The Bay Area Reporter - August 10, 1998
Matthew Sharp, ACT UP/Golden Gate Writers Pool

Although the Geneva World AIDS Conference focused little on new therapies for HIV, there was a scattering of less exciting, yet important reports of new drugs in early testing. Talk of new targets for drug delivery was probably bigger news, but certainly therapies in this area are much further away.

In the old days of the epidemic, before protease inhibitors, conference members, the media, and especially people with AIDS anxiously awaited news of promising new treatments at AIDS conferences. But today we are experiencing a slowing in drug development which was certainly apparent in Geneva. Industry and research institutions have deferred development for various reasons, which do not offer hope to those who need new treatment. AIDS is not over, and we clearly need development of new generations that may not be cross resistant, new targets to add therapies to the present armamentarium, and new drug delivery systems with easier dosing schedules.

Encouragingly, news of the immune system and immune based therapies such as IL-2 received more attention than at past conferences. (See last week's Health Perspective.) Combination therapies are lowering viral load and partially restoring immune function which can allow for immune based therapies to be safely studied.

Protease inhibitors

In the protease inhibitor (PI) arena two new drugs are reaching clinical importance in terms of efficacy. In 24 weeks of data on 32 people, Abbott's ABT-378 was shown to lower viral levels below 400 copies in all participants. The drug has to be administered with its sister drug Ritonavir at 100 mg. twice a day to reach appropriate blood levels. Patients in the study had never been on PIs before the study. It will be interesting to see how this no-name Abbott drug will play out in other people who have taken other PIs. Also, with the current Ritonavir production problem, Abbott has a lot to answer for since the two drugs must be used together.

Pharmacia Upjohn has a new PI with a catchy name: Tipranivir. In a small Phase I/II study three doses of the drug were studied with "background" antivirals, with 10 pills three times a day as the current formulation; 1500 mg. proved to lower viral load best by 1. to 1.3 logs. The most common side effect was diarrhea, which was managed with over-the-counter diarrhea medication. The company has made overtures in improving the current high volume regimen, but there is no confirmation of this report. Upjohn is also bragging that the drug is not cross resistant, but there is only four weeks of data showing no new mutations developing, not enough to verify resistance.

Both drugs will prove they are worth something if they bring virus levels down in heavily treated folks in larger, longer studies. Now they are in the "me-too" category of PIs that may not do much good for anyone.

DMP-450 by Triangle Pharmaceuticals and PD-178390 by Bristol Myers Squibb were other reports of other new PI drugs in Phase I to keep your eyes on.

New generations

FTC (not 3TC) is another drug being developed by Triangle Pharmaceuticals. It is a different, more potent version of 3TC. However, the same mutation caused by 3TC is seen with FTC, but fortunately it only has to be taken once a day. If you have taken 3TC, this may not be an option for you. Results of a Phase I trial demonstrated up to a 2 logs drop and was well tolerated.

FddA is a new generation analog of ddI. Phase I/II studies show the drug also would only need to be taken once a day and doesn't require the buffer that causes much of ddI's side effects. Less diarrhea is good news with any new therapy.

The non-nucleoside S-1153, another no-name drug made by Lexigen Pharmaceuticals has a 10 times more potent effect than the two approved NNRTIs (non-nucleoside reverse transcriptase inhibitor), nevirapine and delavirdine. In this Phase I dose escalation study no other NNRTIs or PIs were allowed. Average viral load decrease was 1.74 logs in 28 days of treatment. No doubt, people who have never been on nevirapine and delavirdine will probably have the best outcome with this drug. Unfortunately data was not collected on prior use of NNRTIs in the participants.

Another NNRTI that has been synthesized from the rain forest is Calanolide-A. There was little information from the Phase I study on virus inhibition with this dug, but the it stays in the blood stream for 20 hours. Data showed that the drug was tolerated better than current available NNRTIs. However, some side effects such as dizziness, headache, and nausea were reported.

Gilead, the maker of the befuddled drug Preveon, currently available in expanded access, has a new generation of their nucleotide analog PMPA. The drug has to be taken only once a day and showed 2.1 log virus drop in 28 days. Although the potency of this drug appears to be better than Preveon, more data will be needed to prove it is durable and tolerable. The troubling kidney problems seen after several months of Preveon treatment will hopefully not be seen with PMPA. Company officials swear that there is currently no cross resistance with Preveon in viral isolates.

New targets=bull's-eye?

New targets are becoming possible therapeutic options for future drug development. As more is learned about how HIV attaches to, invades, and destroys cells, more targets can be discovered, but unfortunately only if there is appropriate interest and profit motive in the pharmaceutical industry.

There are new targets in virus attachment such as Trimeris' fusion inhibitor T-20. Early studies show substantial anti-viral activity with an increase in CD4 counts. Unfortunately this drug has to be delivered through subcutaneous needle injections, similar to insulin treatment in diabetes. The company is aggressively working with the community in developing early clinical trials.

Chemokine receptors are being considered for new anti-HIV treatments, to target virus entry points such as CCR2, CCR5, and CXCR4, but none have entered clinical trials to date and there are theoretical concerns and problems with use of agents that block these targets.

The integrase enzyme is another target with little pharmaceutical interest. Gag, regulatory, and accessory proteins offer zinc finger antagonists. Tat, Rev, Vif, Vpr, Vpu, Nef gene targets are very far off in development.

Confusion and complications grow as more drugs are developed in this post-Geneva era. Of course newer drugs mean more side effects, more drug interactions, and more mutations occurring in the virus. Clinical trials are becoming more difficult to design and enroll as more patients use up and "fail" existing drugs. But, given all the possibilities more drugs may also give the people who have used all their options another chance to restore immunity and slow virus production and ultimately may prove to extend life. Researchers and the industry must continue to develop new modalities in order for the progress we've made to continue.
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