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

To: Timothy Kross who wrote (3703)	2/1/1998 8:10:00 PM
From: JOHN W.	Respond to of 6136

Abstract 270 / Session 38 Evidence of Potent Antiviral Activity in a Phase l/ll Study of Nefinavir Mesylate (Viracept) in HIV Infected Chidlren.ÿÿÿ P KROGSTAD (1)*, A WIZNIA (2), K LUZURIAGA (3), W DANKNER (4), K NIELSEN (1), B KERR (5), A HENDRICKS (5), M. GERSTEN (5), B. BOCZANY (5), S SPECTOR (3), AND Y BRYSON (1). (1) Univ. of California at Los Angeles, CA; (2) Bronx Lebanon Hospital, Bronx, NY; (3) Univ. of Massachusetts, Worcester, MA; (4) Univ. of California at San Diego, CA; (5) Agouron Pharm, Inc., La Jolla, CA. ÿÿÿ Sixty HIV infected infants and children ranging from 3 mo to 13 yrs of age (median 5.4 yrs) received nelfinavir (NFV) to evaluate the pharmacokinetics, tolerance and potential efficacy of the drug when used in combination with nucleoside reverse transcriptase inhibitors (NRTI). A dose of 20 mg/kg to 30 mg/kg thrice daily yielded steady state plasma NFV levels comparable to those seen in adults during Phase II/III trials. In a subset of older children, NFV plasma levels were found to be similar for the NFV oral powder and tablet formulations. NFV was well tolerated: three patients reported transient Grade 2 diarrhea (resulting in study discontinuation by one). Other Grade 2 or greater clinical events considered to be possibly related to NFV included rash or fever in one patient each. The mean baseline HIV plasma RNA (Roche Amplicor HIV Monitor) was 4 X104copies/ml). By 10 weeks of study, median viral RNA decreased by 1.3 log for the cohort as a whole. The decline in RNA load was greatest and best sustained in children who had >1 NRTI added within six weeks of starting NFV compared to those having only NFV added to their treatment regimen. At 34 weeks of followup, plasma HIV RNA was undetectable in 10/18 (55%), including 8 of 11 (73%) subjects receiving NFV with >1 new NRTI. Children with undetectable viral RNA at 34 weeks of followup had a higher median % CD4+ lymphocyte increase over baseline than those with detectable viremia. (8.5% versus 4.6%) These data indicate that nelfinavir has a predictable and safe profile in children and infants. In addition, improved and sustained suppression of HIV is most readily achieved when nelfinavir is combined with one or more new antiretroviral agents.

To: Timothy Kross who wrote (3703)	2/1/1998 8:12:00 PM
From: JOHN W.	Respond to of 6136

Abstract 373 / Session 50 Comparison of BID and TID Dosing of VIRACEPTr (Nelfinavir, NFV) in Combination with Stavudine (d4T) and Lamivudine (3TC) MARGARET JOHNSON* for the European Viracept Clinical Trial Group, ANNKATRIN PETERSEN, JEFF WINSLADE and NEIL CLENDENINN from Agouron Pharmaceuticals, Inc.ÿÿÿ ÿÿÿ This is a randomized, open- label, two group comparative trial of two nelfinavir dosing regimens, 1250 mg BID vs. 750 mg TID in combination with standard doses of d4T and 3TC, for a total duration of 48 weeks. Twenty-four sites in Europe are participating and have enrolled 279 patients from 3/97 8/97. Patients are 3TC naive with less than 6-months of nucleoside antiretroviral therapy. Mean baseline viral load is approximately 4.80 log copies/ml and the mean baseline CD4+ cell count is 260 cells/mm3.ÿÿÿ ÿÿÿ A subset of patients (N= 21) participated in pharmacokinetic assessments after approximately 4 weeks of treatment. Median steady-state values for postdose plasma trough concentration were 0.7 mg/L (C12 for BID) and 1.0 mg/L (C8 for TID); time-averaged concentration over a dose interval. (Cavg=AUC/tau) was 2.1 vs 1.9 mg/L for BID vs TID respectively. Preliminary viral load data is available for 81 patients and CD4+ cell counts are available for 107 patients followed for 16 weeks. Eighty-three percent of 58 subjects on BID dosing and 78% of 23 on TID dosing are below the level of quantification on the Amplicor Monitor assay (<400 copies/mL). Mean CD4+ cell counts increased 126 vs 123 cells/mm3 in the BID (n=78) vs TID (n=29) groups, respectively. These data suggests that both treatment regimens are effective in inhibiting the replication of the virus after 16 weeks of treatment. Additional data will be presented.

To: Timothy Kross who wrote (3703)	2/1/1998 8:14:00 PM
From: JOHN W.	Respond to of 6136

Abstract 270 / Session 38 Evidence of Potent Antiviral Activity in a Phase l/ll Study of Nefinavir Mesylate (Viracept) in HIV Infected Chidlren.ÿÿÿ P KROGSTAD (1)*, A WIZNIA (2), K LUZURIAGA (3), W DANKNER (4), K NIELSEN (1), B KERR (5), A HENDRICKS (5), M. GERSTEN (5), B. BOCZANY (5), S SPECTOR (3), AND Y BRYSON (1). (1) Univ. of California at Los Angeles, CA; (2) Bronx Lebanon Hospital, Bronx, NY; (3) Univ. of Massachusetts, Worcester, MA; (4) Univ. of California at San Diego, CA; (5) Agouron Pharm, Inc., La Jolla, CA. ÿÿÿ Sixty HIV infected infants and children ranging from 3 mo to 13 yrs of age (median 5.4 yrs) received nelfinavir (NFV) to evaluate the pharmacokinetics, tolerance and potential efficacy of the drug when used in combination with nucleoside reverse transcriptase inhibitors (NRTI). A dose of 20 mg/kg to 30 mg/kg thrice daily yielded steady state plasma NFV levels comparable to those seen in adults during Phase II/III trials. In a subset of older children, NFV plasma levels were found to be similar for the NFV oral powder and tablet formulations. NFV was well tolerated: three patients reported transient Grade 2 diarrhea (resulting in study discontinuation by one). Other Grade 2 or greater clinical events considered to be possibly related to NFV included rash or fever in one patient each. The mean baseline HIV plasma RNA (Roche Amplicor HIV Monitor) was 4 X104copies/ml). By 10 weeks of study, median viral RNA decreased by 1.3 log for the cohort as a whole. The decline in RNA load was greatest and best sustained in children who had >1 NRTI added within six weeks of starting NFV compared to those having only NFV added to their treatment regimen. At 34 weeks of followup, plasma HIV RNA was undetectable in 10/18 (55%), including 8 of 11 (73%) subjects receiving NFV with >1 new NRTI. Children with undetectable viral RNA at 34 weeks of followup had a higher median % CD4+ lymphocyte increase over baseline than those with detectable viremia. (8.5% versus 4.6%) These data indicate that nelfinavir has a predictable and safe profile in children and infants. In addition, improved and sustained suppression of HIV is most readily achieved when nelfinavir is combined with one or more new antiretroviral agents.

To: Timothy Kross who wrote (3703)	2/1/1998 8:18:00 PM
From: JOHN W.	Respond to of 6136

Abstract 310/Session 46 A Comparative Study of HIV-1 RNA Levels Measured by the NucliSens and Quantiplex bDNA Assays in Serial Plasma Samples from Patients on Antiretroviral Therapy C. C. GINOCCHIO*, S. TETALI, D. WASHBURN, and M. H. KAPLAN. North Shore University Hospital-NYU School of Medicine, Manhasset, NY. ÿÿÿ Plasma HIV-1 RNA levels were measured by both the bDNA (Chiron Corp.) and NucliSens (Organon Teknika) assays over a 12 month time period on 14 patients enrolled in the VIRACEPT (Agouron Pharm.) clinical trial studies. Of the 178 specimens tested 109 had detectable HIV-1 RNA and 27 had undetectable levels by both methods. The increased sensitivity of the NucliSens assay (100 copies/ml) as compared to the bDNA assay (500 Eqs/ml) allowed for the detection of HIV-1 RNA in 40 additional specimens (22.47 %). The NucliSens assay detected a sustained rebound in the viral load (VL) in 10 patients sooner than the bDNA assay (range 2 weeks to 5 months). A comparison of the VL results obtained with each assay demonstrated significantly higher values by NucliSens vs. bDNA (p=<0.001). The ratios of bDNA RNA Eqs/ml to NucliSens RNA copies/ml were as follows: 1: 2.130, for values 1,000-10,000, 1:1.640 for values >10,000-50,000; 1:2.066 for values >50,000-100,000; and 1:2.308 for v alues >100,000 (mean ratio 1:2.036, p=<0.001). A linear regression analysis performed indicated a significant relationship between the 2 v ariables (p= <0.0001). Spearman correlation analysis indicated a highly significant positive correlation between the VL quantitated by the 2 assays (r = 0.907, p= <0.0001). These data indicate that the enhanced sensitivity of the NucliSens assay allows for the earlier detection of breakthrough, HIV-1 viremia in patients on antiretroviral therapy. These studies also clearly demonstrate that although there is a significant correlation between, the values obtained by the bDNA and NucliSens assays, the absolute values are significantly different and should not be used interchangeably when monitoring patient response to antiretroviral therapy.

To: Timothy Kross who wrote (3703)	2/1/1998 8:22:00 PM
From: JOHN W.	Read Replies (1) \| Respond to of 6136

Abstract 510/Session65 Virologic responses to a Ritonavir/Saquinavir containing regimen in Patients who have previously failed Nelfinavir. P TEBAS*, E KANE, M KLEBERT, J SIMPSON, WG POWDERLY, K HENRY. Wash Univ, St. Louis, MO.Univ of Minnesota, Minneapolis MN, Regions Hospital,St. Paul, MN Objectives The effectiveness of a second protease inhibitor (Pl) in patients who failed aninitial Pl is unclear but believed to be low. It has been postulated however that patients who fail nelfinavir may respond differently. We therefore assessed the virologic response to aritonavir/saquinavir containing regimen in patients that have previously failed nelfinavir. Methods 27 patients enrolled in the phase 11 nelfinavir clinical trials (AG506, AG511 andAG525) at our 2 sites who failed (two consecutive HIV viral loads > 5000 copies per ml(bDNA assay)) were switched to a combination of D4T 40 mg bid, 3TC 150 mg bid, ritonavir.400 mg bid and sequinavir 400 mg bid. Results Patients had taken nelfinavir for a median of 52 weeks. 33% of them had a complete virologic response to the nelfinavir containing regimen. 20 of those patients were naive or had limited prior antiretroviral therapy prior to treatment with nelfinavir-containing regimens (AG506 and AG511). 1 patient discontinued study at 3 weeks. 19/19 (100%) of the remaining patients reached undetectable viral loads (<500 copies) that were sustained at week 16 in 9/10 (90%) subjects. Only 3/7 (43%) of the patients with extensive prior antiretroviral therapy (AG525) reached undetectability. The regimen was well tolerated. The most frequent baseline mutations in the protease gene prior to switching were D30N(17/25) and L90M (5/25).The presence or absence of these mutations was not predictive of a short-term virologic response. Conclusions Most patients who failed a nelfinavir-containing regimen responded to a switch to a combination regimen with saquinavir/ritonavir. The durability of this response through 24-weeks of follow up and its relationship to baseline protease gene mutations will bepresented.

To: Timothy Kross who wrote (3703)	2/1/1998 9:33:00 PM
From: JOHN W.	Respond to of 6136

Abstract 352 / Session 49 Saquinavir Pharmacokinetics Alone and in Combination with Nelfinavir in HIV infected Patients. MERRY C.*1, BARRY M.G.2, MULCAHY F.M.1, BACK D. J2 , 1. St. James Hospital, Dublin 8, Ireland. 2. Dept. of Pharmacology & Therapeutics, Liverpool University, UK. Combination therapy with Saquinavir plus Nelfinavir is an attractive therapeutic option due to its pharmacokinetic interaction. In this study we examined the effect of Nelfinavir on plasma Saquinavir levels and steady state plasma Nelfinavir in 6 HIV positive patients. All 6 patients were at steady state for Saquinavir and had undetectable plasma HIV RNA (Roche Amplicor). Pharmacokinetic studies using HPLC were performed on Day 1 and Day 3 before and after the addition of Nelfinavir 750mgs 8 hourly to Saquinavir 600mgs 8 hourly. The geometric mean Cmax and AUC0-8h for Saquinavir on the first day were 253 ng/ml (range <25 to 1200 ng/ml) and 1106 ng/ml.h (range <100 to 3479 ng/ml.h) respectively and on the second study day 1204 ng/ml (range 379 to 2755 ng/ml) and 5472 ng/ml.h (1434 to 12538 ng/ml.h). The mean ratio for Cmax was 4.75 and for AUC0-8h was 4.94. The geometric mean Cmax and AUC0-8h for Nelfinavir were 5.55ng/ml (range 1.32 to 8.54ng/ml) and 29.3ng/ml (range 6.52 to 48.8 ng/ml.h) respectively. Nelfinavir increases the oral bioavailability of Saquinavir (hard gel) approximately

To: Timothy Kross who wrote (3703)	2/1/1998 10:07:00 PM
From: Peter Singleton	Read Replies (2) \| Respond to of 6136

Tim, Thanks for your posts sifting through the Viracept abstracts. There are very good data for Viracept presented here, as per the points you raise. There is also an interesting abstract about compliance with PI's among inner city patients. It's a little unclear, but it could be read to indicate that nelfinavir patients were more likely to stay on drug than patients using other PI's. Two other points jump out at me from my first cursory scan of the abstracts. 1 - There doesn't seem to be enough data in the abstracts alone to establish an opinion of Vertex / Glaxo's Amprenavir. It appears to be a quality contender. There's one study (abstract 512) that may be the study that is giving rise to the rumors of very high levels of anti-viral potency ... but there aren't enough data to evaluate based on the abstract ... maybe there will be 16-week data on % undetectable presented this next week. 2 - Saquinavir-SGC (Roche's Fortovase) looks like a real player. From the abstracts, it looks like it has excellent anti-viral potency (on a par with indinavir (Crixivan) and nelfinavir), and is well tolerated. FWIW, it's a higher dose (1200mg TID) than nelfinavir (750mg TID) ... In addition, it's clear that saquinavir-sgc and nelfinavir are more potent together than either one alone. What does this mean? Well, on the plus side, nelfinavir and saquinavir-sgc are a highly potent, well-tolerated dual PI combination. As AGPH has pointed out, the lions share of current dual PI use is saquinavir (hard gel formulation) + ritonavir, but as new data like the saq-sgc / nelf study come out, that should change. However, Roche are not in this to make AGPH or anyone but Roche rich ... and saquinavir-sgc looks like it's a very strong contender as a single PI in combination therapy. Hence, a lot less incentive to push Viracept over their own product than they had when signed the original deal ... saquinavir-hgc of course being an inferior product due to poor bioavailability. As has been pointed out on this thread, AGPH's deal with Roche provides them some benefit if Roche sells their product instead Viracept (there's a royalty rate on Roche's sales of Viracept, a lower royalty rate on Roche's sales of saquinavir, and AGPH gets the greater of the two) ... but still I wonder what implication Roche having data showing their own product equivalent to Viracept in single-PI therapy will have on Roche sales of Viracept, and consequently, AGPH revenue from Roche. BTW, there's a ton of stuff here at the conference website. Well worth the time spent ... Peter