February 26, 2007
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This [trial] is a direct intervention trial to reduce factors associated with cardiovascular risk in HIV-infected patients. Truthfully, I think the whole issue of increased cardiovascular risk in HIV patients has been ignored too much in the media and press. There's a number of papers now, and really an emerging consensus that patients with HIV who start HAART [highly active antiretroviral therapy] are at increased cardiovascular risk -- the D:A:D study -- but other studies have also suggested that using hard endpoints and surrogate markers.
There are two kinds of abdominal fat. There's the superficial abdominal fat, and the deep abdominal fat, subcutaneous and visceral. We were aiming to reduce visceral abdominal fat. So we reasoned that there might be potential efficacy of a GH-releasing hormone analog. You may not be familiar with that, but growth hormone is produced in the pituitary, in normal physiology. There have been many studies now which have given growth hormone. They are efficacious in terms of reducing visceral fat, but they also have a number of side effects, in terms of on glucose and other side effects.
So we did not give a growth hormone. What I'm about to talk about is not growth hormone. It is a precursor hormone made typically in the hypothalamus that stimulates the body to make growth hormone. It's a very important distinction. And because of that, it's much more natural and physiologic than giving exogenous growth hormone. So you give this hormone and the body makes its own extra growth hormone. There's feedback in inhibition, which is intact, and it's a more gentle physiologic way to do this.
We have actually shown in other studies that growth hormone levels and secretion are reduced in this population so it makes sense to try and increase that secretion. [In our trial] we randomized over 400 patients in a 2-to-1 ratio to this drug, TH9507, a GHRH analog, or placebo. It was a six-month trial, which is as long as most of the intervention studies for metabolic complications go. The primary prespecified endpoint was visceral abdominal tissue, changing visceral -- that deep fat I was talking about. And in discussions with the FDA [U.S. Food and Drug Administration], they viewed a significant effect to be more than an 8 percent reduction in visceral fat. So we powered the study to see an 8 percent reduction, but were happy to see a 15 percent reduction in the treatment group, versus a 5 percent increase in the placebo. So, a net effect of approximately 20 percent difference between treatment and placebo.
In contrast, there was a very little effect on subcutaneous fat, or peripheral fat. So it was a very preferential effect on the deep visceral fat. Then, in terms of prespecified secondary endpoints, we looked at lipid levels, as was discussed a few minutes ago. This is not a lipid-lowering drug, per se; I'm not saying that. But it has been shown in other studies to affect lipids positively, particularly growth hormones. So we looked at this, and the prespecified endpoints of triglyceride and cholesterol to HDL improved significantly, as did total cholesterol, as did HDL. The net effect on triglyceride was an approximately 18 percent change between treatment and placebo -- which, I might add, is better than some lipid-lowering drugs (even though this is not a lipid-lowering drug). So, basically, there was a very significant effect on visceral fat, preferential over subcutaneous, and an improvement in lipids.
The next thing to consider is whether it [TH9507] worsened glucose; and that was not the case. Glucose remained stable. There was no evidence of hyperglycemia in the study, which is a nice feature. The IGF-1 levels, a measure of growth hormone secretion, were generally physiologic. In terms of adverse events: there was no overall difference in adverse events, although there was a higher percentage of patients discontinuing due to adverse events. The net difference was 9 percent between treatment and placebo. So about 10 percent of patients in the study discontinued due to an adverse event. But there was no difference in serious adverse events. There were only two adverse events that were more than 10 percent in prevalence: headache and arthralgia, and they were the same between groups.
So if you look at that data compared to data on growth hormone, per se, at the doses used it's much more palatable, yet you get the same thing for the buck. You get the same -- about 15 to 20 percent reduction in visceral fat -- with an improvement across lipids, but without toxicity, in terms of glucose.
That was the first phase III study. There is a second phase III study, which is about to be, or has recently been, initiated in Europe. That will be a confirmatory study. If that's positive, then there will be further discussions with the FDA about potential approval. This is not an approved drug right now. It is not available, other than through experimental studies.
Journalist: I was wondering if you could clarify all of your relationships to who funded you, and their relationship to the drug companies.
This was funded by Theratechnologies. I'm an independent investigator, but I am a consultant with Theratechnologies, and I helped them design the trial.
Journalist: Why does this seem to work on one type of fat, but not on others?
I wish I knew. There are different receptors for growth hormone, both in quantity and quality, on the different fat depos. There's a long history of different fat depos, behaving differently to different stimuli. People with Cushing's, for example, have excess truncal fat and a reduction in extremity fat. And various other hormones affect fat differently. So I don't know the exact answer other than to say that it's probably related to the receptors or the biology of GH on these depos. But it certainly goes in the right direction, in terms of what you would want clinically, for a result. You don't really want to decrease subcutaneous fat too much. It's a myth that all fat is bad. That's a myth. There are some fat depos that are excellent to have. The subcutaneous fat depo is a good depo to have; it actually improves insulin resistance to have more subcutaneous fat. That's the apple/pear, men/women kind of thing. So the fact that this reduces visceral and not subcutaneous is important. But we certainly would like to know more about the biology of that. It's a good question.
Journalist: Is it an injectable drug? And what would be the cost?
I don't know the cost, because this is not available commercially and I do not have access to that information. It is an injectable drug, once a day. Subcutaneous, once a day. There are other GHRH molecules that are twice a day. This has a longer half-life, thus can be administered once a day.
Journalist: Is there an effect on the patient's overall weight?
No. Weight doesn't change, so it's a relative shift in fat. Yeah, so that's an important point.
Journalist: Where does the fat shift to?
Well, it's a good question. It probably shifts to some of the subcutaneous areas. If you look at the graphs on the thing, there was actually a slight increase in subcutaneous fat, and a significant decrease in visceral fat. We haven't done very careful weight balance studies to account for all of it, but suffice it to say it's not a drug that you would take to lose weight. It's a drug that almost preferentially sculpts, decreases visceral fat, but not subcutaneous fat. There's no overall effect on weight.
Journalist: I think you said in your presentation that it seems to be more physiologic to give the releasing factor than to give growth hormone itself. For releasing factor, it seems like 2 mg is a massive dose. Was this optimized, or dose ranging? Or how was that chosen?
There was a phase II study, Falouttes et al., [at] AIDS 2005, that used a 1 mg dose versus a 2 mg dose, so that was sort of a dose optimizing study. And there was a better effect at 2 mg with similar safety. There have also been animal tox studies. It is a large dose, but it's not larger than other drugs in that family of drugs, the hypothalamic peptide factors and stuff. That's what dose is required. But there was a preliminary dose-finding study.
Journalist: So is this a visual difference for the patients?
Yes. That's a very important point. Let me just say: It amounted. ... You probably don't know what is a 15 percent reduction in VAT. It was a 3 cm reduction in waistline. So, pant's size, okay, 3 cm, okay? If that means more to you. But the question is deeper, which is: Did patients notice a difference? I wish I could expound upon that more, but I can't because the data are still under analysis. There was a very, very detailed questionnaire about how they felt -- body distress. Because people are distressed about this. So it would be nice to see that it improved their distress, but I can't say one way or another about that.
Journalist: Beyond that, is it clinically 15 percent of weight ...?
Fifteen percent is a lot. It is 20 percent versus placebo, remember; but it was 15 percent within a group. You tell me another drug that achieves that kind of ... over six months. I'm just saying.
Journalist: So, compare it to what's been seen with growth hormone.
With growth hormone: it's identical to growth hormone. It's not really better; it's not really worse. It's identical. But the difference is, it's achieved at a more physiologic level.
Journalist: What the question really is: Does that really going to improve their health? Their heart health?
I don't know. I mean, based on the associations seen in non-HIV patients, that's a good thing. But the study you're asking for is a long-term, humongous trial looking at hard CVD [cardiovascular disease] endpoints. And I challenge you to help us come up with the money for that, and I'll answer your question.
Moderator Judith Currier: I think we're going to wrap it up there so that we can move on to the next panel. Thank you very much.
To read study abstract, click here.