The eleventh European AIDS Conference (EACS) heard promising results from a trial of tesamorelin, a drug described by conference co-chair Dr Santiago Moreno as “the first really promising drug we have to reduce fat accumulation caused by HIV therapy.”
Tesamorelin, made by biotech Theratechnologies, was previously known as TH 9507. Interim results from halfway through a year-long study were presented at the CROI conference in early 2007 – see this report – but the EACS conference was hearing the final 52-week results.
Tesamorelin is a Growth-Hormone Releasing Factor (GHRF) analogue. GHRF is a natural body chemical that acts on the pituitary gland and stimulates it to release Human Growth Hormone (HGH). Artificially-engineered recombinant HGH (somatotropin) has already been used to treat the abdominal fat accumulation (hypertrophy) associated with HIV treatment, and has been the only substance that works.
Although there is still some controversy as to whether the fat accumulation seen in people with HIV is actually treatment-related, having significant intra-abdominal fat is associated with a higher risk of cardiovascular disease and diabetes, and may also be a cause of significant psychological distress in patients, so is worth treating, presenter Steven Grinspoon said.
The advantage of having a drug that is an analogue of GHRF rather than HGH is that it stimulates the pituitary to produce the ‘right amount’ of HGH. HGH secretion has been found to be reduced in HIV patients with lipodystrophy, and using a GHRF analogue should restore the correct physiological level of HGH in the body, Grinspoon said.
Treating patients with HGH results in higher levels than normal physiological levels, leading to side effects such as fluid retention (peripheral oedema), headache and joint pain, and excess glucose levels. Cases of cancer, haemorrhage and breast development in men have also been reported.
In the study, 410 participants were split into three groups. At the start of the study 273 were started on tesamorelin and 137 on a placebo. By week 26, 95 participants had dropped out of the study, leaving 315. One hundred and fifty-four of these kept taking tesamorelin (the ‘T-T’ group), 50 were switched from tesamorelin to placebo (the ‘T-P’ group) , and 111 who had previously taken placebo were switched to tesamorelin (the ‘P-T’ group).
The average age of subjects was 48, and 15% were women. At the start of the study their average waist circumference was 104cm (40.9 inches), their waist-to-hip ratio was 1.1, and their Body Mass Index was on the borders of clinical obesity at 29.5.
By 26 weeks, those taking tesamorelin had experienced a 20% reduction is visceral fat compared with those on placebo, and an 18% reduction relative to baseline – see the previous report for other details.
By week 52, those who received tesamorelin throughout had maintained the 18% reduction in visceral fat, but not increased it, suggesting a plateau effect, at least in the 2mg a day dose given in the study. Those who started taking tesamorelin at week 26 experienced a 12.5% fat loss between week 26 and week 52. However those who went from taking tesamorelin to placebo quickly regained fat and ended up after 52 weeks with a net overall visceral fat loss of only 1.6%.
Waist measurements decreased in a similar fashion. In the T-T group this reduced by 3.25cm, in the P-T group it reduced by 2.7cm, but in the T-P group a 2cm loss by week 26 had become only a 1cm loss by week 52.
This is therefore a therapy that would have to be taken continuously for fat loss to be maintained. Grinspoon said this was not a surprise: “Change back to baseline after cessation is seen in every study of human growth hormone,” he said. “And we don’t expect statins or hypertension drugs to keep having an effect after people stop taking them.”
Tesamorelin did have side effects. By week 52, 36% of people in the ‘T-T’ group, 18% in the T-P group and 14%in the P-T group had adverse events that were judged to be related to the drug, and discontinuation rates in the three groups were 12%, 6% and 3% respectively. Four per cent suffered injection site reactions.
The most important side effect was joint pain (arthralgia): this was seen in 14.4% of patients in the T-T group, 4% of patients in the T-P group and 3.8% in the P-T group. However most reports of it happened in the first 26 weeks and only 4% of patients reported it in the second 26 weeks. Similarly, peripheral oedema was seen in 8% of patients on tesamorelin in the first 26 weeks, but decreased to 1.3% in the second half of the study.
Will patients want to take an injectable therapy for fat accumulation indefinitely?
Theratechnologies clearly think so, and quote research estimating that as many as 250,000 people with HIV in North America and Europe suffer from fat accumulation. They have a phase III trial still ongoing which will report by spring 2008, and although a small Canadian biotech, Theratechnologies has been granted Small and Medium Enterprise status by the EMEA, the drug licensing agency in the European Union.
HGH has never been licensed in the EU for the treatment of fat accumulation, not only because of side-effects but because of its extremely high cost. An answer to a question about tesamorelin’s likely cost relative to HGH went unanswered, but will clearly be crucial if the product is to gain wide acceptance in Europe.