Forbes: For Arya

-by Robert Langreth

A Wall Street Power Couple Race to Find a Cure for Their Daughter Before It Is Too Late

Arya Singh was born in March 2000, sat up and crawled on schedule but never really walked right. Pediatricians said at first that she was simply a late bloomer. But at 17 months she could take only four or five steps before falling. In August 2001 a doctor friend of Arya’s parents, Loren Eng and Dinakar Singh, saw her stumbling around at a party in New York. Visibly alarmed, she told Loren and Dinakar to take the child to a neurologist as soon as possible.

A frantic round of visits to specialists ensued. It took more than a month to get blood-test results. The wait was particularly harrowing for Loren, who was eight months pregnant with her second child. Finally, two days before Loren was scheduled to deliver, the neurologist called at dinnertime. Arya had spinal muscular atrophy, or SMA, a progressive and fatal disease in which the nerves that control the muscles slowly waste away. He said he was very sorry and hung up before Loren could ask a single question.

There is no cure and not a single proven treatment for SMA. Sometimes known as floppy baby syndrome, it’s a leading genetic killer, hitting one in 8,000 infants and toddlers. Children with it lack a crucial gene that motor neurons need to survive. They seem fine for the first weeks or months of life, but their disabilities quickly mount. Most die before age 2, when their breathing fails.

Loren and Dinakar spent the next 24 hours in a panicked scramble trying to arrange the blood tests to find out whether their second child also had SMA. (He didn’t.) Other doctors tried to put a bright face on the terrible news: Arya had a mild form of the disease–she was likely to live into adulthood, though she faced ever-increasing disability as years went on.

Their shock slowly turned to disbelief when they found out how little was being done to find a cure. The U.S. National Institutes of Health spends $13 million a year researching the disease–one-ninth what it spends on cystic fibrosis, which afflicts twice as many kids. Biotech firms have largely ignored the disease. This despite a plethora of basic research breakthroughs abroad that made SMA ripe for drug development.

Unlike some parents, Dinakar and Loren had the resources to do something about it. Singh, now 35 and manager of $2.8 billion hedge fund TPG-Axon Capital, had been a trader for Goldman Sachs, where he managed a $6 billion internal account. Eng, 36, had worked in investment banking before getting master’s degrees in business and education from Stanford. They put up $15 million to establish their own charity, SMA Foundation, to sponsor new research. Loren, who had planned to go into nonprofit work, became president and day-to-day leader. Their goal: Find a cure for Arya and the 25,000 other young kids with the disease before their time runs out. “It is common and potentially treatable, but [drug research] was poking along because no one was incentivized to get it done,” Singh says.

Even in a nation that spends $28 billion a year on medical research, some deadly diseases simply fall through the cracks. They don’t have celebrity endorsers, are burdened with tongue-twisting names, fall outside of hot research fads or simply kill so swiftly that there are few survivors left to lobby for research support. Pancreatic cancer, one perennial loser, falls into the last category. It gets one-tenth the government funding of prostate cancer, which kills the same number of people but has a network of prominent survivors.

Spinal muscular atrophy is beset by most of these disadvantages. It is too small a market for Big Pharma. Various forms of the disease go by obscure names such as Werdnig-Hoffman and Kugelberg-Welander and weren’t understood to represent the same ailment until the last decade. “SMA has often been misrepresented to the public as muscular dystrophy,” says Columbia University neurologist Darryl De Vivo. Despite some similar symptoms such as lack of motor control, SMA is caused by an unrelated gene defect.

German neurologists first described the most severe form of SMA in 1891, in which babies never become strong enough to sit up. But its genetic origins remained shrouded in mystery until 1995, when French researchers pinpointed a gene on chromosome 5 that was missing or defective in 98% of those afflicted. The gene codes for a nourishing protein that is essential for the survival of motor neurons. Roughly 1 in 45 healthy Americans are carriers of the recessive trait, meaning they are missing one of the normal two copies of the gene. Offspring of two carriers, such as Loren Eng and Dinakar Singh, have a 1-in-4 chance of developing SMA.

The reason kids like Arya live at all is that humans have a slightly defective cousin of the SMA gene that produces only enough nourishing protein to keep patients alive for a while. Kids with milder cases, such as Arya, produce more than those with severe cases.

By the time Arya was diagnosed in 2001, scientists at Ohio State University and others in Germany and Taiwan had engineered mice missing the main SMA gene. Those mice engineered to have better functioning cousin genes had fewer symptoms. Better yet, the Taiwanese scientists had found that a class of experimental cancer drugs appeared to boost levels of the nourishing protein, at least in test-tube studies. Yet little work was being done to rush this promising research toward development of a safe and effective drug.

Loren and Dinakar decided to get the federal government to start paying more attention to this disease. National Institutes of Health neurologist Kenneth Fischbeck had already proposed in early 2002 an innovative crash program to create prototype drugs. But by early 2003 the agency hadn’t yet handed out research contracts for the program, thanks to the painstaking federal contracting process.

The pace seemed glacial to Loren and Dinakar. Loren got 50 scientists, including DNA discoverer James Watson, to petition the NIH for more SMA funding. She hired a lobbyist who helped unite various SMA patient groups, including FightSMA, in a letter-writing campaign to the U.S. Congress. They sent more than 400 pieces of mail in early 2003. Loren and Dinakar met with U.S. Senators Arlen Specter and Tom Harkin and filled them in.

At a hearing in April 2003 Specter grilled NIH officials on why they hadn’t moved faster on implementing Fischbeck’s SMA drug discovery plan. By September 2003 the program was up and running with $22.2 million. NIH officials say the program was already moving ahead, and the timing of events was coincidental.

In an attempt to stave off Arya’s decline until something better came along, her parents and doctors decided to try hydroxyurea, an old cancer drug that had been shown to boost levels of the neuron-nourishing protein somewhat in preliminary lab tests. There was no proof it would help (trials are under way at Stanford, partly sponsored by the SMA Foundation), but it had been safely used before on kids with sickle-cell anemia. Taking it required weekly trips up to Columbia University for blood tests to make sure the drug wasn’t suppressing Arya’s white blood cells, a common side effect.

Getting biotechs to listen was a little tougher. Last spring Dinakar and Loren decided to conduct an investment-banker-type road show to drum up interest among small drug companies, complete with PowerPoint slides estimating potential annual sales for an SMA drug ($250 million to $750 million) and possible spinoff applications for other diseases. Their pitch: Since SMA is well understood and amenable to traditional drug discovery methods, SMA research has a far higher shot at success than research into more murky brain disorders such as Alzheimer’s disease. They promised fistfuls of cash to firms willing to work on a tight timetable.

Only three of seven biotech firms they invited to a dinner at a neurology conference last May bothered to show up. Executives of some companies they met were fearful that diverting from hot fields like obesity would hurt their stock price. Others were scared off because pediatric drugs are viewed as hard to test and get through the U.S. Food & Drug Administration. Still others noted that SMA mouse models and other critical resources necessary to begin drug testing were scattered among universities, some of which were demanding payments to share them.

Loren jetted off to Taiwan and persuaded researchers there to share their SMA mice at cost, at least with academics. The SMAFoundation rented a ballroom at a big neuroscience conference in San Diego in October 2003 and sponsored a seminar, “Progress in Motor Neuron Disease,” flying in renowned SMA researchers to give lectures. This time 100 scientists showed up. By this point Arya was losing ability to control her neck muscles; the hydroxyurea wasn’t working and was stopped. Meanwhile, Singh quit Goldman in July 2004 to start his new fund.

A few daring firms eventually agreed to help. Curis, a firm in Cambridge, Massachusetts, has accepted a three-year, $5.4 million grant from the SMA Foundation to use its unique technology for growing motor neurons in test tubes to identify potential SMA drugs. CombinatoRx in Boston is searching for combinations of existing drugs that may work in a synergistic way to increase levels of neuron-nourishing proteins. Patient groups are sponsoring drug discovery at other firms, including Iceland’s Decode Genetics and England’s Oxford BioMedica, which is plying a gene-therapy approach.

In three to five years Eng and Singh hope that one or more of these efforts will yield a drug ready for clinical trials. “I would put every penny I make from the fund into this [SMA research] if I thought it would help the odds of a cure–in fact, I suspect we won’t be far from that,” says Singh.

Ever so gradually Arya is losing strength. Now 5, she can still walk a few yards with the aid of leg braces by locking her hips and knees in place and balancing her weight above her feet. But her muscles are so weak that she topples over like a broomstick when she gets even slightly off balance, which happens often. She has so little muscle left in her arms that her pediatrician must give her shots in the legs.”The most painful question is when people ask how Arya is doing,” says Loren, who recently ordered a wheelchair for her daughter.

Occasionally at bedtime Arya sobs over her plight. She is starting to ask her mom and dad pointed questions, such as whether she still will be able to walk when she grows up. Her dad tells her that there are no guarantees but that scientists and doctors are working as hard as they can toward creating a treatment that will make this possible.