Entrepreneurs are so possessed by their ideas that they start companies in good times and bad.

They often feel there's nothing they can't overcome. Those with successful track records may find the start-up road familiar but not easy.

Take Maria Maccecchini, who's been in the life-sciences business in the Philadelphia region since the late '80s. She first took the start-up plunge in 1992 with Symphony Pharmaceuticals Inc., which sought to develop treatments for disorders of the central nervous system.

Drug development rarely progresses in a straight line. Over the better part of a decade, Symphony's strategy changed. Symphony merged with a European company and changed names twice before being bought by Transgenomic Inc., of Omaha, Neb., in a cash and stock transaction in May 2001.

Following the sale, Maccecchini said she took time off "to run around the world." She climbed Mount Everest but fell short of the summit. She went dog-sledding in Alaska.

After all that, Maccecchini said she "needed to get my brain moving again." So she joined a local "angel" investment network.

"Angel investing is a great parking lot for people who want to keep mentally stimulated but do not want to commit" to the 24/7 whirlwind that encircles any start-up.

Nearly two-thirds of all angel-backed companies flame out. Maccecchini's experience was no different. Her home run was Protez Pharmaceuticals Inc., which agreed to be bought by Novartis AG last June in a deal with a maximum value of $400 million.

But the entrepreneurial bug bit her again after meeting Nigel Greig, a senior investigator at the National Institute on Aging, at a medical conference and discussing his technology to treat Alzheimer's disease. Some scientists describing potential medical breakthroughs can seem like fishermen exaggerating about their catch. So Maccecchini, who has a Ph.D. in biochemistry, says she's often skeptical.

But she was impressed with the potential of the technology described by Greig, who was among those who started the biotech firm Athena Neurosciences Inc. in the early '90s.

The NIA estimates between 2.4 million and 4.5 million Americans are living with Alzheimer's. There is no cure, only a handful of treatments led by Aricept, which had $1.6 billion in sales in the United States in the year ended March 31, 2008.

Three experimental compounds that embodied Greig's technology had already been licensed by a start-up company. In fact, it had taken one, called phenserine, into late-stage Phase 3 clinical trials in 2005 … where it promptly failed.

That start-up was bought by a La Jolla, Calif., company called TorreyPines Therapeutics Inc. in 2006. The venture capital-backed TorreyPines was chasing a number of central nervous system therapies when the tight credit market that's been cooling off the biotechnology industry froze its momentum.

Maccecchini started QR Pharma Inc. in May 2008, and licensed Greig's compounds to treat Alzheimer's disease from TorreyPines in November. She set out to learn why phenserine failed in the clinical trials so that QR Pharma could avoid repeating those mistakes.

To pay for that investigation, Radnor-based QR Pharma raised $50,000 in "pre-seed" funding from Philadelphia's BioAdvance, which funds early-stage life-sciences companies with money provided by the state of Pennsylvania as part of the massive federal tobacco litigation settlement.

Maccecchini doesn't plan to commercialize phenserine because she sees the two other experimental compounds as more promising.

Last week, QR Pharma said it raised $500,000 from Ben Franklin Technology Partners of Southeastern Pennsylvania, a state-funded nonprofit agency that has been investing technology firms of all kinds for more than 25 years.

Some of that money will be used to develop a once-a-day formulation for Posiphen, QR Pharma's lead compound. But in order to launch clinical trials, QR Pharma will need to raise millions of dollars, not hundreds of thousands. Maccecchini estimates it would cost about $10 million to do a six-month Phase 2 trial with 400 Alzheimer's disease patients.

In the meantime, capital has been drying up for biotechnology and small pharmaceutical companies, which burn through lots of cash when they're in clinical trials. Caught in a cash crunch, TorreyPines said at the end of March it would cut its workforce to three as it considered alternatives, including a possible sale.

It's too soon for Maccecchini to worry, but she said the fund-raising environment is "really tough." She admits to being frustrated by what sounds like a data chase. Potential funders want to minimize their risks, and so ask to see more data about what went wrong with phenserine.

"If you have [results from] one mouse, they want to see two mice. If you have two mice, they want to see a rat. If you have a rat, they want to see a dog," she said.

When you're Merck & Co. Inc. with 55,200 employees, that's not a problem. When you're QR Pharma with one employee and eight consultants, it's a little trickier.

Challenging times? Yes, but Maccecchini is happy to be back on the entrepreneurial mountain with a long climb ahead.