In the Pipeline

An HIV/AIDS Treatment Prognosis

By Tim Kingston from Frontiersweb

A Glossary of Terms In Order of Stages of Viral Infection

Fusion Inhibitors :

This class of drug prevents the virus from fusing with CD4 cells in the first place. This prevents infection from happening. (Further explanation in body of text.)

Nucleoside, Non-Nucleoside and Nucleotide Reverse Transcriptase Inhibitors:

Reverse transcriptase is a protein important in the process of converting the virus from RNA to DNA at an early stage of infection. The virus must be converted to DNA to truly take over the inner workings of cells, and nucleoside, non-nucleoside and nucleotide reverse transcriptase inhibitors each offer slightly different strategies for preventing viral conversion from RNA to DNA.

Protease Inhibitors :

Protease is a protein that chops the virus up and puts it back together again in its final form just prior to budding out of an infected cell. Protease inhibitors prevent that particular protein from functioning and the result is a crippled virus.

 

Dr. Mark Goldsmith, an associate investigator at San Francisco's Gladstone Institute of Virology and Immunology




Dr. John Moore, AIDS researcher at Cornell Medical College in New York City  

If the future of HIV/AIDS treatment could be described in terms of a weather forecast, then the immediate outlook is rather sunny and bright, followed by a medium-term drought with hopes of a rather encouraging climate change in the coming years.

At the moment, there are five drugs close to approval or well on their way to approval. These include Gilead Science's nucleotide Tenofovir, Trimeris' eagerly awaited T-20, Bristol-Myers Squibb's new protease inhibitor and a couple of copy-cat reverse transcriptase inhibitors and protease inhibitors, which are basically updated versions of already available drugs.

Further into the future, a number of companies around the country are investigating fusion inhibitors similar to T-20 that stop HIV dead in its tracks by blocking its ability to lock onto and merge with target cells at an early stage of infection. There are also investigations underway involving small-molecule drugs in tablet form designed, like T-20, to prevent the virus from latching onto target cells by interfering with either the virus' or target cell's receptors.

What is unique about the new class of drugs is that they attack HIV before it even gets into the cell, as opposed to protease inhibitors, which prevent replication at a much later stage in its life cycle, after it has already infected a cell.

"There is a reasonable amount of excitement about the entry inhibitors," says Ron Baker, publisher of HIVandHepatitis.com. "I hope they will have an oral form of these drugs, that will be the next step so that you will not have to deal with needles. But until we have more data I don't know how much we can say to predict how that will shake out."

There remain an awful lot of unknowns for drugs that are in such early developmental stages, most critically whether they will actually be effective in real, live HIV-positive patients as opposed to mice or in the laboratory. "In each case, we will have to see whether that data tells us about clinical benefits and possible resistance," said Mark Goldsmith, an associate investigator at San Francisco's Gladstone Institute of Virology and Immunology.

Another problem is that in between the first batch of drugs now close to approval and those in the development phase, there lies a dry spell during which there's encouraging news but few actual new drugs available. Despite such caveats, enthusiasm about the new classes of drugs is high. As Dr. John Moore, an AIDS researcher at Cornell Medical College in New York City noted, "There are several companies working on entry inhibitors that are at various stages of pre-clinical development and if [these] inhibitors prove to be effective in a clinical setting, that will encourage other companies working in the area."

"I don't think any single drug will turn out to be the Holy Grail," stresses Goldsmith. "[It will not be like] where a single antibiotic eradicates bacterial infection. But, with that in mind, I think we can expand the armory and have more compounds. That is exciting and may create opportunities for patients who have developed resistance to the existing compounds."

SUNSHINE AHEAD:
NRTIs AND FUSION DRUGS

The drug currently closest to approval is Gilead Science's Tenofovir, which is a nucleotide (as opposed to nucleoside) reverse transcriptase inhibitor. Like nucleosides, it works to shut down HIV replication inside the virus itself within infected cells, but as a nucleotide the company says the drug has an extra sulfate group that acts more rapidly within the cell. The drug is orally administered in a once-a-day tablet.

Tenofovir exhibits a "relatively unique resistance profile," says Baker; good news for those who have developed cross-resistance to other NRTIs. "This will fill a needed niche," said Dr. Paul Volberding, chief of medicine at the San Francisco Veterans Administration Medical Center. "It is not as potent as a protease inhibitor; it will still need to be combined with other drugs," Volberding, adds. "But so far Tenofovir looks to be very well-tolerated."

The FDA will hold an advisory panel on the drug in October and a decision about its approval is expected in November, according to a Gilead source.

Next in line is the first of an entirely new class of drugs that acts by preventing HIV from getting into and infecting cells in the first place. Trimeris' T-20 is a peptide--that is, a part of a protein--which works by interpolating itself between the virus's receptors and the target cell's receptors, thus preventing HIV from binding to and merging with the cell. The company is also working on a second-generation version of the drug known as T-1249, which is considered significantly more effective.

"They made T-20 first and [were] then informed to make T-1249 which is better and more potent," explains Gaston Picchio, a researcher at San Diego's Scripps Research Institute. T-20 has received a fast track designation from the FDA and has nearly completed the necessary clinical trials that could lead to formal approval, but T-1249 is not due for approval anytime soon.

T-20 utilizes recent knowledge in HIV pathogenesis indicating that the virus needs to latch onto one of two separate receptor sites (CCR5), as well as the primary CD4 site needed for binding and attachment. HIV requires two proteins, GP120 and GP41, to link to those sites. GP120 binds to the target cell and then GP41 actually penetrates the cell membrane and begins the process of fusion. T-20 gets right in between the GP41 and the cell and prevents the GP41 HIV protein from folding in such a way that the virus and its target are drawn together.

While the drug has shown considerable efficacy in knocking viral loads down to undetectable, its primary drawback is that it must be injected or infused. Baker, however, pointed to a 60-participant study presented at a recent AIDS conference in Buenos Aires indicating that infusion was not as much of a disincentive to using the drug as expected. One huge advantage of T-20 is that it has an entirely different drug-resistance profile from that of current protease, NRTI and non-nucleoside reverse transcriptase inhibitors (NNRTI) treatments. "That," says Baker," will be really helpful, especially for those who have exhausted their [other] choices."

NEW PIs, NRTIs,
NNRTIs AND ME-TOOs

Two new protease inhibitors are in the pipeline, but it is not clear just how soon they will be available. They are BMS-232632, Bristol-Myers Squibb's first, and eagerly awaited, protease inhibitor now known as Atazanavir, and Tipranavir, now being developed by Germany's Boehringer Ingelheim (BI).

Tipranavir has shown activity against all strains of HIV that are resistant to other protease inhibitors in the lab, but that is no guarantee of success in vivo. Like many drugs now under development, Tipranavir is administered in conjunction with Ritonavir (Norvir) which boosts its bioavailability--the amount of drug in the bloodstream and body--and enables it to be given twice a day in tablet form as opposed to the original formulation, which required over two dozen tablets a day. BI expects to launch the drug in 2003.

BMS-232632 is "reasonably potent," according to e-mail correspondence from Keith Folger of the STOP AIDS Project and was designed for once-a-day dosage from the start. The drug is also reasonably well tolerated, but it is not clear if its resistance profile is significantly different from other protease inhibitors now on the market. "The other big news about it is that it does not produce any lipid abnormalities or triglycerides," says Baker, with enthusiasm, referring to blood and cholesterol imbalances that result from protease inhibitors. "We are trying to get this on expanded access for people without any options," adds Baker, who noted that a recent community meeting on the issue was cancelled by the company.

The last four drugs under immediate consideration are all out of Triangle Pharmaceuticals in Durham, N.C. Emivirine is an NNRTI in Phase III trials with apparently similar efficacy to other drugs on the market. One of them, FTC, is considered superior to some degree because it is viewed as more potent and needs only to be taken once a day (It also shows efficacy against hepatitis B). Unfortunately, the drug is also cross-resistant with 3TC and that makes its usefulness for drug-experienced individuals questionable. Triangle also has two other drugs currently in Phase I and II trials, which will not be commercially available for at least a couple of years, if successful.

TINY MOLECULES AND PEPTIDES
OUT ON THE HORIZON

As far as treatment goes, small-molecules are likely to be ultimately preferred by patients, since they can be administered in a tablet form. Peptides generally have to be infused or injected. (The already mentioned T-20 and T-1249 are also peptides operating in a similar fashion, but they affect the fusion stage of viral infection, a slightly later step in the process that can be thought of in a shorthand fashion as attachment, binding and fusion. The small-molecules mentioned above generally interfere with the attachment and binding stages.)

"I am cautiously excited about the prospect of having new classes of compounds," asserts Mark Goldsmith. "The multibillion-dollar investment in understanding the molecular basis of HIV 1 [the most common variant of HIV in the U.S.] replication is yielding opportunities that can be specifically relevant for patient care, so I am very delighted that compounds and research groups are doing their best to exploit these opportunities."

But at the same time there are no guarantees. Offering a cautionary tale is the example of AMD-3100, a CXCR4 inhibitor that was AnorMED Inc.'s lead compound to prevent HIV binding and fusion. That Canadian company halted its trials in late March as a result of "abnormal cardiac activity, referred to as premature ventricular beats, in two patients who each received different doses of AMD-3100." While the company remains optimistic, it has taken a breather from further research at this point.

But progress is being made in other areas. Progenics' Pro542 is designed to go directly after HIV's GP120, the viral receptor proteins, which hook onto a target cell's CD4 site. "Pro542 is designed to neutralize the virus directly," explained Richard Krawiec of the Tarrytown, N.Y.-based company. "This targets and bollixes up GP120 and prevents [it] binding to CD4." Even better, says Krawiec, "It is synergistic with T-20," which attacks a slightly different target. Krawiec is also enthused by the unique manufacturing process Progenics has hit upon to make Pro542: goats. "We have genetically engineered goats to express Pro542 in their milk--they are very well cared for--and you establish herds that produce this protein in their milk. You have got to talk about milk in transgenic goats! This will be milk from genetically engineered goats."

Pro542 is in small Phase II trials, while Pro140, a similar drug, is not even at the point of starting trials, thus availability of such drugs, if they work, is still years away.

The second major focus of investigation is the search for small-molecule compounds to fight HIV--and that means really small. Some of the compounds being investigated are no more than a few amino acids bound together. These compounds are, however, only in the preliminary stages of research. Some have not even achieved basic toxicology status. "What we are hoping they will do is inhibit the virus's ability to attach to a cell, so the virus cannot interfere with the cell and get into the cell for replication," says Bob Consalvo of Schering-Plough, which is developing Sch-D and Sch-C.

Both of Schering-Plough's drugs have just completed most animal studies, but they have only just begun Phase I patient studies and thus will not be available anytime soon. An important side benefit to these compounds is that it may be possible, says Picchio and Pascal Poignard, another Scripps researcher, to make them into some sort of topical cream or gel, or microbicide, that could be used to prevent the transmission of HIV. This would surely be useful all over the world.

But before everyone gets too starry-eyed, Brenda Lein of Project Inform noted that mice used in animal studies, which had their CXCR4 receptors knocked out, all had stillborn offspring. She also noted that both CCR5 and CXCR4 cycle in and out of the surface of the cells targeted by HIV. In each cycle they are likely to release or lose whatever blocking agent or inhibitor has attached to them. That makes them vulnerable to infection once more. "The problem," she says, "is that you have to be constantly pouring things on the receptor."

There are assorted other strategies being investigated, too. These include efforts to lower the cholesterol of both target cells and HIV in an effort to create significantly less virulent virus strains. It turns out, explains Lein, that cells and HIV that have their cholesterol removed are significantly less infectious or infectable. While this has only been attempted in the laboratory, there are commercially available cholesterol-lowering drugs already available.

What these developments show is that we are now in a new chapter of fighting HIV. In the early days, it was a case of try anything and throw anything at the virus. Now drugs are being designed to target specific areas on the virus. That is the result of concentrating on basic research, suggests Gladstone's Goldsmith. "There has always been a tension between investing in immediate clinical-driven trials and ideas versus basic molecular understanding of how the virus works. I think that is an appropriate and ongoing tension, but here is an example of the payoff you can get from basic scientific investigation. These two approaches compete in a world of limited resources. You would like to see a payoff--and here is an example of yield, and I am delighted with that."

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