Novartis’ new $2.1 million drug has roots in Philadelphia. Here’s how the city has impacted treatment of rare diseases.

Take her home. Love her.

That’s the advice doctors gave Steve and Gina Cannady after diagnosing their 3-year-old daughter, Emma, with spinal muscle atrophy (SMA), a rare genetic disorder that affects nerves in the spinal cord that enable children to walk, eat, breathe.

Weeks later, their third daughter, Ruby, was born. She also had SMA.

SMA affects about one in every 11,000 births and is the top genetic cause of death among children under age 2, though children diagnosed with less severe forms of the disease can live into adulthood.

The back-to-back diagnoses were terrifying for the young Abington family, who were told there was nothing they could do to help their children.

“In that darkest time, I told my wife something I didn’t really believe but she needed to hear," said Steve Cannady, a physician at Penn Medicine. “I told her I believed that science was going to help our daughters and there are going to be options we can’t even see right now.”

His comforting words turned out to be prophetic.

As the Cannadys were absorbing their girls’ diagnosis, researchers were hard at work in a Penn lab developing a technology that would eventually be used in a treatment for SMA and other genetic disorders.

Approved just last month, Zolgensma is a onetime treatment for children under age 2. It uses a specially engineered virus called a vector — pioneered at Penn — to deliver a replacement for the defective gene, a kind of technology that until recently seemed more science fiction than medicine. Zolgensma is among the first gene therapy medications in what former FDA Commissioner Scott Gottlieb in January called a “surge” of cell and gene therapy treatments in development. By 2025, the FDA anticipates approving 10 to 20 new cell and gene therapy medications a year, each giving hope to families coping with a genetic disorder with few, if any, treatment options.

Zolgensma also is a potential lightning rod in the debate over drug costs and access, especially with more high-priced drugs in the pipeline. At $2.1 million for a single dose, it is among the most expensive drugs in the world.

“The price of these drugs is pitting people to make a decision: Is life worth that cost?” said SMA patient and advocate Kristen Smith, 34, who says she has learned to manage her less severe form of the condition but uses a power wheelchair.

Zolgensma’s maker, Novartis, says that although the price is significant, it is a better value than the only other treatment for SMA, a spinal cord injection approved in 2016 that must be given every four months, at $125,000 a shot. Industry supporters point to the years of work that went into the innovative treatment to explain the price, which will sound like a familiar argument to anyone following the drug pricing debate.

But behind Zolgensma is an extraordinary story of science and sacrifice in Philadelphia.

The drug itself was developed by AveXis, a Chicago company that was later acquired by Novartis. But the vector used to deliver Zolgensma’s replacement gene was developed by University of Pennsylvania researcher James Wilson, a pioneer of gene therapy. It was in Philadelphia, in one of Wilson’s clinical trials in the late 1990s, that an 18-year-old patient died from an extreme immune response to a gene therapy treatment for a genetic liver disease, an event that some thought would end not only Wilson’s career but also one of the hottest medical research fields.

But 20 years after Jesse Gelsinger’s death, gene therapy is on the rise, and so are Philadelphia’s prospects in what promises to be a billion-dollar business.

The first gene therapy drug approved in the United States, Luxturna, was developed by Philadelphia’s Spark Therapeutics to treat a genetic eye disorder. Wilson’s new research and development start-up, Passage Bio, recently raised $115.5 million to apply his vector technology to new gene therapy medications. Investors pumped a total of $2.9 billion in venture capital into cell therapy, gene therapy, and tissue engineering companies in 2018, according to the Alliance for Regenerative Medicine, an industry group.

What’s more, a leading pharmaceutical-industry group, BIO, drew about 17,000 people to the city at the beginning of June for its annual conference.

“It’s fitting and poignant that it’s back in Philadelphia,” BIO president James Greenwood said of gene therapy. “It is the future.”

The idea of treating genetic disorders by replacing the defective gene was gaining momentum in the 1990s when Wilson’s gene therapy trial became one in a series of major setbacks in the field.

After Gelsinger’s death, an FDA investigation concluded that the Arizona teen should never have been allowed in the trial. The FDA investigation also found that his death wasn’t the first from a gene therapy trial — other deaths in other labs outside of Penn had gone unreported.

Wilson, his co-researchers, and their institutions were sued by the federal government and Gelsinger’s family. The Justice Department settlement fined Penn $517,000 and banned Wilson from working with clinical trial patients for five years.

A few years later, two boys in a gene therapy trial in Paris for an immunodeficiency disorder developed leukemia.

“Those two things together made many people who were interested in drug development feel that this area is not ready for prime time,” said Katherine High, president and head of research and development at Spark Therapeutics, who has also spent her career on gene therapy.

But High and other researchers committed to the idea stayed the course, scouring for private funding to keep their labs running.

Wilson also decided to continue his research. As part of the federal settlement he wrote a journal article on the lessons he had learned and told The Inquirer in 2009 that he had “tremendous regrets about what happened. I feel absolutely awful about what it has done to the family, to this university, to the field.”

But investors were wary of putting money into his research, so Wilson turned to his mentor Tachi Yamada, then the head of research and development for SmithKline, which is now GlaxoSmithKline. The company agreed to a sponsored research agreement for the Penn lab, with licensing options for the pharmaceutical company on any discoveries.

The lab discovered a family of vectors that could be engineered to deliver genes with less risk of the patient getting sick, making them safer than the vector that had been used in Gelsinger’s trial. The scientist and Penn licensed the discovery to RegenxBio, a company Wilson had helped found.

RegenxBio licensed one of those vectors, AAV9, to AveXis, the company that developed Zolgensma.

The drug’s debut is a milestone for gene therapy, Wilson said.

“We went from an era, well over a decade, where there was no interest from the commercial sector — almost none. Then before you know it, everything’s gene therapy,” he said.

But even Wilson tempers his excitement over what Zolgensma can do.

Patients in Zolgensma’s clinical trial showed improvement in the two years following treatment — they did not need a ventilator to breathe and some were able to sit on their own, a developmental milestone that many SMA patients never reach. But the drug isn’t a cure and it’s unclear whether its effects are permanent.

Still, it is considered an improvement over the only other treatment available for SMA patients, Spinraza, a spinal cord injection that patients must receive every four months for the rest of their lives.

There are four types of SMA, based on the age of onset and how many developmental milestones the child ultimately reaches. Even among patients with the same type, abilities can vary.

The most common form, type 1, is also the most severe and often fatal — babies are typically diagnosed within six months and often have trouble breathing and swallowing due to extreme muscle weakness.

Children with type 2 may be able to sit up, but will most likely never walk on their own. Type 3 can be diagnosed in children up to their teens, who slowly lose mobility.

The least severe form, type 4, is rare, with onset among adults and mild impairment.

Emma Cannady, now 9, has type 3. She walks short distances on her own and uses a scooter or walker for longer distances. Ruby, 6, has type 2, and got her first motorized wheelchair when she was 2.

Both take Spinraza, which was in clinical trial when they were diagnosed, to help with their mobility.

They are not eligible for Zolgensma because it is only approved for children under age 2.

“I’d be lying if I said I didn’t wish my girls could get it,” their father said. “But it’s hard for me to not just be grateful for this breakthrough.”

Zolgensma and the pipeline of gene therapy drugs it is part of represent hope for families that, until now, had few if any treatment options. But the high cost that will come with this new generation of drugs raises fresh fears about straining the health-care system and will certainly open a debate about what’s a reasonable price for lifesaving medication.

Greenwood, of BIO, said drug companies need to be able to recoup their expenses; otherwise, they would have no incentive to invest in rare-disease research. Over time, expensive drugs with strong results can be more cost-effective than medications that must be taken repeatedly, he said.

Regina Philipps, 32, of Haddon Heights, has concerns about Zolgensma’s long-term efficacy but she wants her 16-month-old son, Shane, to get it.

Shane, who has type 2 SMA, started Spinraza treatments in January. Since then, he’s been able to hold up his head, and is regaining strength.

Their insurance plan through her husband’s employer has covered the injections. But the treatment is invasive — because Shane is so young, he is put under a light anesthesia for every procedure.

Philipps worries what will happen if Zolgensma doesn’t work as well as Spinraza, and their insurer refuses to pay for both medications.

“My concern is giving up something that’s working for the hope that something else might be better,” she said.

Novartis has said it is working with private insurance companies to establish five-year payment plans for Zolgensma, but private insurance coverage for Zolgensma may vary.

Federal rules about what plans must cover depend on the type of plan, and states may have their own rules about what private health plans must pay, said Rachel Sachs, an associate law professor at Washington University in St. Louis. Self-funded plans, common among large employers, have more flexibility in which drugs to include, which could expose patients to an unrealistic out-of-pocket cost, she said.

But Medicaid, the state-federal insurance program for low-income Americans, is required by law to cover every drug approved by the FDA.

As more high-price drugs enter the market, they could begin to strain programs with tight budgets, she said. Unlike a private health plan that can raise more money to cover members’ bills by increasing premium prices, Medicaid is paid for by taxpayers.

“Any one of these drugs is affordable by the health-care system, but if you have 25, 50, or more, adding them all up, it really becomes a substantial burden,” Sachs said. “If Novartis is setting the bar here, where might we go in a few years?”