Zafgen, a Cambridge, Mass.-based biotech developing novel treatments for obesity, has raised $14 million in Series B funding, according to a regulatory filing dated Nov. 3. Third Rock Ventures was joined by return backer Atlas Venture in this latest financing round.

Although the company launched three years ago, it officially emerged from stealth mode only a few months ago. In early September, the company announced the appointment of Thomas Hughes, former VP and global head of cardiovascular and metabolic disease at the Novartis division Novartis Institutes for BioMedical Research, as the company's new CEO (¹ Also see "Zafgen Finds Plentiful Funding in Slimmed Down Obesity Market " - Scrip, 1 October, 2008.).

With more than $20 million in funding, the company is sufficiently capitalized to push potential lead molecules into the clinic, which could happen as soon as next year.

Traditionally, pharmaceutical companies have tackled obesity indirectly, focusing on drugs that target the gut/brain axis and are supposed to work by reducing appetite or triggering gastric-emptying.

But many of these drugs also come with significant psychological side-effects, if they work at all - witness the stunning flame-out of Sanofi-Aventis' cannabinoid-receptor antagonist Zimulti (rimonabant) in June 2007. Sanofi withdrew the product's NDA for an obesity indication after an FDA advisory committee unanimously opposed it, citing neurological and psychiatric adverse event concerns (² Also see "Sanofi Withdraws Zimulti NDA For Weight Loss" - Pink Sheet, 29 June, 2007.).

Competitors have fared no better. Merck announced in early October that it was suspending development of taranabant due to off-target effects (³ Also see "CB-1 Targeters For Obesity Dropping Fast" - Pink Sheet, 2 October, 2008.). In early November, Pfizer revealed it was jettisoning its CB-1 drug, CP-945,598, citing increased regulatory risk associated with the drug class and its own shifting R&D priorities (⁴ 'The Pink Sheet', Nov. 10, 2008, In Brief).

Nov. 17 was the death knell for that troubled drug class: Solvay announced it was discontinuing its Phase II drug, SLV319, even though the company had confirmed its "clinical activity and efficacy," according to a release.

"The mechanisms resulting in obesity are incredibly well defended biologically," notes Zafgen's Hughes. With these indirect approaches, "other compensatory pathways kick in" and stymie weight loss, he says.

Strategy targets root of obesity

Founded by Maria Rupnick, a cardiologist at Children's Hospital Boston, Zafgen decided to tackle the problem more directly, developing drugs targeted at the root cause, an excess of adipose tissue.

Scientists have known for some time of a complex link between the blood vessels and the body's fat cells. Work by Rupnick and others has suggested that as people gain weight, there is a corresponding increase in the blood vessels supplying nutrients to the fat cells. Moreover, when people lose weight, those same vessels shrink in correspondence with the diminished adipose tissue.

This led Rupnick to wonder what might happen if she were to interfere with the blood vessels that normally feed the adipose tissue. Would the fat cells shrivel the way certain solid tumors do in the face of powerful anti-angiogenesis drugs? The answer, at least in cell culture and mouse studies, was yes.

"It's an entirely new approach to the problem. It almost seems too good to be true," claims Hughes. Best of all, says Hughes, "it's inherently druggable."

Promising data draw additional investment

The heady science attracted the attention of Atlas Venture and Great Point Ventures which originally seeded the company with $5.2 million. As Zafgen gained even more data about the possibility of targeting the adipose tissue directly, Third Rock grew more eager to be involved in the project.

"The point was to capitalize the company with a meaningful investment that [would] allow it to get a molecule into the clinic," said Kevin Starr, a partner with Third Rock who also served as the Zafgen's interim CEO until Hughes came on board.

Although Rupnick's lab tested the concept using well-known anti-angiogenesis drugs, both Starr and Hughes confirm that Zafgen since has developed a portfolio of novel, orally available molecules for which it is pursuing composition-of-matter rights.

"We have very broad intellectual property related to vascular targeting," Starr said. Noting that it would be premature to talk in detail about the exact nature of Zafgen's targets, Hughes did offer that the company was in the final stages of selecting candidates to bring forward into IND-enabling studies.

Like Sirtris Pharmaceuticals, which GlaxoSmithKline purchased in April for $720 million in order to access its innovative pipeline of sirtuin-based drugs, Zafgen aims to develop a platform of products built around the links between blood vasculature and adipose tissue growth. (⁵ Also see "GSK Gobbles Up Sirtris For $720 Million, But Still Prefers Alliances To Big Buys" - Pink Sheet, 28 April, 2008., p. 3).

Sirtris successfully employed a shrewd marketing campaign that kept the company's cutting-edge science in the spotlight until the timing was right to begin licensing and M&A discussions. This approach allowed Sirtris to demonstrate proof-of-principle with its "loss leader"- resveratrol - while simultaneously showing the validity of its back-up compounds.

Current plans call for Zafgen to obtain proof-of-concept data for molecules before seeking a partner. To whet Big Pharma's appetite, it might make sense for Zafgen to make an initial foray into POC clinical studies with a demonstrator molecule, with follow-ons in close succession.

-Ellen Foster Licking (e.licking@elsevier.com)

Obesity-Focused Zafgen Raises Zaftig Series B

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