Gene Therapy

Three years ago, the Food and Drug Administration granted a landmark approval to the first gene therapy for an inherited disease, clearing a blindness treatment called Luxturna.

Since then, the regulator has approved one more gene therapy, the spinal muscular atrophy treatment Zolgensma, and given a green light for dozens of biotech and pharmaceutical companies to start clinical testing on others. Genetic medicines for a range of diseases, including hemophilia, sickle cell and several muscular dystrophies, appear in reach, and new science is galvanizing research. 

But, entering 2021, the gene therapy field faces major questions after a series of regulatory and clinical setbacks have shaded optimism. "The ups and downs of adolescence are on full display" analysts at Piper Sandler wrote in September, summing up the state of gene therapy research.

Here are four key questions facing scientists, drugmakers and investors this year. How they're answered will matter greatly to the patients and families holding out hope for one-time disease treatments. 

Are recent high-profile setbacks a warning sign? 

The FDA was widely expected last year to approve a closely watched gene therapy for hemophilia A, the more common type of the blood disease. Instead, the agency in August surprisingly rejected the treatment, called Roctavian, and asked its developer, BioMarin Pharmaceutical, to gather more data. 

The next day, Audentes Therapeutics reported news came a third clinical trial participant had died after receiving the biotech's experimental gene therapy for a rare neuromuscular disease. The tragedy brought flashbacks to past safety scares in gene therapy, although the current wave of treatments being tested have generally appeared safe. 

Just months later, the gene therapy field grappled with two more setbacks. UniQure reported a study volunteer's diagnosis with liver cance and Sarepta, one of the sector's top developers, faced significant doubts about its top treatment for Duchenne muscular dystrophy after disclosing a key study missed one of its main goals. 

In each case, the drugmakers involved offered reasons for optimism. BioMarin still expects to obtain an approval; Audentes' trial is now cleared by the FDA to resume testing; UniQure has since shown its treatment is unlikely to be the cause of the volunteer's cancer; and Sarepta argued its negative data were the product of unlucky study design. 

But taken together, the developments are powerful reminders of both the stakes and uncertainty still facing gene therapy.

All four events also highlighted lingering worries about one-time genetic treatment. In rejecting Roctavian, for example, the FDA seemed to be concerned the impressive benefit hemophilia patients initially experienced may wane over time. The deaths in Audentes' study, meanwhile, renewed warnings about extremely high doses of gene therapy. Researchers have long watched for evidence that replacing or altering genes may cause cancer to develop in rare instances, particularly after four infants developed leukemia in a gene therapy study in the early 2000s. And Sarepta's negative findings were surprising because early signs of dramatic biological benefit that didn't seem to translate into clear-cut functional gains for all patients.

Experts are still confident gene therapy can deliver on its promise. Bu recent events suggest getting there may take a bit longer than some expected. 

Has the FDA raised its bar?

"The process is the product," is an often-used cliche about gene therapy, which are complex treatments with exacting manufacturing standards. 

Most of the roughly 60,000 pages in Spark Therapeutics' application for approval of Luxturna, for instance, involved what's known in the industry as "chemistry, manufacturing and controls." 

The therapeutic basis for gene therapy, by contrast, is much clearer for many of the rare, monogenic diseases that developers are targeting. If mutations in a single gene lead to disease, replacing or otherwise fixing that gene should have a large benefit. 

"Genetic medicine is not industrialized serendipity," said Gbola Amusa, an analyst at Chardan, contrasting gene therapy with chemical-based drugs. "It often is an engineering question."

In 2020, the FDA gave ample notice that it's watching gene (and cell) therapy manufacturing closely. Sarepta, Voyager Therapeutics, Iovance Biotherapeutics and Bluebird bio were all forced to revise their development timelines after the agency asked for new details about production processes. 

"The FDA is saying to companies that you've got to up your standards," Amusa added. 

For their part, FDA officials have indicated the spate of data requests are a product of the sharply higher numbers of companies advancing through clinical testing.

Can a wave of new startups develop better tools?

Tasked with replacing faulty genes with functional ones, scientists for the most part have turned to two types of viruses to safely shuttle genetic instructions into cells. Adeno-associated viruses, or AAVs, are typically used for infused treatments, while researchers working on cells extracted from patients generally opt for lentiviruses. 

Each virus class has advantages, but also notable drawbacks. AAVs, for instance, can trigger pre-existing immune defenses in some people, making those individuals ineligible or poor candidates for gene therapy. Lentiviruses, by contrast, are known to integrate their DNA directly into the genomes of cells they infect — a useful attribute in some regards but limiting in others. 

Over decades of gene therapy research, scientists have found ways to tweak and modify these viral vectors to better suit their needs, but the basic tools are the same. Jim Wilson, a gene therapy pioneer who ran the study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at a STAT conference last fall that he's "somewhat disappointed" by slow progress in viral vector research. 

And as more and more gene therapies enter clinical testing, the limitations of current viral vectors have become more apparent. 

The pace of research might be picking up, however. Recently, a number of companies aiming to build better delivery tools have launched, including Harvard University spinout Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222 million in an initial public offering. 

Larger companies are interested, too. Roche, Sarepta and Novartis have all partnered with Dyno, for example. 

In gene editing, meanwhile, researchers are developing new ways to cut DNA, while Beam and others are advancing different editing approaches altogether. 

Will large drugmaker bets bear fruit? 

Billions of dollars have flowed from pharmaceutical companies into gene therapy over the past few years, leaving few large multinational drugmakers without a research presence. 

2020 was no different, with sizable acquisitions inked by Bayer and Eli Lilly, as well as an array of smaller investments from Pfizer, Novartis, Johnson & Johnson, Biogen, and UCB. And CSL Behring, best known for its blood plasma products, spent nearly half a billion dollars to buy UniQure's most advanced gene therapy, a treatment for hemophilia B. 

Over the past three years, there's been at least $30 billion spent on biotechs involved in gene or cell therapy. (Four deals account for the majority of that value.)

All of that dealmaking, while following promising and compelling science, is ultimately a bet that one-time genetic treatments can be scaled up and commercialized into a lucrative business. 

Many of the acquired companies are working on therapies for very rare disorders affecting hundreds or thousands of people. A handful, however, are taking aim at more prevalent conditions, starting with still relatively uncommon diseases like hemophilia to ones affecting millions of people like Parkinson's. 

"For gene therapy to meet our lofty expectations — not just for investors, but for society — it has to make the leap from these ultra-rare diseases," said Loncar.

Commercially, the track record for the few therapies on the market in the U.S. is mixed. Luxturna, now owned by Roche, is a niche product. Zolgensma has broader use and earned Novartis about $1 billion in the year and a half it's been commercially available. 

Two cell therapies from Novartis and Gilead, meanwhile, have struggled to gain traction.

Gene therapy's biggest commercial test yet was supposed to come this year, with the expected approval of BioMarin's Roctavian in hemophilia A. The FDA's surprise rejection could mean a yearslong delay in the U.S., but the challenges of pricing, reimbursement and patient access in gene therapy remain dauntingly large.

Article top image credit: Yujin Kim / BioPharma Dive

Nearly $20 billion in funding flowed into biotech companies developing cell-, gene- and tissue-based therapies last year, widely eclipsing the total invested in 2019 and ending up 50% higher than the previous record of $13.5 billion set in 2018.

The numbers, compiled by the industry association Alliance for Regenerative Medicine in a report published in March, reflect a fast-expanding sector that's drawing increased attention from venture capital backers, public company investors and large pharmaceutical companies. 

More than $5.5 billion of last year's investments came via venture capital financing for startups in the space, most notably the $700 million raised by cell therapy developer Sana Biotechnology ahead of its initial public offering last month. Nearly $10 billion came via IPOs and secondary stock offerings, and another $3 billion through upfront payments in partnerships and collaboration deals. 

As a sector, biotech had a strong year in 2020. The Nasdaq Biotechnology index, which tracks the industry's stock market performance, rose by nearly 25%, recovering from a spring slump as COVID-19 became a pandemic to regain ground strongly. 

But cell and gene therapy companies did even better, according to ARM, which calculated in its report stock performance that surpassed the broader NBI index. 

The regenerative medicine sector, which includes tissue-based treatments as well as cell- and gene-based medicines, got larger, too. ARM counted roughly 1,100 developers worldwide, up about 100 from 2019. 

"The future is now," said Janet Lambert, ARM's CEO. "It's not like we're waiting for there to be a big and meaningful cell and gene therapy sector. There is a big and meaningful cell and gene therapy sector."

Recently, however, some of the most advanced companies have run into regulatory roadblocks or revealed disappointing study results. Cancer cases reported in trials of two closely followed gene therapies have renewed safety concerns, even if it appears the experimental treatments were not the cause. 

Setbacks are to be expected amid the sector's fast growth, said Lambert, who noted the roughly 150 late-stage studies now ongoing. Many of those programs likely won't succeed, given the usual rates of clinical trial failure in biotech. 

Unlike in the past, however, the pipeline of cell and gene therapies is so broad, and the number of companies involved so high, that setbacks for any one program are less likely to slow the entire sector than in past decades. And while the Food and Drug Administration has not cleared any new gene therapies since landmark approvals for Roche's inherited blindness treatment Luxturna and Novartis's spinal muscular atrophy therapy Zolgensma, the agency recently OK'd new CAR-T cell therapies for types of lymphoma. 

Across Europe, the U.S. and China, regulators are expected to decide on approvals for eight regenerative medicine therapies this year, according to ARM. One, a cell therapy for multiple myeloma from Bristol Myers Squibb and Bluebird bio, just won FDA clearance in late March. 

Developers and regulators are also learning quickly, particularly in areas like manufacturing and quality control.  

"One of the important things we need to work on is how best to regulate the [chemistry, manufacturing and control] aspects of cell and gene therapy," said Lambert.

"It's clearly a place we've struggled," she added, noting recent disagreements between the FDA and developers over CMC issues like testing assays. 

ARM members are hoping to have more conversations with the agency earlier, Lambert said, although the FDA division in charge of cell and gene therapies has been stretched thin. In comments to the agency, ARM has advocated for the division to receive more resources and staff in renegotiations for the next FDA user fee agreement that will start in 2023. 

Article top image credit: Getty / Edited by BioPharma Dive

Introduction

Logistics is a key part of any advanced therapies supply chain. Failure within it may prevent therapies reaching patients. Therefore, logistics platforms need to be created early and built alongside the therapies clinical and process development programs.

Logistics by Design (LbD) is a framework for logistics decision making. Using a risk based analysis it identifies the areas within the supply chain that need to be addressed to create a logistics platform that can meet the needs of patients at clinical and commercial scale.

The Logistics by Design Framework

Logistics by Design (LbD) seeks to provide structure to, and de-risk, logistics planning and implementation activities and help align it with the development plans of clinical process development teams.

Underpinning LbD is a well-established process development framework. This framework known as Quality by Design focuses on risk mitigation, as opposed to cost reduction. It uses a systematic approach that begins with predefined objectives, emphasizes product and process understanding and process control, and is based on sound science and quality risk management (for further information, download the white paper by completing the form below).

As with clinical and manufacturing development pathways, the key to logistics success is designing in "quality" from the outset. By doing this, challenges in creating a logistics platform can be identified early and allows sufficient time to consult with key stakeholders (e.g. manufacturing, clinical teams and providers). This will help align the various development programs and address any high risk or cost drivers.

To achieve this LbD creates a 6 stage tool kit that aligns with clinical and manufacturing development: 

1. Mapping of and risk identification for the commercial logistics vision - Application of LbD principles
2. Building Collaborations (Technology Selection and Testing)
3. Infrastructure Planning
4. Field Validation
5. Scaling for Commercial Operations
6. Commercial Deployment

Stage 1: Logistics mapping and risk identification for the commercial logistics vision - Application of LbD principles

The key is to set pre-defined objectives that capture the commercial vision of the therapy developer. This a Target Logistics Profile (TLP) and defines the overarching objectives of the logistics platform with respect to supporting business goals, supplying market needs, maintaining regulatory compliance and facilitating clinical adoption.

From this a Focused Target Logistics Profile (FTLP) can be established to provide a prospective summary of the logistics platforms traits. Including all components of the value chain, to ensure successful delivery of the therapy to the patient whilst maintaining chain of custody and identity. Thus, the FTLP describes the design criteria for the logistics strategy.

The Critical Logistics Attributes (CLAs) and resulting Critical Logistics Parameters (CLPs) can then be generated.  From this analysis, a developer will then have a clear understanding of the risk points within their supply chain, and start to identify mitigation or removal actions.

Stage 2: Building Collaborations (Technology Selection and Testing)

Having defined and identified all the logistic activities required to execute the complete value chain, this stage of the framework builds, and manages, collaborations essential to creating a viable logistics platform.

Logistic providers should be viewed as technical experts, with "joint planning" and "collaborative" relationship levels sought for complex and high-risk elements of the logistics chain. Their expertise and experience can then be harnessed to add maximum value. Furthermore, by having this level of co-engagement and investment in the therapy, providers can appreciate the landscape ahead and "co-evolution" of companies can occur, amplifying the probability of success.

Part of these collaborative working relationships will include the selection and testing of specific technologies, whether it be the physical product shippers or complex integrated data management systems. If selected early in the development lifecycle, they can be assessed within early stage clinical trials and a logistics platform built, tested and optimised alongside the clinical and manufacturing teams.

Stage 3: Infrastructure Planning

Early insight into the challenges and technological feasibility of the proposed commercial logistics platform, as provided in stages 1 and 2 of the framework above, will provide developers with an opportunity to revisit any of the original decisions based on data driven assessments of performance.

Once the agreed pathway is defined, then planning can commence for establishing the required infrastructure to support field validation (stage 4) as part of pivotal clinical studies and ultimately full-scale commercial deployment (stage 6).

Activities included at this stage of development may include for example the identification and sourcing of appropriately located warehousing capability within a specific geographic footprint. 

For example, having an allogeneic off-the-shelf cryopreserved product for an acute clinical condition such as stroke, where it may be important to administer the therapy within a small timeframe window (<12h), means it may be more desirable to have several smaller cryo-storage hubs, appropriately distributed globally, than one big master centre.

Stage 4: Field Validation

This stage of the framework is focused on large-scale validation of the logistics platform with a view to gathering "in-the-field" data.  

Stage 5: Scaling for commercial operations

This stage of the framework focuses on the scale-out of the logistics platform to cover the full commercial footprint. Exemplars of activities that may be actioned at this point in the development plan include:

• Bringing on board additional warehousing
• Lane mapping to ensure delivery windows are achievable based on clinical availability, manufacturing schedules, etc.
• Implementation of training in key procedures and processes to new market sectors
• Translation of documents into languages for new market sectors not covered in the pivotal clinical trials
• Embedding novel technologies (e.g. controlled thawing devices) at new clinical sites
• Bringing on-line additional manufacturing facilities to meet expected market demand

Stage 6: Commercial Deployment

This stage of the process involves executing the developed commercial logistics platform, undertaking continual performance monitoring with a view to identifying points of failure (where and why) and where appropriate, implementing further mitigation strategies to correct these in real time. Additionally, once substantial volumes of data are generated, iterative review procedures can be started to identify opportunities to further streamline the logistics platform.

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References

Full white paper reference: Ellison*, McCoy*, Bell, Frend, Ward (*Joint 1st Author), Logistics by Design – A framework for advanced therapy developers to create optimal Logistics Platforms, Cell and Gene Therapy Insights, Dec 2018, 1019 - 103

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The toxic globules of sugar and fat slowly pile up in the body's cells, accumulating in blood vessels and in major organs like the kidney and heart.

Typically, special-purpose proteins within the cell would tear apart and break down the toxins. But for people with Fabry, a rare inherited disease, genetic mutations result in garbled, sometimes missing, instructions for constructing the right proteins.

Without the right disposal tools, cells are helpless to the inexorable buildup of the dangerous molecules. The first warning signs are as varied as they are acute: burning sensations of pain in the hands and feet, abnormally low sweat production and dark skin rashes. Over time, for those most severely affected, symptoms can become dire, leading to organ dysfunction and early death.

Medicines that replace the missing proteins with synthetic versions can check the disease by helping the body clear out the toxins. But the treatments, infused every two weeks, aren't curative and are taken for life.

A handful of drugmakers are developing a different approach, attempting to use one-time treatments to replace broken genes with functional copies. While testing remains in early stages, promising signs are beginning to emerge.

In February, Avrobio, a Cambridge, Massachusetts-based biotech, reported new results from a Fabry patient treated with the company's gene therapy one year ago. A biopsy of the man's kidney showed complete clearance of the disease-causing molecules, known in scientific shorthand as Gb3.

The finding reinforced earlier data from another participant in the small clinical trial, who had an 87% reduction in Gb3 one year after receiving Avrobio's treatment.

The hope is gene therapies like Avrobio's can halt and reverse the disease, while also reducing the heavy burden of the chronic treatment that's now standard care.

"It's a substantial finding," said Jack Johnson, co-founder and executive director of the Fabry Support and Information Group. "If it's a one-time, one-and-done treatment, that's an incredible improvement in convenience, which will definitely be appealing to patients in the community."

Biotech roots

Fabry is one of a wide array of diseases caused by breakdowns in cellular metabolism. In each, genetic mutations leave the body's cells lacking one of the many proteins, or enzymes, used to process complex fats or sugars.

Collectively, the diseases are known as lysosomal storage disorders, referring to the unwanted deposits that amass when the cell's digestive units, or lysosomes, can't function properly.

About 50 different lysosomal storage disorders have been identified, the most prominent of which affect a few hundred to a few thousand people in the U.S. Effective treatments are available for only eight, including Fabry.

Development of enzyme replacement therapy, as the drugs are called, has its roots in the biotech industry's beginning. Genzyme — a company the late Henri Termeer built into a pioneering developer of rare disease drugs — won U.S. approval for the first enzyme replacement therapy in 1991.

Genzyme later developed several other drugs for the lysosomal storage disorders Gaucher, Fabry and Pompe before being acquired by Sanofi for more than $20 billion in 2011.

Shire and BioMarin Pharmaceutical also found success with enzyme replacement therapies, or ERTs. Together, the three biotech companies account for nearly all ERTs approved by the Food and Drug Administration. (Shire is now owned by Takeda.)

Research into lysosomal storage disorders is now helping fuel another biotech boom, this time in gene therapy. Nearly two dozen companies are testing, or plan to test, genetic medicines for lysosomal storage disorders, according to a recent report from Cowen, an investment bank.

Collectively, gene therapy programs aimed at inherited metabolic diseases — mostly lysosomal storage disorders — account for 23% of the roughly 280 gene therapies in the pipeline that Cowen identified. Only treatments for neurological illnesses represented a greater share.

Although gene therapies for blood and muscle diseases like hemophilia and Duchenne muscular dystrophy are currently in the spotlight, the broad pipeline suggests lysosomal storage disorders may be next.

"Gene therapy is galloping [along]," said Mark Thomas, a kidney disease specialist at the Royal Perth Hospital in Australia and an investigator in Avrobio's Fabry study. "There's this beautiful surge forward."

Along with Avrobio, biotechs Orchard Therapeutics and Regenxbio reported data in February for their gene therapies for Hurler and Hunter syndromes, two other lysosomal storage disorders.

Sangamo Therapeutics and Freeline Therapeutics are also testing Fabry gene therapies in human trials, while Sarepta Therapeutics and Roche are studying treatments for Sanfilippo syndrome and Pompe.

However, most efforts directed at lysosomal storage disorders remain in early or preclinical stages, meaning there remains significant ground to cover in the field. Initial study data can capture gene therapy's impact on markers of diseases, but more consequential health benefits can only be measured over years.

Recent setbacks have also renewed questions about gene therapy development, in particular the replicability of promising early results from handfuls of patients.

In the meantime, other developers making more traditional drugs — such as Amicus Therapeutics, Sanofi and Denali Therapeutics — could improve on current treatment, raising the bar for gene therapy. Denali debuted early, but promising, results for a Hunter syndrome drug on Friday.

'How much is reversible?'

As with other gene therapy developers, Avrobio's aim is curative treatment, beginning first by replacing frequent infusions with a one-time therapy.

"We aim to untether patients from biweekly infusions of enzyme," said Geoff Mackay, the company's CEO.

So far, that goal appears feasible in Fabry. Three of five men treated in a Phase 1 study in Canada remain off ERT two or more years after receiving Avrobio's therapy, according to the latest data from the company. Levels of toxic Gb3 in patients' blood were, on average, 25% lower than they were at the beginning of the study.

The data, Thomas said, are "an immediate in-your-face demonstration that enzyme replacement therapy [offers] partial improvement, but not a cure."

But the initial version of the therapy wasn't as potent as Avrobio wanted. The company has since refined the treatment and the process for delivering it to patients — improvements it says make for a more consistent product.

The kidney biopsy data disclosed this week are from the first Fabry patient treated in a mid-stage study using Avrobio's improved treatment. Though the result was a powerful demonstration of the therapy's action, showing 100% clearance of toxin, it is far from proof of curative benefit.

"The disease has taken 20, 30 years to accumulate," said Thomas. "How much of that is ever going to be reversible?"

Kidney biopsy data may be enough for the FDA, though. In a presentation, Avrobio referred to the agency's 2018 approval of Amicus' Fabry drug Galafold, which was controversially cleared on the basis of Gb3 reduction in the kidneys. (Amicus announced mixed data for an experimental drug for Pompe in February)

Two other patients have been treated in Avrobio's Phase 2 trial, but kidney biopsy data aren't available for either. Avrobio intends to expand enrollment in the study, and begin preparing this year for a confirmatory trial of people switching from ERT to its therapy. The company hopes to discuss with the FDA whether an accelerated approval would be possible. 

In addition to its treatment for Fabry, Avrobio is working on gene therapies for Gaucher, cystinosis, Hunter syndrome and Pompe. Results from three cystinosis patients and one Gaucher patient, also disclosed this week, appeared positive, but are also very early.

"It took a long time for the first gene therapy to be approved by the FDA," said Stephanie Cherqui, a gene therapy researcher and an investigator in Avrobio's cystinosis study. "Now we're seeing an exponential increase in the number of projects."

Article top image credit: Danielle Ternes/BioPharma Dive

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

One year after receiving an experimental gene therapy, adults with severe hemophilia A enrolled in a study run by BioMarin Pharmaceutical were producing blood clotting protein at levels associated with mild disease, according to data released by the Californian biotech on Jan. 10.

Treatment with the gene therapy, called Roctavian, dramatically reduced the average rate of bleeding events per year among participants in the Phase 3 study, as well as almost entirely eliminated the need for preventive infusions of blood-clotting proteins, also known as factor replacement therapy.

As in an earlier trial, data appeared to show the effects of treatment on clotting protein levels waned over time, a trend that raises questions about the durability of Roctavian's benefit. BioMarin expects a single Roctavian infusion will work for many years, however, and the Phase 3 results are the strongest evidence yet the gene therapy can better control hemophilia than standard factor treatment.

The full one-year results from the study are an important milestone for Roctavian, which was unexpectedly rejected last August by the Food and Drug Administration after BioMarin had applied for an accelerated approval. The regulator, apparently concerned early findings weren't holding up in the larger study, asked BioMarin for two years of follow-up data.

The trial results released Jan. 10 get the company closer to that goal. Executives plan to discuss the data with the FDA, though they emphasized that they still expect to need the longer follow-up before being able to resubmit Roctavian for approval.

"We're starting to accumulate data that are addressing the concerns they have," said Hank Fuchs, BioMarin's head of research and development, on a conference call with analysts. "It's moving into the zone of: when is this data strong enough, rather than whether."

BioMarin's rejected application included results from a small Phase 1/2 study of 13 adults with severe hemophilia A as well as data from the first 20 participants enrolled into the Phase 3 trial.

The new data, by comparison, cover all 132 Phase 3 study participants, 112 of whom were followed for six months before treatment with Roctavian to assess their bleeding frequency and use of factor replacement therapy.

Prior to receiving the gene therapy, participants experienced, on average, five bleeding episodes per year and reported using about 136 factor infusions per year. Treatment with Roctavian cut those average annualized numbers by 84% and 99%, respectively, to just under 1 and to 2.

Observed side effects were common, typically liver enzyme elevations, headache and nausea. But no participant experienced any thromboembolic events or developed an immune response to Roctavian. About 15% of people in the study experienced a side effect classified as serious, but all resolved

The results are a convincing display of Roctavian's impact, at least initially. Delivered via a modified virus, Roctavian replaces the Factor VIII gene that's damaged in hemophilia A patients with a functional copy. Once in the body's cells, the functional gene instructs for the production of the blood-clotting Factor VIII protein.

Typically, an adult with severe hemophilia A will produce less than 1% the normal amount of Factor VIII protein. If untreated with factor replacement therapy, the low protein levels lead to excessive and spontaneous bleeding. Even with treatment, people with severe disease can still experience "breakthrough" bleeds.

Those with milder disease usually produce between 5% and 40% of normal factor levels. Data from BioMarin has shown Roctavian treatment can raise levels to this range and keep them there for years. The Phase 3 trial, however, was the biggest test yet of how well Roctavian performs over a much larger group of people.

After one year, average protein levels among the group of 112 participants were 43.6 international units per deciliter, a lower number than what was observed in the smaller Phase 1/2 trial but still considered mild. Among 17 participants who were enrolled into the study without a six-month run-in period and followed for two years, average protein levels fell to 24.4 IU/dL.

By comparison, average protein levels were 63.6 IU/dL and 36.4 IU/dL after one and two years, respectively, among the 7 patients given the same Roctavian dose in the earlier study.

Differences in the rate of decline for protein activity between the Phase 1/2 trial and the first cohort of the Phase 3 trial appeared to factor into the FDA's decision to reject BioMarin's bid for a speedy Roctavian approval.

On Jan. 10 BioMarin executives noted a slower rate of decline in protein activity for the 17 Phase 3 study participants followed for two years, and expressed confidence the numbers had stabilized. Durability is a key question for gene therapy as treatment is meant to be given only once.

BioMarin's success in Phase 3, even if currently insufficient to ask again for approval, are positive news for the gene therapy field, which recently hit several notable setbacks. Earlier in January, Sarepta Therapeutics announced disappointing data for a closely-watched experimental treatment for Duchenne muscular dystrophy. And back in December, UniQure reported a case of liver cancer in a trial of its gene therapy for hemophilia B. (The biotech is now investigating whether there's any link between its therapy and the cancer case.)

While BioMarin will wait for two-year results in the U.S., the company this year plans to resubmit Roctavian for approval in the European Union after initially withdrawing its application there.

Article top image credit: Courtesy of BioMarin Pharmaceutical

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

Large pharmaceutical companies have made gene therapy a priority with a series of acquisitions over the past several years, a stamp of validation for a field that's pushed through decades of ups and downs.

One of the latest buyers is German healthcare conglomerate Bayer, which in October inked a $2 billion deal for North Carolina gene therapy developer Asklepios Biopharmaceuticals, also known as AskBio.

For Bayer, the acquisition is part of a broader effort to build a gene and cell therapy division. But the deal is just as noteworthy for AskBio, an unusually large, privately held biotech based on the work of one of gene therapy's pioneers, Jude Samulski.

AskBio chose the security of a wealthy backer over independence and the chance to go public like several of its peers. And the deal helped the biotech quickly hire Katherine High, one of the few executives with experience shepherding a gene therapy through to regulatory approval. All of which makes the efforts of AskBio, now operating as an independent arm of Bayer, worth watching.

"I think we have the right people, the right chemistry, and the right amount of experience to make a difference here," Samulski said in an interview.

A "virtual" sabbatical

As 2019 drew to a close, so did a chapter in High's career. A hematologist by training, High, 69, has spent three decades working in gene therapy, a large portion of which was as a founder, president and chief scientific officer of Philadelphia biotech Spark Therapeutics.

At Spark, High had helped make history by steering the development of Luxturna, a treatment for a genetic form of blindness. When cleared by the Food and Drug Administration in late 2017, Luxturna became the first gene therapy for an inherited disease approved in the U.S. Roche swooped in soon after to acquire Spark, and closed the deal in December 2019.

High decided to take a year off from biopharma. But the coronavirus pandemic dashed her plans to conduct research at Rockefeller University. The institution reduced its staff to essential personnel, and the Harvard Club of New York City, where High, a Philadelphia resident, planned to stay during the week, closed its doors.

"My sabbatical turned into a virtual event, which was good; I got a lot of things done — review articles written, book chapters written, things like that," High said in an interview. "I really needed a break."

She spent time with her first grandchild, swam, and, fulfilling a longtime desire, remotely studied German at Middlebury College's storied language program.

But High couldn't keep away from drug research. During periodic visits to North Carolina, where she has family, High dropped in on Samulski and fellow AskBio co-founder Sheila Mikhail.

High has over the years both collaborated and competed with Samulski, a University of North Carolina researcher and expert in gene therapy delivery tools known as adeno-associated viruses, or AAVs. He formed AskBio in 2001 with another gene therapy researcher, Xiao Xiao, and CEO Sheila Mikhail, a life sciences attorney.

"Our paths have crossed, our students have crossed, our sciences [have] definitely cross-pollinated," Samulski said, describing High's academic work at University of Pennsylvania and his at UNC.

By the time of their meeting, AskBio had grown to become one of the gene therapy field's most unique. Originally bootstrapped with angel investing and backing from the Muscular Dystrophy Association, AskBio had spun multiple gene therapy programs into companies that were later acquired. The returns from those buyouts were then used by AskBio to build its own manufacturing capabilities, a crucial step for gene therapy products.

During High's visits, Samulski and Mikail shared some of the progress the company had made advancing its technology. Among them: the acquisition of a Scottish biotech whose technology may allow the company to more tightly control how much protein a gene therapy can produce. Doing so could help overcome a critical limitations of gene therapy, which can have widely varying effects from patient to patient.

"We have a roadmap, how to get from A to B," Samulski told High. "If you want to come in and champion that, we would love to have you."

The chase

As AskBio was courting High, Bayer was eyeing AskBio, which had put in motion plans for an initial public offering — a typical step for a biotech of its size.

Bayer had already announced plans to develop a cell and gene therapy division, acquiring Bluerock Therapeutics, a maker of "off-the-shelf" cell-based treatments, in 2019.

But the large pharma didn't have an anchor for its gene therapy ambitions. Marianne De Backer, Bayer's head of business strategy and development, had assembled a list of developers to pursue. AskBio was at the top.

"If you look at the [gene therapy] assets that are on the market today, like Zolgensma from Novartis, part of the technology is based on technology from AskBio," she said in an interview, referring to the Swiss company's spinal muscular atrophy treatment. A Duchenne muscular dystrophy treatment in late-stage testing at Pfizer also originated within AskBio, as did a Takeda program being studied in hemophilia.

De Backer faced two obstacles, though. Bayer, for one, didn't know the AskBio team, and couldn't meet them in person because of the travel restrictions that began during the pandemic.

"It was really almost a cold call," she said.

Bayer was also competing against the draw of a deep market for public stock offerings, which helped a record number of biotechs to IPO in 2020. De Backer said she needed to show AskBio that she could get the deal done quickly. So she and Mikhail spent six weeks hammering out terms, including an agreement the company could continue to operate independently — an "arm's length" arrangement like one Bayer made with BlueRock.

Such promises are often made, and eventually broken, when a larger company acquires a smaller one. But Samulski's concerns — that AskBio's work might be stifled within such a massive company — were eased after speaking with BlueRock CEO Emile Nuwaysir.

"[Nuwaysir] said, ‘they have left me alone, they've encouraged me to do what I'm doing,' and I said, ‘OK, that's what I needed to hear,'" Samulski said.

The acquisition allows the company to spend more time on science and less on raising money, he added.

"If I go back and write a grant today, it'll be three years before we can start the project," Samulski said. "In this setting, when we have our meeting ... the decision-makers are at the table and the science starts that afternoon."

The next chapter

For High, AskBio represents a return to a similar role as the one she had left: helping run an advanced gene therapy business newly acquired by big pharma. At AskBio, she's been named president of therapeutics.

The role, however, lines up with High's current career ambitions. AskBio has the manufacturing capabilities, breadth of clinical-stage programs and financial backing to take on diseases like Parkinson's and congestive heart failure — the types of complex, common conditions gene therapy hasn't yet been proven in.

"There are great strengths in pharma, and there are great strengths in biotech, and the ideal situation is one that will let you employ the strengths of both types of organizations," she said.

High considered other options, such as working with a different and unproven drugmaking technology. But as someone who's spent much of her life living the story of gene therapy, she knows more than most the challenges of pioneering a new technology and convincing regulators of its worth.

Sometimes people "may underestimate the amount of time it takes to build all the tools that you need to enable regulators to say 'yes, this is safe,'" she said.

By sticking with gene therapy, much of the groundwork has been laid. She's just looking to take it a step further.

"I'm probably not going to work for another three decades," High said, with a laugh.

Article top image credit: Bayer AG

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