Tipranavir development plans announced

Boehringer-Ingelheim has announced further development plans

for its protease inhibitor, tipranavir. Speaking at NAM’s symposium on Emerging Therapies for HIV Infection last Friday at the Royal College of Physicians in

London, Dr Hubert Bland said that the company already had plans for five

studies to commence in 2002 to determine the correct dose and to compare

tipranavir to other boosted protease inhibitors in PI-experienced patients.

Tipranavir was

purchased from Pharmacia in early 2000, and since then, Boehringer-Ingelheim

has been struggling with the formulation of tipranavir. The drug is of

considerable interest because of resistance data showing that clinical isolates

resistant to nelfinavir, saquinavir, ritonavir and indinavir retain sensitivity

to tipranavir.

Boehringer-Ingelheim expects that trial recruitment and data

analysis will take around 18 months, with tipranavir unlikely to be licensed in

the US or Europe before the end of 2004. However, expanded access for patients

not eligible for studies in PI-experienced patients could begin before the end

of 2002.

Dose finding

The first study, a dose-finding study, 1182.52, will compare

three doses of tipranavir with ritonavir (500/100mg 500/200mg and 750/200mg) in

patients with experience of all three classes of anti-retrovirals, including

two three month periods of protease inhibitor therapy. An optimised background

regimen of two non-protease inhibitor ARVs will be selected after genotypic

resistance testing. Participants will be able to include tenofovir in the

background regimen.

Participants will receive two weeks of treatment with

tipranavir/ritonavir before adding the optimised background regimen, in order

to assess the anti-HIV impact of different doses, and will then receive two

further weeks of treatment. The optimal dose will be selected on the basis of

antiviral response at week 2 and adverse events profile at week 4.

This study will recruit patients in the United States,

Canada, Australia, Italy, the United Kingdom, Germany, France and Spain, and

will commence recruitment in March 2002.

Efficacy in PI-experienced patients

After an interim analysis of the 1182.52 study has selected

the optimal dose, four studies will commence. Studies 1182.12 and 1182.48 will

have the same entry criteria as the study described above, but will compare the

selected tipranavir dose with another ritonavir-boosted protease inhibitor in

people with at least two three month periods of protease inhibitor experience

and experience of all three classes of ARVs.

Study 1182.12 will recruit 494 patients in North America,

Argentina, Brazil and Australia, and the optimal background regimen will be

selected using genotypic testing, while study 1182.48 will recruit 808 patients

in the European Union, with the optimal background regimen selected by Virtual

Phenotype.

These studies will both follow patients for 48 weeks, and

will be open label studies. If T-20 is licensed before the end of the study,

the protocols will be amended to allow people joining the studies to use T-20

as part of the optimised background regimen.

Two studies for people with multiple drug resistance are

also planned: 1182.51 will study the safety and effectiveness of adding

saquinavir/ritonavir, amprenavir/ritonavir or lopinavir/ritonavir to tipranavir,

while study 1182.13 will roll over patients from the 51 study after a safety

and pharmacokinetic analysis at week 8 of the 51 study. To join either study,

participants must have virus sensitive to less than two licensed

antiretrovirals (including tenofovir).

Boehringer-Ingelheim will also be looking at the interaction

of tipranavir and atazanavir, and at the interaction of nevirapine and tipranavir.

In the case of nevirapine, the company is particularly interested to examine

whether its non-nucleoside can moderate the effect of tipranavir on lipid

levels; data presented at the First International AIDS Society Conference on

HIV Treatment and Pathogenesis in Buenos Aires earlier this year showed that

around 20% of participants in BI 1182.2, a comparison of 500/100 or 1000/100mg

of tipranavir/ritonavir, developed hypertriglyceridemia after 24 weeks. If

nevirapine did show a moderating effect, Boehringer-Ingelheim will look at

co-formulating tipranavir with nevirapine, said Dr Hubert Bland.