A Mother’s Moonshot
When drug makers said no to finding a treatment for a rare disease, Loren Eng mobilized a pioneering effort that saved thousands of lives.
Doctors told Loren Eng her daughter wouldn’t live past high school. She was determined to change that outcome. | Harriet Lee-Merrion
Loren Eng was a new mom, and like all new moms, she celebrated each milestone her infant daughter reached — sitting up, standing, walking. But as her little girl, Arya, reached 18 months, Eng began to worry that something was wrong. “When she was standing, the muscles and bones in her legs appeared to almost dissolve and she would collapse unexpectedly,” recalls Eng, MBA ’96, who was eight months pregnant with her second child at the time.
Doctors had tried to reassure her, saying it was just muscle weakness or that Arya was a late bloomer. But when a pediatrician friend at a dinner party observed Arya, Eng’s growing anxiety was validated. “She got down on the floor where Arya was playing and did an impromptu neurological exam,” Eng recalls. “I could see the panic on her face. She said, ‘You need to get her to a specialist right away.’”
A month of testing ensued. Then, two days before Eng delivered her second child in October 2001, she got the news: Arya had inherited a rare genetic disease that could kill her. There was no treatment and no cure.
It was called Spinal Muscular Atrophy. The condition appears in about one of every 10,000 babies, caused by a mutation in the Survival Motor Neuron 1 gene (SMN1) that supplies an essential protein for motor neurons, which control muscle movement. Without that protein, those neurons die, muscles weaken and wither, and people with SMA begin a steep decline that leads to severe disability and death.
When Arya was diagnosed, Eng had never heard of SMA. Today, she is an expert on it. Over the past two decades, defeating the disease became her life’s work, a prodigious effort that involved mobilizing a community of scientists, drugmakers, and corporate partners, and resulted in medical breakthroughs that have changed the lives of tens of thousands of people with SMA, including Arya.
But on that evening 22 years ago, all Eng could think about was how to save her child and whether the baby in her belly would be healthy. Two days later, “I was sobbing hysterically as they were doing the C-section,” Eng says. “Everyone was confused because they didn’t know why a mother would be sobbing like that in the delivery room.”
It was a boy, Kiran. Doctors took his DNA and rushed the samples through testing. “With the most severe form of SMA, the kids die right away; and those with milder forms live with tortured disability and get worse and worse every day for the rest of their lives until they die,” Eng says. “So what do you pray for? A quick death or a long, miserable one?”
Kiran was okay, as was Eng’s third child, Tara, born five years later. And to her great relief, Arya had a milder form of the disease, which meant she would probably survive early childhood. But with no treatment in sight, her life would be a hellish series of hospitalizations and painful, relentless physical attrition. “The doctor said she might live to finish high school,” Eng recalls.
Eng devoted herself to changing that outcome.
Before treatments were available, the most serious form of spinal muscular atrophy resulted in death before age two. Loren Eng’s daughter Arya, who had a somewhat milder form of the disease, developed normally as an infant but began to decline at around 18 months.
The R&D Race Begins
In 2003, Eng, with her family and close friends, established the SMA Foundation to identify and fund promising research that could lead to a treatment. Like other rare diseases, Spinal Muscular Atrophy suffered from poor public awareness, and because of the relatively small number of people affected — about 10,000 in the United States — there was little money for research beyond basic studies conducted by the National Institutes of Health.
Little Money for Research
Only about 500 of the more than 7,000 rare diseases with known molecular causes have approved treatments. In 1983, Congress passed the Orphan Drug Act to provide tax and other incentives for pharmaceutical companies to develop drugs for rare diseases.
“NIH funding is fantastically important, but it can only get you so far,” says Jonathan Leff, MBA ’96, a partner at the venture capital firm Deerfield, where he specializes in biotechnology and pharmaceuticals. “The hundreds of millions of dollars required to actually develop a drug has got to come from investors or from industry.”
Someone needed to convince drug companies and investors that financing research on SMA could lead to profitable products. As president of the foundation, Eng assembled a team of advisers drawn from academia and the pharmaceutical industry and put together a powerhouse board that collectively supplied both influence and expertise. “I had never heard of SMA before I got involved with the foundation,” says Leff, who joined the board. Nevertheless, “It didn’t seem to me like a disease that was so small that you couldn’t build a business case around it.”
The foundation had a key advantage: SMA was scientifically tractable. In what Eng describes as “a lucky break,” a backup gene, SMN2, produces the same protein as SMN1, but in amounts too small to arrest the muscle degeneration that characterizes the disease. If scientists could coax this “extra” gene into producing more of the protein, it could provide a potential pathway to a treatment.
Calling on her GSB training, Eng developed what amounted to a private equity prospectus that demonstrated why pharmaceuticals should allocate research dollars to SMA. Her instinct was to lead with the science, not a mom’s desperate plea. “You don’t want to come in and just say, ‘I’m a sad parent of a child’ — what are they going to do with that? But it does resonate if you can walk them through the reasons why this is ultimately good for their shareholders.”
However, science really wasn’t her thing. “I took astronomy as an undergraduate to pass my science requirement,” she notes with a chuckle. “It’s kind of a cruel joke to have this thrown upon you.”
But what she lacked in technical knowledge, Eng made up for with tenacity. She vigorously tapped into and expanded her network, “talking to anybody who would talk to me” about SMA. She made connections at the NIH who put her in touch with prominent doctors, some of whom she convinced to accompany her on her visits to pharmaceutical companies.
“Loren has been brilliant at bringing together the investment community and the pharma community with the best scientists in the field,” says Leff, whose friendship with Eng began when they were classmates at the GSB. “She doesn’t hide the fact that she’s the mom of a child with SMA, but at the same time she comes across as a businessperson who understands that investors need to make a return, and that the science has to be there.”
Even so, the answer at every major pharmaceutical company was no. It was clear that the foundation would have to find and fund its own researchers.
Drug Discovery is Hard
Tens of thousands of human clinical trials are conducted annually in the United States; 90% fail.
Eng acknowledges that she was naïve in the beginning, anticipating that with enough money injected into the research, Arya might have a better life in three to five years. “It doesn’t work that way,” she says now, her perspective seasoned by years of disappointment. “Drug discovery is hard and there are many more failures than successes.”
Waiting for a Breakthrough
By the time she was five, Arya was in a wheelchair. Each succeeding year brought new challenges as her physical capacity diminished, and the effects of her condition led to serious, sometimes life-threatening problems. As the muscles in her chest weakened, Arya lost the ability to cough, which is critical for clearing the airway during a respiratory illness. As a result, common colds could turn into pneumonia, a leading cause of death among people with SMA. “I missed tons of school because every time I got a cold, it would turn into two weeks of respiratory therapy,” Arya says.
Gradually, her muscles weakened so much that they could no longer hold bones in place. Her hips dislocated. Scoliosis twisted her spine; orthopedic deformities developed throughout her body, requiring multiple corrective surgeries. Pain shadowed her constantly.
The physical trauma takes a terrible toll, but young people with SMA also endure heartbreaking emotional pain as they watch children around them thrive. “They see that other kids are doing things that they can’t do,” Eng says. “That is the worst part.”
For nearly a decade, Eng watched Arya suffer as experiment after experiment funded by the foundation failed. She did her best to soften the arduous litany of medical procedures Arya faced. “Once, when we were heading into the hospital for another operation, we ran into a man selling goldfish on the street. I bought every goldfish he had, and we named them for all the doctors,” Eng recalls. “I did whatever I could to keep her spirits up and stay positive.”
During this time, a lot of Eng‘s work involved meeting researchers, making introductions, and promoting dialogue and collaboration within the scientific community. At one such meeting, she met Adrian Krainer, a researcher at Cold Spring Harbor Laboratory in New York, who had been conducting basic studies on SMA. The SMA Foundation made a grant to Krainer’s lab, which helped spur a dedicated effort to repair the genes associated with the disease.
A breakthrough came in 2007. The Krainer lab found a way to fix the SMN2 gene by introducing chemically modified pieces of RNA. Using mouse models of the disease, this therapeutic approach showed promise.
Frank Bennett, the chief scientific officer at Ionis Pharmaceuticals, had read a paper describing Krainer’s method, which led to a partnership that expanded on the research and developed protocols that would ultimately be used in human clinical trials. The first trial began in November 2011. The second participant was Arya.
The drug, later named Spinraza, was administered by injection into the spinal fluid, a procedure that had to be repeated periodically. But it worked. Very early on, Bennett says, “we were getting whispers from the physical therapists who were working with patients that they were getting stronger.” It would take years to get conclusive results and the data to back them up, but for Arya, Spinraza was transformative. Her condition stabilized, and the disease progression stopped.
Occasionally, the grueling regimen of operating-room visits and spinal injections tested Arya’s resolve. She was a little girl, and this was not how little girls were supposed to live. When she was scheduled to receive a dose on her 12th birthday, Arya broke down in tears and declared to her mother, “This is the worst birthday ever!” Eng tried to console her. “This is the best birthday present you will ever get,” she told Arya. Recalling the moment, Arya acknowledges that her mom was right. “I didn’t agree with her then, but I do now.”
In December 2016, Spinraza became the first FDA-approved drug to treat SMA, and the pharmaceutical giant Biogen reached an agreement with Ionis to take it to market.
Getting a Drug into a Person
Typically, it takes 10 to 15 years and more than $1 billion to research, develop, test, and commercialize a new drug.
That same year, Arya participated in a clinical trial for Risdiplam, an oral medication that enables the protein from the SMN2 gene to reach nerve cells. That drug was developed by PTC Therapeutics, which then collaborated with Roche to perfect it and move it through clinical trials. Stuart Peltz, the CEO of PTC, says the SMA Foundation was a crucial partner, supplying both money and momentum. “Next to putting someone on the moon, getting a drug into a person is about the hardest thing you can do,” Peltz says. “The foundation pushed us, and in the end we did something that was truly pioneering.”
The ability to repair a splicing defect in a gene and correct the core biological process for which it is responsible cracks open a door that could lead to other drug discoveries, says Paulo Fontoura, the global head and senior vice president of neuroscience, immunology, ophthalmology, infectious and rare diseases at Roche. “This is a real landmark in science.”
In 2020, the FDA approved Risdiplam (marketed under the brand name Evrysdi) as the first oral medication available for SMA treatment. For Arya, the daily dose of liquid medicine has been life-changing. Not only has it continued to arrest the progression of SMA, but the drug also unshackles her from the multiple hospital procedures required with Spinraza.
Leff was involved in the development of a third treatment, which delivers a healthy SMN1 gene intravenously into children under two using a virus as a vector. The virus transmits this new gene to motor neurons, effectively replacing what children born with SMA lack. Known as Zolgensma, it was developed by AveXis (later acquired by Novartis), a drug company that Deerfield invested in and where Leff was a board member.
It came too late to help Arya and other patients too old for the gene therapy, but the arrival of Zolgensma means that SMA will have a much less profound impact on children born with the disease, especially those with its most severe form. Although there is insufficient data to draw firm conclusions, kids with Type I SMA are now reaching developmental milestones that weren’t possible before Zolgensma.
Treatments That Found Their Way to Market
New treatments for rare diseases are extremely costly to produce and to acquire. When Zolgensma was approved in 2019 it was the most expensive drug ever, at $2.1 million for a one-time dose. Both Spinraza and Risdiplam cost hundreds of thousands of dollars for a yearly course of treatment. Although these prices have been criticized, an analysis by an NIH researcher said the cost “seems reasonable” given the massive investment required to develop the drugs and the small number of patients.
The role of the SMA foundation, and Eng in particular, was crucial to the success of the treatments that found their way to market, says Bennett. Whether it was finding and funding mouse models in Taiwan or making connections between organizations, Eng and her team built a scaffold upon which pharmaceutical companies could stand and advance their work. “It was critical to the field.”
Stanford President Marc Tessier-Lavigne, a neuroscientist, is chair of the SMA Foundation’s science advisory board. The foundation’s success, he says, “is due in large part to Loren’s vision, leadership, and persistence over decades. She continually deployed her passion, powers of persuasion, and organizational skills to coax diverse stakeholders to work together in unison… to develop therapies at breakneck speed.”
Eng is now focused on finding ways to restore the loss of function that many people with SMA endure. “We’re trying to rebuild the key parts of the bodies that are broken, such as neural circuits and muscles, and give those kids who didn’t make big gains a way to further improve,” she says. “These treatments will benefit not just SMA patients but other neuromuscular disorders and diseases of aging.”
Arya’s symptoms were worsening until she began new treatments as a preteen. “I always loved school,” she says, “because it was something I was good at.” She is now completing a master’s in public health.
A Moment to Celebrate
On May 22, 2022, hundreds of students, faculty, and staff gathered for Yale’s traditional Class Day exercises. The students had chosen Arya Singh as their speaker.
She had arrived at the university, Arya said, full of anxiety that her disability would define her, that she would be shamed and shunned as she had been earlier in her life. At a pre-college summer program, she recalled, her fellow students had asked that she be removed from a group photo “because my wheelchair ruined it.” They asked a bus driver to leave without her because the wheelchair lift took too long. “The experience jaded me,” she said, and she prepared herself for four more years of “perpetual exclusion.”
But at Yale, Arya said, she found a tribe that embraced her and gave her the courage to lead with empathy and vulnerability, rather than fear of rejection. The school had “restored the hope that I had lost.”
When she finished, the audience stood for a long, loud ovation.
As the moment washed over her, Loren Eng felt a jumble of emotions: pride, joy, but also fear. “Arya has been blessed to be part of a community that supported her. What happens when she leaves Yale and doesn’t have that mosh pit that elevates her?”
In May, the young woman who wasn’t supposed to live past high school will graduate with her second degree from Yale, a master’s in public health. She hopes to work in drug development. “I want to make a difference in kids’ lives,” Arya says, “especially kids with rare diseases and disabilities.”
And whereas she once resisted an identity as “the kid in the wheelchair,” she now embraces the fact that SMA has shaped who she is. And that understanding empowers her to help others. “I don’t want a different life,” she says. “I know how to do this one.”
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