Durban World AIDS Conference
Wednesday, July 12
Durban, South Africa
Reported by Jules Levin

Report 15

ENTRY INHIBITORS TRIMERIS
Entry Inhibitors: The Next Frontier in HIV Treatment

This presentation started at the ungodly time of 6:30am. I'm writing this report at 10am in the press room after viewing today's posters on clinical trials of antiretrovirals. The overall conference is better and has more information than I or others had anticipated. There's a lot to report. NATAP will be providing much coverage from me and a number of others  including Graeme Moyle on lipodystrophy and switching therapy due o lipodystrophy, Mike Youle, Mike Norton, and possibly others. I ran into Julio Montaner again this morning at the T-20 symposium and he told me that his study on when to begin therapy  included over 1000 people. He stratified people by CD4 and viral load (<50,000, 50,000-100,000, >100,000), As well, CD4s were stratified by <50, 5-200, and several categories over 200. Importantly, the follow-up is only for 2 years so far but I think they will continue to follow people. He related to me that for those with >200 CD4s there was no difference in progression (I think he said the measure was death, but I'll check the poster tomorrow), but when CD4s are <200 progression occurs. Regarding viral load the magnitude of difference in terms of between viral load categories was not much. They looked at up to 200,000 copies/ml. So, the decision about when to start treatment is multi-factorial. But, he told me he would generally not make decision about when to treat based on viral load, mostly on CD4. If a person's viral load were maybe up to 150,000 copies/ml he might wait til their CD4s were 250. The reason we talked about 150,000 as a cut-off is because treatment is less likely to reduce viral load to undetectable when viral load reaches a certain level which might be 150,000 copies/ml.  

Roche & Trimeris held this satellite symposium to discuss entry inhibitors. Their drug--T-20-- is the furthest along in development in this new class of drugs. T-20 is a fusion inhibitor, which is a type of entry inhibitor. Several researchers gave nice talks this morning about the overall class of entry inhibitors as well as a decent discussion on T-20, and about salvage therapy. It's in the area of salvage therapy where T-20 will be most utilized. You will see why in the following report. Julio Montaner opened today's early morning symposium by saying that the Durban meeting has been a moving experience. He thanked people for coming to this symposium so early in the morning. He and Joep Lange , the next speaker, talked about how the need for additional therapies is growing.

Joep Lange talked about how about 50% of people who have detectable HIV and/or who are on their 2nd or third treatment regimen. By 2002 its estimated that over 50% will be multi regimen experienced. The response rate in triple class experienced people is 40-50%. In ACTG 398, 43% with double class experience responded to undetectable viral load with study therapy. Those with triple class experience had 16% response rate. He said poor adherence and poor presecribing ("Better see a good doctor", said Lange) are causes for viral failure. Non-adherence is the major cause of viral failure. But there are other reasons--blood levels, poor prescribing, etc.  For example, Lange showed study data saying that 80% were adhering to IDV but 40% were adhering to food restrictions.  From a Steve Deeks study individuals with 2-3 active drugs identified by resistance testing responded well to data but those sensitive to only 0-1 drugs did not respond well virologically. He showed analysis data showing overall that patients with treatment experience who used phenotypic or genotypic resistance testing do better on their selected regimen.  There is short term virologic evidence in choosing regimens in pre-treatred patients. But the results are far from spectacular. They don't pick up minority species (<20%), may not pick up wild-type reversion virus, beware of standard interpretation of test results (we need better interpretation reported, cut-offs are not accurate). What is cut-off? For example, Virco phenotypic test uses 4.0 fold increase in IC50 to call  intermediate resistance. But resistance testing can be useful, Lange said.  He referred to ABT-378, saying its drug levels are so high it ought to overcome resistance for a number of individuals. Individuals with <4> fold resistance to current protease inhibitors responded to ABT-378 in study of multi-PI experienced individuals. He referred to this to make the point that pharmacology and drug levels are key in treatment.

Structured Therapy Interruptions-

As reported in Sitges at Resistance Workshop in June, using sensitive testing you can find resistance although its not detectable by commercial tests. Lange said STIs are not the way to go at least for treatment experienced individuals. He referred to Deeks fitness studies saying if you have few otions or no options it may be preferable to stay on your drugs. However, the remaining question is which drugs do you have to stay on.

In other words, SALVAGE THERAPY is needed. But Montaner warned not to get alarmed. In the near term we are generally ok, but over longer term it will be needed to have new treatments to transfer into. We need new drugs for new targets and existing targets. He mentioned RVT/SQV/APV as an interesting combination for salvage, which has yet to receive attention. He also mentioned that in vitro tipranavir looks promising. Fusion inhibitors is the first of entry inhibitors and drugs for new targets. He also warned of adding only one new drug. You should add as many as possible (2-4).  He mentioned hydroxyurea and mycophenolic acid (MA). He said there is no data convincing that hydroxyurea makes a difference in salvage. He mentioned that MA is the new focus of attention.  Studies are planned to look at MA in combination with several NRTis. MA acts like HU. MA may increase activity of abacavir or overcome abacavir resistance, or may have similar affect on other NRTIs. Again he warned not to add one new active drug.

David Ho spoke about the biological aspects of entry inhibitors, the steps in viral entry. . We now have drugs that target two points of processing NRTIs-NNRTIs & Pis. He explained the technical biologic process by which HIV interacts with, attaches to, and fuses thru the cellular membrane and inserts itself into the CD4 cell through CD4 receptors and co-receptors. He characterized most of the process but he said some of the process is still not understood..

A number of entry inhibitors are under development--attachment inhibitors (gp-120, CD4 are the targets), CXCR4 target - AMD-3100 is the drug), CCR5 target - Schering compound is the drug), gp-41 -target: T-20, T-1249 fusion inhibitor). Ho discussed the difficulties with attempts to develop most of these potential drugs and target problem issues. Howver, AMD-3100 is in early clinical trials. In addition, the effort to target CCR5 may work out although there are some potential side effects related to this. But he said its still promising. The Schering project has such promise. Early in vitro & animal studies look promising for the Schering CCR5 drug. The last event in viral entry is fusion and T-20 works at that level and is so far the furthest in development. In the early 90's the first work was done regarding this fusion approach showing it may have promise. Ho showed some very nice color videos depicting how fusion occurs and how T-20 can jam that process.

T-20: Possible Advantages- potency, safety, lack of interactions, lack of cross-resistance. Possible disdvantages-- not orally available, inadequate penetration, development of antibodies, cost.

He talked about how yet undeveloped D-peptides (T-20 is a c-peptide) may be useful in preventing fusion or entry, but at this point in the process they are screening potential molecules so far have not found something.

T-20 in combination with AMD-3100 (CXCR4 inhibitor) are synergistic in vitro. T-20 + PRO-542 may be combinable.

Ho concluded it appears we will have a new class" entry inhibitors. He said it would be very helpful to have drugs that work both inside & outside the CD cell to work on inhibiting viral replication.

Joe Eron discussed the clinical experience with entry inhibitors. In vitro PRO-542 neutralizes a broad range of HIV variants. In a mouse model its been shown to be active against HIV. He described 2 human studies--in single injection dose trial & in multi-dose (4 weekly injections) they were able to show viral load reduction in kids (4/6 „0.7 log, 3/5 sustained response). He said it may be possible to have weekly injections with this drug, but more trials are needed.

CCR5 inhibitors: Schering Plough compound; PRO-140
CXCR4 inhibitor: AMD-3100
CXCR4 & CCR5 are 2 receptor sites where HIV can enter the CD4 cell.

Schering product is potent in vitro and has been shown to inhibit a broad range of HIV variants. In vitro its been shown to be synergistic with AZT & IDV. Eron said itís a small molecule which means it may be orally bioavailable. In small animal models (scid mouse) it was active against primary HIV. Phase 1 human trials are to begin in July. Eron raised the concern about the risk of switch to SI virus by targeting one receptor, Its possible that HIV could become more virulent if it switches I think it was from SI to NSI, which theoretically could happen when blocking one of these coreceptor sites. And it's possible that if you block both of these coreceptor sites HIV could find another receptor site.

AMD-3100 has to be administered by IV infusion or  subcutaneous injection (SC), resistance has been seen in vitro, IV infusion under study now at Hopkins.

T-20

Active against both SI & NSI viruses, synergistic in vitro with ART drugs. 6 studies have been implemented. So its into full clinical development. Adminstered by SC injection. In 18 day study 100 mg dose showed 1.5 log reduction in humans. In highly experienced indivuals (hi VL, lo CD4)--PK was good (constant drug levels throughout dosing period), drug will be taken twice a day.

In this highly experienced group where Eron said it was like T-20 monotherapy although it wasn't. --100mg twice daily produced peak response of -1.2 log. Resistance can develop to T-20. I think this was a 28 day study.

In a second study of highly experienced individuals. 48 week data is being shown at this conference. The study investigators & Roche say study shows that the drug was safe to take for 48 weeks. The study was conducted to establish safety. Eron said no one discontinued due to T-20 toxicity. And toxicity was ok. He said that in his clinic people could continue taking the drug and he has seen good CD4 responses. Administration can cause bumps at the injection site. But Trimeris is developing new formulation that hopefully will reduce this side effect, and it's hoped it will be available for upcoming pivotol studies starting this Fall. T-20 has to be dissolved and patients will have to learn how to dissolve it, Refrigeration will be required. There is enough drug for phase 3 and looks ok for approval.

T-1249

Entry inhibitors are likely to be able to be used together.

Concluding comments

Ho saidcombination entry inhibitors appear promising. We need to explore other entry targets. Resistance will develop to current inhibitors and so we'll need new entry inhibitors. Eron said that use of entry inhibitor may address that space problem raised by Fauci yesterday and so may make therapy more potent. Drugs don't penetrate or get distributed to all tissues, organs, cells, etc. Adding T-20 may help plug those "spaces". Use of T-20 in induction in naÔve is being explored but will be difficult because of its difficult administration. T-20 study in peds is ongoing.  

Regarding Fauci's talk yesterday on the NIH studies looking at intermittent therapy, Eron warned that intermittent therapy can be dangerous if done outside clinical trials. Stopping & starting therapy 15 times in a year can be dangerous. Lange said it appears unlikely to him that intermittent therapy will be helpful. Montaner agreed. One concern is that tolerability may be problem when starting & stopping. Lange related concerns, as well.