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Coming Down the Line

Several New Drugs in Development Offer Hope for the Future

March/April 2010

It has now been over two years since a new anti-HIV medication has come on the market. Some are tired of waiting for new drugs and new classes to be approved. However, with over 60 new drugs in development, it's time to get excited again. Here are some highlights of drugs from both existing classes and new ones that are in the pipeline.


New Nukes

The oldest class of drugs, the nucleoside reverse transcriptase inhibitors (NRTIs) or nukes, may have some new drugs on the horizon. The advantage of new medications is the hope that they will be active against HIV if an older nuke no longer works due to drug resistance.

Apricitabine, being developed by Avexa, is structurally similar to Epivir and Emtriva. Side effects include nausea, diarrhea, nasal and chest congestion, and increases in triglycerides. It was in a Phase 3 study, but was stopped early for analysis -- more information coming soon.

"One of the most exciting drugs in development is a new 'booster' drug, GS-9350, being developed by Gilead. It may be the first alternative to taking low-dose Norvir to increase concentrations of other drugs, including elvitegravir, and may be more lipid-friendly when compared to Norvir."

Amdoxovir (DAPD) is another NRTI currently under development by RFS Pharma, and is currently in Phase 2. Studied doses are 300 or 500 mg taken by mouth twice daily. Reports of eye problems or visual disturbances have been noted, and resolved upon discontinuation of the medication.

Elvucitabine is currently in Phase 2 and is being developed by Achillion Pharmaceuticals. Studied doses are 5 or 10 mg by mouth once daily. This drug shows activity against hepatitis B as well as HIV.

However, apricitabine, mdoxovir, and elvucitabine may have activity against HIV strains that are resistant to other NRTIs, including Epivir and Retrovir.

Racivir is an NRTI being developed by Pharmasset, Inc. and also has activity against hepatitis B as well as HIV. Currently in Phase 2 studies, a standard dose has yet to be determined. However, it will most likely be once daily. Racivir is structurally similar to Epivir and Emtriva, but it is undetermined whether or not it has activity against HIV strains already resistant to Epivir and Emtriva.


More Non-Nukes

Rilpivirine (TMC-278) is a second generation non-nucleoside reverse transcriptase inhibitor (non-nuke or NNRTI) in development by Tibotec. It is in Phase 3 studies. Similar to Intelence, it seems to be active against HIV strains that are resistant to other NNRTIs. Current dose is yet to be determined, but will most likely be once daily. Tibotec is going to work with Gilead using their blockbuster drug Truvada to make a once-daily fixed dose tablet to compete with Atripla.

RDEA806 by Ardea is in Phase 2. It has been shown to be active against HIV strains resistant to Sustiva. Secondary effects have shown it can reduce uric acid levels.

Another NNRTI in Phase 2 is GSK 2248761 (formally IDX899). It is being developed by ViiV Healthcare. This drug is less susceptible to resistance when compared to the older NNRTIs on the market (Sustiva and Viramune).


Integrase Inhibitors and a New "Booster"

Elvitegravir is an integrase inhibitor (same class as Isentress) being developed by Gilead, and is now in Phase 3. Like Isentress, it does not require dose adjustments for individuals with kidney problems. This drug needs to be "boosted" for it to be effective. Norvir was used in earlier studies.

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However, one of the most exciting drugs in development is a new "booster" drug, or pharmacokinetic (PK) enhancer, called GS-9350, also being developed by Gilead. It may be the first alternative to taking low-dose Norvir to increase concentrations of other drugs, including elvitegravir. It may also be more lipid-friendly when compared to Norvir. It should be noted that it has no activity against HIV.

GS-9350 is currently in two Phase 2 studies, one comparing a once-daily, fixed dose "Quad" regimen (four-in-one drug combo with GS-9350, elvitegravir, and Truvada) with once-daily, fixed dose Atripla. The "Quad" was non-inferior to Atripla, based on 24-week data.

Another study compares either GS-9350-boosted or Norvir-boosted Reyataz, both combined with Truvada. Similar efficacy was seen at 24 weeks.

ViiV Healthcare, formerly GlaxoSmithKline (GSK), in collaboration with Shionogi, also has several integrase inhibitors in development. S/GSK1349572 (or 572 for short) is a once daily unboosted drug. Last year, GSK reported a significant 1.5 log drop in viral load to a very substantial 2.5 drop in people taking 2 to 50 mg of 572 during a 10-day dose-ranging study. Limited cross-resistance to Isentress and elvitegravir is expected. The drug is now in Ph. 2 study.


Maturation Inhibitors, CCR5 Antagonists, and Monoclonal Antibodies

Bevirimat (PA457, now MPC-4326) is one of two drugs in a new class called maturation inhibitors being developed by Myriad Pharmaceuticals, Inc. It is taken twice daily. They are now enrolling individuals in their Phase 2 study. The direct link is http://clinicaltrials.gov/ct2/show/NCT01026727?term=mpc-4326&rank=1.

Vivecon (MPC 9055) is the other maturation inhibitor in development. It is currently in Phase 2 and is available in a pill or capsule form.

Selzentry is the only CCR5 antagonist currently on the market. With the recent setback of vicriviroc (being developed by Schering-Plough/Merck), it may stay that way for a long time. There were two Phase 3 studies of vicriviroc in treatment-experienced patients. Both failed to meet their primary endpoints. The company is not giving up on this drug. They are continuing a Phase 2 study for use in treatment-naive individuals (those who have never been on HIV treatment before). It is being used once daily, with respiratory infection being one of the most common side effects. The drug levels are increased significantly by Norvir and reduced significantly by Sustiva. Vicriviroc is active against HIV strains that are resistant to other entry inhibitors, like Fuzeon.

Two new entry inhibitors are currently being developed, PRO-140, by Progenics, and ibalizumab (TNX-355), by Tanox, which was bought out by Genentech. Both are monoclonal antibodies that bind to CCR5 receptors on CD4 cells, preventing HIV from entering the cell. Because of the different mechanism of action when compared to the CCR5 inhibitor Selzentry, there seems to be low cross-resistance. Both are administered intravenously every two weeks. Both are now in Phase 2 as well.


Summary

It's exciting to see what the future of HIV therapy will bring. But remember, highly active drugs are already available. Make sure to be compliant on your current regimen to avoid resistance and live a long, healthy life.


Got a comment on this article? Write to us at publications@tpan.com.


  
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This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.
 
See Also
More on HIV Medications
HIV Drugs in Development

 

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