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Editor’s Note: This is the third in a series of articles we are running on the major manufacturers of HIV medications. The articles do not focus on the companies themselves as much as the life-saving drugs they manufacture. The company featured this time around is Bristol-Myers Squibb, which makes four important HIV medicines. BMS has been a leader in producing HIV meds that only have to be taken once-a-day.

We had the opportunity to talk with Laura Bessen, MD, Bristol-Myers Squibb’s Vice-President for Global Medical Affairs, and Dr. Richard Colonno, PhD, the company’s Vice-President for Virology Drug Discovery. We asked them to fill us in on the current line-up of BMS drugs, and also give us an idea of what we can expect from BMS in the future. We went through their current drugs in chronological order, starting with their first: Videx EC.

VIDEX EC (didanosine, ddI)

Videx was approved by the FDA on October 9, 1991 – it was the second HIV medication approved by the FDA, preceded only by Retrovir (zidovuine, AZT). The compound was originally developed by scientists in the National Cancer Institute, and licensed to BMS by the National Institutes of Health.

“There’s a focus at BMS to bring simpler and better regimens to the patient, especially those that can be taken once-a-day,” says Dr. Bessen. “The history of Videx is a good example of that. Initially it was a sachet that the patient had to mix with water. Then we developed a tablet, then a smaller tablet. Finally, we developed an enteric coated version that comes in a capsule and only needs to be taken once-a-day.” The enteric coated version of Videx, called Videx EC, was approved by the FDA in 2000.

In addition to making the dosing more convenient, enteric coating eliminated problems the original version of the drug had with stomach upset and drug interactions. The original formulation used a strong buffering agent to keep the active ingredients from being destroyed by stomach acid. In the current version, the drug is encased in little beadlets that pass right through the stomach into the small intestine, where the medicine is released – a much better solution.

Sales of Videx EC have declined as newer nucleoside reverse transcriptase inhibitors (“nukes”) have come on the market, many of them available in convenient multiple-drug formulations. But Videx EC is still a viable drug. “Videx EC still has an important role,” says Dr. Bessen. “It is one of the more potent ‘nukes.’ In the US, it is predominantly used by experienced patients, but globally it is often used as first-line therapy.”

ZERIT (stavudine, d4T)

BMS started working on Zerit in the late 1980s, and it was approved by the FDA in 1994, with pediatric dosing approved in 1996. Zerit was the fourth HIV drug approved by the FDA.

The standard dose of Zerit is one pill, twice-a-day, making it the only drug in the BMS arsenal that breaks the once-a-day dosing mold – but not for lack of trying. The company worked on a version of the drug to be called Zerit XR, which was actually approved by the FDA for once-a-day dosing, but has never come to market. “It was a goal of the company to make a once-a-day version of Zerit ,” says Dr. Bessen. “But we couldn’t manufacture it reliably. It was too technically difficult.”

Like Videx EC, Zerit has been largely eclipsed by newer “nukes,” but it still has a place. “Zerit is used more for later treatment in the US,” Dr. Bessen notes. “But worldwide it is used as a first-line treatment because it is well tolerated compared to AZT in people who have anemia.”

SUSTIVA (efavirenz)

Sustiva was approved by the FDA on September 17, 1998 and it proved to be a revolutionary and highly successful drug.

First of all, Sustiva was the first anti-retroviral drug that could be dosed once-a-day, because of its long half-life. And it is potent. In clinical trials comparing Sustiva to Crixivan (indinavir), Sustiva was the clear winner. It was the first time a non-nucleoside reverse transcriptase inhibitor (“non-nuke”) had outperformed a protease inhibitor, and people were amazed.

“I remember there was some skepticism at the time,” Dr. Bessen says. “But multiple trials have proven it out.” Sustiva has become the gold standard for first-line therapy. It has been a “preferred” agent under Department of Health and Humans Services guidelines ever since the “preferred” rating has been used. Sustiva has become the standard against which most new drugs are tested and judged. Sustiva outsells all other “non-nukes” and also all protease inhibitors.

Sustiva is about to be even more popular: BMS and Gilead Sciences have joined forces to develop a combination of Sustiva and Truvada (emticiabine/tenofovir) which will be the first complete three-drug HIV regimen all wrapped up in one pill, taken just once-a-day. What could be easier?

(Editor's note: Since this article was written, the FDA has approved the combination of Sustiva and Truvada. The new drug is called "Atripla.")

“Adherence, pill burden and pill frequency contribute to outcomes,” Dr. Bessen notes. “Hopefully, this new medication will really fill an unmet need. The pill is no bigger than some of the other combination medications, and it’s film coated so it’s easy to swallow.”

Most people think of the new Sustiva/Truvada combination drug as the obvious choice for people newly diagnosed with HIV, but Dr. Bessen points out that it can also be used in combination with other drugs for more experienced patients.

REYATAZ (atazanavir sulfate)

The newest BMS drug is a protease inhibitor called Reyataz, which was approved by the FDA in June, 2003.

“Reyataz has a number of unique benefits,” Dr. Bessen says. “It was the first protease inhibitor that can be taken just once-a-day. In trials, it proved to be as effective as Sustiva. And it is very well tolerated – unlike other protease inhibitors, it doesn’t cause gastro-intestinal problems, and it has minimal impact on blood lipids.”

Reyataz can either be taken with a Norvir (ritonavir) booster or without. (Most other protease inhibitors are always taken with a ritonavir booster.) “Reyataz has a unique resistance profile,” Dr. Bessen notes. “If you take Reyataz first without ritonavir, you can later take any of the other protease inhibitors. There’s no cross-resistance.”

The current dose of Reyataz is two capsules once-a-day, but Dr. Bessen says the company is working on reducing that to one.

What’s next?

For a glimpse into the future, we turned to Dr. Richard Colonno, who is responsible for virology drug discovery at BMS.

“My job is to figure out what patients will be looking for in 2010 and beyond,” Dr. Colonno says. “How will resistance evolve and how will we overcome it? In 2010, it is unlikely that we’ll need a new protease inhibitor. Instead, we’ll need new classes of drugs, with distinct mechanisms. If two or three new classes can be introduced in addition to existing classes, we should be able to provide patients with sufficient options to fight HIV for a lifetime.”

BMS is placing its bets on two new classes of HIV drugs: attachment inhibitors and integrase inhibitors.

“Attachment inhibitors block the very first step in the process of HIV infecting a cell,” Dr. Colonno says. “Attachment inhibitors were first discovered at BMS in 2002, and proof that they are capable of reducing viral loads in patients was first demonstrated in 2004. These inhibitors have the potential to be very potent, and can bring down viral load very quickly. We have generated a series of these inhibitors in this class and are focusing our efforts on reducing pill burden and dosing frequency."

“Integrase inhibitors block a later step which is critical to inserting the viral genome into the DNA of a cell,” Dr. Colonno continues. “These compounds exhibit good potency even when used as monotherapy. We’ve been working on this class of drugs for several years, and are profiling a series of these compounds in trials. Preclinical studies look very encouraging, but at the end of the day, you really needs to see how a drug performs in human studies.”

“BMS is tremendously committed to HIV,” Dr. Colonno notes. “As other companies have transitioned away from this area, we continue to invest for the long run looking for new classes of drugs. We’re also heavily invested in developing new drugs for Hepatitis B and Hepatitis C, both of which are frequently encountered among HIV patients.”

Copyright 2008, Positive Health Publications, Inc.

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