A researcher's unrelenting pursuit of an MS therapy

Every day, Dawn Freney looks at her six children with fresh gratitude, amazed to think each of them protected her while growing in her womb.

It's a logical thought. Last spring, the busy West Chester volleyball mom was diagnosed with multiple sclerosis. Her neurologists, who estimated she's had the crippling disorder for at least nine years, marveled at her vigor, considering she'd had no MS treatment.

What she did have, one after another, were babies. And pregnancy is a time when women with MS usually get a reprieve from the intermittent immune-cell attacks that damage the nervous system.

"I definitely do see, thinking back, where symptoms cleared up," said Freney, 38. "I always felt great while I was pregnant."

Although doctors have long recognized this temporary protective effect, it was neurologist Rhonda Voskuhl who focused on a possible reason: estriol, a form of the female hormone estrogen that is sold as a generic drug. Estriol is made by the placenta and normally surges only during pregnancy.

In a quest to get estriol approved as a therapy for women with MS, Voskuhl is leading a $5.6 million clinical trial at 16 medical centers, including the University of Pennsylvania - where Freney recently became a participant.

If this sounds like a poignant success story, it isn't. As Voskuhl has learned the hard way, generic drugs lack the one thing that drives the costly business of drug development - the prospect of hefty profits. Even if the current trial is successful, getting estriol approved will take many more millions of dollars (money the researcher doesn't yet have) and at least another decade.

Voskuhl, director of the MS program at the University of California Los Angeles, initially thought estriol was a can't-lose proposition. After all, MS strikes three times as many women as men - 300,000 in the United States alone. Unlike the seven brand-name MS medications on the market, estriol comes in a capsule rather than injections or intravenous infusions. It has no notable side effects. And as a generic drug, it's inexpensive.

"The science is great, the idea is great," said Voskuhl, a speed-talker with a faint Oklahoma twang. "I had no idea it would be this hard."

After more than a decade working to bring estriol to patients, Voskuhl, 49, tries to keep her frustration in perspective.

"It's really not so bad for me to go from young to old," she said, "but it's pretty bad to see them go from walking to wheelchairs."

In 2001, shortly after the birth of her fourth child, Freney started to feel an electric shock every time she bent her chin to her chest.

A neurologist told her it was Lhermitte's sign, a classic symptom of MS. But a brain MRI scan and other tests showed she was fine, or so he said. And the disturbing jolts stopped.

Freney would later obtain the original MRI report and discover that the doctor wrote: "Thoracic lesion. Could be MS."

But first, she spent almost nine years chasing an explanation for mysterious bouts of numbness, migraines, and vision problems. A Penn neurologist finally diagnosed relapsing-remitting MS, the most common form.

During relapses, which occur about once a year, immune cells gnaw on the protective covering of nerves in the brain, spinal cord, and eyes. This produces patches of swollen, injured tissue that can be seen on MRI scans. The attacks are followed by periods of recovery, or remission.

Research shows that half of patients who go without any treatment for as long as Freney have trouble walking.

She remains remarkably unscathed.

"I've never needed a cane," she said. "I exercise. I was the coach of my oldest child's volleyball team. Knock on wood, I don't have tremors."

MS typically goes into remission during the prenatal period. A 1998 study by French researchers who followed 254 women found that relapse rates fell 80 percent in the last three months of pregnancy.

In comparison, the five first-choice MS drugs cut relapses by a third, and even the biggest gun, Tysabri, reduces the flare-ups by 67 percent.

Further, because MS drugs disrupt or suppress the immune system, they often cause flulike symptoms, increase infections, or both. The two most powerful drugs can even have fatal effects.

Pregnancy, in contrast, shifts the balance of disease-fighting cells to protect the fetus from being attacked as an invader. Researchers speculate this shift also subdues the damaging immune attacks of MS.

Voskuhl had a hunch that hormonal changes were the foundation of this mysterious respite and that estriol was the keystone.

In the late 1990s, Voskuhl's UCLA lab began testing her hypothesis in an animal model of MS.

Sure enough, diseased mice treated with slow-release estriol pellets remained nimble, while mice given a placebo rapidly became paralyzed.

The results, repeated in eight groups of mice, were "clinically dramatic," according to a 1999 paper published in Neurology.

The next year, Voskuhl obtained an "investigational new drug application" - the FDA's permission to experiment on humans in three incremental clinical trials designed to show safety and effectiveness.

Estriol had a benign history, having been used as a menopausal therapy for 40 years in Europe and Asia. Although never approved by the FDA, it was available in the United States through so-called compounding pharmacies that fill customized prescriptions.

The thing was, estriol had never been used long-term in doses high enough to mimic pregnancy. Potentially, that could increase the risk of breast cancer and blood clots.

Before trying to assess such what-ifs, Voskuhl had to show estriol was worth pursuing in the first place. So with $500,000 from the National MS Society and the National Institutes of Health, her team recruited six women with relapsing-remitting MS for the pilot study.

Monthly brain MRIs showed that the size and number of lesions decreased 80 percent during six months on estriol. When treatment was suspended and then resumed, lesions grew, then shrank.

Six women wasn't many. And the trial was too short to measure relapse rates, a more definitive indicator of effectiveness than lesion activity.

Still, all six patients responded, so statistically, it wasn't just luck. Plus, their mental test scores and immune-cell changes were good signs.

With hopes high, Voskuhl partnered with Adeona, a small company in Ann Arbor, Mich., to make the estriol capsules, christened Trimesta - an allusion to pregnancy's last trimester.

Voskuhl calculated the second trial would have to follow 150 women for two years, at a cost of about $5 million.

And that's when her troubles began.

Big drug companies recoup costs and make profits by patenting the chemical composition of a newly invented drug. The patent provides exclusive marketing rights for 20 years.

Developers of old drugs, in contrast, can patent the new use - Voskuhl did - but not the composition. Thus, competitors can sell the drug.

Practically, this means that shepherding a generic chemical through to FDA approval takes a lot of money, but it won't make a lot of money.

"With a new drug, sales are tightly controlled," explained Alex Sluzas, a Philadelphia patent attorney. "With a generic drug, in theory you have exclusive rights to the new use, but it's not easy to enforce those rights."

Voskuhl turned to the only agency that routinely spends millions on profitless research: the taxpayer-funded National Institutes of Health.

Her application was "peer reviewed" by MS experts around the country but fell short. She revised and resubmitted it. Another rebuff. Five years in a row this happened.

No one faulted her credentials or her quest. Indeed, throughout the years of rejections, she published evidence that estriol not only reduced immune attacks but also nurtured nerve-cell growth - a neuroprotective effect, she pointed out, that no other MS drug has.

What foiled her was the simple but harsh reality that, aside from big pharmaceutical firms and big government, deep-pocket underwriters are as scarce as miracle cures.

Walter Koroshetz, deputy director of the NIH's Institute of Neurological Diseases and Stroke, said it was "nobody's fault" that some worthy proposals missed the "payline."

"The system has flaws, I'm sure, but it's democratic," he said. "It's purely a competitive thing."

Nonetheless, some patients believe the NIH favors the pharmaceutical industry, for which MS has become a $5 billion market. The NIH last fall announced it would fund a $44 million trial to see if combining two MS drugs, Copaxone and Avonex, boosts their effectiveness.

Economist Dean Baker, codirector of the Center for Economic and Policy Research in Washington, said he believed the existing drug-development system discouraged "large areas of potentially useful research."

"There's not an easy way to fix it," he said. "There's so much money at stake."

In 2007, the National MS Society decided to intercede, said Patricia O'Looney, the MS Society's vice president of biomedical research. It pledged $4.8 million for the estriol trial, one of its largest grants ever.

That grew to $5.6 million after the NIH came up with a portion, and economic-stimulus funds paid for expansion from seven to 16 sites, including Penn.

"It aggravates me," said Freney, "that the funding was so difficult to come by. I think unless it's a drug that can benefit men, it doesn't get pushed."

The second trial has enrolled about half the intended 150 women. For two years - long enough to assess relapse rates - they will take estriol or a placebo plus Copaxone, because it would be unethical to deprive them of proven treatment for that long. However, they must provide their own Copaxone, so effectively, only women with health insurance can volunteer.

"If we covered the Copaxone, it'd cost another $2 million," Voskuhl said.

Freney is unwavering, even though she may not personally benefit, no matter the outcome.

"If I'm on the placebo, that's part of the trial," she said. "I wouldn't be mad. I wouldn't feel cheated. What I'm doing is my contribution to finding out" if estriol works.

Results should be available in 2013. Then she would have to do the third trial - the largest, longest study, meant to definitively prove safety and effectiveness.

But if there is a final trial, it will be a tribulation.

"I'll have to start this whole rigmarole again to get even more money," Voskuhl said. "Probably $20 million."