Today Zafgen announced its initial results from proof-of-concept study in patients with an obesity-related orphan disease called Prader-Willi Syndrome (PWS). The news was also covered by Andrew Pollack in the NY Times this morning (here) so I won’t bother with the specifics – it showed meaningful improvements for several parameters affecting PWS patients and offers real promise.
I thought I’d touch on a few strategic points around Zafgen’s approach to patient segmentation and our increasing confidence in the mechanism.
Obesity has historically been seen as a mass-market indication, defined by weight alone and unsegmentable, and the FDA’s more challenging stance on the field reflects that (as I described here a couple years ago). But morbid obesity is a very serious medical condition with significant co-morbidities and Quality of Life issues. So one of the big challenges in the obesity field is how to define a narrow treatable population (medically-relevant morbid obesity) where therapeutic interventions are truly beneficial vs the broader “healthy” obese population who would have a very different risk-benefit calculus, especially in the eyes of regulators.
Historically, this definition has been tough for therapeutics. One of the big reasons is because the existing approaches have such modest effects. Working on centrally-acting mechanisms instead of on peripheral pathways, most try to control weight through appetite. This does little for the morbidly obese. The only viable treatments for significant body mass reductions have been surgeries – lapband and bariatric surgeries offer real promise for correcting obesity and even treating related diseases like diabetes. Drugs, on the other hand, have only seen very modest efficacy (losing 5-8% of your body mass beyond placebo over a year), with highly varied patient response rates, and this just doesn’t move the needle in morbidly obese populations.
Zafgen’s beloranib is different. The drug targets metAP2, which appears to be an incredibly powerful node in a novel pathway for regulating metabolism and obesity in a highly penetrant manner (nearly 100% of the patients treated with the drug respond). Less effective drugs targeting poorly penetrant approaches have to go to broader populations in the hope of seeing effects. Earlier in 2013, we demonstrated impressive efficacy in a high risk morbid obesity population – patients with an average BMI of 38 and body weights of ~100kg lost nearly ~1% per week and showed significant beneficial changes in LDL, HDL, Trigs, CRP and markers of inflammation, adipokines, etc… The data were striking in their efficacy and tolerability (here).
Importantly, this potent, penetrant mechanism allows us the opportunity to choose between populations affording the right balance of medical need and suitability for development, and to focus our energies on patients in whom real efficacy is critical – opening up a regulatory and commercial path that is viable for a venture-backed company.
This is where addressing the needs of orphan obesity-related diseases comes into the picture, and specifically Prader-Willi Syndrome patients (for more see here). As described in the press release:
Prader-Willi Syndrome (PWS), the most common known genetic cause of life-threatening obesity in children, causes constant hunger that drives children to gain more weight on fewer calories than the average person. As a result, many of those affected become morbidly obese before the age of five. There is currently no cure for this disease. Although the cause is complex, it results from a deletion or loss of function of a cluster of genes on the 15th chromosome. PWS typically causes low muscle mass and function, short stature, incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes drastically fewer calories than normal, can lead to excessive eating and life-threatening obesity. It occurs in males and females equally and in all races, with the same incidence around the world. Prevalence estimates have ranged from 1:8,000 to 1:50,000 with the most likely figure being 1:40,000. To the best of our knowledge prevalence is about 5,000-7,000 people in the United States needing treatment.
Beyond presenting a very attractive patient segment for which we can develop beloranib, it also provides further confidence in the mechanism. There was a real risk going into this study that the chromosome 15 gene deletions in PWS patients would impair the pathways by which beloranib manifests its benefit in the broader population: today’s positive data is proof that those pathways are intact and targetable in PWS patients. In fact, to my knowledge this is the first successful randomized, controlled clinical trial with a drug treatment aimed at obesity-related endpoints in the PWS population. This is further spine-strengthening for our confidence that the drug will also work in other hypothalamic-linked obesity diseases, such as craniopharyngioma (here for a recent video on the condition), another ultra orphan disease condition.
Taken together, PWS and craniopharyngioma offer two high impact opportunities: very defined patient segments with no current effective standard of care, both are homogenous disease states related to obesity, where we are confident the underlying pathways are at work, with a clear risk-benefit favoring active intervention and pharmacotherapy. By approaching the introduction of beloranib via a measured approach, tackling very defined obesity-related populations, we can ensure only those patients deemed appropriate for the drug are receiving it (preventing abuse through inappropriate usage by “healthy” overweight or mildly obese population).
With these initial indications as early entry points, we will continue to identify and develop the approach for medically-relevant, high risk, morbidly segments of the obese population – which in the U.S. has a prevalence of close to 20 million people. This drug and other emerging approaches in play at Zafgen offer real promise to address the medical needs of one of the biggest healthcare challenges we face today. It’s exciting to be a part of the story.
