Here is a 2nd report on new drugs presented on at Retrovirus. More reports on Retrovirus are being prepared on neurology/neuropathy, pharmacology & drug interactions (once a day dosing), STIs, lipodystrophy/body changes/lipids/bone problems/adverse effects/switching regimens/risk of accelerated heart disease, HCV/HIV coinfection & transplants, OIs, Women's Health/perinatal transmission, Resistance & Resistance Testing, pathogenesis of HIV, reservoirs, drug studies (Trizavir/NFV vs NVP/Kaletra/APV-RTV once daily).
--JL

New Drugs Reported at Retrovirus

     Reported for NATAP by Nancy Shulman, MD, Asst Prof of Medicine at Stanford University, Palo Alto, California

Entry Inhibitor in Early Development: CCR5 antagonist

One of the most exciting new class of drugs in development was presented by Schering-Plough at a state-of-the-art lecture. They have two new drugs that block the binding of HIV to the CCR5 co-receptor, a step required before the virus can fuse and enter into a cell. We know that people who have a genetic defect in all their CCR5 co-receptor are resistant to HIV infection (homozygotes) and if they carry half this defective gene (heterozygotes) they are slow progressors of HIV. These people are otherwise totally healthy, so we think that blocking CCR5 should be safe (although there are some lingering concerns about safety). They are developing two compounds (SCH-C and SCH-D) that can be taken by mouth, are well absorbed into the bloodstream and are potent inhibitors of HIV in vitro and in animal models with no significant toxicities to the animals. They also have a long half-life so will probably be once a day. They are synergistic with nucleosides and should also be synergistic with other drugs that block HIV from entering at different steps such as T-20 and T-1249 as well AMD3100. We all have been hoping for other drugs to give T-20 with in our patients with resistance to the available drugs. HIV spontaneously changes co-receptor preference from CCR5 to CXCR4 in 40% of patients with HIV during their illness, usually late in disease. This switches the favored cells of HIV from macrophages to lymphocytes and can be associated with a rise in viral load and drop in CD4 count. One fear of using this drug is that this may promote this switch. In vitro, resistance developed to SCH-C, but fortunately, it was not due to a CXCR4 switch. (abstract L11)

(Editor's note: I believe Greg Reyes, who presented the data on SCH-C, said they did not see a switch to CXCR4 in in vitro experiments, which of course needs to be confirmed in human studies).

Several posters discussed using CCR5 inhibitors with CXCR4 inhibitors like AMD3100 for synergy and to block the co-receptor switch by the virus. Phase I trials are in progress. The only side affect seen (with SCH-C) is at high doses was prolongation of the QT interval on EKG which poses a threat of developing an arrhythmia (heart rhythm problem) called Torsades that can be fatal. Lots of drugs on the market prolong the QT interval including common antibiotics like Zithromax, Cipro, Levoquin, and Quinine to name a few. Progenics is also developing a CCR5 inhibitor (PRO-140).

Protease Inhibitors For Resistance to Current Protease Inhibitors

Descriptions of three protease inhibitors DMP681 and 684 from Dupont and TMC126 from Tibotec, all early in development were presented by the companies. All are very potent inhibitors of HIV-1 in vitro and retain activity against many isolates with substantial PI resistance. Unfortunately no data was presented on what resistance mutations are selected for in vitro with these compounds. That type of data provides important information on cross-resistance. All these agents are entering phase I trials soon. (abstract 11)

NNRTI for NNRTI Resistance

Tibotec also presented phase I/II data on their new NNRTI, TMC-120 (previously called R147681). The drug was administered to antiretroviral naïve patients as one week of monotherapy prior to initiation of a standard HAART regimen. At one week, both 50mg and 100mg BID resulted in about 1.5 logs reduction of viral load. Side effects were mild and included somnolence, insomnia, and rare headaches (sounds like Sustiva). No liver side affects were seen. No one developed detectable resistance mutations during the 7-day study. In vitro resistance data was presented in a poster. It retains activity against G190A mutants (as does delavirdine), has only 4-fold reduced susceptibility against K103N isolates (EFV is about 40 fold and NVP and DLV are even higher), and 7-fold against Y181C (2-fold with EFV, and over 1000- with NVP and DLV). Again, no data on what mutations it selects for in vitro was presented. (abstracts 13 & 304)

T-1249: fusion inhibitor cousin of T-20

Joe Eron presented phase I/II data on Trimeris' son (or daughter) of T-20 called T-1249. This is an injectable fusion inhibitor that retains activity activity against T-20 resistant isolates. This was a study of 72 predominantly advanced patients (CD4 counts 85-135) who were not on any therapy for one month prior to receiving 2 weeks of T-1249. Multiple doses were tested and there was a dose-dependent reduction of HIV. The highest dose tested (25mg BID) yielded a 1.4 log viral load reduction at 2 weeks. PK data was collected and support the use of a once daily subcutaneous dosing regimen. The next study will need to test even higher once daily doses to see if it could reduce the viral load even further. 71% had adverse reactions, mainly injection site pain, irritation, or less frequently redness. One person had an allergic reaction with rash, fever, and oral ulcers that resolve when drug was stopped. Another had neutropenia (low white cell count). Overall the drug looks good so far and is tolerated well. (abstract 14 & 473)

FTC: once a day NRTI for treatment naive

Charlie Van Der Horst presented results from 2 phase III studies of FTC, a new drug similar to 3TC that is somewhat more potent and has a longer half-life so can be dosed once daily. FTC-303 was a randomized, open label switch study in patients who were on D4T, 3TC, and either NVP or EFV and undetectable. Two-thirds of the 440 patients were switched to FTC 200mg once a day, and the other one-third remained on their 3TC. The other study (302) took place in South Africa and was a randomized, double-blinded study looking at D4T with 3TC or FTC (each in half the patients) with NVP (for VL <100,000) or EFV (for VL>100,000). I am not sure why they didn't give everyone efavirenz or nevirapine, but they didn't. There was a substantial amount of nevirapine-related liver toxicity in this study (17%) with two women dying of liver failure. One had chronic hepatitis B. They have not unblinded the study to see if this was associated with FTC. This study enrolled mainly women (59%), and most were African (88%). The liver toxicity was disproportionately in the women. It could be a hormonal-related, a pharmacokinetic, or a weight-related issue. Ultimately both studies showed that FTC was equivalent to 3TC in suppressing and keeping people's HIV suppressed. (abstract 18)

BMS-232632: once a day protease inhibitor

Kate Squires presented phase II data on BMS new PI, BMS-232632, a once daily PI that appears not to raise the serum glucose, cholesterol or triglycerides like the rest of the PI's. Two studies have been conducted: stage I (safety& efficacy) 48 weeks, n=98) and stage II (24 weeks, n=322). The first part of the studies were two weeks of BMS at 3 different doses (200, 400 & 500 mg), followed by a comparative study looking at the three doses with D4T and DDI vs. nelfinavir 750mg TID with D4T and DDI. BMS has chosen 400 mg for further studies due to consideration of safety & antiviral activity. The efficacies in stage II were about 65% <400 (ITT) at 24 weeks and 30-35% <50 (ITT) in the two higher dose arms of BMS and the NFV arm showing comparability with NFV in naïve subjects (median baseline CD4 was 305 & viral load 51,000 copies/ml). Viral load 48-week data in stage I showed durability, as reduction was 2.3 to 2.8 log. Lipid abnormalities were only seen in the NFV arm. Although it was no more effective than NFV, this is the first once daily PI and it really seems not to have the lipid abnormalities we see in all the other PIs. Unfortunately no data was collected on lipodystrophic body habitus changes in this study. Side affects were nausea and diarrhea (20% vs.50% with NFV), and a dose dependent elevation in the bilirubin (like indinavir) that occurred in 70% of patients. Grade 3/4 ALT elevations in stage II were 6%(n=4) in the BMS 500 mg, 12% (n=10) in the BMS 400 mg arm vs 4% in the NFV arm (n=3). Phase III studies are planned that compare this PI at 400mg per day vs. efavirenz both with two nucleosides, probably D4T and DDI.

(Editors note: Criticism from observers was that antiviral activity did not appear very potent, and response from Squires was that additional studies are planned comparing BMS to other treatments which I think she said was efavirenz). (abstract 15)

Protein Design of an HIV-1 Entry Inhibitor

In the late-breakers, researchers from the Whitehead Institute at MIT described another drug that inhibits HIV entry different from the other inhibitors of entry like fusion inhibitors (T-20 and the like), the chemokine receptor antagonists (SCH-C, D, and AMD3100). This is a small protein inhibitor called 5-helix. HIV-1 cellular entry has a step where it forms a trimer-of-hairpins structure. This serves to bring the N- and C-terminal regions (ends) of the gp41 together, enabling fusion of the virus with the cell. 5-Helix was engineered to contain five of the six helices that make up the core of the gp41 trimer-of-hairpins structure. 5-Helix lacks a third C-peptide helix, and therefore binds tightly to the C-terminal of the GP41 protein. 5-Helix inhibits diverse HIV-1 strains in vitro. (Edit note: this may be difficult drug to develop; the presenter suggested drug may have utility in development of vaccine.) (abstract LB1)