Gene Therapy

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

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

"The issue is really how do you cover Zolgensma, not how you say no to it," said Michael Sherman, the chief medical officer for Harvard Pilgrim Health Care, in an interview with BioPharma Dive on the sidelines of the 2019 BIO conference in Philadelphia. A similar logic applies to Spark Therapeutics' Luxturna, a gene therapy approved in the U.S. in December 2017 to treat a rare form of blindness.

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

Not all of those products, though, are guaranteed to have the compelling efficacy that make Luxturna and Zolgensma relatively easy choices for insurers to cover. (Zolgensma's approval was subsequently put under the microscope after revelations Novartis submitted manipulated testing data from mice to the FDA, an issue that will be explored later in this Trendline.)

The next critical test of the gene therapy era will likely come in hemophilia. Multiple companies are racing to market with candidates for hemophilia A, with BioMarin Pharmaceutical the furthest along.

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

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

Payer pains in adapting to the new era

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Some biotechs are already going after those tougher, multigenic targets. Marks highlighted Parkinson's disease as one such example. Axovant and Voyager Therapeutics are both developing gene therapies for that neurodegenerative disorder.

In 10 or 15 years, the CBER head suspects the gene therapy space may end up looking quite like the small molecule industry of today.

FDA keeping pace, with caution

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

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

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

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

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

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

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

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

Article top image credit: Getty / Edited by BioPharma Dive

The Food and Drug Administration on Jan. 28 finalized a slate of policies for the development and assessment of gene therapies, clarifying its views as it prepares for a coming surge of new treatments in diseases like hemophilia and muscular dystrophy.

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

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

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

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

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

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

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

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

In its document — titled "Interpreting Sameness of Gene Therapy Products under the Orphan Drug Regulations" — the FDA said it would, when assessing two treatments, consider both the therapeutic gene and the inactivated virus used to deliver it.

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

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

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

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

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

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

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

Article top image credit: Jacob Bell

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.

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

In 2017, the US Food and Drug Administration (FDA) approved its first gene therapy, a chimeric antigen receptor T-cell (CAR-T) product to fight acute lymphoblastic leukemia (Kymriah).  That same year, another CAR-T therapy was approved to fight certain types of B-cell lymphoma (Yescarta).  Since then, 4 additional products have been approved to treat serious diseases such as B-thalassemia, spinal muscular atrophy, a rare forms of vision loss and a rare form of primary immunodeficiency.  There are currently over 450 gene therapy and gene-based medicine companies worldwide and around 800 gene therapy and gene-modified cell therapy clinical trials being conducted (ARM Q3 update). 

Significant progress has been made in developing safe gene therapy products in recent years.  Just over 20 years ago, the tragic case of 19-year old Jesse Gelsinger who died during a gene therapy trial led to a temporary collapse in the gene therapy field.  Since then, the gene therapy industry has come a long way.  In a joint statement made in January 2019, FDA Commissioner Scott Gottlieb and CBER Director Peter Marks noted that based on an assessment of the current pipeline and clinical success rates of gene therapy products, the FDA anticipates that by 2020 they will be receiving more than 200 INDs per year for cell-based or directly administered gene therapies and by 2025 that the FDA will be approving 10 to 20 cell and gene therapy products a year.

The basics – what is gene therapy?

Gene mutations can be inherited or occur as cells age or become exposed to certain chemicals.  Small changes to our genetic material can have large impacts on cellular function. 

Gene therapy products mediate their effect by transfer of genes or alteration of human genetic sequences.  It can be thought of as the introduction, removal, or change of genetic material within patient cells – for instance, repairing a faulty gene in order to produce new or modified proteins, increase proteins that will fight disease, or reduce proteins that cause disease. This can be achieved by gene replacement, gene silencing, gene addition, or gene editing. 

The genetic material is typically transferred into patient cells using a specific type of delivery mechanism (described below). Once inside the cell, the gene will make functional protein or target the disease-causing gene.

Gene Delivery Mechanisms

Gene therapy administration can occur via ex vivo or in vivo mechanisms.  With ex vivo gene therapy, targeted cells (eg, chimeric antigen receptors (CAR) T cell therapies, T cell receptor (TCR) therapies) are extracted from the patient and the cells are genetically modified in vitro before they are transferred back into the patient.  In vivo administration occurs via direct delivery to the patient using a viral or non-viral vector and the target cells remain in the body of the patient.

Vectors (carriers of the gene), can come in the form of viral vectors, which are genetically engineered viruses that replace the virus genome with the therapeutic gene.  Examples of viral vectors are retroviruses, lentiviruses, and adeno-associated virus (AAV; of note, the AAV method is believed by many to be the future of gene therapy).  Plasmids (small DNA circles or “naked” DNA), engineered bacteria, and liposomes are other vectors of gene therapy administration to either carry and deliver a replacement gene or to help or silence an existing gene.

Another type of gene therapy product is genome edited cells, which can be generated using zinc finger nucleases (ZFNs); transcription activator-like effector-based nucleases (TALEN), or nucleases such as Cas9 and Cas12a that derive from the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas).  For instance, one company is using a genome editing platform called ARCUS derived from a natural genome editing enzyme called a homing endonuclease in their CAR-T development programs.

Challenges and Benefits in Developing Gene Therapies

The unique benefits of gene therapy are that it targets the cause of the disease and has the ability to treat or maybe even cure rare, debilitating diseases that have few to no treatment options, often with a single administration.  Over time, the high price tag of gene therapy could reduce or eliminate the need for a lifetime of expensive and/or painful ongoing treatments that many in this patient population would require.

Although gene therapy offers a number of unique benefits, a number of challenges exist that make the development of gene therapies difficult as well as expensive. Those include:

• Length of clinical trial process –  long term safety follow up due to uncertainty surrounding the potential durability of effect and long-term safety effects or complications;
• Manufacturing is complex and time intensive, and many sponsors have faced capacity constraints due to the difficulty in mass production (of viral particles, for instance);
• Individual response variability;
• Some conditions have many mutations leading to a given disease and one gene therapy approach may only work for a subset of affected individuals;
• May stabilize disease pathology but not actually reverse existing damage;
• The efficiency of gene transfer with vectors and the limited control over where integrating viral vectors will integrate;
• Dose of vectors may be high and large doses may be needed to reach target tissues; vectors could be filtered out in the liver or cleared by an immune response;
• Unlike other therapeutics, once administered there is no dose titration and no ability to control expression levels; gene therapy cannot be turned on or off.  It is also very likely that there is no ability to do repeat dosing due to immunity developed during initial treatment.

An Advancing Field

Gene therapy offers the potential for significant breakthroughs and a lot of exciting progress has been made with scientific advances in gene therapy and the recent FDA approvals.  Their complexity to develop should not be underestimated, as evidenced by the FDA’s release of 6 additional guidances in 2018 intended to help product developers.  The gene therapy industry is poised for the future, but due to its complexity the development process needs to be thoughtfully planned and managed.  Critical to the success of the field will be the capacity to scale up for AAV manufacturing or other gene therapy manufacturing factories and a streamlined regulatory landscape.

Rho Can Help

There are several unique aspects of gene therapy clinical trials. Rho is currently leading several gene therapy studies and has conducted over 20 gene/cellular therapy trials in over 1000 patients.  One of our sponsors commented, “Our collaborative relationship with Rho has been instrumental in the implementation of a complex and rigorous first in human genetic medicine study, including strategic solutions for unique challenges faced in rare disease gene therapy trials.  Rho has leveraged existing relationships with patient advocacy organizations and worked closely with a centralized biosafety review partner early in study startup to help identify and mitigate potential challenges."

From both a clinical and regulatory standpoint, our experts can offer advice on your gene therapy trial from the preclinical phase through post-submission. For additional gene therapy considerations from our experts, please look at our webinar, "Development Advice for Gene Therapy Products"  and for regulatory considerations,  David Shoemaker's article, "The Gene Therapy Product Development Process."

Article top image credit: Depositphotos

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

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

Zolgensma was only the second gene therapy for an inherited disorder to be cleared for commercial use in the U.S. Its keenly awaited approval marked another milestone for a fast-moving field, and validated the decision by Novartis last year to acquire its developer, the biotech company AveXis, for $8.7 billion. (A scandal over manipulated data, addressed in an article to follow in this trendline, has clouded Zolgensma's arrival, however.) 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

"We believe Zolgensma will be a very strong option for patients who are already being treated by the currently approved therapy," said Novartis CEO Vas Narasimahn on a May conference call with reporters. 

With Zolgensma's approval, families of infants born with SMA now have two disease-modifying treatment options when less than three years ago there were none. 

Recent research presented by Roche suggest the Swiss pharma could have a third in the experimental oral drug risdiplam, which analysts view as competitive to both Zolgensma and Spinraza. Roche plans to file the drug for approval this year. 

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

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

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

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

Article top image credit: Novartis

The Food and Drug Administration sent Novartis an unambiguous signal in August 2019, indicating the drugmaker could face civil or criminal penalties for manipulating data used to support approval of its gene therapy Zolgensma. 

That warning was also directed at other pharmaceutical companies, former agency officials say, a reminder that's particularly relevant for those working on gene therapies and other cutting-edge treatments. 

"This is a rapidly evolving field where there are going to be accelerated approvals. The quality of the data is critical," said former FDA chief Robert Califf in an interview with BioPharma Dive. 

"People who are working in a lab on a cure for a disease in children should be aware that falsifying data is a crime and it's huge betrayal of public trust." 

The FDA's May 2019 decision to clear Zolgensma was a landmark moment for Novartis, which invested $8.7 billion in buying the treatment's biotech developer, AveXis. 

The Swiss pharma company needed data from only three dozen infants to convince the regulator of Zolgensma, which treats a rare neurodegenerative disease called spinal muscular atrophy. Results were dramatic, showing the treatment helped keep alive infants who would otherwise have almost certainly died or seen their disease progress. 

Yet that approval is now under the microscope, after revelations Novartis knew of problems with some of the preclinical data in its application but didn't tell regulators until after Zolgensma's approval. 

The faulty data, according to the FDA, was confined to results from an assay used to test in mice two different versions of Zolgensma. Clinical data was not manipulated, and the agency affirms Zolgensma should remain on the market. 

Even preclinical data can be important, though, and more so for drugs with limited data from human testing.

"Ensuring truthful, complete and accurate data in product applications, regardless of priority review status, is a critical component of industry's responsibility as they work to demonstrate the safety, purity, and potency of biological products," the FDA wrote in an emailed statement, referring to the accelerated evaluation granted Zolgensma. 

"The submission of such truthful, complete and accurate data is also critical for the FDA to be able to protect the public health, and the law requires it." 

Zolgensma is only the second gene therapy for an inherited disease cleared for market in the U.S., but others — with varying sizes of clinical evidence — are nearing regulators' desks.

As Novartis tells it, the company acted quickly to substantiate and fully investigate the allegations of data manipulation. At no point did the company believe the inaccurate data risked patient harm, informing its decision to wait until it had findings in hand before informing the FDA. 

"I would say it was normal course of business and pretty typical for how we handle these items," said Novartis' head of regulatory affairs, Rob Kowalski, on a call with investors and Wall Street analysts in August 2019. It's worth noting that Novartis has also informed health agencies in the European Union and Japan, where Zolgensma is not approved, of the data issues. 

Normal course of business or not, the FDA's response has been anything but. In an agency memo, an FDA official indicated that, had the regulator known of the data issues beforehand, it would have delayed its decision to approve Zolgensma. 

"I suspect there will be wrongdoers here. And consequences," tweeted former FDA Commissioner Scott Gottlieb in the wake of the revelations. 

Novartis has blamed a "few individuals" for the manipulated data — which involve discrepancies in time stamps and the recorded number of survival days for treated mice — and is in the process of "exiting" those employees.

In early May, the company placed AveXis' chief scientist and head of R&D, two brothers, on administrative leave and both have since left the company. Novartis did not announce their departure until mid-August. 

It's not clear how the FDA would determine whether to pursue civil or criminal sanctions against AveXis or Novartis. The agency plans to continue its assessment and could require supplemental applications for Zolgensma, a process that might take some months. 

Historically, settled violations between drugmakers and the government most often involve the overcharging of health programs or unlawful promotion.

A few in recent decades, however, have involved concealed data or poor manufacturing practices, according to data compiled by Public Citizen. Those centered on marketed or generic products, however, rather than manipulated data in a drug approval application. 

The FDA declined to respond to BioPharma Dive's questions on historical precedents for Novartis' situation. 

"The FDA frequently finds problems with manufacturing when scale up [from clinical testing] happens," said Califf, adding "there's always a judgment about whether you require that everything be fixed." 

"I think it's good for the FDA to make a statement for the world to say you'd better button down the quality of your information," he added. 

Patti Zettler, an assistant professor of law at The Ohio State University and a former associate chief counsel at the FDA, echoed Califf's comments. 

"There's benefit to the agency publicly expressing how serious its concerns are, using its enforcement authorities when it discovers violations to send that signal," Zettler said.

At least one gene therapy biotech, Sarepta Therapeutics, has already fielded questions from investors on whether they should be concerned about similar occurrences. Sarepta is developing a gene therapy for Duchenne muscular dystrophy that emerged from the same lab which developed Zolgensma.

Article top image credit: Getty Images

Pfizer aims to be the third big pharma with a significant presence in gene therapy. Its plans to initiate in 2020 three Phase 3 trials targeting mutation-driven blood and muscular diseases would make it a large player in this cutting-edge area of medicine.

The difference between Pfizer and its Swiss rivals Novartis and Roche is that its treatments for muscular dystrophy and hemophilia do not look like they will be the first to market. With hopes that gene therapy could be a one-and-done treatment, arriving second could put Pfizer at a disadvantage if eager patients rush for curative therapies.

Having spun of its off-patent drugs business, the pharma is now trying to talk up the "new Pfizer." Its gene therapies are among seven pipeline projects that it cited during a Jan. 28 earnings call as critical to its strategy of becoming a more innovation-focused company.

Company executives weren't, however, asked to answer how Pfizer views the emerging gene therapy competition. BioMarin Pharmaceutical looks set to get to the market earlier in hemophilia A than Pfizer, while Uniqure in hemophilia B and Sarepta Therapeutics in Duchenne muscular dystrophy appear ahead.

Pfizer's hemophilia A project, the Sangamo Therapeutics-originated SB-525, is up against BioMarin's valrox, which has been submitted to the Food and Drug Administration for an approval decision later in 2020.

In hemophilia B, fidanacogene elaparvovec, licensed from Roche subsidiary Spark Therapeutics, is in a neck-and-neck race with UniQure's etranacogene dezaparvovec in Phase 3 testing. Duchenne research, meanwhile, is led by Sarepta, which is launching a Phase 3 trial of its drug this year, putting Pfizer's at a disadvantage.

Other than announcing its intent to launch Phase 3 trials in hemophilia A and Duchenne, Pfizer didn't provide much more detail about these clinical programs. Mikael Dolsten, Pfizer's chief scientific officer, said more could be revealed about the DMD program at an upcoming research & development day.

Progress on that project had been delayed after one patient was hospitalized with kidney complications, but Dolsten said trial investigators had dosed additional patients. The Phase 2 will wrap up this spring, and the new data and longer follow-up will help guide a Phase 3 trial design, the company said.

Dolsten also described the hemophilia A project as having a 'best-in-class profile," even though BioMarin's valrox has impressed hematologists with its ability to increase expression of a key blood-clotting protein.

In addition, he said the company hopes it can bring one new gene therapy into its pipeline per year.

Building its drug development portfolio is one reason why the company has chosen not to buy back shares, said CEO Albert Bourla.

He pointed to the company's need in the past to buy back shares to support their valuation because of revenue declines, but now he said the company is in a different strategic position.

"The company is going to have a best-in-class revenue growth story," he said. "We can use the capital to invest in good Phase 2, Phase 3 assets to grow our pipeline."

Article top image credit: Depositphotos

Roche wasted no time in getting back into the gene therapy game. After the Federal Trade Commission cleared the way in December for it to acquire Spark Therapeutics and its portfolio of treatments for genetically driven diseases, Roche followed up Dec. 23 with a massive $1.2 billion collaboration with Sarepta Therapeutics for the biotech's experimental Duchenne muscular dystrophy gene therapy.

The scale of the deal confirms Sarepta's asset has a clear lead in DMD as its rivals have stumbled: $750 million in cash and a $400 million share purchase gives Roche rights to the therapy, called SRP-9001, in markets outside the United States. The collaboration will also include cost sharing for global development, and up to $1.7 billion in regulatory and sales milestones, with royalties on sales estimated in the mid-teens percentage.

Sarepta CEO Douglas Ingram estimated the total value of the deal could amount to $10 billion. "It's a number one gets to fairly easily with even modest penetration ex-U.S.," Ingram told analysts on a conference call Dec. 23.

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

Moreover, the deals reveal a race in rare forms of degenerative diseases. Roche has rights to a non-gene-therapy treatment for SMA called risdiplam, while with AveXis, Novartis acquired assets to treat Rett syndrome and amyotrophic lateral sclerosis.

The Sarepta deal came after a "robust, competitive process," Ingram said, although he did not reveal what other bidders were involved. Big pharma's interest in SRP-9001 was probably heightened by the struggles of other experimental gene therapies: Solid Biosciences' SGT-001 is under a clinical hold from the Food and Drug Administration and Pfizer's also has had safety complications.

In addition, Ingram said the company's plans to market independently worldwide helped lift the value of the winning offer.

A Roche spokesperson said the timing of the Sarepta announcement was not related to the FTC's decision the previous week to clear the Spark deal.

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

SRP-9001 is currently in a placebo-controlled trial. The company plans on initiating a trial using the commercial gene therapy supply in mid-2020.

Sharing clinical development costs also will be essential to establishing the clinical benefit of SRP-9001. "We're doing a very significant set of other studies that gets at ambulatory patients, non-ambulatory, younger kids, older kids" Ingram said. "It's multi-national, multi-center and much larger than [the current clinical trial]. There is a significant amount of research [funding] requirements."

Article top image credit: Courtesy of Roche

On the cusp of having a marketed gene therapy for hemophilia, BioMarin is readying itself for the commercial challenges that lie ahead. The California biotech's CEO says he's assured patients and doctors will go for the therapy, despite a price tag that, at least in the U.S., is likely to fall in the range of $1 million to $3 million.

"There is definitely some significant interest," Jean-Jacques Bienaime told BioPharma Dive in a Jan. 13 interview.

Bienaime's comments previewed the first full day of the biopharma industry's bellwether event, the J.P. Morgan Healthcare Conference. There, BioMarin delivered two announcements that affirm its gene therapy ambitions.

The first was that U.S. and U.K. regulators cleared the company to begin human testing of an experimental gene therapy for phenylketonuria, a rare metabolic disorder also known as PKU. BioMarin plans to inject the first patient before the end of March — a timeline which would put its treatment in competition with gene and cell therapies being tested by Homology Medicines and Rubius Therapeutics, respectively.

BioMarin also unveiled it had more than doubled capacity at a California manufacturing site responsible for making both the PKU gene therapy as well as another, called valrox, for hemophilia A. The company says it can now produce up to 10,000 doses of PKU or hemophilia A gene therapy each year.

Combined, company executives say these developments put BioMarin in a leading position among gene therapy developers. A valrox approval, for instance, would usher the treatment to market possibly years ahead of rival hemophilia gene therapies from Roche and partners Pfizer and Sangamo Therapeutics. And with its new manufacturing capacity, Bienaime says his company could treat all hemophilia A patients in the U.S. within two years.

"I hear the first-mover advantage is pretty dramatic," in gene therapy, Bienaime said, "because every time you treat a patient, the patient is then off the market."

Others have made similar arguments. Mani Foroohar, an analyst at SVB Leerink, told BioPharma Dive in 2019 that it's "very difficult to be the second curative product for a rare disease," because patients will have little incentive to try out an experimental gene therapy if there's already another that's proven safe and effective enough to gain approval.

Being first to market comes with uncertainties, though, namely whether hemophilia doctors and patients will gravitate toward a gene therapy when there are already highly effective options available, such as Roche's drug Hemlibra.

BioMarin executives are confident they will, citing results from a recent Citi Research survey of 60 U.S. hematologists who collectively expect to switch almost half of their hemophilia A patients from infusions of other drugs to gene therapy within five years of valrox's launch. The company highlighted, too, that the doctors said they would switch close to 40% of their Hemlibra-treated patients to a gene therapy within three years of valrox's launch.

"The data that's been generated for valrox to date shows that we can achieve a sufficient degree of correction of the genetic problem, and you're actually going to be bleed less frequently than you did when you were taking the infusions," Robert Baffi, BioMarin's head of technical operations, said in an interview.

How long such a benefit will last is a key question facing BioMarin. Recent three-year follow-up results from an early study of valrox showed efficacy appeared to wane over time, albeit to levels well above what's considered mild hemophilia.

BioMarin filed valrox for approval in the U.S. in December 2019. The company has yet to hear whether regulators have accepted the application, according to a spokesperson, but expects to hear back by the end of February.

Article top image credit: NPR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article top image credit: Getty Images

Vertex will spend as much as $2 billion to join a growing list of biotech companies seeking to develop gene therapy for muscular dystrophies, announcing in June 2019 it will expand a partnership with CRISPR Therapeutics and buy privately held Exonics.

It's a particularly sizable investment, as research at both CRISPR and Exonics into muscular dystrophy treatment remains preclinical. Unlike others currently in the space, though, Vertex's focus is on gene editing via CRISPR rather than the gene transfer strategies now favored by Sarepta Therapeutics, Pfizer and Solid Biosciences.

In addition to the two deals, Vertex also announced former Audentes executive John Gray as its head of genetic therapies, and said it will establish a new site in the Boston area to house its gene therapy research.

Alongside sickle cell disease and beta-thalassemia, muscular dystrophies have become an attractive target for companies working in gene therapy.

Duchenne muscular dystrophy, in particular, is the focus of a half dozen companies' research, with Sarepta, Pfizer and Solid considered the most advanced. Vertex's entry, by way of CRISPR and Exonics, adds another well-respected biotech to the mix.

Duchenne, or DMD, is one of the more common and severe forms of muscular dystrophy, and almost exclusively affects boys. Most of those affected don't live past their mid-twenties, and progressive muscle weakness means many require a wheelchair as the disease advances.

Treatment options remain limited, with Sarepta holding the most recent DMD approval for its controversial drug Exondys 51.

Experimental drugs from Sarepta, Pfizer and Solid propose a genetic fix for the mutated dystrophin gene behind the disease. By delivering a functional copy of gene to muscle tissue — an approach known as gene transfer — the companies aim to spur production of the needed dystrophin protein that’s missing in DMD patients.

Vertex's approach with CRISPR and Exonics will be different, relying on CRISPR gene editing to repair DMD-related mutations in the body and thereby restore dystrophin production.

The biotech, which is best known for its trio of cystic fibrosis treatments, will pay a substantial sum to enter the space, however.

Under deal terms with Exonics, Vertex will acquire all shares of the private company for $245 million upfront, and as much as $755 million in milestone payments.

CRISPR and Vertex are already working together, having partnered in 2015 in sickle cell and beta-thalassemia. The first patient in a Phase 1 study of the CRISPR-based gene editing therapy covered by that deal was treated in February.

Expanding the CRISPR partnership into DMD and myotonic dystrophy Type 1 (DM1), another research focus, will cost Vertex $175 million upfront and potentially up to $825 million more.

Such financial commitment shows "a real appetite to pursue non-small molecule R&D," wrote Stifel analyst Paul Matteis in a note to clients. Small molecules like Vertex’s cystic fibrosis drugs have to date been the company’s strength.

Vertex CEO Jeffrey Leiden, however, sees opportunity in gene therapy, telling BioPharma Dive in a September interview that "it wouldn't be unreasonable to expect us to do one or more gene therapy deals."

Per the agreement with CRISPR, Vertex will hold exclusive rights to both the smaller biotech’s existing and future intellectual property concerning the use of CRISPR and related delivery platforms for DMD and DM1 gene editing candidates.

Exonics is centered on the research of Eric Olson, a professor at the University of Texas Southwestern Medical Center.

The company raised $40 million in Series A funding in late 2017 and has attracted the likes of Merck & Co.'s Roger Perlmutter and the noted gene therapy researcher Jerry Mendell to its corporate and scientific advisory boards.

CureDuchenne Ventures, the investment arm of the similarly named patient group, helped found Exonics in 2017.

So far, Exonics has only researched its approach in mice and dogs. Results from the latter group of animals showed Exonics' gene editing therapeutic restored dystrophin expression in skeletal muscle tissue of up to 90% of normal.

DMD gene therapies with clinical data, meanwhile, have had mixed results.

Sarepta widely impressed in 2018, showing that four boys treated with its microdystrophin gene therapy could stand up, walk and climb stairs more quickly than normally would be expected.

Readouts from Solid, though, were less encouraging and Phase 1 data from Pfizer spurred safety concerns. 

Article top image credit: Ryan McKnight, Vertex Pharmaceuticals Inc.

Nationwide Children's Hospital, a hot spot for gene therapy research, on Jan. 13 launched a biotech spinout dedicated to constructing the complex one-time treatments.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Biopharma companies wanting to treat rare diseases are increasingly pressed to be invested in gene therapy. 

Novartis and Roche have recognized this with their multi-billion-dollar acquisitions of AveXis and Spark Therapeutics for marketed or nearly-marketed products. Down the food chain of the biopharma ecosystem, rare disease specialists have been scouring university laboratories for pre-clinical assets.

A recent example is Amicus Therapeutics, which in May expanded a gene therapy collaboration with the University of Pennsylvania, a hotspot for research in the field.

Amicus has targeted rare diseases called lysosomal storage disorders, in which genetically driven enzyme deficiencies lead to a buildup of toxic materials in tissues.

This led to approval of Galafold, which treats some patients with Fabry disease by stabilizing the protein alpha-galactosidase A, thereby allowing it to be removed from cells. Amicus is working on a similar project in Pompe disease. These are advances on older approaches to treatment, which relied on merely replacing enzymes.

But Amicus sees the future as gene therapies.

Last year it struck two deals securing assets from the most prominent laboratories in the space, Nationwide Children's Hospital and University of Pennsylvania. The company bought Nationwide spinout Celenex for $100 million to secure a portfolio of Batten disease projects, and signed a collaboration deal with UPenn for access to gene therapy technologies to treat Fabry and Pompe disease, along with another condition called CDKL5 deficiency.

The expanded deal with UPenn adds access to specific treatments for two types of mucopolysaccharidosis (MPS) and Niemann-Pick type C, along with a majority of UPenn's lysosomal storage disorder treatments. Twelve other types of rare non-lysosomal diseases are also subject to the deal, including treatments for Rett syndrome, Angelman syndrome, and myotonic dystrophy.

Amicus will pay UPenn's gene therapy laboratories $10 million a year for five years, a term that can be extended.

The New Jersey-based biotech may have seen the emergence of competition from the likes of Sangamo, which has a pre-clinical Fabry disease candidate, and Avrobio, which has a Fabry gene therapy in Phase 2 study. Sangamo and Regenxbio also have candidates in MPS types, but would not compete directly with those emerging so far from the UPenn-Amicus collaboration.

In an interview with BioPharma Dive, Amicus CEO John Crowley said the company has been encouraged to invest in gene therapy because of Food and Drug Administration approvals, including that of Novartis' Zolgensma, as well as the progress made by Bluebird Bio, Biomarin and others.

"We really are coming into this golden age of research and development, and approved therapies, and really on the cusp of providing cures," he said.

Article top image credit: Bryan Y.W. Shin [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], from Wikimedia Commons

Unlike most pharmacological interventions, gene therapy raises numerous ethical issues. In most cases, the technology has involved attempts to alter genetic expression in patients to correct for faulty proteins behind disease, research that has resulted in the marketed drugs sold by Spark Therapeutics, Novartis and Bluebird bio. 

These use viral vectors or engineered autologous cells to deliver corrected genes into affected tissue, with little risk that the alterations could be passed to subsequent generations because the therapies do not affect "germline cells," or sperm, eggs or embryos.

Genetic editing of germline cells is newly in focus, though, following research by Chinese scientist He Jiankui, who edited the genomes of at least three embryos that were implanted for birth. 

In late 2018, He, a researcher at the Southern University of Science and Technology, announced to the scientific community's shock the birth of twin girls whose genomes had been edited as embryos using CRISPR-based techniques. He said he sought to make the girls resistant to HIV.

As the backlash grew, He was fired from his job and put under house arrest by Chinese authorities.

In August, 13 biopharma companies, including Sangamo Therapeutics and Bluebird bio, signed a statement of principles opposing gene editing of human sperm, eggs or embryos because of the risks of passing on modifications to subsequent generations.

The statement of principles, released by the Alliance for Regenerative Medicine, supports gene editing of "somatic" cells, which cover most tissues, because most genetically driven diseases can be treated in those cells.

The 13 gene therapy companies said they are only focusing on somatic tissues and are opposed to germline gene editing.

"Unless and until ethical and potential safety questions with respect to germline gene editing are adequately addressed, we do not support or condone germline gene editing in human clinical trials or for human implantation," they wrote.

The companies said the Food and Drug Administration, European Medicines Agency and other national agencies provide the best framework for regulating the development of gene therapies, and warned against adding additional levels of oversight.

"It is our belief that arbitrary and ancillary oversight bodies or processes may carry the risk of delaying research and development efforts, which in turn would adversely impact afflicted patient populations," the statement of principles reads.

They added they support the work of standards settings bodies, such as the U.S. National Institute of Standards and Technology and International Organization for Standardization, to develop guidelines for identifying off-target effects on tumor suppressors and oncogenes. 

James Burns, CEO of Casebia Therapeutics, one of the co-signers, said the call for a moratorium on gene editing of germline cells could be reversed as researchers gain more experience with the technology.

"I think that's one of the things that we still have to talk about: What is that standard that we have to have on the ethical as well as scientific and safety questions?" Burns said in an interview with BioPharma Dive. "I think we'll know when we get there, but it's hard to actually prospectively define it."

Companies signing the statement were Audentes Therapeutics, Bluebird Bio, BlueRock Therapeutics, Caribou Biosciences, Casebia Therapeutics, CRISPR Therapeutics, Editas Medicine, Homology Medicines, Intellia Therapeutics, LogicBio Therapeutics, Precision Biosciences, Sangamo Therapeutics and Tmunity Therapeutics.

Article top image credit: Getty / Edited by BioPharma Dive