Kinetix Pharmaceuticals hoped that a focus on a particular class of targets that shares structural similarities--the protein kinases--would yield small molecules for a variety of therapeutic areas. But in order to realize synergies between multiple research projects in protein kinases, the company couldn't partner the projects out to numerous pharmaceutical partners, each requiring exclusivity and confidentiality. After technological rival Vertex signed a multi-million dollar protein kinase development partnership with Novartis, Kinetix began to rethink its original business model. A $170 million acquisition offer by Amgen Inc. made strategic sense for the start-up.

Big Pharma's valuations are depressed; biotech is red-hot. Alliance volumes have fallen, but average deal values are up. The valuation divide masks the subtler cracks dividing biotech's elite from a mass of undifferentiated technology providers. Drug companies are recognizing that basing discovery programs around new, proprietary targets is highly risky and lengthens R&D time. Targets themselves, absent optimized lead compounds, are increasingly commoditized. Therefore, companies who don't provide integrated discovery capabilities aren't going to get the high-value deals that will justify their current, sky-high valuations. Meanwhile, companies with integrated solutions must back up their promises of productivity enhancement with their own money--though they also get a richer share of the end proceeds.

Pharmaceutical companies face two giant risks; compound risk and target risk. So, despite an abundance of so-called validated targets emerging from genomics efforts, and novel high throughput tools for compound synthesis and screening that yield plenty of hits against each target, at the end of the day, pharmaceutical company productivity, as measured by approved drugs, remains low. Recently, several former big-pharma executives have founded private companies that hope to speed up the time it takes to come up with optimized small molecule leads. Each has staked out a particular niche where it thinks it can do better than big pharma at coming up with clinic-ready compounds. Kinetix Pharmaceuticals and Triad Pharmaceuticals hope to leverage their knowledge of particular gene families to come up with optimized leads; Enanta Pharmaceuticals hopes to morph peptides into drugs with a combinatorial approach to binding pharmacophores, and Sunesis hopes to tackle some of the targets that prove intractable for others, or in which only large molecules have been able to intervene. The new small molecule companies share a vision of drug discovery that is based on targets, rather than diseases.

A preview of the emerging health care companies profiled in the current issue of Start-Up. This month's profile group, Drug Delivery, features profiles of Cell Based Delivery Inc., Solgene Therapeutics LLC, Spherics Inc. and Zars Inc. Plus these selected Start-Ups across Health Care: Helios Health Inc., Optimize Inc., Triad Therapeutics and Protiveris Inc.