Hope For Hypothalamic Obesity And Beyond?

Craniopharyngoma

Hypothalamic obesity, is a rare but serious condition that occurs in about 50% of individuals who have suffered injury to their hypothalamus (e.g. because of a craniopharyngoma or trauma).

Severe weight gain in these patients may not be all that surprising given that the hypothalamus plays a key role in the regulation of hunger, satiety and other aspects of energy balance.

Now, Zafgen, a US biopharmaceutical company, announces surprising early results of treating such patients with beloranib, an inhibitor of methionine aminopeptidase 2 (MetAP2), an enzyme that modulates the activity of key cellular processes that control metabolism. 

According to Zafgen, their small proof-of-principle trial (ZAF-221), conducted in 14 obese patients (nine women and five men) who were confirmed by magnetic resonance imaging (MRI) to have had hypothalamic injury, the results look most promising.

Here is the description of their findings taken from their press release:

“ZAF-221 was a randomized, double-blind, placebo controlled study of twice-weekly subcutaneous injections of 1.8 mg beloranib or placebo in patients with HIAO to evaluate weight reduction and safety over four weeks, followed by an optional four week open-label extension. Beloranib treatment resulted in mean weight loss of 3.4 kg and 6.2 kg in patients with HIAO after four and eight weeks of treatment with beloranib, respectively, in contrast to 0.3 kg mean weight loss in patients treated with placebo for four weeks (p = 0.01). Improvements in cardiovascular disease risk factors of lipids and inflammation (measured by C-reactive protein) were also observed. Beloranib 1.8 mg was well tolerated in this population, with no serious or severe adverse events reported. Safety measures such as laboratory, electrocardiogram, and vital sign measurements revealed no signals of concern, and all subjects randomized to beloranib completed the trial.”

What I find most surprising about these findings, is that this drug appears to work in people where key centres for appetite regulation are no longer intact. This points to the existence of a non-hypothalamic mode of action for this drug – an action that is powerful enough to work independently of the centres in the brain known to play a key role in energy regulation.

The company is also pursuing beloranib for individuals with Prader-Willi Syndrome, another hypothalamic form of obesity as well as patients with severe obesity.

Needless to say, this finding may well also hold promise for other forms of obesity, reason enough to closely watch the further development of this compound.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a paid consultant to Zafgen.