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.