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Obesity Drug Moving to Clinical Trials Following Success in Mice, Dogs, and Women

Published: Thursday, January 27, 2011 11:33 AM EST     2263 Views
Author: Ann Delphus
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The affectionate Yiddish adjective "zaftig" for voluptuous, Rubenesque women is generally positive and accepting; however, the reality of the zaftig body is one that is vulnerable to diabetes and heart disease. With a nod to zaftig in creating their company's name, the founders of Zafgen, Inc., a five-year-old, private, venture-backed biopharmaceutical firm, has recast a another company's discontinued tumor-fighting drug into the winning role of an innovative new anti-obesity drug.

A successful trial on a small number of obese women in Australia demonstrated that those treated with intravenous Zafgen-433 lost an average of approximately two pounds per week. In addition to the weight loss, the women experienced a decline in hunger and reductions in triglycerides and low-density lipoprotein (LDL) cholesterol levels, all with no serious, treatment-related adverse events. Now, following the positive results of this initial double-blind, placebo-controlled, proof-of-concept trial, Zafgen expects to have a subcutaneous form of the drug ready by the end of summer which will be used for the next phase of clinical trials (for both men and women) expected to begin sometime later in 2011. Ultimately, though, the company plans to create a conventional, oral form of the medication. (Zafgen advises anyone interested in participating to ask their physician and check for the Zafgen-433 announcement at www.clinicaltrials.gov.)

Zafgen-433 is not like any other obesity therapy available or under development today: it is "as far from the me-too drug trail that a developer can get,"according to FierceBiotech.com, the online industry newsletter that awarded Zafgen "Fierce 15" status in 2009 in recognizing it as among the best emerging companies.

Zafgen's innovative approach to reversing obesity targets adipose tissue (fat cells) because, unlike the traditional view of obesity that fat accumulation is a "passive result of other factors," Zafgen views adipose tissue "as playing an active role in the disease," a view that represents a "fundamentally new paradigm" in how obesity is regarded and potentially treated. Indeed, obese people release fat from their adipose tissue at a slower rate than the non-obese, and they convert it to ketone bodies – a form that is usable as fuel for muscles – at a slower rate. (Much of this process encompasses the metabolic syndrome and insulin resistance that doctors described when discussing obesity as a risk for type 2 diabetes.) Zafgen-433 acts on adipose tissue by inhibiting an enzyme called methionine aminopeptidase 2, or MetAP2, an enzyme that is associated with the body's tendency for preserving its stores of fat. When this enzyme is inhibited by the drug, it allows the body to metabolize fatty acids at a more normalized rate as the body re-establishes its balance, leading to a substantial loss of body weight in overweight individuals. This was true for the overfed mice (pictured above), for overweight dogs, and for the initial trial of obese women in Australia. Adipose tissue samples from the treated mice revealed that their fat cells actually shrank.

Dr. Maria Rupnick was studying a class of tumor reduction agents called anti-angiogenics when she discovered that some of them (but not all of them) caused weight reduction in obese lab animals. (Anti-angiogenics suppress the growth of new blood vessels to reduce the blood supply to tumors.) In fact, one molecule triggered surprising weight loss in these obese animals, and subsequent investigation at Zafgen led to the discovery that MetAP2 inhibitors reduced body fat at much lower doses than Dr. Rupnick was studying. Additional investigation led to the selection and refinement of a different molecule - the Zafgen-433 molecule - as being particularly effective in inhibiting the enzyme MetAP2 and driving weight loss; the previously completed safety study of it enabled Zafgen to proceed expeditiously. Using a low dose of anti-angiogenic agent to affect adipose tissue represents a radical departure from existing strategies for obesity treatment, which typically have targeted the brain (appetite) or fat absorption.

It appears that almost everything about Zafgen, Inc. is novel and innovative. The company – a venture capital start-up founded in 2005 – is a "virtual company" in that there are only three full-time employees: Thomas Hughes, Ph.D., president and CEO; Matthias Jaffe, CFO and VP of business development; and James Vath, Ph.D., head of discovery and development. These three orchestrate the company's drug research and development, taking advantage of the freedom to use the best-suited experts to perform the necessary tasks in the drug development process without regard to physical location. In fact, Zafgen has relationships with roughly 50 companies on four continents.

Before-and-after photos courtesy of Zafgen, Inc.

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