Mixed Results (and Lots of Diarrhea) for the Tipranavir Studies; Plus Salvage Study Designs for JNJ/Tibotec’s PI and Non-Nuke
“Boosting to Break the Bank”
Boehringer Ingelheim filed its new drug approval applications for tipranavir in the United States and the European Union last month. The plan is to receive U.S. FDA imprimatur by May 2005 and a green light by Europe’s EMEA by late summer. Meanwhile, JNJ/Tibotec’s protease inhibitor and non-nuke me-toos head into their final lap. (If only they had something innovative and truly useful. But then, the same could be said of BI. Remember when that crazy Kalamazoo outfit was trying to figure out what to do with tipranavir — way back in 1998!) Rob and Mike stitched together this short update.
Update on Tipranavir (ok, TPV/r)
BI’s two pivotal trials for tipranavir (TPV) are RESIST-1 (in the U.S. and South America, n=630), and RESIST-2 (in Europe and Australia, n=876). RESIST is their more clumsy than clever acronym for “Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir.”
RESIST-1 is a 48-week trial (the 24 week data presented here) in people with viral load >1,000 copies/ml with at least one — and no more than two — primary mutations at codons 33, 82, 84 and 90. The primary end point is a viral load reduction of 1.0 log. No CD4 requirement, and lack of a Karnofsky score at entry meant that some people in the trial died before getting drug. The 24-week results of RESIST-1 were presented at this autumn’s ICAAC meeting, by Dr Charles Hicks of Duke.
Baseline Demographics
In RESIST-1, participants were 90% male, 21% black. In both RESIST studies, 80% of people were on tenofovir, 60% on 3TC, 30% on ddI. The average viral load at baseline was over 5.0 log (that’s 100,000 copies). All study participants were PI resistant, with an average of 15 protease mutations as well as having previously used an average of 12 antiretrovirals.
Both RESIST studies compare TPV+ritonavir (ritonavir at a total daily dose 400 mg) to what is called the “comparative PI+ritonavir” or CPI/r. Protease inhibitors used in the CPI/r group were: lopinavir/r 61%, saquinavir 20%, amprenavir 14%, indinavir 4%. RESIST-1 enrolled 311 people in the TPV/r group and a total of 309 on the various CPI/r regimens.
RESIST-1: 24-Week Results
41.5% of study participants on TPV/r had a viral load reduction of >1.0 log vs. 22.3% on other PIs. At week 8, 42% of tipranavir participants achieved log reductions of 1.4 log or greater, but at week 24 this reduction was only 0.88 log.
At week 24, 35% of TPV/r people had viral load <400 copies/ml (25% under 50 copies) compared to 17% of those taking CPI/r reaching <400 (vs. 10% under 50). Median viral load drop at week 24 was 0.88 log for TPV/r vs. 0.28 log for CPI/r. There was an increase of 36 CD4 cells at week 24 in the TPV/r group compared to an increase of 6 CD4 cells in the CPI/r group.
By week 24, 28 people (9%) had discontinued TPV/r due to side effects (n=15) or virological failure (n=13). 33 people (11%) in the CPI/r group discontinued.
T-20 Effect in RESIST-1
36% of RESIST-1 participants were taking T-20, 19% adding it as they started this study. T-20 takers were generally more ill than the average study participant and yet, at least in RESIST-1, fared better than average (33% <400 with TPV/r vs. 45% <400 with TPV/r + T-20). This “T-20 effect” was not observed in the CPI/r group, where the percentages of people who achieved a viral load <400 were almost identical: 10% without T-20 vs. 14% with T-20.
Interaction Data
Both clarithromycin and fluconazole raise tipranavir levels. Maalox lowers tipranavir levels by 23%.
Side Effects
Rates of diarrhea and nausea (all grades) were high, as were elevations in ALTs, cholesterol and triglycerides. Boehringer would recommend pravastatin, or low-dose atorvastatin for those who need it. (TPV/r raises atorvastatin levels some 9-fold.) Discontinuations due to adverse events were higher with TPV/r (9.3% vs. 5.2%) than with CPI//r. Discontinuations due to high ALT were 6% for TPV/r vs. 1% for CPI/r.
RESIST-2: 24-Week Results
The 24-week results of RESIST-2 were presented at the 7th Drug Therapy conference (Glasgow, Scotland) in early November. The RESIST-2 study was almost identical in design to RESIST-1, but recruited volunteers from Europe and Australia rather than the Americas.
863 people were enrolled into RESIST-2. As in RESIST-1, study participants were required to have a viral load >1,000 copies/ml, with at least one primary protease inhibitor mutation from the group 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, 90M and two or more mutations at codons 33, 82, 84 or 90. Again, they were randomized to receive an optimized background regimen plus either tipranavir/ritonavir (500/200 mg) or a ritonavir-boosted comparator protease inhibitor (CPI/r), consisting of lopinavir, indinavir, saquinavir or amprenavir.
After 24 weeks, an intent-to-treat (missing equals failure) analysis showed that 41% of the tipranavir group had a drop in viral load of more than 1.0 log from a median baseline of 58,900 copies/ml. This compared to 15% in the comparator group (p <0.001). The median drop in viral load was also larger in the tipranavir group (0.72 vs. 0.22 log, p CD4 cell counts rose more in the TPV/r group than the CPI/r group (31 cells vs. 1 cell/mm3, p= 0.022). Fewer people taking TPV/r discontinued treatment (17 vs. 29). (RESIST-1 saw opposite results.)
T-20 Effect in RESIST-2
Twelve per cent of the study participants in RESIST-2 were taking T-20 as part of their optimized background regimen. In contrast to the results from RESIST-1, the inclusion of T-20 did not cause a significant increase in the effectiveness of TPV/r: 38% of these participants had viral loads below 400 copies/ml, compared to 13% in the CPI/r group, while 23% and 5%, TPV/r and CPI/r respectively, had viral loads below 50 copies/ml. Grade 3 or 4 adverse events were similar in the two groups (14% vs. 12%), with diarrhea, nausea and vomiting being most common. People in the TPV/r group, however, experienced a greater incidence of laboratory abnormalities — particularly rises in cholesterol, triglycerides and the liver enzymes (ALT; 5% vs. 2%, p < 0.05; (AST, 4% vs. 1%, p < 0.05). This observation was consistent across both RESIST-1 and RESIST-2.
Tipranavir: The Near Future
The BI people say they haven’t been told if they will have an actual AVAC hearing with the FDA. Meantime, they are conducting a study of the pediatrics liquid in 52 kids, by age, 2-5, 6-11, and 12-18.
Tipranavir Price
If TPV is priced according to its usefulness, a policy which hasn’t appeared to quite yet catch on, it would be given away virtually free — as T-20 should be. Meanwhile, Abbott says that it will give out ritonavir for free to those using the high-dose booster; the dose (200 mg twice a day) used in both RESIST studies. (This unusually high dose of ritonavir as a PI boost may be responsible for many of the side effects reported in RESIST, along with perhaps the general advanced clinical status of the participating population.) TPV devotees boosting with a lower dose of ritonavir will apparently have to pony up the cash. Abbott refers these people to its Patient Assistance Program. (But, duh, why not simply have your clinician prescribe the high-dose boost and give the extra ritonavir to AID FOR AIDS or some similar ARV access group?) BI says its having “coformulation” talks with Abbott, which Rob suspects will go nowhere. Abbott has never co-formulated with any other PIs. Why would they start with Boehringer?
ATAC and The Fair Pricing Coalition have formally asked all pharma companies to institute an immediate price freeze on their HIV (and HCV) medicines, as well as to institute a “smart policy” regarding the pricing of new drugs. BI says it has personally passed this letter on to the Chairman of the Board.
Update on the TMC Sisters
Tibotec (a division of Johnson & Johnson) is developing an NNRTI and a PI almost in parallel: TMC125 is the NNRTI and TMC114 is the protease inhibitor. Because of this fact, and perhaps because Tibotec is claiming that the non-nuke and PI me-toos will work in people already NNRTI and protease inhibitor resistant, ATAC as well as some European clinicians (in a Lancet letter recently) are asking that Tibotec/JNJ look at the two drugs together in the same study. This would allow a person in a salvage situation to know a lot of the information needed, such as drug-drug interaction experiences, with the other drug as well as with other antiretrovirals and other frequently used medicines in salvage situations.
TMC114 is a sulfa-based drug, and rash has been reported in up to 17% of people taking TMC114 full strength.
The folks at Tibotec have suggested a trial that would compare the now pedestrian Optimized Background Therapy (“OBT”) in combination with its NNRTI vs. OBT in combination with its PI vs. OBT in combination with both its drugs:
OBT + 125
OBT + 114/r
OBT + 125 + 114/r
(Tibotec’s protease inhibitor must be given with small doses of ritonavir, so it frequently appears in writing as 114/r.)
Or you could throw Pfizer’s edgy CCR5 (still without a proper name and know only as UK471) blocker into the mix:
OBT + 125 + UK471
OBT + 114/r + UK471
OBT + 125 + 114/r
But a study such as this, which essentially pits drugs from two separate companies (in this case JNJ vs. Pfizer) head to head, is unlikely to ever get off the ground. Rob says that the potential benefits of being able to throw an entry inhibitor into two of the study’s three treatment groups could be enormous. One little wrinkle, though: the proper dose of Pfizer’s UK471 has not yet been decided on. But Rob says the FDA would tend to recommend the lowest dose tested, which apparently has shown decent antiviral efficacy.
Tibotec/JNJ is still working out the best doses of its drugs as well, and the formulations have not been 100% established. Treatment activists are to meet with them — perhaps along with FDA reps — in early 2005.