Entry inhibitor updates from the 1st IAS
Mike Youle, MD for HIV i-Base
In addition to the plethora of good news on immunotherapy, attempts to block entry into the cell by HIV also got significantly favourable press. In his round-up of new antiretroviral agents in late stage development, Rob Murphy from Northwest University in Chicago, noted the advancing potential of the fusion inhibitors T20 and T1249.
Although these drugs have to be given intravenously tolerability is relatively good and no significant safety concerns have arisen to date. New information on T20 came from Cal Cohen of the Community Research Initiative, Brookline MA, USA . Fifty-five subjects single arm roll over Phase II study completed quality of life questionnaires at baseline and week 48. The majority of respondents agreed that sub-cutaneous T20 did not limit surveyed activities and approximately two-thirds (62%) reported the T20 injections and similar in convenience to other HIV/AIDS drugs. Of the patients completing 48 weeks of the treatment 98% would choose to continue T20 and 85% rated the ease of injection as not bad to very easy. This is good news since the injection schedule had been deemed the major problem likely to limit the utility of this agent.
Jay Lalezari from San Francisco showed data from 20-208 that evaluated the plasma pharmacokinetics of three formulations of T20 . Forty-eight subjects received T20 as either 75mg/mL or 100mg/mL formulations with carbonate or TRIS buffers for 14 days and then were switched to the standard 50mg/mL. The Cmax and area under the curve (AUC) for the newer 100mg/mL (90mg deliverable) form showed no difference from the current form and will result in a reduction in injections to one twice daily.
In a session that drew the glitterati of entry inhibitor researchers together, Joe Eron from Chapel Hill NC, USA presented an overview of fusion inhibitors that focused on T20 and T1249 . Studies of the former have shown at least a 0.5log110 drop in HIV RNA in subjects highly resistant to other antiretrovirals and phase III studies are ongoing. A dose response appears to be present but resistance does develop in some subjects. Study T124-101 evaluated 61 subjects who received drug from 6.25mg to 50mg once daily exhibiting a 0.6-1.2log10 reduction in viral load. T1249 extends to the high affinity (deep pocket) region of gp41 and therefore theoretically should be more active than T20. It also should be available as a once daily injection. In isolates already resistant to T20 T1249 worked in vitro and would be assumed to have some effect in vivo. Eron raised concern over the feasibility of long-term administration of these injected agents, about resistance profiles, antibody formation and manufacturing capacity.
Cecile Tremblay then gave a summary talk on co-receptor blockers that commenced with some impressive computer graphics to demonstrate the complexity of virus-cell receptor interactions . Entry into a target cell involves specific recognition of two surface cell molecules (CD4 and CCR5/CXCR4) by the membrane spanning, trimeric glycoprotein (Env) spikes of the virion. Key stages in the entry process – interaction of gp120 with CD4, conformational altered gp120 with the co-receptor molecule and the protein-protein membrane-binding interaction – are postulated to be novel targets for therapeutic intervention. There are several co-receptor molecule analogues currently under investigation by several companies and exist as CCR5 inhibitors such SCH-C and SCH-D and CXCR4 blocking drugs such as TAK-779 and AMD3100. The use of these agents together with fusion inhibitors would be logical since a combination approach with antiretrovirals has shown significant benefit over mono-or dual therapy. Also preliminary data suggest that interactions between various attachment/entry inhibitors might e dependent on multiple factors including polymorphisms in the envelope of HIV-1 clinical isolates, the expression (both quantitative and qualitative) of the co-receptors on host cells as well as pharmacokinetics. Tremblay presented work done by her in Martin Hirsch’s laboratory, at Massachusetts General Hospital showing marked synergism between all tested antiretrovirals and SCH-C and T20 and between T20 and TAK-779 or SCH-C. It would appear that combination of agents might improve potency and potentially prevent co-receptor switch, although it has been suggested that this is unlikely in vivo.
Bahige Baroudy from Schering-Plough Research showed exciting data from the two lead compounds from this group SHC-C and SCH-D . These CCR5 blockers can be made as oral formulations, a huge advantage over the only agent to reach the grade at the moment T20. He showed the complex series of assays and screening tests that had produced these two lead compounds. The SCH-C studies were put on hold early this year as in the first studies a prolongation of the Q-T interval was seen on the electrocardiograms (heart tracings) of subjects given the higher doses of the drug. This could be an early marker of heart toxicity of the agent and needed a thorough evaluation by the regulatory agency the FDA before they would allow further studies. This has now been completed and the drug is being moved into more advanced development. SCH-D is likely to take over as the prime drug to be developed and he presented data showing this to be a stronger agent with a half life in the blood of 6 hours and which had been tested for toxicity in animals. Definitely a drug to watch.
A further therapeutic target on the cell surface that is under investigation is DC-SIGN which was thoroughly reviewed by Vankooyk from the University Medical Centre, Nijmegen, the Netherlands . This is a novel dendritic cell-specific lectin that acts as a surface receptor. It captures HIV through a mannose dependent interaction with gp120. Dendritic cells (DC) capture organisms then enter the periphery such as the skin and mucous membranes and take them to the secondary lymphoid tissues where they present them in an antigenic form and thereby initiate some immune response. As such this interaction is important to deliver HIV to lymph nodes and could be a target for HIV intervention. An additional similar receptor, called L-SIGN has recently been identified raising the likelihood that multiple of these receptors will be found and that a combination blockade approach may be necessary.
Finally Mark Wainberg from McGill University AIDS Centre in Montreal, Canada gave an excellent talk on potential new areas for drug development that spanned the totality of the virus life cycle . It included discussion of targets such as de-stabilisation of the viral nucleocapsid protein, affecting RNAase H activity and more carefully examining the capacity to affect the tat gene. One group, from the Karolinska Institute in Stockholm presented data on novel tri-peptides GPG-NH2 and ALG-NH2 that interact at the carboxyl terminal and result in an arrest of the budding process . GP-NHS is current in phase II studies.So overall a fascinating array of new agents that can be used to block the entry into cells by HIV. What will be even more interesting is to see how these compounds can be used to treat HIV in combination with the currently available drugs and what benefit and toxicity this may result in.
- Cohen C, Dusek A, Johns E et al. Patient satisfaction and activities of daily living (ADL) in HIV infected adults using T-20 given by subcutaneous injection (SC) over 48 weeks. Abstract 708
- Lalezari J, Wheeler D, Kilby M et al. Improved carbonate (CO3) formulation of T-20 reduces number of injections required to administer 100mg bid dose. Abstract LB-P20
- Eron J. Fusion inhibitors in clinical development. Abstract 46
- Tremblay C. Combination therapy with attachment/entry inhibitors. Abstract 47
- Baroudy BM. Second generation CCR5 antagonist that inhibits HIV-1 entry. Abstract 70
- Van Kooyk Y. DC-Sign on dendritic cells, novel HIV receptor related molecules. Abstract 48
- Wainberg M. Confronting HIV: New Targets, New Strategies. Abstract L7
- Vahlne A, Su J, Hoglund S et al. The tripeptides GPG-NH2 and ALG-NH2 interfere with HIV-1 budding and capsid assembly: A new strategy for antiviral therapy. Abstract 119