Editor’s note: On Thursday, May 27, after this report was published, the 16-member Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously to recommend the approval of Egrifta (tesamorelin) for the treatment of abdominal fat increases in people with HIV-associated lipodystrophy. Though the FDA is not required to follow an advisory committee’s recommendation, it usually does. The agency has until mid-July to announce its final decision.

In some respects, George Lowe has been very fortunate. Though the 48-year-old social worker from Asbury Park, New Jersey, tested HIV positive in 1986, he didn’t need to start antiretroviral (ARV) therapy until 1998. Since then, he has maintained good control of his virus, and his CD4 count is high. Like hundreds of thousands of others, however, HIV and the drugs to treat it have taken a severe toll on Lowe’s body. He developed a distended belly and a thick pad of dense hard fat on the back of his neck. “My waist is much smaller than my stomach,” Lowe says. “So it looks like I’m pregnant. I’m that fat.”

These abnormal fat deposits are known as lipohypertrophy, one possible manifestation of a broader lipodystrophy syndrome. Unlike many other consequences of HIV, there is currently no effective drug treatment available for this disfiguring and sometimes disabling condition—but that could change very soon.

A Food and Drug Administration (FDA) advisory panel will be reviewing an application for approval of a new experimental treatment called Egrifta (tesamorelin) on May 27. The injectable drug stimulates the pituitary gland to make human growth hormone (hGH). Growth hormone is key to maintaining adequate levels of testosterone and other hormones that encourage formation of lean muscle mass and reduce fat storage. It has demonstrated modest success in reducing gut fat in people with lipohypertrophy, and thus far it appears to have a fairly mild side-effect profile. Though activists and researchers say they are hopeful and will urge the FDA’s Endrocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to recommend approval, Egrifta’s path is far from certain.

An earlier drug, Serostim—a synthetic version of hGH approved to treat HIV-related wasting and weight loss—also reversed abnormal fat deposits in both the belly and the upper neck in clinical trials. Its benefits, however, came with a price. Among other side effects, the treatment also significantly increased the risk of developing diabetes. Though the drug’s maker, EMD Serono, aimed for an approval to treat lipohypertrophy, the FDA was skeptical of the drug’s risk-benefit ratio and opted not to approve the med based on the data provided to the agency.

Egrifta, being developed by Montreal-based Theratechnologies and to be sold in the United States by EMD Serono, appears to have a much milder side effect profile than Serostim. Activists are encouraged by the data and argue that the drug’s benefits clearly outweigh its risks.

“People’s lives and their quality of life are at stake here. It’s hard to quantify, but quality of life is so very, very important to living and thriving with HIV,” says Jeff Berry, who will be testifying at the FDA hearing on behalf of the AIDS Treatment Activists Coalition (ATAC).

Berry says that convincing the panel about the dire need for a treatment like Egrifta to alleviate the intense psychological and physical toll of lipohypertrophy is likely to make the most difference. “[Activists are] all pretty much in agreement that this is a treatment that works, that people need it, that it is safe enough and should be approved,” he concludes.

Modestly Effective, But Apparently Safe
Egrifta works on the deep hard belly fat known as visceral adipose tissue (VAT), which differs from the softer flab people often accumulate when they gain significant weight. In two Phase III studies, people on Egrifta had an average 15 percent reduction in VAT over 26 weeks—a “modest reduction” in deep belly fat, according to an ATAC Drug Development Committee (DDC) letter submitted to EMDAC supporting approval—compared with about a 5 percent increase in people on a placebo.

These averages, however, may actually hide the drug’s potential efficacy, says Morrie Schambelan, MD, a professor of medicine at the University of California at San Francisco and an Egrifta researcher. Some people had no response at all, Schambelan explains, while decreases in VAT were sometimes dramatic in those who did have a response.

Some people taking Egrifta developed some of the same side effects that are common with other hGH products, such as mild pain and swelling. It did not, however, appear to put people at a significantly greater risk for diabetes, unlike Serostim.

Berry points out that there may be long-term side effects, which are difficult to discern from the two Phase III studies completed thus far, both of which ended treatment after one year. This is an important concern, he says, given that people will likely remain on Egrifta indefinitely.  

“The effect goes away when you stop the drug,” Schambelan explains. “So it’s kind of a lifelong therapy, or at least it’s a therapy that you take long enough until something else comes along, or until there is some mitigation of the factors that result in lipohypertrophy.”

In addition to limited information regarding Egrifta’s long-term side effects, there are no data regarding the long-term benefits of treatment, notably the effect of VAT reduction on cardiovascular disease (CVD) risk. Numerous studies have shown that people with more VAT are at a higher risk of CVD, as well as diabetes and a number of other ailments. What isn’t known is if decreases in VAT using drugs like Egrifta actually reduce the risk of CVD.

Lowe follows a vigorous exercise regime and a strict diet; nonetheless, he has experienced potential CVD problems along with his fat accumulation. “I’m borderline everything,” he says with frustration. “I’m borderline hypertensive. I’m borderline diabetic. I’m borderline being on cholesterol medication. I think the exercise is keeping me from crossing over. I’m doing everything to keep it from happening, but I have to work harder than the average person.”

Berry says the drug’s approval would probably be a shoo-in if Theratechnologies could show that it directly reduces CVD risk. Schambelan says that doing so would take a 5,000 person, multiyear study—something very unlikely to occur.

It’s the lack of improved survival markers that has Schambelan, Berry and others concerned. Not only does this place Egrifta’s approval in jeopardy, but it also means that access to the drug could be severely limited even if it is approved.

Cosmetic or Medically Necessary
“I think it is really important that this not be approved as a cosmetic treatment, but as a medical necessity, such as has more recently been the case with breast reconstructive surgery [following mastectomies],” Berry says.

Cosmetic versus medical necessity is more than just semantic. It means the difference between getting your health insurance to cover the cost of treatment or dipping into your life savings to pay for it yourself. As most people with HIV don’t have substantial financial resources, failure to achieve an approval for medical necessity would mean that the drug might only ever make it into the hands of the few who can afford it.

Lowe knows all too well how that distinction can affect people. He and his doctor applied to his insurance company to get liposuction for the fat accumulation behind his neck, a condition that is scientifically referred to as dorsocervical adiposity, or in layman’s terms, “buffalo hump.”

Lowe says that in the five years since the fat started to accumulate, his neck has gone from a size 17 to a size 22. He never wears T-shirts now, and he has pain and a limited range of motion. Lowe says that when he exercises, “I can’t put my back down on the bench. There’s so much fat there, my neck is not on the board, and I’m in pain. And driving—I’ve had to add things to my rear-view mirrors because I can’t turn. I don’t have that mobility to turn my whole head around, because of the fat back there.”

Despite the obvious disability, Lowe’s insurance company still defines the liposuction procedure as cosmetic and refuses to pay for it. Lowe says that he’s got a lot riding on Egrifta’s approval. Though there are no data on the treatment’s ability to reduce dorsocervical fat, its predecessor, Serostim, did prove useful in this regard in clinical trials. Lowe realizes that even if Egrifta is approved, he might still need to find a way to pay for liposuction on his neck. Even if the treatment only reduces his belly fat, however, Lowe would be glad. As he explains, you can’t do liposuction on VAT in the gut because there is a significant risk of puncturing abdominal organs in the process.

The ATAC DDC letter submitted to EMDAC acknowledges the known benefits and side effects of Egrifta, along with some of the unknown variables regarding the drug’s long-term safety and efficacy.

For example, many patients develop antibodies to Egrifta. Though this does not appear to limit the drug’s efficacy and has not been associated with side effects—at least in the 52-week studies completed thus far—there is the potential that the antibodies will turn on the body’s own growth hormone.

As a condition of approval, the DDC letter asks the FDA to require longer-term follow-up on safety issues and to collect data on signals that Egrifta might have a benefit on cardiovascular disease risk.

Seeing Is Believing
Getting the panel to recommend FDA approval—and better yet, getting it approved as a medically necessary drug option—could very well rest on the ability of those testifying to vividly document the emotional devastation that lipohypertrophy rains down on people’s lives. “You have to convince the panel that this is not your grandmother’s obesity, number one, and number two, that it is extraordinarily uncomfortable for people, disfiguring, and again, there is no therapy that has been approved that works,” Schambelan says.

A market analysis published by Theratechnologies and Serono, two companies that are developing and marketing the drug, claims that about 380,000 people in the United States and Europe suffer from lipohypertrophy. Moreover, as Berry and Schambelan—who will be presenting at the advisory committee hearing—will try to make clear, the need is significant, and an effective product could substantially improve the lives of people with lipohypertrophy.

Lowe, who will not be at the EMDAC hearing, offers some advice to Egrifta-treated patients who are expected to testify at the hearing. “I think the most powerful thing at the hearing would be for someone to take their shirt off and show [the panel] what they like now, compared with a picture showing what they looked like before they [developed the condition].”

Schambelan, who will be showing photographs of some of his patients, heartily agrees. “I think one picture is worth 10,000 words.”