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8th Annual Retrovirus Conference |
T-20 and Beyond: "Entry Inhibitors" at the 8th CROI
Written for NATAP by Christopher D. Pilcher, M.D., UNC at Chapel Hill Center for AIDS Research
Finding agents that are more tolerable, convenient and potent has become an increasing priority as the long-term toxicities and burdens of current antiretroviral agents have begun to sink in for both HIV/AIDS treaters and patients alike. This year's retrovirus conference highlighted many recent advances in antiretroviral therapy; in this report I focus on developments in a new class of drugs that is coming into its own: HIV entry inhibitors (including the fusion inhibitors T-20 and T-1249).
What Is Known About the Virus Entry Process
Entry inhibitors are distinct from the existing classes of drugs that fight
HIV. Other drugs work inside the infected cell. Nucleoside reverse transcriptase
inhibitors such as AZT and abacavir and non-nucleoside reverse transcriptase
inhibitors like nevirapine and efavirenz all act by shutting down the reverse
transcriptase enzyme that HIV uses to replicate itself once it is inside the
cell. Protease inhibitors shut down the viral protease enzyme HIV uses to package
itself up for export. By contrast, entry inhibitors are drugs that interfere
with the processes involved in the virus' initial assault on the cell's outer
membrane.
The events of virus entry into cells were reviewed by a number of investigators at the meeting, most prominently in invited talks by Robert Doms of the University of Pennsylvania [Abstract L4] and by Gregory Reyes of Schering-Plough [Abstract L11]. As they summarized what is known of the process, the first step in the HIV-cell interaction that leads to virus entry is "attachment", followed by "fusion" that is necessary for entry into the cell:
Attachment Inhibitors
In a Symposium [Abstract S25] on Thursday, Roy Gulick from Cornell briefly reviewed
the status of a number of drugs in preclinical or clinical development that
target CD4, CCR5 or CXCR4 binding to gp120.
CD4 blockers
Progenics' PRO 542, a gp120-blocking protein incorporating part of the CD4 molecule
into the frame of a human antibody molecule. This molecule is able to bind to
gp120 with high affinity and seems very potent in the test tube. Initial, phase
I/II clinical trials in both adults and children have shown no dose limiting
toxicities, no antibody formation against the protein, significant antiviral
activity using the intravenous route (since it is a protein, it would not be
feasible to give it by mouth) and a prolonged half life of 3-4 days. Phase II
studies are underway, but no results are yet available.
CCR5 blockers: SCH-C on hold, SCH-D in
early development
Although also reviewed in Gulick's talk, several co-receptor blockers under
development (i.e., drugs specifically blocking CCR5 and CXCR4) received considerable
specific attention at the 8th CROI. Early results from Schering-Plough's CCR5
antagonist SCH-C (on partial clinical hold by the company) were the focus of an invited
talk by Gregory Reyes. [Abstract L11]. Unlike most other attachment and entry
inhibitors, SCH-C is a small molecule that not only had excellent absorption
from the gut (60-90% bioavailability) with low protein binding in the blood,
but also a prolonged effect after ingestion (~25 hours) and potent antiviral
properties making it an attractive drug candidate. In addition it demonstrated
"synergy" when used together with AZT and Indinavir in the test tube
(meaning the activity of the drugs given in combination was greater than the
sum of the activities for the individual drugs added together). See other NATAP
reports on SCH-C in Retrovirus Section on our web site in New Drugs by Nancy
Shulman & Hope From This Year's Retrovirus:
http://www.natap.org/conf/8thretroconf020501.htm
General Safety Concerns with Coreceptor
Blockade
One interesting preliminary finding presented by Reyes was that no "coreceptor
switch" was observed in SCID-hu mice infected with HIV when treated with
SCH-C. This went part way toward allaying some fears about the use of CCR5 antagonists.
Researchers have traditionally been wary of blocking CCR5 because although viruses
usually start by using CCR5 preferentially, they tend to mutate to use CXCR4
around the time of the onset of clinical AIDS. The fear has been that by purposely
blocking CCR5 use, the so-called "X4 switch" would be induced and
patients would be hastened on the road to AIDS. At least in the few mice and
humans treated with SCH-C so far, this has not been shown to happen.
Other unanswered questions about general safety for co-receptor (CCR5 and CXCR4) blockers persist, however. Co-receptors themselves are extremely common on the surfaces of all kinds of cells in the body-not just infected cells, but healthy cells. They may play key roles in embryo development and proper immune function as well as numerous other body processes. The consequences of blocking these receptors for the body are not known and an extra note of caution is probably warranted.
Indeed, significant side effects have now been demonstrated for SCH-C. The first small scale trials in humans showed an effect on electrical conduction in the heart at the highest dose studied-cancelling any plans for further development. (Edit Comments from Jules: Although I've heard that Schering can reformulate this drug. They also have other related drugs--SCH-D). For people waiting for new drugs, the important news regarding SCH-C still seemed to be: these compounds are out there, they are findable and they are potentially effective. In fact Reyes showed some very preliminary findings for a candidate compound called SCH-D with supposedly 10-fold higher antiviral potency and a longer half-life than SCH-C; further testing for this and other compounds is underway. Other CCR5 blockers such as PRO 140 (an antibody molecule that specifically targets CCR5) and some Merck compounds are also undergoing preclinical development and the results of these studies will be the subject of future meetings.
CXCR-4 blockers: AMD 3100 still in early
clinical testing
Among the CXCR-4 inhibitors, the granddaddy of compounds is AnorMed's AMD3100,
a bicyclam compound that is highly potent but has thus far been given by either
subcutaneous or intravenous injection. It is currently being studied in humans
in Phase II studies using continuous IV infusion. There was no news as far as
further clinical testing for the retrovirus meeting.
Other agents: a role for Pertussis Toxin?
One very interesting poster [Abstract 313] demonstrated potent inhibition of
CCR5 and CXCR-4 mediated HIV entry by a subunit of "pertussis toxin".
If borne out in human testing, the potential of this compound for use in HIV
therapy is staggering since it has a proven safety record from years of use
for prevention of pertussis infection.
"Coreceptor Trap Therapy" works
in mice…
In another poster [Abstract 311], the idea of combination therapy using CXCR-4
and CCR5 inhibitors together ("coreceptor trap therapy") was proven
to work in mice, in whom it prevented infection with CCR5-using viruses and
prevented a switch-over to CXCR-4 use during therapy. The general safety concerns
that attend use of either CCR-5 or CXCR-4 inhibitors individually would of course
go double for this type of combination strategy.
HIV Fusion Inhibitors…ready for
prime time?
T20 is the most studied of all the entry inhibitors and is the only fusion inhibitor
to have advanced to phase III clinical trials. T20 is a small (36 amino acid)
protein molecule that basically binds to gp41 and prevents it from coiling up
to reel the cell and virus together-preventing fusion. It has been shown in
early, single-arm clinical studies to be about as potent as a protease inhibitor
by itself-giving greater than 10 fold reductions in viral load-and to be safe
in combination with other antiretrovirals. Unfortunately the drug must be given
by subcutaneous injection twice daily and has a tendency to elicit local skin
reactions. One major study of T20 was presented at Retrovirus by Lalezari and
colleagues in the Late Breaker session [Abstract LB5]. This was the first controlled
study of T20, T20-206, in which 71 patients failing their first PI containing
regimen but NNRTI naïve were randomized to receive either abacavir, amprenavir/ritonavir
and efavirenz + T20 at one of several doses (50, 75 or 100 mg given once or
twice daily), or the oral salvage regimen alone without T20. The study's important
findings were that a there was a 0.7 log (5-fold) greater drop in viral load
in the highest dose T20 group than in the control arm, that this difference
was even greater if you didn't count the patients with very low viral loads
(<20,000 copies) at entry (about 1.0 log, or 10 fold) for that dose group.
Lower levels of response were seen for the lower dose cohorts.
As in other studies of the drug, the most frequently reported treatment related adverse events were mild to moderate local injection site reactions, occurring in 65% of the patients given T20. These consist of mild pain, temporary swelling and redness at the site of injection. Lalezari emphasized hope that these types of skin reactions might be much less of a problem in the ongoing phase III studies using a much more concentrated form of T20, such that the effective dose can be given in a much smaller volume.
Church and colleagues presented the results of P1005 [Abstract 561] a phase II pediatric trial testing the activity and safety of T20 in combination with oral antiretrovirals. Patients all had >10,000 copies viral load on a failing regimen, and were allowed to switch oral drugs after 7 days of getting only T20 added on top of their old regimen. T20 was dosed at 30 and 60 mg/m2 and achieved 0.8 and 0.9 log reductions in viral load at those doses. Again, the most frequent treatment related adverse events were local injection site reactions occurring in 8/12 children; these were graded as "mild" in all but one child. Pharmacokinetics were favorable in the group. After oral antiretrovirals were added, the early, observed suppression was sustained and no T20 resistance was noted to appear. Further testing of T20 in children is planned.
A second, "son of T20" peptide fusion inhibitor called T1249 has activity in the test tube against T20 resistant viruses. This compound now been through its first phase I/II trial and the results were presented Monday by Joe Eron [Abstract 14]. T1249-101 was a dose escalation trial, successively testing the safety and activity of three doses of T1249 (6.25, 12.5 or 25 mg) given as once or twice daily injections for 14 days in a group of 63 patients. Individuals had low CD4 counts (mean 84-146 cells depending on the dosing group) and very high viral loads at study entry (4.95-5.54 logs depending on group). Viral load drops during therapy were proportional to dose and no "plateau" of response was seen, suggesting that further dose escalation could further increase activity of the drug. The highest dose tried (25 mg twice daily) gave a 1.32 log (21-fold) reduction in viral load over the 14-day course of T1249.
Pharmacokinetics supported once or twice daily administration. Like T20, T1249 caused injection site reactions in many individuals (41%) but all but one reaction were graded as "mild". One individual apparently developed a low white blood cell count (neutropenia) but only during followup from the study after stopping the drug. Of concern, one person did have an allergic reaction to T1249 with a generalized rash and fever; symptoms resolved after discontinuation of therapy. (Such reactions have not been seen before with T20). Eron concluded that T1249 has significant activity and limited evidence of systemic toxicity, so that further investigation of higher doses of the drug is warranted.
As far as other potential peptide fusion inhibitors, Root and colleagues from MIT presented a design for a new, conceptually similar but larger peptide drug ("5-Helix") targeting the opposite end of gp41 in a Late Breaker [Abstract LB1]. They recently published these findings in the Journal Science. 5-Helix is early in development and clinical trials are some time off.
Future Directions for Entry Inhibition
Although a number of drugs appear to be heading into wide scale clinical trials,
these new entry inhibitors as a group remain somewhat unwieldy. The drugs nearest
to FDA approval-T20 and T1249, AMD 3100 and PRO 542, for instance-must all be
injected. And even if time does show us that these compounds are safe and active
against HIV, questions about the feasibility of producing huge quantities of
proteins will have to be addressed by the manufacturers. The "holy grail"
of entry inhibition is the search for "small molecule" entry inhibitors
that may be given orally. [Abstract 309 gave an update on this search at NIH].
For now, clinicians are trying to figure out ways that injectable fusion and
entry inhibitors may be used-for instance as part of "deep salvage"
therapy for treatment-experienced patients, "induction" therapy for
treatment naïve patients, or in eradication protocols. If "cellular
resistance" proves to be important as some people think (with cells actively
pumping drug out of the interior), then drugs working on the outside of the
cell may be critical tools in our armamentarium.
Perhaps the most important development for Entry inhibition reported at Retrovirus this year was the finding that significant "synergy" could be seen among the different classes of molecules targeting HIV entry when used together. Robert Doms [Abstract L4-also see abstract 310] explained in his talk that the by delaying the process of attachment and fusion, coreceptor and CD4 antagonists can keep the uncoiled gp41 molecule exposed for longer than normal-opening up this target to attack by gp41 blockers like T20 or T1249. This provides a theoretical basis for hope that an even higher level of potency can be obtained by fusion and entry inhibitors in the future, and that these so far troubled drugs may have an important place in HIV treatment.
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