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Biotech / Medical : Agouron Pharmaceuticals (AGPH) -- Ignore unavailable to you. Want to Upgrade?

To: Steve Fancy who wrote (4716)	7/3/1998 12:44:00 AM
From: Peter Singleton	Read Replies (1) \| Respond to of 6136

Steve, mind you I'm passing on Testact's post without evaluating what he says ... I just thought it was important to enter his comments into the debate. To pass on my opinion, I have a lot of confidence in AGPH's management, and until I hear otherwise I expect PI's to be standard of care for some time to come (albeit including an NNRTI), and after Geneva, I think tolerability of all HIV therapies will become an even greater issue ... playing into Viracept's strengths. I don't know enough to have a strong opinion on Remune, though it looks promising and important. All that said, it's important to listen to folks that don't have the same opinion as I do, having a healthy respect for the fallibility of my own judgement. Also, Testact is credible, and he's offered opinions on the Japanese inlicensed products, which I know almost nothing about. I have a substantial stake in AGPH, and have no plans to sell, especially at these levels ... but I'm constantly scanning the horizon for information that would cause me to reassess my opinion. There are some very smart folks around ... I suspect they can help us puzzle some of this out, but it may take a little while. Peter

To: Steve Fancy who wrote (4716)	7/3/1998 2:35:00 AM
From: Peter Singleton	Read Replies (1) \| Respond to of 6136

Folks, When you guys get over your hangover from the stiff drinks you've been downing trying to drown your sorrows over the world ending for AGPH, here's some more info to show you the sky has not fallen ... There's lots of positive info on Viracept from Geneva. Just a little snippet below from the healthcg's reports, this one on dual PI therapies (highly effective, btw), and the quoted section on dual PI as salvage: key quote: "What are we to make of these studies? Together they suggest that it may be possible to sequence protease inhibitors (especially if the primary failure is with nelfinavir) but the odds are greatly improved if the switch is done early (when the viral load is still relatively low, such as below 5,000-10,000 copies/ml)." Peter btw, if you're short AGPH, welcome back from your hangover from your celebrations ... : ) healthcg.com /* quoting a section below Dual PI Combinations As Salvage Regimens There is evidence that the resistance profiles of different HIV protease inhibitors overlap, such that patients with high level drug resistance to one PI (as a result of the accumulation of multiple mutations in HIV protease while on therapy) are unlikely to respond to the introduction of a subsequent PI or combination of PIs. Thus, there is an increasing and urgent need to define strategies for "salvage" of patients failing PI-containing antiviral regimens. Using a retrospective chart review, Gallant et al [8] from Johns Hopkins set out to assess the magnitude and durability of response to saquinavir/ritonavir in patients failing single PI regimens containing either indinavir or nelfinavir and to determine the correlates of success or failure. Virologic failure was defined as viral RNA >400 copies/mL on two occasions or >1000 copies/mL on a single occasion after 16 weeks. 41 patients meeting this definition were identified. In contrast to a number of previous studies, ritonavir/saquinavir, in combination with new or previously used NRTI or NNRTI drugs, gave an effective and durable antiviral response in a significant proportion of patients (13 of 23 indinavir-treated patients, mean duration of response 42 months; 4 of 6 nelfinavir-treated patients, mean duration 39 months). An important predictor of response to salvage therapy in the indinavir-treated group appeared to be a low viral load at time of treatment switch (median 9,280 copies/mL in responders vs. about 25,000 copies/mL in non-responders, p=0.04). The authors postulate that a relatively low viral load at the time of switch may explain the greater success of salvage therapy in this study compared with previous studies. Additional evidence supporting an early switch to alternative PI therapy in the face of virologic failure comes from a study by Scerpella and colleagues in Miami [9]. Thirty four patients (24 men, 10 women) failing therapy (including but not exclusively PI-experienced patients) were switched to a ritonavir/saquinavir combination. Virologic response (>0.5 log viral load reduction) was observed in 26 patients (76.5%). On-treatment analysis revealed an 87% response rate (one patient did not start therapy; 3 did not return for follow-up). Eighteen of 26 responders had a sustained response lasting up to 12 months. Characteristics of sustained responders compared with partial responders are shown in the table below. Sustained responders had higher CD4+ counts and lower viral load at the time of switch and higher increases in CD4+ count following switch (mean maximum increase 273 vs. 99 cells/mm3, p<.05). Fourteen of 18 patients (78%) with sustained virologic responses had undetectable plasma HIV RNA at a mean follow-up of 12 months. Despite lack of sustained viral suppression, partial responders received some benefit as indicated by increases in CD4+ counts. Sustained response Partial response P Number of patients 18 8 Mean duration prior antiviral therapy (months) 46.1 33.4 Used any PI (duration in months) 15/18, 83% (6.9) 7/8, 87.5% (8.4) CD4+ mean 246 228 >.05 CD4+ median 197 110 Viral load (log10) mean 102,000 (5.01) 300,790 (5.48) <.05 Viral load (log10) median 20,140 (4.30) 221,285 (5.34) Alternative salvage regimens will continue to be the subject of intensive investigation. In a retrospective observational study [10], Lyle et al found that the introduction of the combination nelfinavir/indinavir/delavirdine, usually together with 2 NRTI agents, in 25 patients with extensive prior antiviral experience (72% PI-treated) led to mean viral load reductions at 6 months greater than 1 log, with 50% of patients suppressed to less than 400 copies/mL. Brooks and colleagues [11] studied four patients enrolled in clinical trials of nelfinavir who experienced initial suppression followed by rise in viral load, and were then treated with indinavir-containing combination regimens. Mean duration of nelfinavir therapy prior to switching was 7.2 months. All four patients had a sustained virologic response to indinavir, with three suppressed to below 400 copies/mL, and the fourth to approximately 600 copies/mL at mean follow-up of 12 months. Three of the four patients had pre-existing protease gene mutations prior to nelfinavir and all four developed additional mutations while on nelfinavir (3 of the 4 developing NFV resistance associated mutations including D30N and N88S). Mutations associated with high level indinavir resistance at codons 48, 82, 84 or 90 were not observed during NFV therapy. What are we to make of these studies? Together they suggest that it may be possible to sequence protease inhibitors (especially if the primary failure is with nelfinavir) but the odds are greatly improved if the switch is done early (when the viral load is still relatively low, such as below 5,000-10,000 copies/ml).