[pronut-hiv] Lipodystrophy study halted after patient death

["ProNut-HIV" <pronut-hiv@healthnet.org>]

Aidsmap

Lipodystrophy study halted after patient death 
 
Edwin J. Bernard, Monday, July 31, 2006 

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. 

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." 

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. 

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. 

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.