Gene Therapy

The bleeding doesn't show right away. A couple days pass before the skin puffs and the bruises form. But the people who have this disease recognize its early symptoms. A familiar warmth builds in the ankles, knees, hips or wrists, then flares into sharp, sometimes pulsating bursts of pain. For Ryan Hallock, the telltale sign was not being able to move the afflicted joint normally. "It's kind of like getting a hug from a significant other," he said. "You just know what it feels like."

Hallock has a severe form of hemophilia, a rare, inherited disorder that causes excessive bleeding, often from the most innocuous activities. Hallock would get bleeds if he slept on his arm wrong or hit an odd stride while walking. As a teenager, he started taking medication to manage the disease, but hasn't needed any for a while. Before, Hallock would have two to three minor bleeds each year. Since receiving an experimental gene therapy five years ago, the 27-year-old nurse said he's had none.

In late August, the Food and Drug Administration was expected to approve, for the first time, a gene therapy for hemophilia. After decades of unfulfilled hopes, the gene therapy called Roctavian could have finally delivered the closest thing yet to a permanent fix for one of the earliest identified genetic diseases.

But in a shocking move, the agency rejected Roctavian and asked its developer, BioMarin Pharmaceutical, for more evidence that it provides a long-lasting effect on bleeding rates.

An approval could have been transformational not only for certain patients, but for BioMarin too. Roctavian is a billion-dollar product by some Wall Street estimates, the kind of an asset that could lift up BioMarin, which hasn't been profitable in 21 of its 23 years in business. Now, the Californian biotech likely won't be able to sell its therapy until mid- to late-2022, at the earliest.

Roctavian is not the same gene therapy that was given to Hallock, who has the less common, hemophilia B form of the disease. Rather, it's specifically designed to treat hemophilia A. Clinical studies of Roctavian and other gene therapies have shown these one-time infusions allow some people to go years without reaching for the anti-bleeding treatments they were using every few days.

The chance at a yearslong, maybe even lifelong treatment for hemophilia has doctors and patients excited. Yet, even before Roctavian's upset, their hope also came with a fear that this big leap forward would leave many patients behind, either because their bodies or the healthcare system won't take to gene therapy.

The stakes are higher still, given that Roctavian was poised to be the most expensive drug ever. Should it come to market, and patients who do get treated don't perform as well as expected, a difficult precedent could be set for the next generation of gene therapies to overcome.

"Gene therapy is the future," said Len Valentino, CEO of the patient advocacy group National Hemophilia Foundation. "The worst thing that could happen is we lose the opportunity to develop gene therapy products because people don't believe in them anymore."

A promising target

Broadly speaking, gene therapy tries to fix disease-causing defects in a person's DNA by introducing new, helpful genetic material. As the technology gained legs in the late 1980s, researchers looked for illnesses where it could make a difference. Hemophilia, which affects an estimated 20,000 people in the U.S., rose to the top of the list.

The disorder's genetic links were well established. Mutations in one of the sex chromosomes left the body without proteins critical for clotting blood. The missing protein in hemophilia A is called Factor VIII, while in hemophilia B it's called Factor IX. In both types, patients need only generate small amounts of these proteins to live fairly normal lives, which sets up a manageable goal for gene therapy developers.

Hemophilia patients also desperately needed more treatment options. Blood transfusions had become a staple of care, but inadequate screening measures led to a contamination crisis in the early 1980s that resulted in thousands of patients contracting HIV or hepatitis C.

In spite of the early interest, a series of high-profile setbacks near the turn of the century grounded the field of gene therapy research. Only in the last decade, as scientists came to better understand the technology and how our bodies react to it, has confidence returned.

By 2012, Spark Therapeutics, a company spun out of the Children's Hospital of Philadelphia, had begun human testing of a precursor hemophilia B gene therapy to the one that Hallock would later get. Another, from the Netherlands-based biotech UniQure, emerged soon after.

Hemophilia A gene therapies from Spark, BioMarin and Sangamo Therapeutics followed suit, with BioMarin ultimately taking the lead position. Roctavian was the first of the field to reach regulators, making the FDA's rejection of it consequential both for BioMarin and for gene therapy's role in treating hemophilia.

Roctavian's approval chances rested on two clinical trials of patients with severe hemophilia A, defined as having less than 1% the normal amount of clotting protein.

The smaller, earlier trial found treatment nearly eliminated bleeds in the 13 patients given higher doses of the therapy, a benefit that has persisted through several years of follow-up. Within months of infusion, clotting protein rose to levels almost as high as people without hemophilia. That was much more than the 5% of normal that researchers initially hoped to see, according to lead investigator John Pasi.

"To be honest, we thought that was hugely optimistic," said Pasi, who also directs the hemophilia center at The Royal London Hospital. "We ended up with results that knocked the ball right out of the park, and that has had a huge impact on changing people's perceptions of what gene therapy can deliver."

BioMarin was then able to replicate those promising results in a larger study. A preliminary analysis showed similarly sharp reductions in bleeding rates, factor use and a rise in protein activity.

Longer follow-up, however, has also eroded some enthusiasm. Updates last May and in June showed Roctavian's effect appeared to wane over time, although protein levels were still much higher four years after treatment compared to when patients started. Additionally, the updates measured less protein activity from the high dose of Roctavian than what was seen in earlier testing.

According to BioMarin, the FDA wants to see two years of follow-up data from all patients in the larger study before it gives the greenlight to Roctavian, a task that can't be completed until November 2021. CEO Jean-Jacques Bienaime said agency staff had "never, ever discussed" such a requirement in "any meetings we had with them." Bienaime said he suspects the differences in protein activity seen between the smaller and larger studies are what pushed to FDA want more data on durability.

The agency's apprehension may also have to do with the fact that Roctavian probably can't be given a second time, so if its effects diminish, patients may have to either wait for a different gene therapy to come along or go back on older treatments.

"The reward is quite high if they're successful, but patients really need to understand all of these issues before going into it and not think it's a one-and-done approach," said Robert Sidonio, a pediatric hematologist at Children's Healthcare of Atlanta. Sidonio has consulted for both BioMarin and Spark.

Not for everyone

Researchers were already planning to follow Roctavian-treated patients for years to provide continual updates on safety and durability. Ahead of the FDA's surprise decision, the therapy was generally viewed as long-lasting but not necessarily curative — a disappointment to some, though still an attractive option for those who've grown tired planning their lives around multiple weekly infusions.

Hallock, for example, said that since receiving Spark's drug, it's been a relief to go on hikes with friends or short trips with his wife and daughter without doing the math on how long beforehand he should infuse. Not having to keep needles around the house, or deal with getting his replacement factor treatment through airport security, are a few more perks he's noticed.

"I think most patients would consider that to be worth it," said Courtney Lawrence, an assistant professor of pediatric hematology at Johns Hopkins Children's Center.

Others aren't so sure. Valentino expects that, excitement aside, many patients will be slow to choose gene therapy because of the uncertainties surrounding its long-term effects.

Gene therapy is also irreversible, something that Michelle Rice, who has mild hemophilia, has seen weigh on her two adult sons as they consider whether it's the right treatment for their severe disease.

"This is a community that doesn't necessarily jump at the next bright, shiny thing," said Rice, who works alongside Valentino as the head of external affairs at NHF. "Gene therapy is kind of a bell that you can't unring. It's a big commitment. So the decision becomes much, much harder."

And in some cases, patients don't get much choice. The pivotal studies of Roctavian didn't enroll patients with HIV infections, active hepatitis infections or "inhibitors," a phenomenon in which the body develops antibodies to attack replacement factor protein.

It's unclear whether these patients, who typically are at greater risk of health complications, will be cleared to receive Roctavian if it comes to market. BioMarin had expected an approval from the FDA to cover about 2,400 patients with hemophilia A in the U.S., a minority of the total population.

Another type of antibody will further limit who's eligible for hemophilia gene therapy. For these treatments to work, they must get the genetic instructions for making factor protein into cells. Most accomplish that by using certain viruses like a shipping service. This group of "adeno-associated viruses," or AAVs, have been shown to safely deliver genetic cargo.

Yet, like with most viruses, the immune system sometimes sees AAVs as invaders and deploys antibodies to stop the threat. If present, these antibodies will not only neutralize the gene therapy in question, but every other gene therapy that uses the same viral vehicle.

The problem is made worse by the fact drugmakers pull from a small crop of about a dozen AAVs. Roctavian uses genetically engineered AAV5, as does UniQure's hemophilia B gene therapy. Patients therefore don't need many types of antibodies before they're ineligible for the bulk of gene therapies now in development.

As such, hemophilia doctors worry a substantial portion of patients can't receive gene therapy because they already have antibodies. A presentation BioMarin made in January cited estimates that about 20% of patients in the U.S, and 30% globally, would be ineligible for Roctavin for this reason.

"To have expression and then lose it five to six weeks later. That will be very difficult, I think, for a patient to accept," Sidonio said.

Insurers on the fence

Insurance companies will also be hard pressed to accept such an outcome, as the starting price for Roctavian looked likely to fall within the $2 million to $3 million range. While insurers now have more time to figure out payment methods, they may still try to limit risk by restricting access to gene therapy to just the patients who have the most severe disease or whose bleeding isn't controlled with currently available options.

"That's what we're worried about," Sidonio said, "having to bleed into your next therapy."

Gene therapy does, however, offer certain advantages that incentivize insurers to cover it. A one-time treatment that can keep clotting protein levels up for an extended period of time may save the healthcare system money, since replacement factor and other hemophilia drugs often cost hundreds of thousands of dollars per year. Hemlibra is one of the newer drug options, and has grown popular because it can be taken as infrequently as once a month. It comes at an annual list price of about $450,000.

These offsets have helped gene therapies for other rare diseases secure coverage. The Zolgensma gene therapy, approved last year to treat spinal muscular atrophy, has overcome insurance barriers despite carrying a list price of $2.1 million. Until Zolgensma came along, the only treatment option was a drug priced at $750,000 for the first year of treatment and $350,000 each year thereafter.

"Even a gene therapy that comes in at a couple million dollars, presuming durability, can be worthwhile financially speaking," said Michael Sherman, chief medical officer at Harvard Pilgrim, a New England insurer.

Still, hemophilia isn't like other rare diseases. It affects more patients than what's typical for a gene therapy target, meaning insurers that didn't have a patient eligible for Zolgensma likely can't say the same for Roctavian. If enough patients qualify for and are interested in BioMarin's drug, that would present a budget challenge for payers.

Hemophilia also has north of a dozen treatments approved by the FDA, with a new slate of long-lasting options inching closer to market. This abundance puts added pressure on BioMarin and the other leading gene therapy developers to set prices that won't surprise insurers.

"We're all excited about this for the sake of the patients," Sherman said. "But if the pricing were to be egregious, there is the option to wait for the next gene therapy or to keep people on traditional hemophilia drugs."

Cure is a big word

Hallock has several things in common with Eric Burgeson. Both are in their late 20s, living with severe forms of hemophilia. They found replacement factor mostly kept their diseases in check, allowing them to go about day-to-day activities like work or exercise without much issue.

But a key difference is Burgeson, a program coordinator at the Hemophilia Federation of America, has not gone through gene therapy.

Burgeson said he trusts the technology and understands its appeal. Yet he's always been a "slow adopter" of new treatments — hence why he's taken the same kind his entire life. Though there are times when his medication seems less effective, Burgeson said it's hard to shake the fear that switching to something else could open the door to bigger complications, such as inhibitors developing or insurers denying coverage.

These fears run deep in the hemophilia community. BioMarin, if it eventually gets the FDA's stamp of approval, will try to ease them with a successful launch of Roctavian, but that could be tough on several fronts. For example, of the 150 or so hemophilia treatment centers in the U.S., relatively few participated in the clinical trials of Roctavian. Getting the others up to speed on how to administer the therapy presents challenges that are made more daunting by the current pandemic.

"There isn't going to be a reason why someone has to come in right away to do this," said Sidonio, who foresees Roctavian being a niche product used in less than 5% of eligible patients.

Burgeson, too, expects uptake to be slow, with many taking a wait-and-see approach to Roctavian and gene therapy more broadly.

"Gene therapy seems to be this golden hope," he said. "But for something that severe, to just dip your toes in it? I don't see anywhere near the majority of the population being on this for the first decade of its availability."

Of course, some patients will still seek out Roctavian.

For those who do, doctors and patient groups say it's critical to set appropriate expectations. Gene therapy won't work for everyone. Patients might only get one shot at it. And it may not have the lifetime effect with which it's become synonymous.

"If it were me — and my oldest son has talked to me about this — I would always be waiting for when it's going to stop working," Rice from the NHF said. "And that sounds like I'm not a fan of gene therapy. I absolutely want to see gene therapy come to fruition. I just want to make sure that people understand what it is and what it isn't."

"Cure, to me, is a really big word."

Article top image credit: Danielle Ternes/BioPharma Dive

A landmark regulatory approval vaulted the cell and gene therapy space to the front of the drug industry's mind. But speedy progress has also brought forward significant challenges.

Novartis' Zolgensma, approved for infants with spinal muscular atrophy, is a remarkable advancement for a disease that in its most severe form is fatal before age two. In clinical tests, almost all babies given the therapy remained alive and off permanent breathing support.

"The issue is really how do you cover Zolgensma, not how you say no to it," said Michael Sherman, the chief medical officer for Harvard Pilgrim Health Care, in an interview with BioPharma Dive last year. A similar logic applies to Spark Therapeutics' Luxturna, a gene therapy approved in the U.S. in December 2017 to treat a rare form of blindness.

Novartis' Zolgensma and Spark's Luxturna are just the first in what's expected to be a wave of experimental gene therapies to make it to market. The Food and Drug Administration foresees approving 10 to 20 cell and gene therapy products each year by 2025.

Not all of those products, though, are guaranteed to have the compelling efficacy that make Luxturna and Zolgensma relatively easy choices for insurers to cover.

The next critical test of the gene therapy era will likely come in hemophilia. Multiple companies are racing to market with candidates for hemophilia A, with BioMarin Pharmaceutical the furthest along. The company's surprise setback in August delays the arrival of a hemophilia gene therapy, perhaps by years, but hopes remain high one will emerge in the near future.

"Hemophilia A is going to force the problem [with payers] to be solved," said Sandy Macrae, CEO of Sangamo Therapeutics, which is developing a rival gene therapy to BioMarin's.

"If it's SMA, it's a few dreadfully impacted children," he said. "No one's going to stand in the way of that, and they're just going to make it available. If it's hemophilia A, there are alternatives."

Payer pains in adapting to the new era

Novartis priced Zolgensma at $2.1 million, making it the most expensive drug ever brought to market.

The Swiss pharma intends for that cost to be spread over multi-year payment plans, the result of lengthy discussions with payers.

New England-based Harvard Pilgrim Health Care, for instance, began talks on Zolgensma more than a year ago, before Novartis bought the therapy's original developer, AveXis.

Still, the payment plan is less substantive than both sides had hoped for, Sherman said, reflecting limits within the U.S. healthcare system in paying for these one-time treatments.

Medicaid "best price" regulations enacted over 25 years ago require that state Medicaid agencies receive statutory discounts, either at a fixed rate or, if greater, matching what drugmakers provide elsewhere. That's proved a roadblock in constructing outcomes-based or annuity-based agreements with payers.

"I want to stress that the issue wasn't Novartis' lack of willingness to participate," Sherman said. "It was the best pricing regulations that have been the largest challenge."

"As someone who is trying to operationalize this on the front lines," he added, "the Medicaid best price restriction is the largest barrier to some of the innovative kind of agreements that both the pharma companies and myself would like to engage in."

Sherman said he's had similar talks with other gene therapy developers, including BioMarin, Spark, Sarepta Therapeutics and Bluebird bio that have all been predicated on that barrier being removed.

In hemophilia, Sherman noted that having existing treatments gives insurers the ability to say no, and uncertainty over the durability of gene therapy's benefits makes outcomes-based agreements even more critical.

Recent three-year data from BioMarin, for example, appeared to show a continued drop in clotting factor expression, albeit to levels considered "mild" hemophilia.

Gene therapy's rapid emergence may bump up against other limits, too.

Most treatments now being developed use inactivated viral vectors, such as adeno-associated viruses or lentiviruses, to deliver corrected genes. Those vectors can concentrate in the liver, potentially narrowing the universe of readily targetable diseases that also carry commercial appeal, Sangamo's CEO predicted.

"I think in the next three to five years, gene therapy will have mined all of the liver diseases that are liver-centric and really saturate that space," Macrae said.

Peter Marks, the director of the FDA's Center for Biologics Evaluation and Research, noted gene therapy will face additional challenges in addressing diseases spurred by multiple genes rather than the single gene defects that treatments like Luxturna and Zolgensma target.

"The challenge for gene therapies in areas where we don't understand the pathophysiology is that becomes a much larger development program, much more expensive," Marks said in an interview at BIO last year. "You lose the benefit you normally get with gene therapy, which is that you have a high probability of success if you're dealing with a single-gene disorder."

Regulatory review for the cell and gene therapies brought forward has so far heavily focused on what's known as chemistry, manufacturing, and controls — the details of how a therapy is made. Less focus has been on the clinical questions of how the treatment works, since single gene defects cause clearly identifiable deficiencies.

That's made interpreting clinical results from these first gene therapies like Zolgensma pretty simple.

"How many kids do you need to see that would be floppy babies on ventilators that instead are walking around at age three?" Marks said. "You don't need tons of those, and you don't need sophisticated statistics, patient-focused outcomes, because they're normal. You go from very abnormal to normal."

More uncertain mechanisms of action would add back in the "biological" risk of many current experimental drugs, which are often supported by hazy notions of how they work.

"The worry is that you're going to devolve back to conventional drug development, where clinical data will actually be important, because you'll have to figure out 'Is that actually really working' and 'Is it working over the long term?'" Marks said.

FDA keeping pace, with caution

Even as gene therapy companies bolt ahead, the head of CBER remains cautious of leading the agency too far forward in "leaps of faith with using preclinical data."

While recent years have been marked with success, gene therapy's history has its share of setbacks.

"We don't want to have another Jesse Gelsinger," Marks said, referring to the U.S. teenager who died in 1999 after being treated with an experimental gene therapy. "We don't want to go backwards."

"The good news is people have more understanding now for this, but if you look at what happened with some of the Phase 1 trials that went bad in Europe, it doesn't take much to get people to really pull back," he added.

Caution, though, is balanced against the FDA's interest in promoting gene therapy development, even when it's for just a few patients.

The regulator is considering new ideas for regulatory review of so-called bespoke, or extremely personalized therapies, Marks said. If there's a level of similarity, the FDA is looking for ways to streamline oversight so each tiny tweak won't require a different drug application.

"If you treated those each as individual drugs, people are never going to get the therapies because you can't expect anyone to put in the effort," he said. "And so you'll never have any business venture going after making these."

"We want to be forward-leaning," Marks added, but "we don't want to be cavalier and create problems."

Article top image credit: Getty / Edited by BioPharma Dive

The Food and Drug Administration in January finalized a slate of policies for the development and assessment of gene therapies, clarifying its views as it prepares for a coming surge of new treatments in diseases like hemophilia, beta-thalassemia and muscular dystrophy.

By 2025, the FDA expects it will be reviewing and approving between 10 and 20 cell and gene therapies each year. Guidance documents like the seven issued in January give drugmakers a clearer sense of how the agency will respond.

Unlike traditional small molecule drugs or biologics, gene therapies are designed to be one-time fixes for inherited genetic defects, raising critical questions about how companies should measure the durability of a treatment's benefit. The FDA acknowledged this uncertainty in its documents, emphasizing the need for long-term follow-up to complement the information drugmakers provide via pre-market testing.

FDA approvals for Roche's blindness therapy and Novartis' muscular atrophy treatment were landmark moments for the gene therapy field, showing what's possible through gene-based medicine.

The next several years look set to feature many more milestones, with nearly 1,000 gene therapy studies currently underway and some half dozen treatments advancing quickly toward regulatory review.

"These therapies, once only conceptual, are rapidly becoming a therapeutic reality," FDA Commissioner Stephen Hahn, who was sworn in as agency chief last month, said in a statement.

The guidance documents were expected, as the agency had previously issued draft versions of six and signaled in July 2019 that finalized forms would be forthcoming.

In addition, regulators issued a draft guidance on how they plan to determine whether gene therapy products qualify as orphan drugs, and whether a new product should receive the corresponding seven years of market exclusivity.

It's an important point, as the advancing wave of research will likely bring forward competing medicines that offer patients the possibility of one-and-done treatment. Should an initial therapy secure a regulatory monopoly, subsequent drugs may arrive to a much reduced market.

In its document, the FDA said it would, when assessing two treatments, consider both the therapeutic gene and the inactivated virus used to deliver it.

A treatment relying on a different viral vector, for instance, would be considered by the FDA as a different product and eligible for orphan drug exclusivity.

Currently, two types of viral vectors are commonly used as the vehicle for delivering a gene therapy to its target cells: lentiviruses and adeno-associated viruses. Different serotypes exist of each. Thirteen different AAVs, for instance, have been isolated, although some are more popular among drugmakers than others.

The FDA said it would assess differences between vectors from the same viral family on a "case-by-case" basis.

The other five guidance documents, which are largely similar to their draft versions, cover manufacturing, testing and long-term follow-up, as well as specific considerations for therapies for hemophilia, retinal disorders and rare diseases.

Long-term follow-up is a particular concern for the FDA, which wants to ensure that no safety risks crop up in gene therapy patients over time.

"The clinical review of these products frequently poses more challenging questions to regulators than reviews of more conventional drugs, such as questions about the durability of response." the FDA said.

"For some gene therapy products, therefore, although they have met the FDA's standards for approval, we may need to accept some level of uncertainty around questions of the duration of the response at the time of marketing authorization."

Article top image credit: Jacob Bell

The Food and Drug Administration cleared the first two gene therapies for inherited diseases in short order, with just a year and a half separating historic approvals for the blindness treatment Luxturna and the spinal muscular atrophy drug Zolgensma.

Since the May 2019 OK for Zolgensma, however, another year and a half has now passed without an addition to the ranks of approved gene therapies, despite a broad and growing pipeline. A recent spate of regulatory setbacks, including a surprise rejection for BioMarin Pharmaceutical's hemophilia treatment Roctavian, have spurred questions about whether the agency is enforcing a tougher line on new candidates.

One sign of increasing scrutiny is delays involving cell and gene therapy manufacturing. Between September and early November, Sarepta Therapeutics, Voyager Therapeutics, Iovance Biotherapeutics and, most recently, Bluebird bio, were forced to reset development timelines as the FDA has requested more information about production processes.

"It's in part due to the general evolution of the field," said Timothy Cripe, hematology and oncology division chief at Nationwide Children's Hospital and an early stage gene therapy researcher. "The technology is improving and the methodology is improving for measuring purity and potency and genome copy numbers," he added, referring to assessments of manufacturing quality.

"This is increasing [the FDA's] bar a bit, as would naturally occur," Cripe said.

Manufacturing-related delays, however, have come in addition to clinical trial pauses for Solid Biosciences and Astellas Pharma's Audentes division due to safety concerns, most notably the death of three participants in a trial of an Audentes gene therapy.

"That also gives the agency pause. That gives us all pause. We're asking, 'Are we dosing the kids appropriately? Is dosing by kilogram appropriate?'" Cripe said.

FDA officials, for their part, say the delays and holds aren't related to any change in policy, but rather are a reflection of the agency's increasing workload as more gene therapies are tested in humans.

"I think what you're seeing is the increase in activity in the field," Wilson Bryan, director of FDA's Office of Tissues and Advanced Therapies, said in a session of the virtual Biopharma Congress held by the analyst group Prevision Policy.

"We have over 1,000 active [Investigational New Drug applications]," Bryan said. "As we get more and more active INDs more and more bad things are going to happen. What gets attention are the bad things."

That view is shared by Patricia Zettler, an associate law professor at Ohio State University and a former associate chief counsel at the FDA. "It's more likely that there just have been some bumps along the road," she said. "It would be more surprising if no gene therapies ever encountered those kinds of bumps in the road."

Some of the "bumps" may also be the product of gene therapies moving out of academic labs, where many of the ones furthest along were birthed, and into large-scale clinical or commercial production at big pharmaceutical companies. A data manipulation scandal over animal testing for Zolgensma, for example, was blamed on this type of handover.

Successful reviews of manufacturing data or sites, meanwhile, may not be the sort of event that companies disclose to their investors.

"If you're a company like BioMarin and you put out a press release that said, 'We had an FDA inspection and everything is fine,' investors would be calling up and asking what is wrong," said Jacob Sherkow, a University of Illinois professor who is an affiliate of the university's Carl R. Woese Institute for Genomic Biology.

Current setbacks aside, the two approvals and a review, albeit eventually rejected, of a third show an agency much more open to considering gene therapies than it was after safety scares two decades ago, most notably the death of teenager Jesse Gelsinger in a clinical trial. So too do new guidelines for developers and FDA officials' predictions of a near future with many more cell and gene therapies approved.

"[Gene therapy] was the third rail of FDA policies for a long time," Sherkow said. "They're a lot more open now. We have actual guidance about how to do this, how to do a clinical trial and what endpoints you should use."

Cripe, at Nationwide Children's, agreed the FDA's comfort with the risk-benefit balance of gene therapy has shifted. "With Zolgensma and with Luxturna and reports of successful trials in muscular dystrophy, the benefit part of that equation is becoming more clear," he said.

One variable potentially at play as more gene therapies go under FDA review is the relative urgency for approval when other therapies exist. Luxturna, for example, treats an otherwise incurable form of blindness, while, at the time of Zolgensma's approval for spinal muscular atrophy, only one alternative treatment existed for the disabling and often fatal neuromuscular disorder.

BioMarin's Roctavian, on the other hand, treats hemophilia A, a bleeding condition that while potentially severe has multiple treatments that can limit or prevent spontaneous bleeds in most patients.

Treatment availability could given FDA reviewers more leeway to carefully consider the risks and benefits of experimental gene therapies, including controversial questions like the durability of benefit.

While Bryan did not directly address the rejection of Roctavian at the Biopharma Congress, he said the agency wants gene therapies to represent substantial improvements over existing treatments, if they exist.

"Sometimes people look at gene therapy and [talk about] the advantages: it could be a one-time treatment versus the drugs that are out there that may require repeated administrations, or it might replace a more invasive administration," he said. "We don't take that into account so much."

More and more gene therapies for inherited diseases with few or no treatments are advancing, however, while second-generation therapies for more common diseases are under study as well.

"Cell and gene therapy," Bryan said, "is a growth industry."

Article top image credit: Yujin Kim / MedTech Dive, original photo courtesy of U.S. Food and Drug Administration

Babies born with a severe form of a rare genetic condition known as spinal muscular atrophy almost always die before their second birthday.

Novartis Zolgensma, approved in May 2019 by the Food and Drug Administration, promises to change that by offering a potential one-time fix for the genetic deficiency behind the neuromuscular disease. 

Zolgensma was only the second gene therapy for an inherited disorder to be cleared for commercial use in the U.S. Its keenly awaited approval marked another milestone for a fast-moving field, and validated the decision by Novartis last year to acquire its developer, the biotech company AveXis, for $8.7 billion. (

A scandal over manipulated data, addressed in an article to follow in this trendline, clouded Zolgensma's arrival, however.) 

The therapy is also notable for its price. At $2.125 million per dose, Zolgensma is the most expensive treatment ever brought to market. Novartis intends for that price to be paid in installments of $425,000 a year for five years.

Novartis justifies that unprecedented cost with Zolgensma's life-saving benefit. In the clinical trial used by the FDA to make its decision, all 15 infants treated with Zolgensma were alive and off permanent breathing assistance at two years. 

Follow-up results presented by Novartis in May 2019 showed the 10 who continued with follow-up study maintained all motor function gains from treatment, such as sitting without support, and were alive at three to five years of age. 

"It has the potential to be a cure if patients are treated early before they have manifestations of the disease," said Jerry Mendell, a physician at Nationwide Children's Hospital in Ohio and a lead investigator for the initial study of Zolgensma, in an interview. 

Each year in the U.S., roughly 450 to 500 people are born with SMA, about 60% of whom are diagnosed with a severe form of the condition known as Type 1. In affected babies, a gene called survival motor neuron 1 is defective, hindering or preventing production of a crucial protein responsible for motor neuron development. 

For those with Type 1, typical motor milestones are never attained and affected infants quickly develop problems breathing and swallowing. Natural history data cited by Novartis suggests less than 10% are alive and off ventilation support at two years. 

The FDA approved Zolgensma for pediatric patients under the age of two with bi-allelic mutations in the SMN1 gene. This label includes both babies newly incident with the condition, as well as those previously diagnosed who are still younger than two. Notably, that also would include patients with the less severe SMA Types 2 and 3. 

Novartis estimates the current treatable patient population to be roughly 1,100 in the U.S. 

Until recently, no approved treatments were available for SMA. That changed in December 2016, when Biogen won an OK from the FDA for Spinraza, which works by altering gene expression to help create a back-up version of the needed protein. It's approved to treat SMA Type 1, as well as later-onset forms.

Spinraza can help babies survive and improve motor function, but is not a cure. After an initial 4 injections, doses are taken chronically every four months. Each vial costs $125,000 at list price, a figure that the Institute for Clinical and Economic Review determined "far exceeds commonly accepted thresholds" for cost effectiveness.

Zolgensma presented patients, prescribers and payers with even greater sticker shock, but is intended as a one-time, curative therapy. While unprecedented, Novartis' price does come close to what ICER deems to be cost-effective, according to a newly released estimate.

By a measure of cost per life-years gained, ICER judges an appropriate value-based price for Zolgensma to be between $1.2 million and $2.1 million. 

A third drug for SMA, an oral medicine from Roche, was approved in August 2020. 

Due to their high costs, gene therapies like Zolgensma and Spark Therapeutics' blindness treatment Luxturna before it could force changes in how drugs are paid for and reimbursed. 

"Our insurance system is not designed for one-time, very large payments," Michael Sherman, chief medical officer for the New England-based insurer Harvard Pilgrim Health Care, told attendees at a gene therapy conference in Washington, D.C. in 2019. 

A key question in valuing Zolgensma is whether benefits shown to date will endure. In principle, addressing the genetic cause of the disease should reverse the progressive muscle weakening seen with SMA.

"This is one of the longest clinical trials where we have evidence of sustained gene expression," said Mendell. "I think it's very encouraging and we have every reason to believe it will be sustained." 

Beyond the longer-term data Novartis has from the first small study of Zolgensma, though, there's limited clinical proof of how long a one-time dose of Zolgensma could be effective. 

Three patients in the extension arm of that initial trial did go on to receive combination therapy, but that decision was made by either physicians or parents rather than due to loss of motor function, Novartis said at the time of Zolgensma's approval. 

For the SMA patients for whom Zolgensma is approved, Novartis believes Zolgensma should be the preferred treatment option over Spinraza. 

"We believe Zolgensma will be a very strong option for patients who are already being treated by the currently approved therapy," said Novartis CEO Vas Narasimhan in May 2019.

With Zolgensma's approval, and later Roche's drug's, families of infants born with SMA now have three disease-modifying treatment options when four years ago there were none. 

The accelerating research in SMA is reflective of an industry-wide turn toward rare disease and the RNA- or DNA-targeting medicines that hold hope for improved treatment. 

Gene therapies for hemophilia, muscular dystrophies, sickle cell disease and retinal disorders are advancing rapidly through drugmaker pipelines and could reach patients over the next several years. 

Their eventual success or failure will depend on clinical results foremost, but whether drugmakers and insurers solve payment and reimbursement will matter nearly as much. 

"A therapy that can cure disease in a single treatment isn't a unit of drug," wrote former FDA Commissioner Scott Gottlieb in a 2019 op-ed. "It's a public health solution."

Article top image credit: Novartis

The Food and Drug Administration in March quietly closed out an investigation of data violations tied to Novartis' gene therapy Zolgensma, indicating it will not penalize the Swiss drugmaker for submitting manipulated testing results last year. 

​The violations, documented in an August 2019 inspection of Novartis' AveXis unit, were at the center of a scandal which last year engulfed the pharma and marred a landmark approval for its high-profile spinal muscular atrophy treatment.

In securing the FDA's blessing for the therapy, Novartis had knowingly filed an application containing altered data from preclinical tests in mice. At the time, the FDA warned it would consider civil or criminal penalties against the company, indicating its displeasure that Novartis was aware of the issue but proceeded to ask for approval anyway.

The statement was highly unusual and a signal, former FDA officials said, to other companies in the fast-growing gene therapy field. After seven months of review, however, the FDA has decided against leveling such sanctions, a spokesperson for the agency confirmed to BioPharma Dive. 

Instead, the FDA has classified its inspection review as "Voluntary Action Indicated," or VAI, which means violations were found during the inspection but didn't cross the threshold for regulatory action.

"FDA has completed its review of the information and records of the inspection, the evidence collected, and the firm's responses as well as the corrective actions to the inspectional observations, and the agency has classified the inspection as Voluntary Action Indicated," the FDA spokesperson said.

"Based on its review of the information available, FDA continues to find Zolgensma to be safe and effective for its intended use," added the spokesperson. Throughout its investigation, the FDA maintained that it found no evidence human data were changed. 

FDA inspections, such as the one conducted of AveXis last August, result in what are known as Form 483s, technical documents that detail potential violations of the Food Drug and Cosmetic Act. Companies are allowed to respond, after which the FDA decides whether to proceed with a formal warning.

Novartis submitted its response to the FDA's inspection in late August last year, pledging to retrain employees and improve quality control oversight. The company placed much of the blame for the manipulation on two senior AveXis executives, Brian and Allan Kaspar, who were fired in mid August. Through his lawyer, Brian Kaspar has publicly denied any wrongdoing. 

Novartis also committed to informing the FDA within five business days of any credible allegations related to data integrity questions with any pending drug application in the future. 

Novartis disclosed the FDA's Form 483 classification in a March presentation of new clinical data for Zolgensma, briefly noting the FDA's decision.

"We are pleased with this positive outcome and reiterate our firm commitment to data integrity and transparency in our engagements with regulators," a Novartis spokesperson said in a statement.

Zolgensma was only the second gene therapy for an inherited disease to win U.S. approval, showing in clinical studies it could keep alive infants who otherwise were likely to die from spinal muscular atrophy, or SMA. The neuromuscular disease robs newborns of a protein needed for muscle development, usually leading in its most severe form to death or permanent ventilation by age two.

Some 200 infants received Zolgensma in 2019, earning Novartis $361 million last year. The one-time therapy costs $2.1 million per patient, making it the most expensive drug in the world on a per-dose basis.

Article top image credit: Novartis

Gene therapy could dramatically alter how dozens of inherited diseases are treated. It's also transforming how the academic institutions working in this growing field move research from the laboratory to the clinic.

Private sector skepticism a decade or more ago spurred institutions like the University of Pennsylvania and Nationwide Children's Hospital to advance experimental projects much further before selling their ideas to biopharma companies — a departure from the previous model of identifying a molecular target and letting industry do the heavy lifting.

As a result, university technology transfer officers are much more involved in the technical and commercial details of preclinical drug development, from assembling financing and creating private companies to building manufacturing capacity. The product is a host of new startups, such as AveXis, Spark Therapeutics and Bamboo Therapeutics, that in recent years have been swallowed up by large pharmaceutical companies.

"The old way is, 'I have a patent, I'm going to throw it over the fence to you and you throw me a sack of money,'" said John Swartley, managing director of the University of Pennsylvania's Penn Center for Innovation, in an interview. "This is completely different. This is co-development."

"We're directly involved over multiple years in helping to move the technology forward. And our commercialization partner is going to take it hopefully all the way to the market."

A paper published earlier in JAMA in March quantifies the shift. Together, hospitals, universities and the National Institutes of Health sponsored 206 of the 341 identified gene therapy trials that were active in 2019. Biotech and pharma companies led the remaining 135.

Measured by funding, hospitals, universities and the NIH had a hand in more than 280 of those studies, as some trials had multiple funders. Fourteen trials were funded by other federal sources or non-profit charities.

Hospitals and universities were most active in early-stage studies, with industry sponsoring only 22% of Phase 1 trials. But, in gene therapy, those initial human tests can hold more weight, as the benefits of a genetic fix can be quickly apparent.

"This is a sign that the model of drug development that was prominent in the past — academia does basic science and finds some targets and then pharma develops the actual drug product — is pretty different with gene therapy," one of the paper's authors, Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, wrote to BioPharma Dive.

The changing academic model also raises questions about the rich price tags being sought by drugmakers for gene therapies, given the greater role played by universities and other non-profit entities.

"The paper, I think, informs discussions about how high prices really need to be in order to encourage private risk taking for gene therapies — it may be a different number than for other drugs that have less late stage involvement by academia and NIH," wrote Gellad.

University involvement in gene therapy development was driven in part by the private sector's reluctance to get involved in a therapeutic approach perceived, until several years ago, as risky. The death of Jesse Gelsinger in a Penn gene therapy trial in 1999 inflicted severe reputational damage on the field, driving away drugmaker interest.

Scientists kept the faith, and their institutions carried the field forward for years afterward. When Swartley began working at Penn in 2007, one of his first meetings was with the university's gene therapy director James Wilson, who was in charge of the tragic trial that led to Gelsinger's death.

"From an external perspective, from an industrial perspective, there was almost nothing happening," he said. "But it was evident from the kind of research that Dr. Wilson and his colleagues were sharing with us, they made a very convincing case that this was going to rapidly shift into a more of a developmental paradigm."

"They were anticipating a tremendous amount of industry interest when that shift occurred," Swartley added. "It turned out to be very prophetic."

At the University of North Carolina, the situation was similar in the early part of the 2000s. The institution reached a slightly different solution, however, spinning out companies like Asklepios BioPharmaceutical to advance gene therapy beyond the walls of the university laboratories.

"We had a lot of vector technology, but the market was not receptive to gene therapy at the time," said Kelly Parsons, associate technology commercialization director at UNC, in an interview. "We had a startup company that had to work very diligently to try to establish the merits of gene therapy."

Asklepios is still an independent company today, some of its gene therapy work having been folded into a Pfizer-owned Duchenne muscular dystrophy project that was previously developed by Bamboo Therapeutics.

But the time spent building the knowledge and expertise at universities or closely affiliated startups has been one of the reasons why big pharmas have rushed into the space. By advancing the technology, the universities reduced the risk of failure, making pharmas more willing to buy in.

"We had a recognition that if we wanted the for-profit sector and the investment sector and the [venture capital] world to give gene therapy a chance, it was important as an institution we were able to start that process of de-risking the asset," said Matthew McFarland, vice president of commercialization and industry relations at Nationwide, in an interview.

Doing so was a greater commitment than they expected. "What we did is say: 'What stage would these assets need to get to before external dollars would be interested in investing?'" he said. "And the reality is, oh my gosh, you have to de-risk it all the way to the point it's ready to go into the patients."

That included the initial Phase 1 study of the spinal muscular atrophy gene therapy now known as Zolgensma, which was licensed to AveXis and later acquired by Novartis.

More broadly, development included building production capabilities compliant with Good Manufacturing Practices, which govern quality and consistency standards for finished drug products, and a regulatory team that was able to prepare Investigational New Drug applications within the hospital's technology transfer office.

Building up manufacturing expertise has resulted in a new business for Nationwide: the for-profit Andelyn Biosciences, which will run a commercial scale gene therapy production facility.

Solving the manufacturing question is something many academic gene therapy centers are still grappling with as they near the point of handing off to private-sector partners. Biopharma companies want to have confidence that the therapies manufactured by university scientists will work as well in clinical trials and in wider use as they did in earlier study.

"There's no university that has the ability to ramp their early production manufacturing production to a level to get enough doses … that industry doesn't have to recapitulate it," said Jim O'Connell, director of technology transfer at the University of Florida's UF Innovate, in an interview. "It's notorious for university labs, small molecules and others, to not be able to have their work reproduced out in the real world."

This very question may have been behind data quality issues for Zolgensma. In 2019, Novartis was chastised by the Food and Drug Administration for having submitted manipulated preclinical data, a scandal that the Swiss pharma tied to AveXis co-founder and former Nationwide trial investigator Brian Kaspar. Through his lawyer, Kaspar has denied all wrongdoing.

"Academic institutions have got to ask themselves: How far into this do we want to go?," said O'Connell. "It's going to have a whole bunch of costs that universities aren't used to taking on. How do we share the expense? How do we share the risk appropriately?"

Thorny questions notwithstanding, the increased investment has led to better returns for universities. Technology transfer offices interviewed by BioPharma Dive report the licensing deals are much richer for gene therapies that have advanced to human testing or near it — money which gets returned to scientists and their departments to fund new research.

Returns aren't equally shared, however. Schools blessed with research that is sought-after by private industry flourish, while others struggle, said Lee Vinsel, a Virginia Tech assistant professor who is writing a book called "The Innovator's Delusion."

Indeed, broadly speaking, universities reported a little more than $3 billion in licensing revenue in 2017, but spent $68 billion, according to the Association of University Technology Managers. Less than 1% of licenses yielded more than $1 million in revenue.

Moreover, Vinsel argues the potential for licensing revenue incentivizes universities to only conduct research the private sector wants to license.

"One reason why we need federal funding and university research is to do basic science that corporations aren't going to pay for and do," Vinsel said. "If we tack more university research towards the profitable, who is going to do this basic work, including research that could really help society but will enrich no one?"

McFarland of Nationwide, however, points to less lucrative licenses it has signed, such as a device to prevent pressure ulcers in patients with tracheostomies, along with a mental health research and treatment facility the institution has launched, as ventures that were enabled by bigger deals like in gene therapy.

"If we can take that return and continue to foster research not only in [gene therapy] but even further spread that out and have an impact across all of research," he said.

"There are a lot of times when we're not the office of tech commercialization, but instead we're the office of tech realization, because what we go into is just about getting it out there to the public, and we're not going to get a return on it."

Article top image credit: Permission granted by University of Pennsylvania

Bayer in October agreed to acquire Asklepios Biopharmaceuticals, a privately held gene therapy developer formed nearly two decades ago by one of the field's pioneers, University of North Carolina researcher Jude Samulski.

The German healthcare conglomerate will pay $2 billion in cash for AskBio, which has several programs in preclinical and early development as well as its own contract gene therapy manufacturing business. The deal's value could as much as double if AskBio's research hits certain development milestones.

The buyout should help establish Bayer as an emerging player in the cell and gene therapy field, something it's sought to accomplish through dealmaking. A partnership with, and then later buyout of, BlueRock Therapeutics gave Bayer off-the-shelf cell therapy technology, while the AskBio deal hands it a foundation on which to build a broader gene therapy business.

Large pharmaceutical companies have made their interest in gene therapy increasingly clear over the past several years. Drugmakers like Novartis, Roche, Pfizer and Johnson & Johnson have each made high-dollar bets on the field, either through acquisitions or through strings of partnerships and smaller deals.

Bayer's planned takeover of AskBio adds the German company to the growing list.

AskBio is an unusually large, privately held gene therapy developer with a wide reach. The company was formed in 2001 by Samulski, a UNC scientist and pioneer in the development of gene therapy delivery tools known as adeno-associated viruses, or AAVs. In its early days, AskBio relied on angel investing and backing from the Muscular Dystrophy Association, as interest in gene therapy had waned following several high-profile setbacks.

Over the past decade, however, technical advances have fueled a renaissance in gene therapy research and led to the approval of multiple gene therapies. AskBio has grown during that time, spinning some of its work out into companies that were later acquired.

Baxter, for instance, bought Chatham Therapeutics in 2014 for hemophilia gene therapies that stalled within Shire and are now owned by Takeda. Pfizer acquired AskBio spinout Bamboo Therapeutics in 2016 for a Duchenne muscular dystrophy gene therapy that's now on the cusp of late-stage testing.

Returns from those buyouts helped AskBio fund the creation of its own AAV manufacturing capabilities, a critical step for treatments which are complex and expensive to produce. That, in turn, led to the development of a pipeline of gene therapies for neurological, neuromuscular and metabolic diseases, and a $225 million investment from TPG Capital and Vida Ventures in 2019 to support it.

Three programs, for Pompe disease, Parkinson's and congestive heart failure are now in early human trials. AskBio also has operations in Europe, and has formed partnerships with companies like Editas Medicine, SQZ Biotech and Selecta Biosciences, each focused on overcoming some of gene therapy's limitations.

That work will now continue under the ownership of Bayer. As with the 2019 buyout of cell therapy maker BlueRock, Bayer intends to allow AskBio to operate as an independent unit. But Bayer will lean on AskBio to become its gene therapy arm, highlighting in a statement both the biotech's pipeline and its manufacturing capabilities, which may "form the foundation of future partnerships" for AAV gene therapies, the company said.

"We've crossed a threshold where we know what to do and how to do it, we just need bigger muscle [behind us]," said AskBio's Samulski, in an interview.

"Instead of going to Wall Street and every quarter trying to make milestones, we have one financial partner with which we're trying to bring this technology to fruition."

Bayer also noted AskBio's technology may lend itself to treating diseases caused by more than one genetic mutation, a step beyond the monogenic disorders which early gene therapies have largely targeted.

About 75% of the up to $2 billion in milestone payments Bayer offered AskBio would be due over the next five years, Bayer said.

Ned Pagliarulo contributed reporting.

Article top image credit: Bayer AG

By next year, two companies could have gene therapies for Duchenne muscular dystrophy in late-stage clinical trials. The start of those studies will mark the culmination of years of research, a milestone that could finally put a gene therapy for the debilitating disease within reach.

Both treatments, along with a third a little further behind, hold the potential to change Duchenne's course, driving excitement and hope of a potential breakthrough for patients, most of whom don't have good treatment options.

But the data supporting that promise have come from small, early-stage trials, which compared results to historical controls rather than a placebo. The true effectiveness of these therapies, or how long any benefit will last, remains uncertain — questions that will only be answered by the studies just now getting underway.

Next year, then, could be a defining one for Duchenne gene therapy. Here's where things stand:

How is Duchenne treated now?

Duchenne is a potentially deadly genetic disease that affects some 300,000 people, mostly boys, worldwide. An inherited DNA defect leaves Duchenne patients lacking dystrophin, a critical muscle-protecting protein. Without it, they progressively lose the ability to walk or function independently, often dying at a young age from lung or heart problems.

The only available treatments are steroids like dexamethasone and, for two small subsets of patients, gene-targeting medicines from Sarepta Therapeutics and NS Pharma. At best, these drugs may slow the progression of Duchenne. But neither Sarepta nor NS Pharma have proven that yet. The Food and Drug Administration cleared the therapies after studies of a few dozen boys each showed treatment helped patients produce tiny amounts of dystrophin — sufficient, the companies claimed and the FDA agreed, to possibly help.

Confirmatory tests by Sarepta and by NS Pharma are ongoing, but may not produce results for a few years.

How could gene therapy be used?

Duchenne has long been a prime target for gene therapy, but several tough technical challenges proved difficult to overcome. The dystrophin gene, for instance, is too large to fit into the adeno-associated viruses, or AAVs, commonly used to deliver gene therapies. Researchers also needed to ensure they could get enough gene therapy product into muscle tissue to make an impact.

Instead of using the full dystrophin gene, scientists engineered smaller, modified genes that produce a shortened form of dystrophin meant to function like the real protein. The gene therapies now in testing help patients produce these proteins, dubbed either "micro" or "mini" dystrophin, for potentially many years. These treatments are delivered at high doses, with specific AAVs that are meant to shepherd the genetic instructions through the blood and into various muscles.

Once successfully delivered, the companies hope their treatments could slow or even halt disease progression, giving patients a chance to avoid Duchenne's devastating effects. Both outcomes would be a significant advance, though it's not yet clear whether either is achievable.

Duchenne gene therapy also represents a business opportunity for drugmakers, catalyzing large investments by Pfizer, Roche and other companies. Some analysts have projected billions of dollars in peak sales for Sarepta's experimental gene therapy, a lofty total that would make it among the best-selling rare disease drugs.

Which companies are working on gene therapies?

Three companies — Sarepta, Pfizer and Solid Biosciences — have similar Duchenne gene therapies in human testing.

Sarepta's and Pfizer's are furthest along, with late-stage studies testing commercial-grade products starting soon. Both have produced evidence showing their treatments can help patients produce what appear to be meaningful levels of shortened dystrophin, and that those numbers may translate to better outcomes. Neither have had to halt testing for safety reasons, though Pfizer has seen a couple worrisome incidents in early testing that caused it to modify its study rules.

Safety concerns have slowed Solid's research, but the FDA in October cleared the company to restart clinical testing. Soon after, Ultragenyx licensed technology from Solid to develop a different variation of Duchenne gene therapy.

Others could soon be in the mix as well. Astellas Pharma has a program that combines elements of gene therapy and the gene-based medicines that have won FDA approval. Recruiting hasn't yet begun for a Phase 1 study.

Editas Medicine, as well as Vertex and CRISPR Therapeutics, have each said they intend to use CRISPR gene editing to spur long-lasting dystrophin production. Neither has advanced beyond preclinical stages.

What's next?

Sarepta expects results from a placebo-controlled, Phase 2 trial early next year in what could be a crucial test for the treatment's potential. Both Sarepta and Pfizer are racing to start their respective Phase 3 studies, which would be the first late-stage tests of a Duchenne gene therapy.

Sarepta has long been in the lead, and CEO Doug Ingram has said the company aims to apply for approval based on the Phase 2 data and an interim look at the Phase 3 study, which it aims to have by the first quarter of 2021.

The FDA recently complicated those plans, however, when it asked Sarepta for an additional lab test before starting the new trial, which threatened to narrow the biotech's lead on Pfizer. Sarepta said in November it will first run a small, open-label study to validate its commercial-grade product — with dosing expected to begin by the end of 2020 — before conducting the larger Phase 3 trial. Pfizer plans to start its big clinical test by the end of the year.

Solid, meanwhile, could dose more patients in its early stage study in the first quarter of 2021.

Article top image credit: Getty / Edited by BioPharma Dive

Roche wasted no time in getting back into the gene therapy game.

After the Federal Trade Commission cleared the way in December 2019 for it to acquire Spark Therapeutics and its portfolio of treatments for genetically driven diseases, Roche followed up that same month with a massive $1.2 billion collaboration with Sarepta Therapeutics for the biotech's experimental Duchenne muscular dystrophy gene therapy.

The scale of the deal confirms Sarepta's asset has a clear lead in DMD as its rivals have stumbled: $750 million in cash and a $400 million share purchase gives Roche rights to the therapy, called SRP-9001, in markets outside the United States.

The collaboration will also include cost sharing for global development, and up to $1.7 billion in regulatory and sales milestones, with royalties on sales estimated in the mid-teens percentage. Sarepta CEO Douglas Ingram estimated the total value of the deal could amount to $10 billion. "It's a number one gets to fairly easily with even modest penetration ex-U.S.," Ingram told analysts last December. 

The deal establishes Swiss pharma companies as the biggest global players in gene therapy. Cross-town rival Novartis bought AveXis for $8.7 billion for the spinal muscular atrophy treatment Zolgensma, and with the $4.8 billion acquisition of Spark, Roche got Luxturna, a gene therapy for a rare form of blindness, as well as experimental drugs for hemophilia.

Moreover, the deals reveal a race in rare forms of degenerative diseases. Roche has rights to a pill for SMA approved in August as Evrysdi, while with AveXis, Novartis acquired assets to treat Rett syndrome and amyotrophic lateral sclerosis.

With Roche, Sarepta believes it can reach markets that it couldn't have on its own, such as China. "There are 60,000 DMD patients living in China," Ingram said. He acknowledged, however, that "Roche has a lot of work to do before it figures out how to get to China."

SRP-9001 is currently in a placebo-controlled trial. The company had planned on initiating a trial using the commercial gene therapy supply in 2020, but that could be delayed. 

Article top image credit: Courtesy of Roche

Peter Marks, head of the Food and Drug Administration's Center for Biologics Evaluation and Research, has said his top concern for gene therapy's future is manufacturing, and how companies will scale up production to match scientific advances.

"When the cost of goods are very high, they help justify when people charge astronomical prices," Marks said in a June 2019 interview with BioPharma Dive. "If we can help see cost of goods and ability to manufacture reproducibly improve, I think that'll be a big thing. That's something we're working on but something that keeps me up at night."

The FDA has taken steps to keep pace with the field's rapid expansion. The agency aims to finalize six draft guidance documents by the end of 2019 related to gene therapy, including some that will address specific manufacturing issues, Marks said.

While it's far from the only challenge facing gene therapy, manufacturing is particularly critical for drugmakers developing the potentially one-time treatments.

Packing functional genes into inactivated viruses to deliver to humans has brought new production problems to solve. Manufacturers used to small molecule drugs and biologics, meanwhile, have had to retool.

In response, contract development and manufacturing organizations have stepped up their dealmaking. In March 2019, Thermo Fisher Scientific bought Brammer Bio for $1.7 billion, and Catalent purchased Paragon Bioservices the following month for $1.2 billion.

In explaining the decision to buy Brammer, Thermo Fisher's pharma services head said about 65% of total spending on gene therapy manufacturing is outsourced, as few companies have built their in-house capabilities yet.

Acquiring manufacturing capabilities and know-how has also factored into decisions by big pharma to enter the space, such as in Roche's $4.8 billion deal for Spark Therapeutics and Novartis' $8.7 billion buy of AveXis.

Sandy Macrae, CEO of Sangamo Therapeutics, another biotech working on experimental gene therapies, called manufacturing "a limited resource that everyone's competing over" in an interview last week with BioPharma Dive.

That scarcity and value led the biotech to build its own manufacturing facilities in addition to previous deals with CDMOs. Macrae said the site will allow Sangamo to produce therapies for commercialization on a smaller scale.

More involved manufacturing means gene therapy costs more to produce than the technologies before it. While Marks and others express concern such expenses will keep prices sky-high, it's not clear how much cost of goods dictates what drugmakers will charge.

"Cost of goods does not drive our thinking around pricing," said Dave Lennon, head of AveXis, in a 2019 interview. "We believe in a value-based approach to pricing that is based on the condition we are treating and the value that the product brings to that condition."

Sangamo's Macrae, meanwhile, called the current level of costs for gene therapy products "manageable," noting the biotech took such costs into account when choosing which doses to focus on in testing.

"Sangamo is not just a science company, it's a company that is going to make products, and therefore we think about that and only go into things where the cost of goods is sensible," he said. "I think some of the other people are more enthusiastic and are not always factoring that in."

Which diseases drugmakers target matters, too. For conditions like the inherited form of blindness that Spark Therapeutics' Luxturna treats, less viral vector is needed to deliver the therapy —​ meaning lower production costs.

Diseases like spinal muscular atrophy, Duchenne muscular dystrophy or hemophilia, though, require much more virus. Zolgensma, for example, uses a dose many hundred times that of Luxturna.

As gene therapy makers become more ambitious, that could raise the manufacturing bar even more.

"I wouldn't call it unreasonable. I would call it unsustainable," Macrae added, on the high-dose vectors.

Article top image credit: Getty Images

Nationwide Children's Hospital, a hot spot for gene therapy research, in January launched a biotech spinout dedicated to constructing the complex one-time treatments.

In creating Andelyn Biosciences, as the new company is called, Nationwide aims to build on its decade-long experience in developing, testing and manufacturing gene therapies for deadly inherited diseases like spinal muscular atrophy and Duchenne muscular dystrophy.

Andelyn will operate as a for-profit subsidiary of the Columbus, Ohio-based hospital, producing gene therapy components for biotech and pharmaceutical companies running clinical trials. By 2023, Andelyn also plans to contract with drugmakers to make commercial products from a larger facility that's yet to be built.

As the gene therapy field has surged forward — yielding two pioneering drug approvals and at times remarkable clinical results — manufacturing has emerged as a persistent challenge.

Current treatments are delivered via hollowed-out, inactivated viruses that must be made in enormous quantities to deliver sufficient copies of the target gene. Scaling up from small studies to late-stage tests and commercial marketing, meanwhile, requires a company either own a dedicated manufacturing plant or turn to existing contract manufacturers, many of which currently have long wait times for production.

"We're tracking the growth, maturation and evolution of the field," said Dennis Durbin, chief scientific officer of the Abigail Wexner Research Institute at Nationwide, in an interview. "Commercial-scale manufacturing represents one of the next significant barriers to the continued development of the field."

For years, Nationwide has produced gene therapies for its research at a small clinical facility. As Nationwide's work expanded, the hospital added space, increasing the number of production suites dedicated to viral vector manufacturing from one to three.

More recently, Durbin said, Nationwide's industry partners began asking the hospital if it could make preclinical or early-stage clinical product, requests that spurred Nationwide to consider launching Andelyn.

"Part of the reason we feel we can do this is because of our track record of success in doing it at the scale we've been doing it for several years," said Durbin, who joined Nationwide two years ago from the University of Pennsylvania. "We don't feel we're starting out from scratch here."

That track record includes a Phase 1 study led by researcher Jerry Mendell that proved the promise of a gene therapy for spinal muscular therapy, later taken forward by the biotech AveXis and approved as Zolgensma.

Other notable examples include two spinouts, Celenex and Myonexus, later acquired by Amicus Therapeutics and Sarepta Therapeutics, respectively. Sarepta has also licensed from Nationwide a Duchenne muscular dystrophy treatment that has since become the company's leading experimental drug.

With Andelyn, Nationwide expects to offer manufacturing support from the start of clinical testing all the way through to a gene therapy's potential approval — something its current clinical facility can't do.

Durbin also hopes Andelyn will be able to keep pace with a field that's unlikely to look the same in several years' time.

"The manufacturing methods in this space are still what I would consider barely first-generation," he said. "So we anticipate continued improvements and innovation and we want Andelyn to be on the forefront."

Nationwide isn't the only academic center investing in gene therapy manufacturing. The Children's Hospital of Philadelphia, another focal point in gene therapy research, opened in late 2018 a clinical production site to make viral vectors. The facility, which accepts outside projects from industry as well as academia, is slated to begin full operations this year, a spokesperson for CHOP confirmed to BioPharma Dive. 

But structuring Andelyn as a for-profit contract manufacturer appears unique, particularly from a not-for-profit hospital.

Durbin, though, doesn't see a conflict between the two, noting that Nationwide will reinvest some of the revenues from Andelyn back into its own research programs.

Additionally, by helping gene therapies advance, Andelyn could usher in new treatments for children, Durbin said. That would be in keeping with the company's name, which honors Andrew Kilbarger and Evelyn Villarreal, two children who participated in Phase 1 gene therapy studies at Nationwide.

Article top image credit: Courtesy of Nationwide Children's Hospital