Gene Therapy

Three-and-a-half 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 several diseases, including hemophilia, sickle cell and some muscular dystrophies, appear in reach, and new science is galvanizing research. 

But, through the first half of 2021, the gene therapy field has faced 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 last fall, 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

An infusion of an experimental CRISPR gene editing medicine has shown early promise as a treatment for a rare inherited condition, an encouraging finding that marks the latest, significant step forward for a technology awarded a Nobel prize last year.

Treatment with the medicine, which was developed by Intellia Therapeutics and Regeneron Pharmaceuticals, dramatically lowered levels of a misshapen protein that causes the disease transthyretin amyloidosis. Side effects in the six patients enrolled in Intellia's study were few and mild.

The results, which were published in The New England Journal of Medicine in late June, are the first clinical evidence that CRISPR gene editing can be used successfully inside a person's body to treat disease.

"This is a landmark event in modern medicine," said Kiran Musunuru, a professor of medicine at the University of Pennsylvania who specializes in CRISPR gene editing and wasn't associated with the study. "I think it's going to open the door to a whole new class of therapies."

While encouraging and powerful proof of concept, the initial data from Intellia's study don't yet answer many of the most pressing questions facing CRISPR. It's unclear how long the effects researchers observed will last, or whether they'll vary as more patients are treated. The long-term safety consequences of gene editing are also unknown.

Additionally, multiple drugs are available in the U.S. to treat transthyretin amyloidosis, potentially complicating Intellia's path forward with regulators, doctors and patients.

"We have effective tools that suppress [the protein] at this point," said John Berk, a physician who treats amyloidosis at Boston Medical Center and associate professor of medicine at Boston University School of Medicine. "And we have the luxury of regulating them."

Improving prospects

Transthyretin amyloidosis, or ATTR for short, can either be inherited or acquired. The less common hereditary form is estimated to affect some 50,000 people worldwide. Its telltale sign is the buildup of misfolded clumps of TTR, a protein the body normally uses to ferry vitamin A.

ATTR impacts each patient differently but is consistently progressive, worsening over time. Some have nerve damage that begins with toe numbness and creeps upwards, causing health problems like a loss of bowel control or compromised mobility. For others, the disease corrodes the heart, leading to heart failure and death within a few years. Many have elements of both.

For many years, the only treatments were liver transplants or a generic drug called diflunisal that could stabilize the transthyretin protein and slow nerve damage.

Since 2018, however, three new medicines have won approval in the U.S. Alnylam Pharmaceuticals, a pioneer of a gene silencing method known as RNA interference, secured Food and Drug Administration clearance of an infused medicine called Onpattro that can improve nerve function. Akcea Therapeutics followed with Tegsedi and Pfizer's Vyndamax, which is similar to diflunisal, was OK'd for ATTR patients with heart problems.

"When these drugs were approved it was like, 'Oh finally, at least there's something we can do,'" said Mary O'Donnell, the president of the nonprofit Amyloidosis Foundation.

But the drugs have limitations. O'Donnell says patients often have trouble accessing or covering the costs of Vyndamax. Onpattro requires a multi-hour infusion every three weeks so its effects won't wane, along with steroids to prep patients for each treatment. Tegsedi can have a negative impact on kidney function and blood-clotting platelets. All three must be taken for life.

Those drugmakers, and others, are working on longer-lasting and more convenient options. But none offer the potential of gene editing, which is meant to permanently halt, or even reverse, the disease's downward course.

"When we think about what gene editing can bring, it's not just convenience," said Intellia CEO John Leonard. "This is about improving prospects."

The first look

The clinical success of Onpattro and Tegsedi proved suppression of the TTR gene could change the trajectory of the disease.

In some ways, Intellia is building on what Alnylam has already done. Alnylam spent years figuring out how to safely and effectively deliver RNA drugs into cells. The biotech finally succeeded by focusing on the liver, a large organ that filters blood, and using tiny fat bubbles known as lipid nanoparticles to get them there.

"I think what Intellia has done is sort of take the playbook from Alnylam," said Berk, of BU. Berk has been an investigator in the trials of multiple approved ATTR drugs and advised Intellia in the past.

Like Alnylam, Intellia uses lipid nanoparticles to shuttle its medicine into the liver. Inside each, however, are the genetic instructions for CRISPR editing tools. Once absorbed into liver cells, those instructions are deployed to precisely cut the segment of DNA that encodes for TTR, thereby breaking it and halting production of the harmful protein at its genetic source.

Intellia is co-developing its treatment with Regeneron, which partnered with the smaller biotech in a wide-ranging alliance signed in 2016. 

As with other drugs just beginning testing in humans, Intellia's trial was primarily designed to find the optimal dose to move into further testing — one that strikes the right balance between safety and efficacy. Intellia is enrolling adults between 18 to 80 years old with inherited ATTR and symptoms of nerve damage. Some, not all, have heart damage. They'll be tracked for two years.

The results published in NEJM are from three patients who received a low dose and three given a higher one. After four weeks, results from the first three on the lower dose showed TTR protein levels fell by an average of 52%. For the three given a higher dose, the reduction was much greater — on average 87%, with a range of 80% to 96%.

Those latter numbers surpass the 80% reduction reported in testing of Onpattro, an important bar for efficacy.

"It's not just that it worked, it's that it worked so well," said Musunuru, of UPenn. For TTR levels to fall by up to 96%, he added, essentially all of the liver's cells must be edited.

"That's essentially saturation editing," he said. "That's a home run."

Reported side effects, which included headaches, nausea and an infusion-related reaction, were minor. Abnormalities on lab tests for blood clots or elevated liver enzymes — a key concern given the stress the treatment could put on the liver — were "barely detectable," Intellia's Leonard said.

Saturday's results are the first glimpse at how well Intellia's treatment might work. They do not yet prove CRISPR gene editing can benefit patients any more than existing drugs. While Onpattro and Tegsedi require chronic dosing, they've already been shown to keep transthyretin levels down for multiple years, with their effects leading to better health outcomes for patients with polyneuropathy. It's unclear whether greater TTR suppression would offer an improvement.

"Kudos to Intellia for crafting a CRISPR/cas9 that worked," said BU's Berk. "The novelty is employing new biology to suppress TTR — but the concept of TTR suppression in this disease is well established."

Berk is wary of permanently driving down transthyretin levels, as Intellia's medicine is designed to do, even though that hasn't yet been shown to negatively affect people other than requiring vitamin A supplements.

The potential for accidental, off-target edits to DNA also exists, which could have real health risks such as damage to a gene that helps suppress cancer. Laboratory testing of extremely high doses of Intellia's medicine in human liver cells found no evidence of off-target editing and researchers expect the DNA changes introduced by treatment to be "of low risk." But that may not be known definitively for years. Study participants will have long-term monitoring for safety.

"It's exciting to see that there's evidence of efficacy," said Matthew Wheeler, a Stanford University cardiologist who specializes in genetics and works at Stanford's Amyloid Center. "But there are a lot of safety-related questions that are unanswered."

Wheeler also remains concerned about the potential of gene editing-induced changes being passed on to children, although Intellia's treatment isn't meant to affect sperm or egg cells.

The FDA appears to have taken a stricter stance on genetic medicines for diseases that already have effective treatments. The agency, for instance, is requiring lengthier follow-up for multiple gene therapies in development for the blood disease hemophilia. It's not known what the regulator will require of a gene editing treatment for ATTR. So far, the FDA has asked developers to prove benefits beyond TTR reduction.

"We will draw from some of the work that's been done by others," said Leonard.

Intellia intends to test an even higher dose as well as prove its treatment can similarly lower TTR levels in people with heart damage. A dose will then be selected for pivotal testing in both types of patients, so the drug "can be approved for patients with whatever form of amyloidosis," Leonard said.

CRISPR's reach

Intellia's results are the latest milestone in a string of research landmarks set since 2012, when a paper from Jennifer Doudna and Emmanuelle Charpentier laid out the biochemical components of how CRISPR gene editing worked.

Scientists in academic labs and biotech companies like Intellia have harnessed the tool, which is both more powerful and easier to use than previous methods, across medicine and agriculture. The outpouring of research has made many careers as well as led to immense controversy, such as when Chinese researcher He Jiankui shocked the world with his announcement of the birth of two girls from embryos edited by CRISPR.

Other CRISPR-focused biotechs have made history before Intellia, which was founded by Doudna and others. CRISPR Therapeutics entered clinical testing with a CRISPR gene editing medicine first. Study results over the past year and half have proven its treatment can dramatically alter, and potentially cure, the blood diseases beta thalassemia and sickle cell.

But the biotech creates its treatment by editing patient cells outside the body. Those cells are modified using CRISPR and then reinfused. The complex process has safety risks of its own and limits the reach of gene editing to diseases that can be treated through altered stem cells.

That's why Intellia's results represent a step forward for CRISPR. The inside-the-body approach involves its own set of challenges, most notably delivering the medicine to the right place and ensuring the right cells are edited. But proving it can be done opens a new chapter in gene editing research.

Intellia has several experimental treatments meant to edit genes with a single infusion. So does Editas Medicine, which will report initial results in September for an in vivo CRISPR treatment it's developing for a rare form of genetic blindness. Verve Therapeutics, which Musunuru co-founded and went public this month, also has an inside-the-body gene editing treatment for heart disease that could enter clinical testing next year.

"Until now we really didn't have any evidence that if you put CRISPR or any gene editing tool directly in the human body, it would be both effective as well as — as far as we can see from this study — safe," he said. "This is the first clinical trial that convincingly shows that yes, [in vivo] gene editing can work and can work very well."

Article top image credit: del Aguila III, Ernesto. (2018). "CRISPR Cas9" [Illustration]. Retrieved from Flickr.

This past February, a man with a rare inherited disease showed early signs an experimental gene therapy he received last year was working as intended. 

The patient was part of a clinical trial run by Avrobio, a Cambridge, Massachusetts-based biotech that's developing what it hopes could be a one-time treatment for the disease, called Fabry. A biopsy of the patient's kidney showed the gene therapy led to complete clearance of the toxin that builds up in the cells of people with Fabry. 

The promising finding is one several companies are trying to replicate in clinical trials of their own gene-based treatments. The goal is for gene therapy to not only halt progression of Fabry, but also to replace the burdensome, twice-weekly infusions patients now rely on to clear out the toxic buildup.

As things stand halfway through 2021, the trials remain both small and early stage studies, so the long-term prospect of gene therapy for Fabry remains uncertain. Nonetheless, companies are pressing forward with the optimism that gene therapy could be the most promising approach for treating the disease. Here's where things stand now:

How is Fabry treated now?

Fabry occurs when toxic globs of fat accumulate in the body's cells, particularly those that line blood vessels in major organs such as the kidney and heart. 

Normally, special-purpose proteins within the cell tear apart the toxins. For people with Fabry, however, mutations in the gene that codes for these proteins result in jumbled or missing instructions for how they're supposed to be constructed. As a result, cells are left without the right tools to break down the fatty substrate, known as Gb3. 

The disease, which impacts one in 40,000 to 60,000 males and one in 118,000 females, manifests in a variety of ways, from pain and burning sensations in the hands and feet to low sweat production and dark skin rashes. In the more severe cases, symptoms can lead to organ dysfunction and even early death.

The most commonly used treatment right now is enzyme replacement therapy, or ERT. In the U.S. Sanofi's Fabrazyme is the only ERT approved, while patients in Europe have access to Shire's Replagal as well. These drugs replace the missing proteins with synthetic versions, which then helps the body clear out the toxins. 

But treatment is time-consuming and expensive, requiring bi-weekly infusions and costing roughly $1.7 million for a five-year period, according to Avrobio.

ERT is also not curative, and Fabry still progresses even with consistent infusions.

How could gene therapy be used?

A one-time infusion with a lifelong duration would "represent a huge advancement [for Fabry]," according to Jack Johnson, co-founder and executive director of the Fabry Support and Information Group, which advocates for Fabry patients and caregivers across the U.S.

Depending on the company, the specific type of gene therapy being developed differs. One type being tested, by Avrobio and others, is an outside-the-body approach that starts with a patient's own stem cells, collected from their blood. An engineered virus is used to deliver a copy of the gene that's damaged in Fabry into each cell, where it integrates into the cell's DNA. The engineered cells are then re-infused back into the patient.

In the days following, the cells are expected to settle back into the bone marrow while dividing and producing billions of daughter cells carrying the therapeutic gene. 

Another gene therapy type being tested uses an adeno-associated virus containing the α-galactosidase A gene, which is damaged in patients with Fabry. Infused into the bloodstream, the virus shepherds its genetic cargo into cells, which then use the instructions to produce the missing enzyme.

Companies hope these approaches could halt or even reverse the progression of Fabry, although that remains a theoretical goal.

"If the treatment is able to halt the disease in its tracks, that would just be fantastic and hopefully help treat younger individuals before they have any kind of significant organ involvement," Johnson said.

Gene therapy is also designed to be a one-time treatment, offering patients independence from chronic ERT infusions.

Which companies are working on gene therapies?

Every company trying its hand at gene therapy targeting Fabry is in relatively early stages.

Avrobio, Freeline Therapeutics and Sangamo Therapeutics are all in Phase I/II trials. Behind them, Abeona Therapeutics, Amicus Therapeutics and uniQure remain in preclinical testing with their gene therapies.

While Avrobio's therapy has now shown promise in a few patients, the company's results don't yet prove a clinical benefit. The Phase 1/2 trial is still enrolling patients and Avrobio is planning for a larger trial as well.

But kidney biopsy data could be enough to merit review by the FDA. In a presentation, Avrobio referred to the agency's 2018 approval of Amicus' Fabry drug Galafold. The drug was cleared on the basis of toxin reduction in the kidneys. 

Freeline, meanwhile, announced in June it dosed a second patient AAV gene therapy and said it plans to disclose mid-stage data by the end of year.

And Sangamo has dosed four patients with its treatment but has yet to provide any data on how the therapy has performed.

What's next?

Avrobio plans to initiate a late-stage trial by mid-next year, a change of strategy from its initial expectation of seeking accelerated approval based on mid-stage results. The new plan was disclosed after the FDA granted a full approval to Sanofi's Fabrazyme on March 11.

"We plan to design a registration trial with a scope, size and duration comparable to other gene therapy trials," said Geoff MacKay, CEO and president of Avrobio, in the company's May announcement.

The company intends to seek advice from the European Medicines Agency for a planned registration trial there, too.

Fabry is not the only lysosomal storage disorder with growing momentum in gene therapy development. Clinical trials are ongoing for diseases including Hurler and Hunter syndromes, Sanfilippo syndrome and Pompe.

Article top image credit: Danielle Ternes/BioPharma Dive

Shares of Bluebird bio fell sharply in early August as the biotech company, already in the midst of a major reorganization and just getting past a serious challenge to one of its leading programs, disclosed two more significant setbacks.

The first is that another of Bluebird's more advanced programs has been placed on clinical hold because of safety concerns. According to the company, a patient treated with its eli-cel gene therapy has developed a kind of bone marrow cancer known as myelodysplastic syndrome. Bluebird said the disease was likely "mediated" by eli-cel's design, which uses a so-called Lenti-D lentiviral vector, or LVV, to deliver helpful genetic material into stem cells extracted from patients.

Though they're considered safer than what was used in the earlier days of gene therapy research, lentiviruses like the ones Bluebird uses are still thought to pose potential risks. These viruses integrate with the genetic code of cells, but if they do so incorrectly, it may trigger unwanted mutations that could, at least in theory, lead to cancer.

Bluebird knows the risks well. Earlier this year, two clinical studies of its gene therapy for sickle cell disease — a therapy that also uses lentiviral vectors — were put on hold after one patient developed leukemia and another looked to have myelodysplastic syndrome. The trials have since been resumed, after an investigation concluded the myelodysplastic syndrome case was a misdiagnosis and the cancer case was "very unlikely" to be tied to Bluebird's therapy.

According to Bluebird, the clinical hold for eli-cel shouldn't impact its other programs targeting rare blood diseases and cancer. If the hold is resolved, the company expects to finish submitting eli-cel for approval by the end of the year.

Eli-cel is meant to treat a rare metabolic disorder known as CALD, which is caused by mutations in a specific gene. Regulators in Europe last month cleared the treatment under the brand name Skysona for use in treating certain children with CALD.

"Given what we know, we remain confident that eli-cel can offer hope for patients and families impacted by this devastating disease who have very few treatment options," Bluebird CEO Nick Leschly said in an Aug. 9 statement.

Meanwhile, Bluebird also disclosed alongside its second quarter earnings plans to wind down operations in Europe.

The decision, according to Bluebird, has to do with challenges the company's faced making money from its Zynteglo gene therapy. Zynteglo treats a blood disease known as transfusion-dependent beta-thalassemia, and was given conditional authorization in Europe in mid-2019. But it wasn't until this past February that the first patient was treated outside of a clinical trial and Bluebird hasn't earned any material revenue from sales since.

That's partially because Bluebird and payers can't agree on Zynteglo's price, which starts at $1.8 million. The figure hasn't sat well with certain health authorities, as was evident in April, when Bluebird said it was withdrawing Zynteglo from the German market due to disagreements with regulators there, who reportedly offered to pay up to $950,000 in the event treatment is successful.

Bluebird's announcement suggests this problem isn't isolated to just a few European countries, either. The company said that, moving forward, its severe genetic diseases business will focus on the United States market, its core three programs for sickle cell, beta-thalassemia and CALD, and programs exploring new disease targets that would be suitable for "in vivo" LVV technology.

"European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products," Andrew Obenshain, Bluebird's president of severe genetic diseases, said in the Aug. 9 statement.

Bluebird said it's planning an "orderly wind down of operations in Europe," and is considering licensing rights to its gene therapies outside the U.S. to a company with "European experience and capabilities."

The latest updates come at an already busy time for Bluebird, which has been trying to spin off its cancer drug business into an independent, publicly traded company.

While Bluebird clearly sees these moves as necessary, the uncertainty — and the new setback to the eli-cel program — don't seem to be sitting well with investors. On Aug. 9, the day of the two announcements, Bluebird shares were worth roughly a third of the value they were at a year ago.

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 last year, 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 last September and early November, Sarepta Therapeutics, Voyager Therapeutics, Iovance Biotherapeutics and Bluebird bio were all 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 followed 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

Sickle cell disease is one of the world's most common inherited blood disorders, though that isn't reflected in the number of treatments for it. Three new drugs hit the market between 2017 and 2019. But before those additions, nearly two decades had passed since the Food and Drug Administration last approved a sickle cell medicine.

Now, a handful of companies are looking to not just treat the disease, but potentially cure it. Their goal, broadly, is to fix the mutations that cause sickle cell through the use of cutting-edge gene editing technologies. One of these treatments has already advanced to the final stage of human testing, and is expected to be submitted for approval late next year or early in 2023.

A one-time, possibly curative treatment would be momentous, as the median life expectancy for someone living with sickle cell is estimated to be between 45 to 55 years in the U.S. The disease also causes strokes, organ damage and episodes of severe pain known as vaso-occlusive crises. Genetic medicines developed by Bluebird bio and by CRISPR Therapeutics and Vertex Pharmaceuticals have shown promising signs that they can mostly eliminate vaso-occlusive crises, although further testing is needed to better understand if they have limitations or if their effects might wear off over time.

Such treatments raise tough questions, though. Gene-based treatments are very expensive and fairly difficult to make, which presents a major problem in sickle cell given that many people with the disease live in lower-income countries. Drug developers like Novartis say they're tailoring their work to address some of these issues, but it's unclear how well they'll be able to remedy long-standing problems of access and equity.

How is sickle cell treated?

Sickle cell is caused by mutations in the gene that creates hemoglobin, the protein on red blood cells responsible for carrying oxygen.

Patients therefore experience the disease differently depending on their genetic make-up. Those with two copies of the mutated gene have more serious symptoms, like anemia, which happens because sickled red blood cells die much sooner than their healthy counterparts.

Sickled cells are also hard, sticky and misshapen, so they pose the threat of clumping together and causing a stroke.

In more severe cases, the symptoms require patients to get blood transfusions. There are also a few medications available specifically for complications of the disease, in particular the painful episodes that happen when sickled cells clog a blood vessel. The FDA approved a drug called hydroxyurea in the late 1990s for adults experiencing these vaso-occlusive crises. Then it approved another, an oral powder, in 2017.

In 2019, the FDA cleared two more medicines for market: Novartis' Adakveo, which helps reduce the frequency of vaso-occlusive crises, and Global Blood Therapeutics' Oxbryta, which is meant to inhibit red blood cells from sickling and breaking down. Novartis and Global Blood set the monthly list prices for their drugs between $7,000 and $10,400.

Additionally, a cure for sickle cell exists in the form of bone marrow transplants, though the treatments can cause life-threatening side effects and even death.

How could gene therapy be used?

As with other diseases, genetic medicines for sickle cell are being positioned as long-lasting and, potentially, curative treatments. 

If the therapies now showing promise continue to prove effective over time, they could eliminate the long-term symptoms of sickle cell, allowing patients to go without blood transfusions. Lessening or removing the need for blood transfusions would both lower the cost of care as well as avoid the related buildup of iron in the blood, which can require separate treatment.

Gene-based treatments could also prevent vaso-occlusive crises — a main reason for hospitalization among sickle cell patients, who sometimes need strong painkillers like opioids.

Some clinical studies of sickle cell gene therapies are enrolling children. However, should any therapy come to market, older children or adults would likely be the first recipients, given the risks and uncertainties. 

Which companies are working on gene therapies?

A handful of companies have ushered genetic medicines for sickle cell into clinical trials, with the majority still in earlier stages. The farthest along is Bluebird's LentiGlobin, which is designed to deliver an engineered version of the gene that codes for hemoglobin.

To make LentiGlobin, Bluebird takes a patient's stem cells, uses special viruses to outfit them with the corrected gene and then reinfuses them.

This is different from the gene-editing approach favored by several other main developers. At least two sets of partners — CRISPR and Vertex, and Novartis and Intellia Therapeutics — are using the Nobel Prize-winning CRISPR-cas9 technology to get stem cells to produce high levels of what's known as fetal hemoglobin. Fetal hemoglobin is a form of the vital protein, but it stops being produced roughly six months after a person is born. Gene editing, in theory, keeps the switch for this protein on, helping remedy the main problems associated with sickle cell.

Genetic medicines have already shown promise treating sickle cell. A small study of Bluebird's found that, after treatment, hemoglobin levels were close to what's considered normal, and almost no patients experienced vaso-occlusive crises or acute chest syndrome, another symptom of the disease.

CRISPR and Vertex gave a similarly positive update on their program last month. The companies' said that the small group of sickle cell patients given their therapy, named CTX001, had yet to experience vaso-occlusive crises following treatment. Data also suggest their therapy can have a long-lasting effect.

The breakthroughs didn't come without setbacks, however. Bluebird's LentiGlobin program has faced multiple delays tied to manufacturing and safety concerns. In February, the company halted two of its sickle cell studies after one participant developed leukemia and another appeared to have a disease of the bone marrow. Bluebird has since conducted an investigation and determined its therapy was "very unlikely" to be related to the cancer case.

In April, Bluebird said the bone marrow diagnosis had been revised to a condition known as transfusion-dependent anemia.

What's next?

Bluebird was allowed to resume its sickle cell studies in June. Prior to the study halt, the company had said it planned to ask for approval in late 2022, although that may now be delayed.

Sticking to that timeline would put Bluebird well ahead of rival therapies, according to an analysis by the investment bank Raymond James. The next closest is CRISPR and Vertex's treatment, which Raymond James analysts think could be submitted for approval in two to three years. Testing, after a slower start, is now moving quickly, however. 

Behind that, genetic medicines from Aruvant Sciences and partners Sanofi and Sangamo Therapeutics are on track to be filed in three to five years, according to Raymond James.

In the meantime, there are many uncertainties to contend with. Researchers are still trying to understand whether genetic medicine will work for all sickle cell patients, or whether it'll live up to its potential as a lifelong fix for the disease.

Even if these treatments do reach the market, they'll likely still face challenges. For example, therapies currently in development use toxic conditioning regimens to prepare patients' bodies for cell reinfusion, and that may restrict who's able or willing to receive them.

In a recent note, analysts at Stifel wrote that they see the toxic regimens as "limiting the commercial opportunity" for the kinds of treatments being developed by Bluebird, Vertex and CRISPR. "We of course view these events in the context of profound efficacy," the analysts wrote, "but even so, we don't expect the risk/benefit of these agents to resonate with younger, more mild patients."

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 August 2020, 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 in May 2019 and in June 2020 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 2020 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 in 2019 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

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 2020 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 now owned by Bayer, and some of its gene therapy work was earlier 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

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 2020 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