Take-No-Prisoners Tack on TAG Pipeline Report Snubs Host of Drab Wannabes; Cozies up to Fevered Few
“Burned One Time Too Many”
Someone’s been reading too many Dow Jones publications this summer. For what began as a kind of no-nonsense clinical relevance approach to the latest drug pipeline offerings, turned into something of an amateur stock screen — whittling 44 candidate compounds down to just over half a dozen.
Three basic tests were applied to TAG’s summer pipeline report. First, anything that has already received FDA approval (e.g., Fuzeon, Reyataz, Emtriva) or is ostensibly on its way to approval (e.g., fos-amprenavir) was deleted from the list of pipeline candidates.
Second test: no me-toos. Any remaining nukes, non-nukes, PIs were similarly expunged — (yes, ACT UP/Paris, even the life-saving tipranavir). Even though some of the compounds may in fact live up to their claims of “novelty” (e.g., the TMC compounds or the calanolide non-nukes), we have been burned enough times in the past to look beyond these dodgy promises. (For the record, Fuzeon’s step sister, T-1249, should probably also be foisted aside. But if T-1249 proves easier to administer [or more potent?] than feckless Fuzeon, it would clearly represent a significant clinical advance.)
Finally, anything that hasn’t made it into humans yet fails to meet our toe-tapping, finger-drumming time line test. So any compound that is still being tinkered with in test tubes, cell cultures or anesthetized rodents and primates — while, granted, one day, potentially a breakthrough — simply fails to address our short- to intermediate-term therapeutic needs.
Once these three tests were applied, we were left with a lineup of 14 compounds — from an original field of 44. A good half of these 14 were listed only in the report’s impressive introductory table — with nary a mention of their mechanism, clinical development or study results to date. On top of that, two entire drug classes (zinc fingers and maturation inhibitors) disappeared from the report entirely. (Cue John McLaughlin: Bye-bye.)
What then, are we left with? A pair of integrase inhibitors; another duo of co-receptor antagonists (that is, if we can really even count the arrhythmia provoking Schering compound); one throwback from the days of therapeutic nihilism (a soluble CD4 receptor that may very well wind up meeting its 20th century predecessor’s fate); a monoclonal antibody that blocks viral entry; and, oh yes, T-1249. As always, the complete report is available at www.treatmentactiongroup.org/pipeline-report/2003.
Extracellular Agents: Attachment and Entry Inhibitors
With the exception of T-20 (Fuzeon), all FDA-approved anti-HIV drugs act inside HIV-infected cells by interfering with reverse transcriptase or the HIV protease enzymes. The third major drug target that has been successfully exploited is HIV gp41 — a molecule on the virus’ surface that changes its shape in a specific way to allow viral fusion.
Why are investigators looking here, outside the cell? HIV drugs that work inside the cell can be efficiently neutralized by some cells, using primitive, innate self-defense mechanisms such as efflux pumps which sense toxins and eject them out of the cell. This kind of “cellular resistance” may be an important reason for viral persistence and evolution in people on seemingly potent combination therapies. Extracellular antiretroviral therapy might circumvent this problem. More immediately, any drug working on a separate part of the virus’ life cycle would have little or no potential for cross-resistance with the current drug regimens.
Entry Inhibitor: T-1249
T-1249’s development is roughly three years behind T-20. And as there are no orally available fusion inhibitors in current development, where we are in 2003 is where we are likely to be for the foreseeable future.
T-1249 is another injectable Roche peptide, similar in design to T-20 but binding to gp41 just downstream of T-20’s binding site. It has been tested in phase I/II trials for activity against T-20-resistant viruses.
In one small study, T-1249 was given to 23 people with both genotypic and phenotypic resistance to T-20 for 10 days. 19/23 (79%) people had at least a 0.5 log drop in HIV RNA at day 11, which is in the range of non-significant. People failing T-20 for 24-48 weeks appeared to have better responses (7/7 people achieved >1 log decrease in HIV RNA; median day 11 decrease in HIV RNA -1.6 log) than those who had been failing for >48 weeks (8/17 achieved >1 log decrease in HIV RNA; median day 11 decrease in HIV RNA -0.94 log). Frequency of injection site reactions was not reported.
This was an interim analysis. The full data set from this study was expected to be presented at the IAS meeting in Paris.
Extracellular Agents: CD4 Receptor Antagonists
- Attachment Inhibitor: PRO 542
Progenics’ Pro 542 is sort of rsCD4 revisited. A soluble CD4 receptor, Pro 542 binds to and neutralizes gp120 before binding can occur. The CD4 receptor region is integrated into an immunoglobulin molecule to form a protein synthesized via monoclonal antibody technology.
Results from phase I/II clinical trials of Pro 542 involving HIV-infected adults and children were published in 2000. In the adult phase I study, volunteers were treated with a single intravenous infusion of Pro 542 at doses of 0.2-10 mg/kg. Pro 542 was well tolerated, and no dose-limiting toxicities were identified. Transient HIV-RNA decreases were reported after single-dose administration.
In the phase I/II study, enrolling 18 HIV-infected children, Pro 542 was evaluated by single and multidose intravenous infusions. The drug was well tolerated, and, as seen in the adults, dose proportionality was observed in terms of AUC and serum concentrations. Decreases of approximately 0.7 log copies/mL in plasma HIV-RNA levels were seen in four of six children treated with four weekly 10 mg/kg doses. After two weeks of treatment, three children had sustained reductions in serum HIV-RNA; the other children had rebounded to baseline levels.
A second set of phase II clinical trials, which are also being conducted in adults and children, were kicked off in 2000. These studies include people with HIV resistance to current antiretroviral options. The drug is currently being evaluated in an improved formulation for subcutaneous administration.
- Entry Inhibitor: TNX-355
TNX-355 (formerly HU5A8) a humanized IgG4 anti-CD4 domain that acts by binding to the CD4 receptor, and thus keeps HIV from entering after binding. It has demonstrated potent anti-HIV-1 activity in vitro, and studies in rhesus macaques and human peripheral blood lymphocytes indicated that it is not immunosuppressive. It is broadly inhibitory across all clades of HIV and inhibits both CCR5 and CXCR4 tropic virus.
The antibody attaches to the side of the CD4 receptor in a way that does not interfere with its regular function as a chemokine receptor. Nor does it interfere with HIV’s docking with the CD4 receptor, but it does block HIV from taking further steps in the process of entering the cell.
Does it also then block the entrance of other normal agents? Based upon these preliminary data, a study was performed to determine the safety and preliminary anti-HIV activity of a single dose of TNX-355 in HIV-infected people.
A human study of TNX-355 enrolled five sequential cohorts of six HIV-infected people who received single IV doses of TNX-355 in an open-label dose-escalation study. They had a mean baseline CD4 count of 354 cells/mm3 and viral load of 5.1 log copies/mL. All were HAART-experienced and almost 2/3 of the people were on failing HAART regimens at study entry.
Duration of complete CD4 cell coating with TNX-355, ranged from 1-2 days at 1 mg/kg to 15-27 days at 25 mg/kg, which correlated with the day of viral load nadir. No significant adverse events were reported.
The single dose did not generate any natural antibody reaction. Peak reduction in viral load occurred out to days 14 and 21. The study team is in discussions with researchers who do kinetic modeling to try to understand the process. Further assessment of therapeutic potential awaits data from longer duration trials; a phase 1b multiple-dose study is planned.
One advantage of TNX-355 may be the possibility of administering it on a schedule of once a week to once every three weeks. Macaques with multiple exposures to the monoclonal antibody developed antibodies to it that blocked activity of the drug. This issue, not seen in the single-dose human study, is one that will be closely monitored as the drug moves into phase II trials.
Extracellular Agents: Co-Receptor Antagonists
- Co-Receptor Antagonist: SCH-C
Schering C (SCH-C) is one of several small-molecule agents that have been studied as potential antagonists of CCR5.
Earlier, there had been some concern regarding QT prolongation seen in individuals receiving the highest dose of SCH-C. These observations led the FDA to put the SCH-C development program on hold. However, the hold on development has since been lifted.
Three doses have been selected for further evaluation — 25 mg, 50 mg, and 100 mg, all administered twice daily — and additional safety reviews will be conducted. One clinical trial had 12 people with SCH-C 25 mg twice daily and 12 people with SCH-C 50 mg twice daily. After ten days, the average reduction in HIV-RNA was approximately 0.7 log copies/mL in the 25 mg twice daily group and 1.1 log copies/mL in the 50 mg twice daily group.
There were no discontinuations because of adverse events, the most common being headaches and altered taste. Some QT prolongation was observed — the mean increase was 11.5 msecs after ten days of treatment — an observation that originally had led the FDA to put clinical development of SCH-C on hold.
SCH-D, Schering-Plough’s second CCR5 antagonist, has been shown to be more potent than SCH-C in vitro.
- Co-Receptor Antagonist: UK-427,857
This small Pfizer molecule is a prototype CCR5 antagonist for the treatment of HIV. It is already in phase I dose-ranging trials in humans. Thus far, it appears that this compound has potency against isolates that utilize CCR5 for entry; however, it has no activity against CXCR4-tropic viral isolates. It is non-competitive with respect to chemokine binding. While it binds the receptor reversibly, it has a long binding half-life, which may lead to advantageous pharmacodynamics.
- Integrase Inhibitor: S-1360
S-1360 is a diketo acid being developed by Shinogi Pharmaceuticals and GlaxoSmithKline. Preliminary data from early preclinical and clinical studies were reported at the 2002 Retrovirus conference and at the XIV International AIDS Conference in Barcelona. According to in vitro data reported at the Seattle meeting, S-1360 is synergistic with all of the available antiretrovirals and has potency that is on a par with lamivudine. In animal models, S-1360 was found to be 70% to 80% bio-available and had a half-life ranging from one to two hours.
As for clinical data, 18 HIV-negative study volunteers received single doses of S-1360. In all 18 people, the plasma half-life ranged from 7.7 to 16 hours, meaning that once-daily dosing is possible. Phase I and II studies of S-1360, in HIV-infected people, are under way.
- Integrase Inhibitors: L-870,812, L-870,810
Merck’s twin contenders, L-870,812 and L-870,810, are napthyridine carboxamides compounds, which have demonstrated potent antiretroviral activity in vitro. The 812 compound has an oral bio-availability of 64%, and the 810 an oral bio-availability of 49% (both in rhesus macaques).
L-870,812 has been tested in macaques infected with a recombinant SIV/HIV virus. SHIV-RNA was reduced by 1 to greater than 3 log in the treated laboratory animals, and 4/6 macaques experienced an SHIV-RNA decrease to undetectable levels. (Samples collected from the two macaques that did not achieve maximal SHIV-RNA suppression had evidence of an N155H mutation in the integrase gene.)
Despite the structural differences between the Shinogi and Merck integrase inhibitors, a report at the 2003 Retrovirus meeting noted a significant potential for cross-resistance between these two integrase inhibitors, which are both currently undergoing clinical development. A conflicting report, however, by investigators from the Rega Institute, concluded precisely the opposite: saying that the resistance profiles are in fact distinct. Guess we’ll just have to wait and see.
Making the Grade: Seven Agents to Keep Your Eyes On
Class of Compound
|Entry inhibitor (blocks fusion)
|Promised new data for IAS but there was none. Earlier results showed median RNA drop of 1.1 log (at Day 1) 1 in T-20-resistant subjects.
|Entry inhibitor (blocks attachment)
|Mean RNA drops of 0.4-0.6 log copies/mL after single sub-cutaneous infusion. PK may allow for monthly infusion.
|Entry inhibitor (CD4 antibody)
|Tantalizing results from single dose (IV) PK/safety study (N=30): initial RNA drop of 1.0-1.5 log by day 7 with little to no rebound until Day 21.
|Entry inhibitor (blocks CCR5)
|Three (oral!) doses tested, with RNA drops of 0.7-1.1 log (N=24). QD dosing.
|Entry inhibitor (blocks CCR5)
|Promised data for IAS but there was none. Oral dosing may be QD. Food interaction.
|S-1360 (a.k.a. GSK810781)
|Not any efficacy data, really. Human trials under way. PK might allow for QD dosing.
|L-870,810 (also 870,812)
|Monkey data is kind of impressive, but ain’t much human data. Of note, 1/3 of macaques showed pre-existing resistance!? (Mutation at N155.)