New drugs: perhaps some genuine excitement this time
10 April 2002. Related: Conference reports, Antiretrovirals, CROI 9th (Retrovirus) 2002.
Graham Moyle, MD, MBBS, Chelsea & Westminster Hospital, London, for NATAP
For the first time in a number of years the majority of presentations in the new drugs session at the Retrovirus conference focused on genuinely novel compounds. Several companies have lead compounds with adequate pharmacological characteristics and in some cases demonstrated short-term clinical activity focusing on the novel targets of viral integration and viral entry.
Additionally in more advanced development are compounds from currently available drug classes which have genuine activity in people with HIV infection against viruses with significant resistance to currently approved drugs within those drug classes.
Two second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) reported clinical trials data. The more novel of these compounds from Tibotec is TMC 125. In a short-term study in treatment naive individuals previously presented, this agent demonstrated reductions in viral load of around 2 log in seven days. The study presented at this meeting was a proof of concept study to test drug activity in individuals with virus resistant to efavirenz and nevirapine. In vitro panels (test tube studies) demonstrate that virus with greater than 100-fold shifts in sensitivity [resistance] to efavirenz have generally less than 10-fold and often less than four-fold shifts in sensitivity to TMC 125. Specifically viruses with mutations typically selected for by nevirapine and efavirenz remain sensitive to TMC 125. However, resistance to this drug can be observed in the presence of multiple non-nucleoside binding site mutations.
The study evaluated 16 HIV-infected male individuals with viral load detectable above 2000 copies/mL while receiving triple drug regimens containing either efavirenz or nevirapine. Individuals were required to have virus with shifts in sensitivity of greater than 10-fold to efavirenz or nevirapine as assessed by Virco’s Antivirogram. The median baseline characteristics included CD4 cell count of 389 cells/mm3 and viral load of 10,753 copies/mL. The median fold change in sensitivity to efavirenz and nevirapine was greater than 100-fold whereas changes in sensitivity to TMC 125 range from <1 to 8.3-fold with the median of a 2.6-fold shift in sensitivity. The study included individuals who had single, double and triple mutations typically associated with non-nucleoside resistance. Patients entering the study discontinued the NNRTIs which they were failing substituting TMC 125 at baseline. Patients were then followed for eight days before being offered a new regimen. Viral load fell rapidly with all patients at day eight having viral load below baseline values and the median change in viral load of -0.89 log. The majority (75 percent) of participants had a viral load declined of at least 0.5 log. Only one patient discontinued, this was due to non-adherence. No grade three or four adverse events were reported, the most common adverse events being diarrhoea and headache. This agent is now advancing to larger phase 2 and phase 3 studies.
A second non-nucleoside currently in phase 2 clinical development is DPC-083, an agent related to efavirenz. This drug has an elimination half life approaching 100 hours and in vitro has less than ten-fold shifts in sensitivity in the presence of virus resistant to efavirenz and nevirapine with single and some double codon substitutions. Data from a phase 2 study evaluated 100 and 200 mg of this agent in 51 individuals failing nevirapine or efavirenz was reported. Baseline genotypes in these patients included individuals with both single and double mutations including at codon is 101 (44 percent), 103 (52 percent), 181 (17 percent), and 190 (25 percent). Patients discontinued their failing NNRTI and when available changed NRTIs, although 10 individuals did not change nucleoside analogues and 17 individuals only changed a single nucleoside analogue.
Individuals who did not change nucleoside analogues responded less well to DPC-083. Whilst 72 percent and 67 percent of individuals changing one or two nucleoside analogues, respectively, achieved viral load less than 400 copies/ml, only 40 percent of individuals who did not modify nucleoside responded.
Adverse events included central nervous system effects similar to those reported with efavirenz, and skin rash which was only seen in the 100 mg population. A second study of this agent in treatment naive individuals in combination with ZDV/3TC provided comparative data across different doses of DPC-083 and efavirenz. The study compared groups of around 30 treatment naive individuals who received either DPC 083 at doses of 50, 100, and 200 mg per day compared with standard 600 mg dosing of efavirenz. Baseline characteristics included viral load of 4.52 (33,000) log copies/ml and CD4 of 402 cells/mm3. Response rates as assessed by ITT non completer = failure analysis did not demonstrate differences between treatment groups with between 65 and 72 percent of individuals having a viral load less than 50 copies at week 16. This is unlikely to represent peak response. Adverse events leading to discontinuation were most common in the 200 mg DPC-083 dosing group, with 20 percent of individuals discontinuing predominantly due to skin rash. Discontinuation rates for efavirenz were 15%, and 12% with 100 mg DPC-083. Central nervous system effects appeared less common amongst individuals receiving DPC-083 at least at the 50 and 100 mg dosing groups relative to efavirenz. For example, dizziness was reported in 30 percent of efavirenz recipients but only 4 percent of 100 mg DPC-083 recipients. Based on these results the 100 mg dose is the likely candidate dose for further development of this product.
The conference also saw new information presented with regards to candidate agents from the protease inhibitor class. The drugs of most interest in this regard are atazanavir and tipranavir.
Atazanavir is a two pills once a day agent which in studies in naive populations has indicated efficacy at least as good as nelfinavir with an absence of lipid disturbances. This conference saw a presentation addressing the potential for this agent in individuals with a history of prior protease inhibitor use. The study compared the dual PI combination of atazanavir 400 or 600mg QD plus saquinavir soft gel (1200 mg QD) to saquinavir / ritonavir each dosed at 400 mg BID plus two nucleoside analogue RTIs.. Atazanavir is known to boost saquinavir exposures, and the dose of saquinavir chosen for the study was based on pharmacokinetic data.
The study randomised 85 individuals with prior protease inhibitor experience and viral loads between 1000 and 100,000 copies/mL and CD4+ T cell counts >100/mm3. Discontinuations for adverse events were most common in the ritonavir/saquinavir group (30 percent) compared with the atazanavir dosing groups (9 -11 percent). Viral load as a proportion of individuals less than 50 or less than 400 copies/mL were not reported. The mean change in viral load at week 48 was -1.44 log, -1.19 log and -1.66 log in the atazanavir 400 mg, 600 mg and saquinavir/ritonavir dosing groups. Changes in total cholesterol, HDL cholesterol and fasting triglycerides significantly favoured the atazanavir/saquinavir dosing group. Analysis by baseline genotypes and response were not reported. Pharmacokinetic data were also not reported. There remain a number of gaps in our knowledge about atazanavir. Studies in naive individuals evaluating its relative efficacy to standard of care agents such as efavirenz are currently ongoing.
More information about the clinical utility of atazanavir on specific viral genotypes are required before the agent can be confidently used in PI experienced individuals. Although this agent has advantages with regards to metabolic disturbances relative to other protease inhibitors, the most common adverse event is increases in indirect bilirubin which in a small proportion of individuals lead to clinical jaundice. This adverse event is typically seen in individuals with a specific genetic variation and availability of a test to select out those individuals at greatest risk of hyperbilirubinaemia would help eliminate the principal obstacle to use of this drug. Wider availability of atazanavir is expected over the course of this year. A patient expanded access program is being planned.
Tipranavir is a new protease inhibitor currently in phase 2b/3 clinical development. It has a different chemical structure to currently available protease inhibitors. The drug has a number of formulation and pharmacokinetic issues and the final development dose is currently still under investigation. Due to extensive first-pass metabolism, tipranavir will require boosting with ritonavir. Data reported at this meeting evaluated tipranavir 500 or 1000 mg BID plus ritonavir 100 or 200mg BID in 41 individuals who had previously received currently approved protease inhibitors. Response was reported by baseline genotype and the number of mutations to approved PIs present at entry. Individuals with less than five baseline protease mutations experienced reductions in viral load of -2.21, -2.39 and -2.10 log at weeks 24, 48 and 80, respectively. Corresponding response is for individuals with more than five protease mutations were -2.37, -2.24, and -1.52 log. Specifically the presence of mutations known to affect approved protease inhibitors such as positions 82, 84 and 90 did not influence virological response to tipranavir. The data indicate that tipranavir is active against viruses with diminished susceptibility to currently approved protease inhibitors. Formulation issues must now be urgently addressed with tipranavir to enable its potential as a salvage drug in persons resistant to currently available protease inhibitors can be fulfilled.
Identification of several new candidates in the nucleoside analogue drug class were reported. Drugs from this class remain the backbone of HAART regimens although concerns exist regarding the potential of some of these drugs to trigger a range of toxicities particularly through inhibition of mitochondrial DNA polymerase gamma. Data with DPC 817 was reported. This agent demonstrated in vitro activity against viruses with resistance to ZDV and 3TC and with as many as 10 nucleoside analogue mutations. However this agent appeared to have diminished activity in the presence of the 151M and the 69S insertion multidrug resistance viral genotypes. Information on the potential of this drug to inhibit mitochondrial DNA polymerase gamma and other human DNA polymerase is what is not reported. However, animal and in vitro toxicity data have led to the discontinuation of this agent’s development.
Researchers responsible for the discovery of 3TC at Shire Biochem reported the anti-viral activity of a new nucleoside analogue known as BCH13520. This drug appears active against viral strains with phenotypic resistance to ZDV and/or 3TC although larger shifts in sensitivity were reported in the presence of 151M (20-fold) or 69 SS insertion (4.4-fold) multidrug resistant viruses. Selection experiments with this agent suggested it may select mutations at positions 75 and 65 although novel mutations including some in the NNRTIs minding region were also described. This agent appears to remain some distance from human clinical development.
Several targets for inhibition of HIV early in its life cycle are being investigated. These include molecules which affect viral attachment to CD4 and to co-receptors and drugs which affect the fusion process. The drug in most advanced development in this regard is T20. This agent is an injectable fusion inhibitor currently requiring twice daily subcutaneous dosing. The study reported included 71 PI-experienced patients randomised to three T20 doses (50 mg BID n=16, 75 mg BID n=20, 100 mg BID n=16 plus a fixed regimen of abacavir 300 mg BID, amprenavir 1200 mg BID and ritonavir 200 mg BID, and efavirenz 600 mg qd). The comparator group (n=19) received only the fixed antiretroviral regimen.
A dose dependent treatment effect was observed. Patients in the control group experienced a viral load reduction of -1.87 whereas reductions of -2.10, -2.62, and -2.39 log were observed in the 50, 75 and 100 mg T20 dosing groups. By ITT analysis, the percentage of patients reaching <400 copies/mL was 37% (7/19) in the control arm and 55% (28/51) in the combined T20 group and for patients reaching <50 copies/mL was 37% (7/19) in control and 47% (24/51) in the combined T20 group.
At week 48, the observed median CD4 + T cell increase was +90/mm3 in the control group and +92, +147, +124/mm3 in the 3 T20 groups. Adverse events attributable to T- 20 were limited to injection site reactions with no adverse laboratory or clinical events observed. The data support the need for the urgent introduction of T20 for use in the salvage setting.
Other agents with oral bioavailability, acting at different sites of virus attachment or entry were also reported during the conference. Many of these drugs are entering phase I human studies or phase 2 studies where proof of principal will be demonstrated or not in HIV-infected individuals. Schering Plough are investigating a series of drugs which are antagonists of the CCR5 co-receptor. The development names for these drugs are SCH C and D. SCH C is active in vitro in the nMol range and has demonstrated oral bioavailability in healthy volunteers. A small phase 2 study of 12 HIV positive individuals not currently receiving antiretroviral therapy and with CD4 cell counts about 250/mm3 was reported. Patients were given 25 mg of SCH see every 12 hours for 10 days. No important adverse events were reported during the study. Pharmacokinetic data indicated that trough values of 90 nMol were achieved, into the estimated therapeutic range. A lag time before reductions in viral load began was noted, such that no change in viral load occurred in the group before Day 3. After that time, declines in the mean maximal viral load at day 10 of dosing was approximately 0.7 log with 10 of 12 individuals experiencing a reduction in viral load of at least 0.5 log. After treatment cessation viral load was noted to only gradually return to baseline suggesting a residual affect. It is not clear whether this agent will go forward in clinical development although a dose finding study at doses of 200 mg of this agent was reported to be ongoing. Concern has been expressed regarding prolongation of the QT interval (on EKG) observed in healthy volunteers given single doses of 600 mg or multiple doses of 400 mg per day of this agent. This study however provides an excellent proof of concept that the CCR5 receptor antagonists represent candidates for clinical evaluation.
An inhibitor of CXCR4 inhibitor known as AMD 3100 also reported proof of concept data. This drug has now been discontinued. The study involved ten-day continuous infusion is of this inhibitor into 40 individuals at a range of doses. Reductions in viral load were observed in some subjects in the study the most impressive responses were observed in individuals with SI virus, the strain that uses the CXCR4 receptor. In some cases individuals with mixed populations of SI and NSI virus experienced disappearance of SI virus during the infusion period. CXCR4 antagonists, are not currently commercially available. These data therefore provide a starting point for further investigation of the potential of drugs in this class.
Bristol-Myer Squibb reported the identification of an entry inhibitor class with activity in vitro against a wide range of HIV strains with activity in the nanomolar range. The activity of this agent appears to relate to binding to surface by HIV in the in the GP41 or GP120 region. Passage of virus in the presence of this drug can select for mutations in either GP41 or GP120 at or near where the virus binds to CD4. Importantly the drug does not appear to be highly protein bound and has demonstrated viral bioavailability in rats, dogs and monkeys. Bioavailability in the primates was in the range of 25 to 30 percent and may be considered the best guide to future bioavailability in the humans. This drug is now poised to undergo safety and bioavailability evaluations in healthy human volunteers before proceeding studies in people with HIV infection.
Both Merck and Shionogi/GlaxoSmithKline have reported integrase inhibitors which are small molecular weight compounds with the potential for oral administration. The Shionogi compounds have entered clinical development. The lead compound is currently known as S-1360. These drugs are of the same chemical class and may select for similar mutations within the integrase genome. S-1360 demonstrates activity in a high nanomolar range and has an acceptable preclinical safety and animal pharmacokinetic profile to warrant clinical investigation. This drug is now entering into phase I/II activity studies. No new information on the Merck integrase inhibitors were presented during the conference.
There appears to be a wealth of new drugs in development for people with HIV infection. These agents include genuinely novel members of currently approved drug classes, which appear to have activity against many of the viruses commonly selected for by current agents. Several of these drugs have demonstrated short term evidence of their activity in both treatment naive and treatment experienced individuals including those with documented resistance to currently approved agents. Additionally agents from a range of new drug classes are poised to enter clinical development or are currently in early phase clinical development promising a range of different drugs to help manage individuals who cannot establish adequate viral control on the currently available drugs.