THERAPY

-Gillian Hill-

Saquinavir ['Invirase'; Roche1 was the first protease inhibitor to be launched for the treatment of IllV infection. Extensive clinical experience has shown it to be an effective and well tolerated component of combination anti-1llV therapy, delaying disease progression and prolonging survival in lllV-infected individuals. Recently, a new soft gelatin capsule fonnulation oC saquinavir has been developed [saquinavir-SGC; 'Fortovase'] which, at the recommended dosage, achieves plasma saquinavir concentrations approximately 8- to lO-fold higher than those attained with 'Invirase', the conventional hard gel Connulation • Since the activity oC saquinavir is directly related to plasma drug concentrations, it is anticipated that this new Connulation will help optimise the antiviral and clinical benefits oC saquinavir. The first data on saquinavir-SGC were presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) [Toronto, Canada; September 1997] and at the 6th European Conference on Clinical Aspects and Treatment oCIllV [Hamburg, Germany; October 1997].

Despite the increased saquinavir exposure achieved with the new soft gel formulation, ongoing clinical studies indicate that its tolerability profile is similar to that of the conventional formulation. Data from several studies investigating the effects of the new saquinavir-SGC were presented at the 37th ICAAC.

Similar tolerability Results of the saquinavir-SGC tolerability study

(NV 15182) were reported by Dr J Gill from the Southern Alberta mv Clinic in Canada. A total of 442 patients with HIV infection were included in the study and treated with saquinavir-SGC 1200mg 3 times daily in combination with a variety of other antiretrovirals for 48 weeks. The entry criteria were unrestrictive, and consequently the study population was broad and considered to be representative of clinical practice.

Saquinavir-SGC was generally well tolerated with only 8% of patients discontinuing the study medication because of clinical adverse events, which were primarily related to the gastrointestinal system. The majority of these adverse events were classed as being of mild intensity and most frequently included diarrhoea, nausea and abdominal discomfort. Less than 1 % of patients were withdrawn because of biochemical abnormalities.

Activity comparable with indinavir Saquinavir-SGC showed similar antiretroviral

activity to indinavir at 24 weeks, according to data presented by Dr J Borleffs from the University Hospital, Utrecht, The Netherlands. Dr Borleffs discussed the results of the CHEESE* study, which was the first trial to directly compare the activity of 2 protease inhibitors, which were administered as part of a triple-therapy regimen.

The study included individuals with mv infection who were either antiretroviral-naive or had < 12 months' zidovudine experience. The patients had a CD4+ cell count of < 500/mm3 and/or a plasma mv RNA level of> 10,000 copies/ml and/or mY-related signs or symptoms. Eligible patients were randomly allocated to receive zidovudine 200mg 3 times daily plus lamivudine twice daily and either

• Comparative trial in HIV-infocted persons EvalwIIing FIJiax:y and Sofety of saquinavir-Enhonced oraJJomwlotion and indinavir given as pa11 of a triple therapy

1173-832419711112..()()()13/$O1 .000 Adlelm.metJonal UmIlH 1l1li7. All rlghla __

saquinavir-SGC 1200mg 3 times daily (n = 21) or indinavir 800mg every 8 hours (n = 23).

Additional effects on CD4+ cells? The two regimens were equally effective in

suppressing viral load. In both groups, plasma mv RNA levels dropped dramatically (from a mean baseline value of 4.9 10g,oCopies/ml) falling to below the limit of quantification of the Amplicor assay « 400 copies/ml) in all patients by week 8; this response was maintained over a further 16 weeks. Only 3 patients withdrew due to adverse events (2 patients who received indinavir and 1 saquinavir­SGC recipient).

'These preliminary data clearly establish the new formulation of saquinavir as one of the most potent protease inhibitors. At week 12, we also found that this new formulation led to an interesting increase in CD4 cells versus indinavir, a result which deserves further investigation. The two regimens were equally well tolerated' , concluded Dr Borleffs.

SUN shines for new option The combination of saquinavir-SGC plus

lamivudine and zidovudine was also evaluated in the SUN study, reported Dr Michael Sension from the North Broward Hospital District, Fort Lauderdale, US. This pilot study included 40 individuals with mv infection (with a mean baseline mv RNA level of 4.8 10gloCopies/ml) who had not received prior antiretroviral therapy. After 20 weeks' treatment, the mean plasma mv RNA level had fallen by a mean of 3.34 10gloCopies/ml and was below the limit of quantification of the Amplicor assay in 91 % of patients. CD4+ cell counts had increased from baseline by a mean of 259/mm3.

Additional studies of the new saquinavir-SGC formulation were presented at the 6th European Conference on Clinical Aspects and Treatment of mY, held in Hamburg 2 weeks after the 37th ICAAC.

Comparison with 'Invirase' Data from a large comparative trial presented at the

European conference confirmed that the new saquinavir-SGC formulation provided more potent suppression of mv than the hard gel formulation with no significant change in tolerability profile, said Dr B Conway from St Paul's Hospital, Vancouver, Canada.

Inphatma8 • Nov 1l1li7 No. 1112

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14 THERAPY

In this study, 171 antiretroviral-naive patients with mv infection and HIV RNA levels> 5000 copies/ml were randomised to receive 2 reverse transcriptase inhibitors (RTIs) of choice plus either saquinavir-SGC 1200mg 3 times daily or the conventional saquinavir formulation 600mg 3 times daily.

In an analysis conducted after 16 weeks' treatment, 80% of saquinavir-SGC recipients achieved plasma viral loads below the level of quantification of the Amplicor assay, compared with 43% of recipients of the conventional saquinavir formulation (p < 0.001). The mean reduction from baseline in plasma mv RNA level in the 2 treatment groups was 2.0 10gJoCopies/ml and 1.6 10gJoCopies/ml, respectively. Both formulations were generally well tolerated.

Getting what we want from SPICE The use of saquinavir-SGC in combination with

nelfinavir was discussed by Dr A Posniak from Kings College Medical School, London, UK. He presented the results from a 16-week interim analysis of the SPICE** study which included 157 individuals with mv infection. The patients had a mean baseline HIV RNA level of 4.8 10gJoCopies/ml and a mean baseline CD4+ cell count of 307/mm3• They were randomised in a 1: 1 :2:2 manner to receive 1 of the following combinations: • nelfinavir + 2 RTIs • saquinavir-SGC + 2 RTIs • saquinavir-SGC + nelfinavir • saquinavir-SGC + nelfinavir + 2 RTIs.

Around 50% of subjects were antiretroviral naive and all started :2! 1 new RTI. The study is planned to run for 48 weeks.

At the 16-week analysis, 84% of individuals treated with saquinavir-SGC plus nelfinavir plus 2 RTIs had viral loads below the level of quantification of the Amplicor assay [see table]. The greatest benefit of quadruple therapy was observed in previously untreated patients, with plasma HIV RNA levels dropping to below the level of quantification in over 90% by week 12.

Promising results in children The activity of saquinavir-SGC in combination

with 2 RTIs is also being investigated in an open-label study in children able to swallow adult capsules. Dr C Fletcher from the University of Minnesota, Minneapolis, US, reported preliminary data from this study which at the time of reporting had recruited 14 children (aged 3-13 years) who had received prior therapy with RTIs for a median of 4 years. Inpharma·' Nov 1"7 No. 1112

After 4 weeks' therapy with the saquinavir-SGC­containing regimen, plasma HIV RNA levels had fallen to below the limit of quantification of the Amplicor assay in 5 of 12 children; this was the case in 7 of 7 children at week 8. To date, the regimen has been well tolerated with no serious adverse events occurring and no patients discontinuing treatment.

** Study of Protease Inhibitors in Combination in Europe

~ Editorilll comment: Roche has filed an NDA with the US FDAfor the saquinavir-SGC formulation.

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