New Drugs in Development
In the last issue of PI Perspective (#28), we reviewed some new anti-HIV drugs in development. Since then, setbacks have occurred that will delay, and in some cases stop, the development of some of these therapies. However, other therapies show promising activity and continue through the development process quickly.
Tipranavir represents the first of a new class of protease inhibitors (PIs). What's different about this one, at least in lab studies, is that the drug is active against viruses that are resistant to the other protease inhibitors. Whether this will actually be the case in human studies is not yet fully known.
The earliest human studies showed the drug suppressed viral load and seemed to work best when combined with a small dose of ritonavir (Norvir®), as do many other PIs.
A report from a small, incomplete tipranavir study in people resistant to other PIs was submitted but not accepted for presentation at the recent Human Retrovirus Conference. The drug's sponsor at the time, Pharmacia & Upjohn, claimed the drug was doing well in the study. Shortly before the Conference, the rights to develop and market tipranavir were sold to Boehringer Ingelheim. It is unclear whether the sale will affect the pace of the drug's development.
Once-a-Day Protease Inhibitor Looks Encouraging
Early results report that a new once-a-day protease inhibitor, BMS 232632, shows encouraging activity. Participants took 200 mg, 400 mg or 500 mg of BMS 232632 once a day or the standard three times a day dose of nelfinavir. After two weeks, d4T and ddI were added to their regimens.
Volunteers had not taken anti-HIV therapy before. They had viral loads around 60,000 copies HIV RNA and 400 CD4+ cells at the start of the study. There were no real differences in anti-HIV responses among the three doses of BMS 232632 and nelfinavir. About 60% of the participants achieved viral loads below 400 copies HIV RNA and 40% were below 50 copies after 16 weeks.
The most common side effects of BMS 232632 were mild to moderate diarrhea and elevated bilirubin levels (a measure of liver function), especially among those using the highest dose. Bilirubin levels normalized after stopping the drug or reducing it to the lowest dose studied.
A once-a-day protease may be a significant advance in aiding adherence. It may also lessen treatment fatigue. It remains to be seen how well this drug will perform in people with resistance to the other protease inhibitors and lab studies are somewhat conflicting in this regard. Also, it is quite unusual that no difference was seen among the three doses used in the current study, raising questions about how much of the current response rates is due to chance and the small number of people studied. This has the potential to slow the drug's development because of the difficulty in picking the proper dose.
Emivirine Interacts with Nelfinavir
A recent study revealed significant interactions between nelfinavir (Viracept) and the experimental NNRTI, emivirine (Coactinon, formerly MKC-442). An earlier study suggested that emivirine decreased nelfinavir blood levels by about 30%. A new study suggests the interaction is far greater.
This study evaluated emivirine added to d4T+3TC+nelfinavir to see if the four drugs might result in better and longer control of HIV. The exact degree of the interaction between emivirine and nelfinavir is still unknown, but it's thought that it reduced nelfinavir levels by over half. As a result, nelfinavir probably contributed little if any anti-HIV activity to this combination.
Triangle Pharmaceuticals, the developer of emivirine, had hoped to file for new drug approval by the end of 1999, but that has been delayed while the company reconsiders the role of emivirine in multi-drug regimens. It is unlikely that emivirine will be combined with a single protease inhibitor as it probably decreases the levels of all protease inhibitors to some degree. However, it may be possible to use emivirine with two protease inhibitors if one is ritonavir (Norvir), since it would counteract the problem created by emivirine. The company is now exploring this possibility, though it is unclear whether this will provide a practical solution.
Lodenosine (FddA) and Liver Side Effects
One of the most serious setbacks has been the emergence of severe liver side effects related to the new NARTI, lodenosine (FddA). Early results from a study comparing three different doses of lodenosine showed potent anti-HIV activity. The study compared lodenosine (100 mg, 200 mg, and 300 mg all taken twice a day) + d4T (stavudine, Zerit) + indinavir (Crixivan) to a standard regimen of 3TC (lamivudine, Epivir) + d4T + indinavir.
After twelve weeks, some participants taking lodenosine developed life-threatening liver problems. Four died from liver failure and others were hospitalized. The study was put on hold as the company studies the cause of the side effects. Considering the severity of the problem, it's likely development will be stopped.
Early Results for dOTC
Early results of a small study of Biochem Pharma's new nucleoside analogue drug, dOTC, show promise. The study compared six different doses: 200 mg, 300 mg, and 400 mg taken twice a day and 400 mg, 600 mg, and 800 mg taken once a day.
Volunteers had not taken anti-HIV therapy before and had an average viral load around 40,000 copies HIV RNA and CD4+ cell counts around 400. After eight days of dOTC alone, 53-100%, depending on dose, had either a lowered viral load of at least one log (10 times) or had viral loads below 400 copies. This suggests that dOTC may be unusually potent for this drug class.
However, the development of dOTC was recently delayed because of deaths in monkeys that were given the drug for over three months. Some developed severe swelling and died soon after. It's possible that this is unique to monkeys since rats were given the drug for six months with no side effects. On the other hand, monkey data may be more predictive of what will happen in humans. Biochem Pharma is starting studies with a slightly different version which is less likely to cause this side effect.
Early Results of DAPD
Early results from a small study of a new nucleoside analogue drug, DAPD, from Triangle Pharmaceuticals show promising antiviral activity. The ongoing study compared four different doses each taken twice a day: 25 mg, 100 mg, 200 mg and 300 mg.
Volunteers had not taken anti-HIV therapy before. They had an average viral load around 10,000 copies HIV RNA and CD4+ cell counts of 300-400 when they entered the study. After two weeks of DAPD alone, people taking the highest dose had the best response (about a 1.5 log or 32 times reduction in viral load). Higher doses will be studied including taking the drug once a day.
Another drug showing anti-HIV activity is tenofovir (PMPA), an NtARTI. Results were recently presented of a study using tenofovir as part of a "treatment intensification" effort. This refers to the effect of adding an additional anti-HIV therapy to a regimen when the viral load starts to rise again after an initial period of suppression.
The study included 189 people with an average viral load around 5,000 copies HIV RNA and CD4+ cell counts around 370. They received 75 mg, 150 mg, 300 mg or placebo all dosed once a day in addition to their current therapy. (After 24 weeks, volunteers receiving placebo had access to tenofovir.)
After 24 weeks, about 25% of those who took tenofovir reached viral loads below 400 copies HIV RNA (15% below 50). No differences occurred among the dose groups.
The results are somewhat disappointing since viral load at study entry was very low. An earlier study showed better activity. It's possible that tenofovir was not used optimally in this study since participants had increased viral loads on their current therapies. It's likely that some drug resistance had already occurred and tenofovir was simply added to a failing regimen. On a positive note, no volunteers showed kidney dysfunction, a common side effect of the chemically related adefovir (PMEA).
Early Results of T-20
Results from a study of pentafuside (T-20), a drug in a new class known as fusion inhibitors, confirm that it is active against protease inhibitor-resistant virus. Seventy-one people who had previously taken protease inhibitors were enrolled in the study. Volunteers had an average viral load around 80,000 copies HIV RNA and CD4+ cell counts around 70. Participants could add pentafuside (50 mg injected under the skin twice a day) to any combination therapy.
After 16 weeks, about 33% had viral loads below 400 copies HIV RNA (about 20% below 50). Volunteers had been on most available therapies. As such, pentafuside was probably the only active drug in their therapy. It's likely that if pentafuside were combined with another new drug, a greater anti-HIV response could be achieved.
Hopefully, safety issues with some of the new drugs can be resolved so people can use them in the future. People who have exhausted their treatment options need new potent drugs, especially against drug-resistant virus.
Unfortunately, these setbacks illustrate some of the difficulties in developing drugs, as animal studies sometimes do not predict what will happen in humans. What is urgently needed are combination studies of new therapies still in development for people who need third line regimens. Project Inform has been working with the Coalition for Salvage Therapy in advocating for just such studies.
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.