Vicissitudes of Medicine and Marketing Take Toll on Me-Too Line Up
By Rob Camp
B-I the New Salvage Outfit?
Pipelines are almost as delicate and fragile as the ecosystems they go trampling through, writes TAG’s Antiviral Project Director Rob Camp. Oft-times the way to get from the beginning to the end is not a straight line. Although that does remain the quickest way geometrically, there may be other factors at play. For oil to get to the Black Sea, sometimes the pipeline has to go around countries and political factions, rather than through them. And on the way, discoveries are made and decisions are taken.
Last year’s pipeline report was warm and hopeful and excited. But over the course of the past year, we witnessed the demise of SCH-C, Roche dropped development of a second generation fusion inhibitor, and both integrase inhibitors (Shinoigi and Merck) have also been given the ‘ole heave-ho.
In other disheartening news, Gilead sold back its Phase II nuke, DAPD, to Emory University. With many difficult side effects (“lenticular opacities,” kidney concerns) and not enough ingenuity regarding how to make a “salvage” drug work better, they gave up. Maybe a “real” salvage company, as Boehringer-Ingelheim now describes itself, would be interested in picking up a Phase II nuke?
So I am putting the TMC compounds (the protease inhibitor, 114, and the non-nuke RTI, 125) and tipranavir back in the pipeline — because otherwise not much will be coming out of it in the near to midterm future.
Reverset is an NRTI with activity against HIV, an intracellular half-life of 17 hours, and no reported mitochondrial toxicity, with in vitro activity against AZT and 3TC resistant mutations (but not the D69 or Q151 mutants). Pharmasset offered up a 10-day monotherapy dose escalation trial in treatment naive people >50 CD4s, at 50, 100, 200 mg QD.
Although 200 mg showed the best pharmacokinetic (PK) data, CD4s increased the best with 100 mg, and viral load at 100 mg dropped by 1.80 log10 (200 mg not reported). Enteropathy (an intestinal disease) and bone marrow toxicity has been seen in rats. Hypopigmentation has been seen around the nose in female dogs. In humans, without grading, headache was seen in 33% of patients, fatigue in 17%, and the cold symptoms in 46%.
ACH-126,443 is a new nucleoside analogue said to have activity against 3TC resistant HIV — and HBV — and is under development by Achillion Pharmaceuticals. Its chemical name is beta-L-Fd4C, and its generic name is elvucitabine. ACH-126,443 is a strong candidate for once daily dosing, with an intracellular half life of more than 20 hours.
In vitro studies have also looked at the impact of this compound on mitochondrial DNA. ACH-126,443 caused no mitochondrial toxicity, and reduced the level of mitochondrial damage caused by d4T when the two drugs were combined in the test tube.
A Phase II study was conducted to assess the anti-HIV activity and safety of ELV in a HAART regimen in persons with the principal 3TC mutation (M184V). Fifty-six individuals remained on their 3TC-containing HAART regimen and then switched their 3TC for ELV (at either 50 or 100 mg, QD). While the drug demonstrated good antiviral activity, unexpectedly high toxicity (4 of 56 patients needed to discontinue treatment) caused the study to be prematurely terminated (one year ago March). Lower doses are expected to be studied.
Also known as DAPD, amdoxovir is an investigational guanosine nucleoside analogue currently in Phase II development for the treatment of HIV. Amdoxovir has also been tested in humans for the treatment of chronic hepatitis B infection and is currently in Phase II clinical trials. In one of the more recent studies of the drug (reported at the Boston ’03 Retrovirus conference), five of eighteen study patients discontinued the study due to “lens opacities.”
Gilead acquired the worldwide rights to amdoxovir, through a licensing agreement with Emory University and the University of Georgia Research Foundation, when it acquired Triangle Pharmaceuticals in January 2003. But this past January 28, Gilead announced that it was giving the drug back to the two academic centers, Emory University and the University of Georgia, and ending the agreements “for strategic reasons.”
Gilead explained it would meet its ongoing obligations with respect to existing clinical trials and is committed to cooperating with the universities during the transition of this technology to a new licensee.
Mary L. Severson, Ph.D., Chief Technology Officer at Emory University, recently stated that “Amdoxovir has great potential for salvage therapy in HIV infected individuals” and that “Emory and the University of Georgia Research Foundation are committed to the continued development of this drug and the ongoing NIH-sponsored clinical trials ACTG 5118 and ACTG 5165.”
MIV-310, alovudine, active against multi-resistant HIV is a patented pharmaceutical compound in the NRTI class. Phase IIb trials are directed towards identifying the optimal dosage to maximize virus reduction with acceptable side-effects.
Phase 1 trials suggest that capravirine is ten times more potent than current NNRTIs. A dosing study reported that 2,100 mg capravirine twice daily produced a 1.69 log reduction in viral load after 10 days of treatment. This was equivalent to the viral load reduction in the triple therapy control arm.
Capravirine is active against HIV variants with single mutations at codons K103N or V106A or L100I which confer resistance to NNRTIs. Capravirine is likely to be active against viruses with resistance to efavirenz. Resistance to nevirapine (usually characterized by a mutation at codon Y181C) would render capravirine useless. However, a mutation at codon 181 or a dual mutation at codons 103 and 100 will confer high level resistance to this compound, calling into question its usefulness.
Clinical trials of capravirine were suspended pending safety checks following the discovery that the drug causes vasculitis (inflammation of the blood vessels) in dogs. Vasculitis may cause severe damage to the tissue supplied by inflamed blood vessels because blood cannot adequately reach the tissue. Development has now resumed. In a phase II study, a higher rate of nausea, vomiting and diarrhea was seen in the 2,100 mg group, and so the 1,400 mg dose has now been selected for further development. Capravirine is currently being tested in two international studies. One is testing the drug in treatment-naive patients, and the other is testing the drug in combination with nelfinavir and two new NRTIs in patients who have failed or did not respond to an NNRTI-containing regimen.
Capravirine is also being tested in studies where it is combined with drugs that are p450 cytochrome inhibitors, because these have been shown to boost plasma levels of the drug. Taking the drug with food also increases blood levels. A study in healthy volunteers showed that capravirine reduced lopinavir levels somewhat, but that lopinavir increased capravirine levels substantially.
One year ago to the month, Sarawak MediChem issued a press release explaining that they had completed a 48-subject (HIV-negative) PK and dosing trial of Calanolide A in combination therapy for HIV. That was March 4, 2003. There’s been little word since. The best clues may be had at the web site of the Sarawak half (not the Advanced Life Sciences half) of the partnership:
“In our Phase IB studies we tested calanolide A with different twice-a-day regimens for 14-days in 32 HIV-infected patients. The studies showed a trend in viral load reduction as the dosing was increased. Furthermore, there was no evidence of the emergence of viral mutants over the period of study possibly indicating that calanolide A can delay the onset of drug-resistant viral strains. We plan to conduct Phase I/II clinical studies throughout 2002-03 and progress quickly to Phase II/III in 2004.”
A lovely resistance poster laid out the susceptibility codons of TMC-125. They seem to be at positions 101, 179, 181 and possibly 227 and 230, decreasing the efficacy of the drug. These four single mutations and one double mutation are worrisome (they cause a >10 fold change, although 4 may be the more realistic fold change to be concerned about. Looking at 4 fold, the 100, the 108 and 238 may be important, along with doubles at 181 + 188, 181 + 190, 179 + 181). A number of (at least six) triple mutations are worrying. No efficacy data were presented; they have just started a number of trials after a nine-month hold due to rash issues that have now been “accepted” by the FDA.
- The DPCs: Dupont Follow-Ups
When BMS bought Dupont, they inherited a lot of non-nuke RTIs (chief among them DPC-086 and DPC-961). We thought they had forgotten about them. While clinical development of DPC-086 (aka BMS-561390) and 961 was officially terminated 2 years ago, tricyclic non-nukes shall be back!
Originally developed by Pharmacia & Upjohn, tipranavir was acquired by Boehringer-Ingelheim, the maker of nevirapine. Following encouraging results in phase I/II clinical studies, tipranavir is now in phase III studies.
The formulation of tipranavir (TPV) used in early trials produced low concentrations of the drug. It was subsequently replaced by a SEDDS formulation. However, average plasma concentrations tipranavir remained mediocre, so investigator have turned to concurrent dosing with low-dose ritonavir, which boosts blood concentrations of tipranavir. The dose of tipranavir that will be studied in the Phase III clinical program is 500 mg of tipranavir taken with 200 mg of ritonavir twice daily. This dosage was found to be safe and effective. Blood levels of TPV are increased with a high-fat meal.
Tipranavir is able to reduce viral load by up to 1.5 log when dosed with 200 mg of ritonavir. This small dose of ritonavir can substantially improve the drug’s pharmacokinetic profile (and reduce the daily pill burden). When taken without ritonavir, tipranavir has reduced viral load by between 0.8-1.3 log after two weeks. The addition of ritonavir may also delay tipranavir clearance for long enough to allow once-daily dosing.
A study known as RESIST (Randomized Evaluation of Strategic Intervention in multi-drug ReSistant patients with Tipranavir) is evaluating tipranavir in people who have taken nucleoside analogues, NNRTIs and protease inhibitors. It is studying the safety and efficacy of tipranavir boosted with low-dose ritonavir versus a low-dose ritonavir-boosted protease inhibitor that is chosen on the basis of treatment history and baseline resistance testing.
The RESIST study is being conducted in more than 280 clinical trial sites worldwide. Studies of drug interactions with other protease inhibitors are also taking place. These studies are likely to report their findings during 2004 and it is expected that the drug will be licensed in the United States by the end of 2004, with Europe following in early 2005. Tipranavir was developed as an alternative to existing protease inhibitors which display a high level of cross-resistance. Test tube studies report that resistance to tipranavir is slow to develop, and that there is no clear pattern of cross-resistance to currently available protease inhibitors.
More recent findings, however, suggest that patients with three or more PI-associated mutations are unlikely to experience an optimal response to TPV/r. When analyzed by the number of baseline PI-associated resistance mutations, successful virologic response was clearly associated with two or fewer mutations. These findings raise the question of whether tipranavir will be able to salvage treatment failure associated with loss of previous PI susceptibility, and have been an important focus of phase III studies.
Resistance mutations associated with tipranavir are I15, E35D, N37D, D60E and A71T. Isolates with resistance mutations at codons 82T and 84 have also displayed reduced sensitivity to tipranavir. Other secondary mutations appear to be important in such cases for determining how much sensitivity is lost.
Unfortunately, TMC-114 needs 100 mg of ritonavir, usually BID, but otherwise may be considered an advance in protease inhibitor therapy. Food also helps exposure (by some 40%). Response rates in this dose escalation study were similar, if not identical (by statistical analysis, not per person studied), for patients with >1 primary protease inhibitor mutation, phenotypic resistance to all protease inhibitors, phenotypic resistance to lopinavir, and viral loads of more than 20,000. Baseline susceptibility to TMC was not predictive of these positive effects.
To the Nines: The Parade of Me-Toos
Class of Compound
Expected Launch Date
|TMC 114/r||PI||Phase I/II||Tibotec/J&J||2007|
|TMC 125||NNRTI||Phase II||Tibotec/J&J||2006|
|Calanolide-A||NNRTI||Phase II||Advanced Life Sciences/Sarawak MediChem||2007|
|Amdoxovir (DAPD)||NRTI||Phase II||Emory Univ./University of Georgia||2007|
|Alovudine (MIV-310)||NRTI||Phase II||Medivir||2006|
|D-D4FC (Reverset)||NRTI||Phase II||Incyte/Pharmasset||2006|
|Elvucitabine (ACH-126,443)||NRTI||Phase II||Achillion||2007|
|Source: Data Monitor (and individual company reporting).|