ICAAC 2011: New Integrase Inhibitor BI 224436 Active against Raltegravir-Resistant HIV


Boehringer Ingelheim's novel integrase inhibitor candidate BI 2244336, which works by a different mechanism than existing drugs in its class, demonstrated potent antiviral activity and a good pharmacokinetic profile in a series of early studies presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) last month in Chicago.

Integrase inhibitors interfere with HIV's integrase enzyme, which the virus uses to insert or integrate its genetic material into a host cell's genome. BI researchers used a high-throughput assay to screen a large number of compounds, identifying a set of agents known as non-catalytic site integrase inhibitors (NCINIs) that bind to a conserved pocket on the enzyme that is also targeted by LEDGF.

Initial laboratory studies showed that compounds from this novel subclass exhibited antiviral activity against recombinant viruses with known integrase inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations. Conversely, the sole approved integrase inhibitor, raltegravir (Isentress), and Gilead's investigational elvitegravir showed activity against HIV that developed resistance to NCINIs.

The lead NCINI, BI 224436, has been evaluated so far in laboratory tests and in a study of healthy HIV negative volunteers.

Investigatorsfrom Boehringer Ingelheim Canada (abstracts F1-1369 and F1-1370) used the PhenoSense assayto measure in vitro antiviral activity of BI 224436 against 200 recombinant viruses encoding integrase enzymes from clade B HIV-1 isolates from 100 U.S. and 100 European treatment-naive patients. They also tested antiviral activity against 40 recombinant viruses containing integrase from raltegravir-resistant HIV-1 clinical isolates.

BI 224436 had a mean EC50 (50% effective concentration) of 14 nM for the 200 clinical isolates tested with PhenoSense; the EC90 was 39 nM. It also retained its potency against the 40 raltegravir-resistant isolates, with a mean EC50 of 26 nM and mean fold change of 1.4 relative to wild-type virus. BI 224436 showed no cross-resistance to other classes of approved antiretroviral agents, including catalytic site integrase inhibitors such as raltegravir.

Furthermore, BI 224436 demonstrated good absorption, distribution, metabolism, and excretion properties, minimal potential for interactions with drugs processed via CYP3A4 and CYP2DG enzymes, and a favorable metabolic profile.

Another Boerhinger Ingelheim team (abstract A1-1725) conducted the first-in-humans study, a double-blind, placebo-controlled, single rising dose Phase 1a trial of an oral solution of BI 224436 in 48 healthy male volunteers. Participants were randomly allocated to 6 ascending dose cohorts (6.2, 12.5, 25, 50, 100, and 200 mg); in each cohort, 6 people received BI 224436 and 2 received placebo.

BI 224436 demonstrated favorable pharmacokinetic (PK) parameters. The oral formulation was rapidly absorbed. Area under the curve (AUC, or total exposure over time between doses) and maximum concentration (Cmax) showed a steep dose-response curve. Inter-person variability was low. Half-life ranged from about 6 to nearly 8 hours.

BI 224436 was generally well-tolerated; 4 people experience mild adverse events (headache, upper abdominal pain, oral paresthesia). No clinically relevant changes in vital signs, ECG, or laboratory parameters were observed.

Based on these findings, researchers selected the 100 mg dose for further trials, as it came closest to the desired therapeutic concentration. PK properties suggest BI 224439 can likely be administered once-daily.

Boehringer Ingelheim and Gilead Sciences announced this week that they have entered into a licensing agreement under which BI has granted Gilead exclusive worldwide rights for the research, development, and commercialization of its novel NCINIs, including BI 224436.

Investigator affiliations:

Abstract F1-1369 and F1-1370: Boehringer-Ingelheim (Canada) Ltd, R&D, Laval, Canada.

Abstract A1-1725: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; Buffalo Clinical Research Center, Buffalo, NY; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

Abstract A1-1726: Ordway Res. Inst., Albany, NY; Boehringer Ingelheim Ltd, R&D, Laval, Canada.



C Yoakim, M Amad, MD Bailey, et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic site integrase inhibitor. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract F1-1369.

C Fenwick, R Bethell, M Cordingley, et al. BI 224436, a non-catalytic site integrase inhibitor, is a potent inhibitor of the replication of treatment-naive and raltegravir-resistant clinical isolates of HIV-1. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract F1-1370.

S Aslanyan, C Ballow, JP Sabo, et al. Safety and pharmacokinetics (PK) of single rising oral doses of a novel HIV integrase inhibitor in healthy volunteers. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract A1-1725.

AN Brown, J McSharry, R Kulawy, et al. Pharmacodynamics of BI 224436 for HIV-1 in an in vitro hollow fiber infection model system. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract A1-1726.

Other Source

Gilead Sciences. Gilead and Boehringer Ingelheim Sign License Agreement for Novel HIV Non-Catalytic Integrase Inhibitors. Press release. October 5, 2011.