Ben Haugstad is 12 years old and loves Taekwondo. He’s been doing it for six years, and soon he’ll be a black belt.
He also has a severe form of hemophilia. His body doesn’t produce the machinery needed to clot blood, and at any moment a bad tumble or a bruise could quickly turn into an emergency.
Three times a week, his mother Kimberly wakes up in the morning and injects Ben with drugs that, for a short time, help his blood clot. “I never thought I’d be a nurse,” she says.
These shots are expensive, about $2,500 a dose. But they’re also life-saving. They prevent cuts from becoming disasters, and ensure that spontaneous internal bleeds don’t seep into joints or organs and cause serious problems. Ben (pictured above) can live a mostly normal life. He does his Taekwondo, participates in gym class. He’s “private” about his condition, his mother says. He doesn’t talk about it or use it as an excuse to stay home from school and miss a test. He’s only had a little joint damage here and there.
“He wants to do what he can do,” Haugstad says. “We’re actually on a six week run [without a bleed] right now, so I’m pretty excited about that.”
Sometime in the near future, Ben’s tri-weekly infusions might become a thing of the past. With gene therapy, a modified virus carrying specific genetic instructions would be infused into Ben’s body and could give him the ability to clot blood for years, perhaps for life.
You’d expect his mom, the inadvertent nurse, to jump at the thought of it. But Kimberly has a much more measured response.
“When he was born, we heard loud and clear that it was going to be three years to a cure,” she says, and her skepticism is all the more notable because she’s also the executive director of the nonprofit Hemophilia Federation of America. In a sense she’s speaking for a lot of parents, not just herself.
Kimberly has good reason to be wary of promises. The idea of gene therapy for hemophilia has been around since the 1980s, and more than 15 years ago, the first hemophiliacs volunteered for tests. Yet no gene therapy product has come close to market.
Clinical failures and high-profile safety catastrophes in gene therapy trials turned hype to dust, and eviscerated most private investment in the early 2000s. Even with the current resurgence in the field, there are many questions to answer—how long will these therapies last? how safe will they be?—before Ben or any of the 400,000 or so people with hemophilia can count gene therapy as an option.
Disease target: Hemophilia B/A
Name: BAX-335 (for hemophilia B; hemophilia A program undisclosed)
Therapeutic gene: Padua mutant Factor IX
Program origin: Chatham Therapeutics
Status: Initial data from Phase I/II clinical trial of hemophilia B reported in February; more data expected in June
Disease target: Hemophilia B/A
Name: AMT-606 (for hemophilia B; hemophilia A program undisclosed)
Therapeutic gene: Wild-type Factor IX
Program origin: St. Jude Children’s Research Hospital, NIH
Status: Started Phase I/II trial for hemophilia B In early 2015; data expected in the third quarter
Disease target: Hemophilia B/A
Name: Undisclosed; hemophilia A program partnered with Bayer
Vector: AAV, undisclosed
Therapeutic gene: Wild-type Factor IX
Program origin: RegenX Biosciences
Status: Expects to start clinical testing in 2015
Disease target: Hemophilia B/A
Name: SPK-FIX (for hemophilia B, partnered with Pfizer; hemophilia A program undisclosed)
Vector: AAV, undisclosed
Therapeutic gene: Padua mutant Factor IX
Program origin: The Children’s Hospital of Philadelphia
Status: Expects to begin Phase I/II trials in hemophilia B in the first half of 2015
Disease target: Hemophilia A
Vector: AAV, Undisclosed
Therapeutic gene: Wild type factor VIII
Program origin: In-house, St. Jude Children’s Research Hospital
Status: Expects to begin clinical testing in “early” 2015
Disease target: Hemophilia B/A
Strategy: Gene editing via zinc finger nucleases
Program origin: In-house
Status: Plans to submit IND in the second quarter of 2015
Disease target: Hemophilia B/A
Therapeutic gene: Undisclosed
Program origin: San Raffaele – Telethon Institute for Gene Therapy (TIGET)
Status: Potential first trial in 2016
Beyond hemophilia, gene therapy is definitely back. Startups are forming again; some have gone public. Big Pharma is investing via partnerships and strategic alliances. One product is approved in Europe—the first in a Western country—for a rare liver disorder; another might help cure a crippling blood disorder, beta thalassemia.
Gene therapies for hemophilia are farther behind, with just one developer so far, Baxter International (NYSE: BAX), reporting the barest of clinical data. (Xconomy has learned more about those data, which we will describe later.)
Following Baxter are several more companies—see the box at the right—and their clinical progress this year and next should be a touchstone for all of gene therapy. And hemophilia could prove to be the most competitive gene therapy race to date.
“The history of gene therapy really follows the story of hemophilia,” says James Wilson, the head of gene therapy research at the University of Pennsylvania, one of the field’s pioneers and most controversial figures.
Judging by the scrum of companies now with clinical trials or about to start, the story is about to add a wild new chapter. Seven groups have emerged so far with hemophilia programs. They are a mixed bag of big pharma companies protecting profitable franchises and smaller biotechs either working with the big companies or looking to one-up them.
What’s more, there are several scientific approaches and strategies involved, as well as the gamesmanship one might expect from a heated race.
“I think the competition is great,” says Wilson, who is also the scientific founder of the Washington, DC-based gene therapy startup RegenX Biosciences. “You know who’s going to really benefit from this? The patients.”
If it happens, that benefit would be a long time coming—even if patients today are better off than they were a generation or two ago. Until the 1980s, hemophiliacs who bled were rushed to the hospital and infused with a concentrated form of the “clotting factor,” or protein, that their bodies don’t produce: Factor VIII, for patients with hemophilia A, and Factor IX for those with hemophilia B.
Hospital stays could last for weeks or months if the bleed was severe, and patients understandably were overly cautious.
Worse, the infused factors came from donated blood samples and sometimes left hemophiliacs infected with HIV or hepatitis C.
The first breakthrough came when scientists genetically cloned Factor IX in 1982, and Factor VIII two years later. This led to the development of recombinant, or genetically engineered factors. The first was a Factor VIII product called Recombinate, from Baxter, approved by the FDA in 1992. These drugs completely changed hemophilia treatment. Not only did they end the risk of contaminated blood, they also paved the way for preventative treatment.
“Now you have teenagers [who] don’t remember ever having a bleed,” says Katherine High, the president and chief scientific officer of Spark Therapeutics (NASDAQ: ONCE), the former director of the Center for Cellular and Molecular Therapeutics at the Children’s Hospital in Philadelphia, and a world-renowned hematologist.
For the roughly 20,000 patients with hemophilia A in the U.S., and the 3,000 or so with hemophilia B, it’s become a chronic, manageable condition, albeit still stressful and expensive to treat.
About 60 percent of the hemophilia population has severe disease, according to the National Hemophilia Foundation. They have less than 1 percent of the necessary clotting factor in their blood, and so they have more bleeds and need bi- or tri-weekly infusions. Milder cases bleed and need treatment less often.
A few companies are working on incremental improvements to the protein replacement drugs, with versions meant to be used once a week or less, or that aim to help patients whose immune systems won’t let them take current therapies. Alnylam Pharmaceuticals (NASDAQ: ALNY) is developing an RNA interference drug meant to be used even less often.
Beyond those improvements, gene therapy is shooting for long lasting solutions, perhaps even “one shot” cures. That’s the goal for many gene therapies, of course, not just in hemophilia. But the fact that even 30 years ago, hemophilia seemed to be the perfect application for gene therapy—and is still years away—speaks volumes about how hard the technology has been to harness.
For a long time, gene therapy seemed like science fiction. Microscopic viruses you’d think are dangerous are genetically engineered and used as little delivery vehicles, or “vectors.” Those vehicles are then packed with specific genetic instructions: go to this location and produce this protein. Or even, go to this stem cell and change its DNA, so every little baby cell that comes out afterward carries these genetic instructions too.
The promise is enormous. Find a disease you understand genetically—say, one known to be caused by a single faulty or missing gene—and engineer a long-lasting fix. Dozens of startups burst onto the scene in the 1990s, but they soon ran into technical challenges, especially around the viral delivery vehicles.
“It took time to figure out which vector systems are either the most easily used, or easy to make, or safest,” says Barrie Carter, the vice president who oversees gene therapy at BioMarin Pharmaceutical (NASDAQ: BMRN).
This was true in hemophilia, too. The disease has always been an ideal target for a gene therapy for a number of reasons. It’s monogenic (caused by a single mutation). It’s recessive (to fix it, a gene has to be added, rather than knocked out). And restoring only a little expression—some 5 percent of a normal person’s level of Factor VIII or IX—has a dramatic effect.
All those effects are easy to measure with a simple blood test. Along with cystic fibrosis, hemophilia was one of the first diseases tested with gene therapy. It was so ideal, in fact, that the pressure to use gene therapy became enormous. As The Scientist wrote back in 1999, “If gene therapy doesn’t work in hemophilia models, in what disease model will it work?”
In the late ’90s, the first wave of hemophilia gene therapy trials were beginning. High led one of the groups involved; she collaborated with an Alameda, CA-based gene therapy startup, Avigen.
High and her colleagues hadn’t focused on any specific technology. For viral vectors, “I tried everything,” says High, including retroviruses and adenoviruses, which are now largely antiquated delivery vectors due to safety and other problems.
According to Wilson, retrovirus wasn’t useful for hemophilia. It wouldn’t get into the liver, the body’s clotting factor production plant. And adenovirus, while adept at targeting liver cells and expressing genes there, wouldn’t produce a lasting effect. Worse, it threatened to set off a potentially dangerous immune response.
That threat became reality in 1999, when an 18-year-old Arizona teenager named Jesse Gelsinger became sick and died in a trial co-led by Wilson at UPenn. Gelsinger had a rare genetic disease of the liver called ornithine transcarbamylase deficiency, typically associated with infants, but he wasn’t sick. His condition was controlled with a restrictive diet and several drugs. The trial was to test the safety of a gene therapy that might ultimately benefit sick babies, and as the New York Times wrote in 1999, Gelsinger had volunteered knowing he wouldn’t benefit. But he paid the ultimate price. The gene therapy, delivered via adenovirus, triggered a wild immune system attack. He became jaundiced, suffered massive blood clots, and several organs failed. He died four days after treatment.
Wilson was soon at the center of a public and legal maelstrom. The FDA launched an investigation and suspended the trial, and later, the rest of UPenn’s gene therapy studies. Wilson became mired in lawsuits. Questions emerged about data that the investigators hadn’t initially reported from their research, including the fact that some monkeys were killed by these gene therapies in early testing. Wilson was also under fire for his ties to Genovo, the biotech that was funding much of UPenn’s gene therapy work (but not the Gelsinger study). Wilson founded Genovo in 1992, and both he and UPenn had an equity stake in the company.
“I was highly criticized, and under attack,” Wilson says. (Many years later, Wilson would write an editorial recounting the mistakes made, and lessons learned from the study, in Molecular Genetics and Metabolism.)
The damage reverberated through gene therapy, and companies in the field went into damage-control mode. Carter remembers how his former employer, Seattle’s Targeted Genetics, wrote a press release just to remind folks that it wasn’t using adenovirus. It got worse: Investors became skittish, the dot-com bubble popped, a slew of gene therapy startups crashed. In what seemed like a final blow to the field, four children in a French gene therapy study who were initially cured of a rare immune disorder later developed leukemia. One of them died in 2003.
Yet the maelstrom drowned out the fact that important progress was being made. A tool that’s become gene therapy’s most commonly used vector, the so-called “adeno-associated virus,” or AAV, was showing promise.
“This was the game changer,” Wilson says of AAV.
The name itself is a misnomer. AAV has nothing to do with adenovirus; its name came from scientists who discovered it on adenovirus lab preparations in the 1960s. It was smaller than adenovirus, and had no known role in any disease. Scientists made the first AAV vectors in 1984; the first AAV clinical trials, in cystic fibrosis, came in 1994 (run by Targeted Genetics). The first hemophilia trials came five years later, run by Avigen and High’s group at the CHOP.
While nearly all for-profit activity in gene therapy ground to a halt after the bubble crash and trial deaths, High, Wilson, and others not only kept the field afloat, but helped make the advances that have led to the current hemophilia race.
Wilson’s path forward took a particularly odd turn. Shaken up and in no position to compete for NIH grant money after the Gelsinger fiasco, he went to an old mentor, Tachi Yamada, then the chief scientific officer of SmithKline-Beecham (now GlaxoSmithKline).
Wilson wanted counsel, but he got more. “He said ‘I believe in you. I think you can do it. So how much money do you need?’” Wilson recalls. “I said ‘What do you mean?’ He said: [SmithKline-Beecham] would love to fund you in this endeavor.’”
Wilson asked for $3 million to $4 million a year, Yamada made a phone call, and that was that. No grant application, no competition, no angst. Wilson got about $40 million from the big British drug maker over the next several years and went “subterranean.” He eschewed scientific lectures, he stayed away from awards banquets, and he avoided the press. “It was all about doing science,” he says.
High had her own brush with disaster. In the Avigen hemophilia study, a patient given an AAV gene therapy produced Factor IX for four weeks but then lost it, and enzymes in his liver spiked, which in some cases can mean inflammation or damage to the liver. In a post-Gelsinger world, with so many unknowns about gene therapy technology, that was particularly scary. Worse, High hadn’t seen this in animal studies; she was at a loss. “We didn’t know what was happening,” she says. “I still remember that as one of the most challenging times of my career. There was nobody to ask, no animal data to fall back on.”
The patient was being treated in Australia. High could only listen helplessly as reports came in twice a week. Slowly, to her relief, the patient’s liver function normalized, and he was never in mortal danger. But the FDA, on high alert after the Gelsinger case, put the trial on hold. When the trial resumed, it happened again to another patient.
Neither case was fatal, but Avigen had had enough and pulled out of gene therapy altogether.
That was a big problem: Avigen was making High’s vectors. So she went to CHOP CEO Steven Altschuler and pleaded for the hospital to set up, in-house, a clinical grade manufacturing facility. The decision wasn’t easy; the Gelsinger case was in litigation, and the sentiment around gene therapy was understandably negative. But High was adamant these problems could be solved. “I know a showstopper if I see one; there’s not a showstopper here,” she recalls telling Altschuler. “It’s always been my belief that if you can transplant an organ, you can transplant a gene.”
After a few days of thought, Altschuler sided with High, on one condition: she had to work on other genetic diseases too, not just hemophilia. The CHOP not only built manufacturing, it created an entire center for gene therapy. High recruited folks from Avigen, and one of them, Fraser Wright (now Spark’s chief technology officer), applied for and won an NIH contract to be the only federally-funded AAV manufacturing facility in the country.
“They had to basically build their own infrastructure to be able to manufacture and run their own clinical studies,” says Ken Mills, a former diagnostics executive who co-founded RegenX with Wilson (and through RegenX has also invested in Dimension Therapeutics).
The CHOP work led to a breakthrough for the problem that shut down the Avigen trial. Because most people have been infected at one point or another with the AAV variant High was using, the immune system recognized it, attacked it, and shut it down. That’s why enzymes in these patients’ livers were spiking. High began thinking of ways to combat this problem, like using steroids to stifle the immune response.
“Sometimes the way that I feel about my career is that I just keep walking along a list of problems, working my way to the end, and then starting back over again getting more refined solutions,” says High with a chuckle.
She also found a home for that variant—called AAV2—as a treatment for a childhood blindness called inherited retinal dystrophy. There was a sweet spot in the back of the eye, where the immune system couldn’t wash it out, and it only needed to have a small effect in a tiny area. That program, now known as SPK-RPE65—it inserts a healthy version of the RPE65 gene—led to the creation of Spark.
“That caused people to stand up and say, ‘Gee, these vectors can really do something that is clinically important,’” says BioMarin’s Carter.
With its SmithKline-Beecham funding, meanwhile, Wilson’s group stayed together and focused on finding better AAV vectors. “We became virus hunters,” he says, isolating AAVs from “whatever source we could”—monkeys, apes, humans—and screening them for differences.
They found about 150 variations, which would be named AAV7, 8, 9, and so on, and started turning them into vectors. (Wilson and Mills would later cut a deal with GSK for an exclusive license to these vectors to form RegenX.)
This flurry of vector work in Wilson’s lab is also part of the hemophilia story. One of Wilson’s post-docs, Lili Wang, had been studying hemophilia B using AAV2 in dogs, but the levels of Factor IX it produced were too low. Wang then tried one of the new variations, AAV8, in the same dogs, and the results were “20 fold higher,” says Wilson.
AAV8 also wasn’t as prevalent in humans as AAV2; perhaps it wouldn’t trigger immune system alarms. Wang and Wilson co-authored a 2005 paper in the journal Blood to share the results.
During this time, Wilson encouraged academics to use these vectors for their own research. High was one of them. Another was a group split between St. Jude Children’s Research Hospital in Memphis, TN, and University College London who were intrigued by the UPenn dog study and wanted to try AAV8 for hemophilia in humans.
Wilson gave them access, and they ran a study with rousing results, which were published in the New England Journal of Medicine in 2011. The researchers—led by UCL’s Amit Nathwani—showed that an AAV8 gene therapy helped six patients with severe hemophilia B produce between 2 and 11 percent of normal levels of Factor IX. That might not seem like a big deal, but raising factor function to between 5 and 10 percent of normal turns a case of severe hemophilia into a mild one. “We believe that if you exceed 5 percent, you have a drug,” says UniQure’s (NASDAQ: QURE) CEO, Jorn Aldag.
As UniQure chief medical officer Christian Meyer says, such a seemingly small improvement could “eliminate” the risk of a spontaneous bleed. (UniQure licensed a genetic tool used in the St. Jude’s/UCL study for its own work.)
Four of the six patients in the study had been suffering from some 20 bleeding events per year before the treatment. The therapy ended those spontaneous bleeds and had lasted as long as 16 months at the time the study was published.
The results weren’t perfect, however. The therapies have now lasted as long as four years, but more than half the patients in the study have had to take a short course of the steroid prednisolone to fend off the type of immune response High first saw more than 10 years ago.
Still, the NEJM paper proved a gene therapy could get patients to “clinically important” levels of Factor IX through a simple injection into a peripheral vein, as Carter says. Mills remembers getting a number of phone calls, from investors and large pharma companies, trying to find the source of the data and where the technology came from.
“It was a huge turning point for the field,” Mills says.
Indeed, the race for AAV rights began. Here’s how all the entrants found their niche:
—Baxter is using AAV8 for hemophilia, which it acquired by purchasing Chatham Therapeutics. Chatham had licensed AAV8 from GSK/RegenX.
—Spark is making its own AAV vectors in-house but won’t discuss details. It’s working with Pfizer on a treatment for hemophilia B.
—Dimension was formed by Fidelity Biosciences and RegenX in October 2013; the startup has a license to RegenX’s AAV vectors, and is teaming with Bayer on a gene therapy for hemophilia A.
—BioMarin licensed a hemophilia A program from St. Jude’s/UCL in February 2013.
The differences between these groups are very technical. Take vectors, for instance. UniQure is using AAV5, and its CMO Meyer contends it should stay in the body making protein for a long time because it’s less likely than AAV8 to provoke an immune response.
Then there are the genes. Some companies, like Baxter and Spark, are using mutant therapeutic genes that clot blood 8 to 12 times more strongly than normal. The original version was discovered in a young Italian man from the city of Padua. The proposed advantage: Patients can get a therapeutic effect with a smaller dose.
Others, like UniQure, BioMarin, and Dimension, are using genes that produce a normal amount of clotting factor. The proposed advantage: The results should be more predictable.
All of these arguments about the different AAV gene therapies for hemophilia are theoretical until they’re tested in people. There are many questions to answer: How durable will they be? If they wear off, would the body’s defense systems prevent a follow-up dose from working? How much factor expression is actually needed? Can they completely cure hemophilia, or just make it less severe? Will any safety issues crop up?
The door is open for other approaches. For example, one potential limitation is that AAVs might not last long in young children. As their livers grow, the AAV-modified cells might get washed out. This is an argument made by two companies using lentiviral vectors (Biogen (NASDAQ: BIIB)) and gene editing methods (Sangamo Biosciences (NASDAQ: SGMO), via a deal with Shire) for the disease. Both methods aim to create permanent fixes by passing genetic changes on to other cells. An AAV, by comparison, does its work as long as the cell it’s in stays alive.
“We think AAV vectors for gene therapy won’t provide persistent expression levels,” says Sangamo chief scientific officer Philip Gregory. “We can offer the ability to extend that long lasting [fix] right into patients who need it the most: newborns and small kids.”
Olivier Danos, Biogen’s head of gene therapy, said similar things a few months ago. Neither Sangamo nor Biogen has any human clinical data as of yet. The only glimpse from any of the competitors, so far, has come from Baxter, which last month produced its first human data—and just a very small sliver.
Here’s a summary of those data, according to Baxter R&D chief John Orloff.
—Six patients have been treated. The two at the highest two doses produced Factor IX levels of 20 percent (after five months) and 10 percent (after eight to 10 weeks). The patient at 10 percent, however, initially hit 25 percent of normal production before his liver enzymes spiked. Baxter responded with immunosuppressive steroids.
—The other four patients were treated more than a year ago at lower doses and have had “low expression,” according to Orloff. He declined to elaborate.
—Patients have been starting out with high factor expression before those levels drop and stabilize.
—All 16 patients in the study should be dosed this year; more data are coming in June.
“It’s a small cohort obviously, we have more patients to treat, so the jury is still out,” Orloff says. “But the early data would suggest that we are seeing higher expression levels than what’s been previously reported.”
The St. Jude/UCL group, by comparison, published an update to their study in November showing that a total of 10 patients have maintained factor IX levels of between 1 and 6 percent over a median of 3.2 years after therapy. In dogs, positive effects have lasted a decade. The companies using AAV vectors for hemophilia view this as proof that they can produce a lasting, meaningful effect in humans. And more data are coming. UniQure has already started its first trial. BioMarin, Dimension, Spark, and Sangamo all could follow with their first studies this year as well. (Biogen is farther behind.)
But everyone acknowledges that there’s no telling when the therapeutic effects will wane, or if gene therapy in this field has really gotten over the hump.
“That’s one of the big questions that will have to be answered,” UniQure’s Meyer says of the staying power of an AAV gene therapy.
Haugstad takes that question very seriously. She worries that children with severe hemophilia will get a glimpse of life without needles, only to have it taken away.
“Maybe little Jimmy is 10 years old, he gets a shot, he’s good for 4 years, now he’s 14, and really is active normal young man—and [all of a sudden] he’s got severe hemophilia again,” she says. “What happens? How would we handle the psychosocial impact to families?”
It shows, despite all the progress that’s been made, just how far gene therapy still must go to get past one of its oldest nemeses. And that has Wilson, approaching his 60th birthday, feeling a bit reflective these days.
“I tell my wife that my career is starting at 60. That the field of gene therapy is now born. That it’s the beginning, it’s not the end,” Wilson says. “She said, ‘Well then, what have you been doing for 35 years?’”
His response: “Trying to figure it out!”
By posting a comment, you agree to our terms and conditions.