Lipodystrophy study halted after patient death

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A Phase II study of a lipodystrophy treatment developed by Canadian biotech company, ConjuChem, has been halted after the death of a study participant. The cause of death and its relationship to the study drug - CJC-1295, a chemically modified version of growth hormone releasing factor (GRF) also known as DAC:GRF - is currently being investigated. However, a Phase III study of another Canadian-developed GRF-based lipodystrophy treatment, Theratechnologies' TH-9507, is continuing.

The multicentre, randomised, placebo-controlled, double-blind Phase II study of CJC-1295 had only completed enrolling a total of 192 participants with HIV-related visceral obesity at various sites in North and South America last month. Participants were randomised to receive once-weekly injections of either a three-week escalating low dose of CJC-1295 (at 60, 90, 120mcg/kg); a three-week escalating high dose (at 60, 120, 240mcg/kg); or a placebo, and then continue for a further nine weeks.

The only information released so far by ConjuChem, which stopped the study on July 17th, is that the participant who died was attending a study site in Argentina. An unconfirmed, anecdotal report from a trial participant at a Canadian study site, suggests that the individual concerned was a man who died a few hours after receiving his eleventh CJC-1295 injection.

About human growth hormone

Human growth hormone (HGH) is a natural hormone produced in the pituitary gland. A genetically engineered, or recombinant, version (rHGH, Serostim) was granted accelerated approval in the United States in 1996 for the treatment of AIDS wasting, although it is not approved for this condition in Europe.

Glossary

hormone

A chemical messenger which stimulates or suppresses cell and tissue activity. Hormones control most bodily functions, from simple basic needs like hunger to complex systems like reproduction, and even the emotions and mood.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.

lipodystrophy

A disruption to the way the body produces, uses and distributes fat. Different forms of lipodystrophy include lipoatrophy (loss of subcutaneous fat from an area) and lipohypertrophy (accumulation of fat in an area), which may occur in the same person.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

Although small studies have found that rHGH is effective in the treatment of central fat accumulation, the use of rHGH is limited by factors such as high cost, and its short half-life, requiring daily or every-other-day subcutaneous injection.

In addition, rHGH can adversely affect glucose levels, which may lead to diabetes. Other common side-effects include joint pain, swelling in the feet and hands, pain in the limbs, and pins and needles. Several serious side-effects thought to be associated with rHGH, reported by Graeme Moyle and colleagues at the International AIDS Conference in Barcelona in 2002, include skin cancers, gastrointestinal bleeding, inflammation of the arteries, and breast development in men.

Two versions of GRF

A genetically engineered version of growth hormone releasing factor (GRF) - a natural precursor of human growth hormone (HGH) produced by the hypothalamus - was first developed by another Canadian biotech company, Theratechnologies.

Although Theratechnologies' own drug, TH-9507, is further ahead in development than CJC-1295, TH-9507 requires once-daily dosing. In contrast, because CJC-1295 delivers GRF through ConjuChem's proprietary Drug Affinity Complex (DAC) technology - which allows the GRF peptide to bond chemically with albumin, a protein found in the blood, resulting in a much longer half-life - it can be given weekly.

TH-9507 is currently in Phase III studies that involve more than 400 HIV-positive individuals with lipodystrophy in the US and Canada. Earlier this month, but prior to ConjuChem's announcement, Theratechnologies announced that the study's Data and Safety Monitoring Board had recommended that the 26 week study - which compares TH-9507 with placebo - continue, after 280 individuals had received thirteen weeks of the treatment.

Results of a Phase II study, published in AIDS last year, and first reported on aidsmap in 2004, showed that TH-9507 was associated with a significant reduction in visceral fat without the negative effects on glucose control seen with rHGH treatment.

Last month, results from a Phase I study of CJC-1295 were presented by Madalina Ionescu and colleagues at an endocrinology conference in Boston. Here, a single dose of either 60 or 90 mcg/kg of the drug was administered to twelve HIV-negative men. After this one injection, and at these lower levels, the investigators concluded that the drug was well-tolerated and that its adverse effects were mild and generally of short duration.

Last year, ConjuChem halted development of another drug that utilised its DAC technology - a diabetes treatment known as DAC:GLP-1 - after Phase II trial results revealed toxicity issues related to the diluting agent used to administer the drug. But ConjuChem's President and CEO, Mark Perrin, told BioWorld Today that the toxicity issues seen with that drug appeared to to be unrelated to the DAC technology, and that he believes that any problems with CJC-1295 would be "quite specific to GRF."

References

Falutz J et al. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS 19(12):1279-87, 2005.

Ionescu M et al. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GHRH analog. 88th Endocrine Society Annual Meeting, Boston, abstract OR21-6, 2006.

Moyle G et al. Recombinant Human Growth Hormone is effective to treat HIV/AIDS associated wasting in the era of highly active antiretroviral therapy. Fourteenth International Conference on AIDS, Barcelona, abstract LbPeB9012, 2002.