have indicated that no patients regard injection as a �very difficult� procedure and only 13% find it a �somewhat difficult� procedure. The potential for T-20 to elicit an antibody response has been raised as a potential issue, but available data to date have indicated that pre-existing antibodies to gp41 that cross react to T-20 do not appear to impact on safety, pharmacokinetics or antiviral activity. Furthermore, development of antibodies reacting to T-20 in patients not previously antibody positive seems to be minimal and with apparently no clinically relevant consequences. As with all antiretroviral agents, the development of resistance is a potential issue and mutations in the gp41 that map to the binding region for T-20 have been observed. Ongoing studies will allow the resistance profile of T-20 to be better defined. Lastly, the issue of complex synthetic manufacture is already being addressed such that large-scale manufacturing is currently being scaled up to meet future potential demand.

In summary, T-20 shows significant promise for treatment of HIV infection, and importantly, is active in patients with extensive prior exposure to anti-retroviral therapies. Promisingly, T-20 has also demonstrated synergy with existing agents and with other entry inhibitors. There is no doubt that T-20 represents a potentially important new addition to HIV therapeutic management tools and further data are eagerly awaited.

References

1. Kilby JM, Hopkins S, Venetta TM et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41- mediated virus entry. Nature Medicine 1998; 4:1302-1307

2. Lalezari J, Eron J, Carlson M et al. Sixteen week analysis of heavily pre-treated patients receiving
T-20 as a component of multi-drug salvage therapy. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, 26-29 September 1999. Abstract LB-18

3. Cohen C, Lalezari J, Eron J et al. Forty eight week analysis of patients receiving T-20 as a component of multi-drug salvage therapy. The XIII International AIDS Conference, Durban, South Africa, July 9-14 2000. Late Breaker Abstract.

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Biography

Dr Anton Pozniak studied medicine at the University of Bristol. He became involved in AIDS in 1983 at the Middlesex Hospital, London. Dr Pozniak worked as Lecturer and Honorary Consultant at the Department of Medicine at the University of Zimbabwe in the early 1990�s. He returned to the UK to join the Academic Department of Genito-urinary Medicine at the Middlesex, then moving as Senior Lecturer and Honorary Consultant at King's Healthcare NHS Trust in 1992. In 1998 Dr Pozniak moved to his current position as Consultant Physician and Honorary Senior Lecturer, Chelsea and Westminster Hospital. Dr Pozniak has published widely on HIV and AIDS. He is a member of various medical organisations including the British HIV Association and the Medical Society for the study of Venereal Diseases and chairman of PACT (Providers of AIDS, Care and Treatment).

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