The following five-part report on NRTI’s is divided into the following sections:

1. Comparison of D4T/3TC vs AZT/3TC both with Indinavir
2. Comparison of D4T/DDI vs AZT/3TC both with Indinavir
3. 1592U89- Resistance; 28 week data; 48 week data
4. 1592+ Indinavir, Nelfinavir, SGC Saquinavir, or 141W94: 2 Drug Combination; week 16 data
5. New NRTIs in Early Development:
        5A. FTC
        5B. BCH-10652
        5C. FddA

Kathleen Squires reported preliminary 24 week data from this open label, randomized study in treatment naive persons comparing the two double NRTI regimens of AZT/3TC vs d4T/3TC both combined with indinavir. At week 12, the mean log decreases in viral load were 1.77 and 1.59, mean increases in CD4 were 150 and 85, and 78% and 80% had undetectable viral load (<500 copies/ml) for those taking d4T/3TC/IDV and AZT/3TC/IDV, respectively.

In the d4T/3TC arm 7/49 (14%) discontinued prior to this analysis. The reasons were: lost to follow-up (5), physician decision (1), and pregnancy (1). In the AZT/3TC arm there were 11/51 (22%) discontinuations prior to this analysis. Reasons were: lost to follow-up (5), physician decision (1), subject voluntarily withdrew (2), adverse event/subject request (1), death (1), subject moved (1).

At week 24, the d4T/3TC/IDV arm (n=40) appeared to have a 1.9 log reduction from baseline based on a visual observation of the line graph on the poster, and the AZT/3TC/IDV arm appeared to have a 1.6 log reduction (n=39). The Chiron bDNA viral load assay was used. At week 24, 87% (34/39) in the d4T/3TC arm had undetectable viral load (<500 copies/ml) and 80% (32/40) had undetectable viral load in the AZT/3TC arm.

At week 24, the median CD4 increases from baseline appeared on the line graph chart on the poster to be about 140 for the AZT/3TC group and about 175 for the d4T/3TC group.

* rebounded is defined as two consecutive measures >500 copies/ml

Lab Toxicities (highest reported toxicity grade 3-grade 4)

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Joe Eron reported preliminary 24 week data for this study of treatment naive persons comparing D4T+DDI vs AZT/3TC, both combined with indinavir. This randomized open label study is 48 weeks. At week 12, the mean log decreases in HIV RNA were 1.56 and 1.61, means increases in CD4 were 106 and 123, and 73% and 79% of participants had undetectable HIV RNA (<500 copies/ml) of those taking d4T/ddI/IDV and AZT/3TC/IDV, respectively.

At week 24, it appeared on the line graph chart on the poster that a 1.65 log reduction was achieved for both groups (n=34 for d4T/ddI arm and n=30 for the AZT/3TC arm).

Percent of Participants with Viral Load <500 copies/ml (Chiron bDNA assay)

 At week 24, the median CD4 increases from baseline were about 140 for the AZT/3TC (n=35) group and about 210 for the d4T/ddI group (n=38).

Participants Experiencing Viral Load Rebound or Who Never Reached Undetectable Through 24 Weeks (<500 copies/ml, bDNA)

* a rebound in viral load is defined as two consecutive values >500 copies/ml

Clinical Toxicities (highest reported toxicity grade 3-grade 4)

Lab Toxicities (highest reported grade 3-grade 4)

See the recent article on NATAP’s web site for extensive data on 1592 resistance for treatment experienced individuals.

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72 of 79 participants enrolled into an early dose escalation study of 1592 were required to interrupt therapy following 12 weeks due to limited animal toxicology data. Six persons received 1592 uninterrupted. 43 of the 72 elected to restart 1592 (300 mg every 12 hours) following interruption of up to 1 year. They were permitted to restart 1592 in combination with any additional antiretroviral therapy. When extended therapy started 16/42 had viral loads <400 copies/ml. At week 12, 27/38 had <400 copies/ml. At week 36, 16/22 had <400 copies/ml. The proportions undetectable at week 24 for NRTI combinations only with 1592 were 14/18, and for those taking 1592 with a protease inhibitor + NRTI 9/10 were <400 copies/ml. During the dose escalating part of the study (first 12 weeks) the viral load reductions from baseline were about 2 log.

This is a comparison of the baseline numbers for the 43 individuals who elected to extend therapy with 1592 with the 75 who originally enrolled in the dose escalation study. They are comparable.

31 individuals took 1592 with NRTI(s), and they were off 1592 a median of 166 days. 12 individuals took 1592 with a protease inhibitor and were off 1592 a median 409 days. At week 48, the median reduction in viral load and increase in CD4 was about 2 log and about 100 cells for the group taking 1592 with NRTI(s), and about 2.4 log and 250 cells for the group taking 1592 with a protease inhibitor+NRTI(s). The Roche Amplicor assay with a limit of detection of 400 copies/ml was used. It appears as though the number of evaluable participants was 10-19 at week 48. The CD4 and viral load changes reported in this report are based upon approximations from visual observation of line graph charts on the poster. The number of evaluable patients were not clearly visible on the poster reprint. At week 48, about 50% (estimated 8/15) of individuals taking 1592+NRTI(s) were undetectable (<400 copies/ml). The percent was higher (60%) at week 36 (17/27). At week 48, 9/10 individuals taking a protease+1592+NRTI(s) had <400 copies/ml. This study was not designed to characterize the antiviral activity of 1592.

Investigators showed data indicating study participants in both groups did not experience increases in LFTs, and did not experience changes in hemoglobin.

A hypersensitivity reaction has been reported due to taking 1592 at an incidence rate of about 3% (reported range 2-5%). If a person has the hypersensitivity reaction to 1592 they are to stop taking the drug, and they cannot take it again. Symptoms resolve rapidly with drug discontinuation. Restarting 1592 after experiencing the hypersenstivity reaction can result in serious effects. As a result of restarting therapy after experiencing hypersensitivity, some individuals have been hospitalized and there is one reported death. It is very important to clearly understand this reaction and to be able to recognize it. It is not dose dependent and is characterized by - a fever first accompanied by one or more of the following- nausea (and/or vomiting), malaise (fatigue or tiredness), rash. Additional effects that can be experienced are swollen lymph glands, diarrhea, and muscle aches. If you think you may be experiencing this reaction please consult with your doctor immediately.

S Staszewski reported preliminary data from this dose ranging trial of 60 persons randomized to 1592 at doses of 100 mg, 300 mg, or 600 mg bid. Participants who either completed 24 weeks of 1592 or met switch criteria based upon viral load, CD4 or new AIDS defining events had the option to switch to open label 1592 (300 mg bid) plus AZT/3TC.

55 persons entered the open label phase; 46/55 remained on 1592+AZT/3TC; 1 stayed on 1592 alone; 3 added protease inhibitors to 1592/AZT/3TC; 1 person substituted d4T for AZT; 4 persons were lost to follow-up.

The median reduction in viral load (n=17) at week 28 from the time individuals switched to open label 1592 where they added therapy was between 2 to 2.5 log. The median reduction from the time they started in the study with 1592 monotherapy at one of 3 doses was about 2.2 log to 2.7 log. Estimations are made based on visual observation of line graph chart in poster. Ignoring the treatment switches and their timing, at week 48 about 62% (n=46) had viral load <400 copies/ml, and about 42% (n=46) had viral load <50 copies/ml. At week 32, the median increase in CD4 (n=22) was about 150 cells.

Adverse Events: During Open label Period (most frequently seen)

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Preliminary week 16 data was reported from a 48 week phase II study in which 78 individuals were randomized to a two drug regimen consisting of 1592 combined with one of 5 different protease inhibitors: indinavir, ritonavir, saquinavir, nelfinavir and 141W94 (amprenavir). The participants were treatment naive. This was an open label comparison where participants were stratified to below or above 100,000 copies/ml. Participants had >5,000 copies/ml of viral load, and >100 CD4 cells.

Participants received 1592 300 mg bid with either indinavir, SGC saquinavir, ritonavir, 141, or nelfinavir. Viral load was evaluated by Roche Amplicor (400 copies/ml limit of detection) and Roche Ultrasensitive assay. Baseline median CD4 and viral load were 349 cells and 4.74 log or about 60,000 copies/ml.

* treatment failure was defined as < 1 log reduction by week 8, or >400 copies/ml at week 16

** because the study regimens consisted of 2 drug combinations rather than the usual 3 drug regimens containing a protease inhibitor apparently used by most doctors, some participants withdrew from the study.

 Adverse Events

There was one drug reaction with dehydration and diarrhea. The person required hospitalization. There were two pregnancies. There was one extreme grade 4 lab abnormality of hypercholesterolemia. There was one neutropenia.

There were 4 eruptions that are now known to be characteristic of an acute 1592 hypersenstivity reaction. This is discussed above in the 1592 48 week study description. Dr Mellors described one patient with systemic symptoms: nausea, vomiting, general malaise and 12 hours after stopping medication developed a skin eruption. In this study the 1592 reaction occurred in 5% (4/78) but overall there is a 2%-5% incidence across 1592 studies. The onset is after 3-42 days (median 9 days). The characteristics are systemic: malaise, nausea, vomiting, fever, with or without rash. It resolves in one to two days after discontinuation of the drug. Dr Mellors continued that treating through it is very difficult. Only one patient has been able to treat through it. The important message is--do not rechallenge with this medication. This has resulted in hospitalization for 6 individuals and one death.

The median viral load reduction at 16 weeks for all 4 arms was at 400 copies/ml. Levels below 400 were assigned a value of 400 copies. This is common practice.

The differences in the study arms are not statistically significant, and the number of evaluable participants is relatively small particularly in the <50 copies/ml evaluation. As you may know it can take longer for some individuals to reach 50 copies/ml. Mellors reported that at week 24 the proportion of persons reaching <400 copies/ml was increasing. 5 individuals have shown an increase in viral load from nadir (lowest point reached), but none equal to .5 log. 4 of them were in the saquinavir arm and one was in the indinavir arm. The CD4 increases range from 50 to 150. Compliance assessments are ongoing. Phenotypic and genotypic testing are being performed on the rebounders.

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Michael Lederman and others reported their findings in investigating the early dynamics of circulating t-cell reconstitution during the therapies used in the study described above of 1592 combined with a protease inhibitor. Report being prepared.

As you will read, two of these new NRTIs (FTC and FDDA) are being tested in early human studies while human studies for the third NRTI (BCH-10652) are being planned to begin soon.

Franck Roussseau, of Triangle Pharmaceuticals, reported that FTC is a nucleoside analogue resembling 3TC, but in the lab its been consistently more potent than 3TC (about 4-10 fold greater in vitro). The data below is from a phase I/II study exploring two doses over a 14 day period. 8 HIV-infected individuals were enrolled in each of these two dose groups: 25 mg bid FTC, 200 mg once daily FTC. Additional dose groups are planned for studies. A pharmacokinetics study was conducted as part of this study and investigators found the estimated to be 9 hours.

Baseline Characteristics:

BioChem Pharma reported early preclinical information about this new NRTI at the Retrovirus meeting. They reported that they found it to be safe in 3 animal types: rat, mice, and monkey. Bioavailability was reported to be 80% in the animals tested. In the CSF in an animal it was found at concentrations higher than 3TC and AZT. Initial human studies are now being planned.

Investigators reported that it may have a preferable resistance profile. (BCH 10652 may have activity against 3TC and AZT resistant viruses). Investigators reported that BCH-10652 was sensitive in vitro to virus resistant to 3TC, ddC, PMEA, AZT and combinations of those drugs. In specific in vitro experiments company investigators reported BCH-10652 was sensitive to half of the 3TC resistant viruses tested, and was not sensitive to the other half of 3TC resistant virus tested. In one in vitro experiment they reported BCH-10652 showed 5 fold resistance to a M84I mutation. They cautioned more work is needed to characterize the response to 3TC resistant viruses. They reported the drug was sensitive to the viruses tested which were AZT resistant. Investigators are suggesting that resistance to BCH-10652 may develop slowly. After 12 passages in vitro, so far no mutation in the reverse transcriptase gene has been identified and no phenotypic resistance has been observed.

Lauri Welles, Richard Little and others at the NCI and NIH reported early data from an ongoing phase I human study of FddA. The drug was initially synthesized and the initial preclinical development was by the NCI (Natl Cancer Institute), but it is now being co-developed by the NCI and US Biosciences Inc. FddA is similar to ddI but it is a capsule, a buffering agent will not be necessary, and so far in early studies they haven’t seen any elevated lipase (pancreatitis) as was a potential serious concern associated with ddI. The investigators reported FddA was well absorbed by the oral route whether given with food or in a fasting state. It was well tolerated in short term therapy at the highest doses tested (3.2 mg/kg every 12 hours). They have not yet reached a dose that cannot be tolerated. It showed antiviral activity in patients with substantial prior NRTI experience. Further studies are being planned. The ongoing trial described herein will be extended by recruiting a new group of patients to receive FddA dosing at once daily in combination with d4T and nelfinavir. Increased dosing to 4.5 mg/kg and 6.4 mg/kg will probably be explored.

In preclinical animal studies FddA was found to be well tolerated at doses that associated with anti-HIV activity, and had good oral bioavailability. In vitro, FddA was active against viruses resistant to NRTI(s) including viruses resistant to multiple NRTIs. Resistance to FddA may be slow to develop. So far after 12 weeks into the clinical study investigators have been unable to detect FddA resistance. In vitro, strains of HIV with Q151M and multidideoxynucleoside resistance remained sensitive to FddA. In the phase I human study, one patient with 151 multi drug resistant virus had a .40 log reduction in viral load. The intracellular halflife appears to be long at 20 hours suggesting dosing of once or twice daily will provide good antiviral activity.

The phase I dose escalating trial of enrolled 24 symptomatic HIV infected individuals for an initial 12 week period to assess safety, tolerability, pharmacokinetics and the drug’s effect on CD4 and viral load. The mean CD4 count was 190 (range 4-418); 5 individuals were antiretroviral treatment naive, 1 had <6 months prior experience, and 18 had >6 months prior experience. Several patients who had experience with several NRTIs and 1 or 2 protease inhibitors showed viral load responses ranging from virtually no response to a reduction of about .50 log, but the FddA dose they received in this study was not indicated.

At the highest dose fully tested (1.6 mg/kg), a median reduction (n=6) in viral load was reported of -0.44 log (approximated range 0.2 to 1.3 log). At the 1.6 mg/kg dose investigators reported a trend towards increased CD4 counts in the first 12 weeks of the study.

The investigators reported the following prior therapy experience and viral load changes for 13 study participants receiving one of three doses: 0.8 mg/kg, I.6 mg/kg, or 3.2 mg/kg.

Safety

The investigators reported FddA to be well tolerated in this short term therapy. The investigators characterized the following toxicities as possibly related to FddA. One person who developed bacterial pneumonia while on FddA experienced grades 1and 2 neuropathy, grade 3 neutropenia, grade 3 elevated LFTs, grade 2 anemia and grade 1 decreased cardiac output. The following toxicities were also reported as possibly related to FddA:

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