BioWorld Today Contributing Writer

Tom Hughes, President and CEO of Zafgen Inc., is not concerned about the FDA's upcoming general advisory committee in 2012 to address requirements for cardiovascular assessments for obesity therapeutics. Whereas the announcement has left late-stage obesity companies like Orexigen Therapeutics Inc., Vivus Inc. and Arena Pharmaceuticals Inc. in a sort of limbo, Cambridge, Mass.-based Zafgen is moving forward with confidence.

"We have a different risk-benefit profile, and we're going after a high unmet need population. That is going to be a game changer for us," Hughes told BioWorld Today.

Zafgen's investors, including Atlas Venture and Third Rock Ventures, evidently agree to the tune of $33 million. Proceeds will support Phase II trials of ZGN-433 (beloranib hemioxalate), a methionine aminopeptidase 2 (MetAP2) inhibitor.

MetAP2 is thought to tone down stress pathways in the body related to high levels of insulin including the storage of fat and biosynthesis of cholesterol. The theory is that by inhibiting MetAP2, the body can achieve a new equilibrium, using its fuel more efficiently.

"Everything we've learned about the target over the last year and a half points to MetAP2 acting as a sentry for that level of cell stress," Hughes said.

The difference in mechanism represents a different approach to obesity treatment. Other obesity programs have focused on molecules that affect the appetite, targeting control of food intake or reward centers in the brain.

But according to Zafgen, food intake is not the key to reversing severe obesity. "People who are obese have rather dramatic changes in the way their bodies metabolize fat," Hughes explained. In the obese body, adipose tissue traps fat, storing it and not releasing it very efficiently, preserving the obese state, he added.

Reducing food intake doesn't really unlock fat energy. Zafgen is targeting the underlying abnormality, attempting to normalize the metabolism of fat in the cell.

Results from preclinical animal studies and a Phase Ib trial suggested that Zafgen is on the right track. The company tested ZGN-433 in severely obese patients, looking at body weight change in the context of a number of cardiovascular and metabolic risk factors.

At a dose that was very well tolerated, according to Hughes, there was a weight loss of 1 kg per week. "That's roughly anywhere from two to four times the rate of weight loss you'll see with any other agent," Hughes said. The study also showed a 64 percent reduction in C-reactive protein, a predictive risk marker for cardiovascular disease and a normalization of blood lipids, all within the four-week period of the trial.

Subjects were not instructed to change their eating habits, or to exercise, although Hughes said those interventions might be included in future studies that are longer term than four weeks.

"Diet and exercise do not work well in the severely obese class," Hughes said. "There is a high failure rate of diet and exercise intervention."

In spite of that high failure rate, the medical establishment continues to emphasize diet and exercise as a treatment for obesity. "It's almost like . . . rather than a war on obesity, there's a war on the obese. It underestimates the importance and need for new therapies," Hughes continued.

Zafgen presented those results at the American Diabetes Association Meeting in late June. Hughes said the results "spoke loudly" to prospective partners and investors, indicating that the mechanism is translating well into humans, with large and significant responses.

Zafgen plans to enter Phase II trials in the next six to 12 months.

In addition to developing a compound mechanistically different from past and current late-stage obesity compounds, Zafgen also is carefully targeting the highest risk, highest unmet need segment of the market, those with morbid obesity.

Three late-stage compounds have recently entered "limbo" while waiting for the FDA's AdCom: Qnexa, Lorquess and Contrave. According to Hughes, the efficacy for those compounds was relatively modest, "on the order of 3 percent to 8 percent of body weight loss" after a period of a year or more of treatment.

Many patients in the study would not have seen any weight loss benefit from the drugs. For a modest benefit, or no benefit, it is difficult to overcome the types of safety issues being flagged by the FDA including cardiovascular toxicity, teratogenicity and carcinogenicity.

Zafgen contended that ZGN-433 may drive substantial weight loss (20 percent of body weight or more), without the safety concerns that have plagued other obesity candidates. It did not observe any treatment emergent or drug-related adverse events in its clinical trial, and the drug was well tolerated.

Zafgen also has the time and ability to incorporate the outcome of the FDA's AdCom into its program, which makes the forthcoming guidance less concerning than if it was entering registration right now.

The $33 million is expected to last through Phase II trials, or until about the middle of 2013, when the company will seek further financing.

In other financings news:

• Aradigm Corp., of Hayward, Calif., agreed to sell $4.75 million in common stock to three existing shareholders including those associated with First Eagle Investment Management LLC and Tavistock Life Sciences. Under terms of the private placement agreement, Aradigm will sell an aggregate of 25 million shares of common stock at $0.19 each. Net proceeds are estimated at $4.4 million.

• Coronado Biosciences Inc., of New York, closed a $25.8 million Series C round led by National Securities Corp., with proceeds expected to support pipeline advancements, including a Phase II study of lead compound CNDO-201 (Trichuris suis ova), an immunomodulator, in Crohn's disease and a Phase I/II study of cancer drug CNDO-109 in relapsed acute myeloid leukemia. That money adds to the series of financings Coronado completed last year, which pulled in about $21.6 million. (See BioWorld Today, Nov. 5, 2010.)

• Vantia Therapeutics Ltd., of Southampton, UK, raised $6.5 million in Series B financing for the development of VA106483 for nocturia and VA111913 for dysmenorrhea. Both drugs are in Phase II. Participating investors included Novo A/S, SV Life Sciences and MVM Life Science Partners, who have all previously invested in Vantia.