Merck buys protease inhibitor from Ambrilia, may be potent booster of other PIs

Merck & Co announced last week that it has licensed an experimental protease inhibitor that does not require ritonavir boosting and which may be active against highly drug-resistant HIV. The compound, PPL-100, was developed by Ambrilia Biopharma (formerly Procyon) and previously by Pharmacor, both Montreal-based companies. PPL-100 appears to be just as potent a booster of other HIV protease inhibitors as ritonavir (Norvir).

So far the only human study of PPL-100 has been a phase 1a single dose pharmacokinetic study in healthy volunteers, which showed that the drug may have a half-life of up to 36 hours at doses of 2400mg a day, making it a strong candidate for once-daily dosing. Drug exposure with and without ritonavir boosting is currently being evaluated in a phase IIB dose-ranging study; this study is testing PPL-100 doses of 600 and 1200mg once daily in order to determine whether the drug can be given with a lower pill burden, without ritonavir, once daily.

In vitro studies suggest that selection of resistance mutations over 52 weeks is limited with this compound, indicating a high genetic barrier to drug resistance. No cross-resistance to amprenavir, lopinavir, atazanavir, saquinavir, indinavir, and nelfinavir was observed for any viral mutants, but resistance mutations associated with PPL-100 led to hypersensitivity to saquinavir.

Ambrilia has also reported that PPL-100 is a cytochrome p450 3A4 inhibitor, like ritonavir, and a pharmacokinetic enhancer for marketed PIs such as atazanavir, amprenavir, lopinavir, saquinavir, indinavir, and nelfinavir. At last month’s Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco the company reported data showing little difference in cytochrome p450 inhibition between PPL-100 and ritonavir when the effects of each compound on clerarance of other marketed protease inhibitors were measured in vitro using human liver microsomes incubated with active drug for 60 minutes (Wu 2006).

If PPL-100 is safe and effective enough to be licensed, it will be a very significant entrant to the market, since protease inhibitor boosting is dominated by ritonavir. Abbott Laboratories attracted severe criticism in December 2003 when it raised the price of ritonavir by 400%, raising the cost of boosted protease inhibitors above the price of its own ritonavir-boosted product Kaletra.

Manufacturers of protease inhibitors will be interested to discover whether PPL-100 has the capacity to boost their own products at a lower cost than ritonavir, and without the lipid elevations and gastrointestinal problems associated with that drug. Pharmacokinetic studies to test the boosting effects in large populations of HIV-positive people will not take place until the drug is closer to licensing, but Merck will face strong pressure to carry out a wide range of studies before licensing, and also to discuss the potential for coformulation of this product as a booster for other protease inhibitors, a path which has not been open with ritonavir due to difficulties in coformulating it with most other protease inhibitors.

A back-up analogue called PL-337 is also in development and Merck has an option to develop this product too. Ambrilia also has an integrase inhibitor development programme that is engaged in preclinical screening of compounds. Merck is already developing one integrase inhibitor, MK-0518, and has an interest in developing a pipeline of similar products.