But at the same time, we have seen headlines around unexpected side effects and, unfortunately, patient deaths. In the past few years, the U.S. Food and Drug Administration (FDA) has worked hard to understand the safety issues associated with gene therapy. Therefore, one of the questions we discussed at the Summit was how do we as an industry elevate safety across gene therapy development? I believe that while there is no one-size fits-all approach, there are four major variables emerging across gene therapy approaches that can influence key safety considerations and impact regulatory requirements.

1. Nature of disease
   First off, key factors about the disease itself will influence safety considerations and clinical trial design. The severity of the disease, its rate of progression, current unmet medical needs, as well as concomitant conditions and medications, are all key factors to consider when assessing the potential risk/benefit profile of a particular gene therapy approach. For example, diseases that involve the central nervous system (CNS) require a gene therapy approach that can cross the blood-brain barrier, which comes with distinct safety implications and methods of evaluation.
2. Mechanism of action
   Whether you take an in vivo or an ex vivo approach, for example, determines the method of evaluation needed to evaluate potential off-target effects. With an ex vivo approach, you can characterize the transduced stem cell population prior to introducing the drug product back into patients. With an in vivo approach, more cell types may have to be considered and evaluated preclinically.
   Similarly, different safety considerations are required depending on the type of vector selected. One of the safety considerations of the adeno-associated virus (AAV) gene therapy approach is immunogenicity against the AAV capsid antigens and the transgene. In contrast, a safety consideration for the lentiviral (LV) gene therapy approach is potential vector integration near a proto-oncogene, and thus LV-based gene therapy approaches should be accompanied with insertion site analysis to understand the likelihood of insertional oncogenesis.
3. Clinical patient population characteristics
   Many cell and gene therapy trials are for small patient populations that have rare, life-limiting genetic diseases, which can make clinical trial enrollment challenging. Certain FDA flexibility in trial design enables trials to be patient-sparing and yet still allows thorough evaluation of patient safety.
   Just as population size can vary, so can patient age. It is particularly important to mitigate concerns and address safety in pediatric trials. Considerations may include creation of an Independent Data Monitoring Committee (IDMC) to enhance scientific integrity and ensure that the interests of patients are being well-served. Additional approaches such as sentinel dosing and staggering of patient cohorts also can reduce risk by phasing dosing
4. Route of administration
   Additionally, the route of administration may have implications that need to be considered. Vectors might be injected intravenously or intracranially, for example, and different routes have different rationales and different levels of risk.

All of these components need to be worked out within the broad gene therapy community and with regulators across geographies. I am sure you have heard this before, but it bears repeating – engage with regulators early and often so you can get their feedback along the way. It is critical to prioritize safety at every step, from the very beginning.

I’ll add two additional long-term safety considerations that I believe are very important areas for us as an industry to address, especially as gene therapy treatment in pediatric populations becomes more common.

1. FDA last issued guidance on long-term follow-up (LTFU) for gene therapies in early 2020. The recommendation was 15 years of safety follow-up for gene therapies using LV vectors and five years for gene therapies using AAV vectors. All LTFU studies have a dedicated clinical protocol that specifies patient-visitation schedules, a schedule of assessments for both safety and efficacy, the methodology that will be used to assess integration sites and immunogenicity against the protein expressed and a means for collecting accurate case histories.
   In designing the LTFU study, it’s important to think through how you will actually obtain these data from patients over a five- or 15-year time period. The basic promise of gene therapy is that a one-time treatment potentially cures the genetic disease. How do you keep a patient coming back frequently in a LTFU study to go through a battery of tests – including sometimes uncomfortable or invasive tests – who in some cases may no longer be considered a patient living with a particular genetic disease? Consider how geography, time commitment as well as assessment frequency may impact your LTFU protocol, and how leveraging digital technology as well as local advocacy groups, foundations and hospitals, may improve the patient experience.
2. Finally, and this point is sadly timelier now than ever before, keep in mind that guidelines emphasize that pharmacovigilance plans must detail how LTFU of treated patients will be conducted even in the event that drug development is halted, or the sponsor or marketing authorization holder (MAH) ceases to exist.

There is no one holy grail for ensuring gene therapy safety. Individual approaches must be customized based on the specific disease, technology, patient population and mode of administration. Taking these variables into consideration while keeping abreast of the larger issues surrounding gene therapy patient safety will allow the industry to take the necessary steps to respond to regulators. While the gene therapy industry has made steady progress, we still have a long way to go – there are still far too many patients who have tremendous unmet need and no solutions in sight. Holding conversations with leaders throughout the industry, as we did at the GTRD Summit, is critical to promoting innovation, enhancing safety and ultimately advancing therapeutics to improve patients’ lives.

With the industry seeing five gene therapy approvals in 2022 and 30 gene and genetically modified therapies in Phase 3 in the last quarter, there is clear momentum in the field. And with nearly a dozen anticipated regulatory decisions on the horizon in 2023, that momentum is poised to accelerate.

That progress is a potential good indicator of improving prospects for the field. The Gartner curve, used by analysts to visualize the adoption of new technologies by businesses, describes a “slope of enlightenment,” which comes after initial excitement around an innovation has worn off and companies are doing the hard work of identifying and overcoming obstacles to its adoption. That’s where gene therapy has been in recent years, as we’ve seen solutions emerging for formerly daunting challenges like manufacturing, analytics, and pricing. What follows the slope of enlightenment? It’s the plateau of productivity, where technology goes mainstream.

While I don’t expect the industry to achieve widespread adoption of gene therapy in 2023, we will be much closer a year from now than we are today. As we continue to accumulate real data, real milestones achieved and real patients’ lives dramatically changed, I expect three themes to play out for the gene therapy industry in 2023: 1) how and to what extent regulatory approvals translate into commercial viability; 2) a growing need for differentiation based on innovation; and 3) pipeline and industry consolidation.

Commercial viability

• The first theme is perhaps the one that generates the greatest anxiety today among gene therapy players. With more gene therapy companies becoming de-risked as they clear both regulatory and reimbursement hurdles, for the first time we’ll have a chance to observe what it takes for a gene therapy addressing larger patient populations – like BioMarin’s hemophilia A gene therapy, which is currently undergoing FDA review – to be commercially viable.
• While there are certain elements that we know are important for a therapeutic to achieve commercial success – including addressing high unmet need, being first to market, having a strong pricing rationale and targeting substantial patient numbers – it will be interesting to learn more about what combination or degree of those elements drive gene therapies forward. Like all health care modalities, there will be winners and losers, but progress through 2023 will provide more clarity on the recipe for gene therapy commercial viability.

Differentiation based on innovation

• People will always invest in great science that meets an unmet medical need. That is why having a differentiated approach is critical for gene therapy companies and what may ultimately set the winners in the gene therapy field apart.
• This also holds true for scientific innovation. Manufacturing cell and gene therapies is not easy; it is even more challenging to manufacture at scale. As more advanced gene therapies move into the clinic and to commercial stage in 2023, having a robust manufacturing process, having that process be scalable will likely be increasingly important. Innovation has been central in the building of AVROBIO, including our approach to manufacturing, and we bring that focus into 2023. plato® is designed as an end-to-end solution covering vector design and vector production, drug product manufacturing, as well as analytics.
• The automated nature of our plato platform is designed to improve consistency and product quality, promote scalability, and reduce cost of goods. Frozen vector can be stored for at least five years, addressing future demand for late-stage development and potential commercialization. And our centralized analytical approach means that assays used to determine elements such as transduction and potency are leveraged across the platform.

Pipeline and industry consolidation

• Finally, market headwinds are bound to force further pipeline and industry consolidation in 2023. Unfortunately, there is a major disconnect between the gene therapy field’s progress and investments. The positive clinical data, multiple regulatory approvals, and strong pricing achievements we have seen over the past 12 months have yet to translate to public equity markets. It may take a long time for the investor community to recalibrate.
• It is estimated that more than 200 biotechnology companies are now trading below their cash positions, and that means intensified strain for many gene therapy companies. As a result, this year will continue to see restructurings, pipeline reprioritizations, collaborations and, increasingly, bankruptcies. I believe that companies built on great science will persevere, but, in the short term, it will be companies with nimble business models to advance that great science that will best navigate this austere financial climate.

As these three themes intersect in the upcoming year, it will be interesting to see how they continue to shape the gene therapy field. Are they the right developments, at the right time, that will push one-time gene therapies to change the world of more patients and families living not only with rare genetic diseases but also diseases with larger patient populations, like heart disease and diabetes? What the field will look like a year from now is anyone’s guess, but every hard-fought win moves gene therapy forward on its course to broadly transform medicine.

And all indicators are that we can expect this cadence to continue. Several companies are expected to file for approval over the next 12 months, and more than 39 gene therapies are currently in Phase 3 clinical trials.

While the financial markets remain repressed, these successes are rightly seen as a sign of improving prospects for gene therapy. I see them as a reflection of increasing adoption that over time has the potential to dramatically change our entire healthcare system. The tech industry often uses a model for the adoption of new technologies called the Gartner® curve, which describes a “slope of enlightenment” that comes after the initial excitement around an innovation has worn off and the obstacles to applying it have become clear. Companies climb the slope of enlightenment by overcoming these challenges to create a formula for success. I believe the gene therapy sector is starting the climb up the slope of enlightenment. As that happens, we can expect to see more gene therapies for more diseases reaching more patients and even changing the face of healthcare across a broad spectrum of rare diseases – and perhaps some not-so-rare diseases, as well.

The evidence of momentum is not just measured in recent approvals, but also in other regulatory milestones, clinical data, manufacturing advances and commercial developments. Our field progresses as gene therapy accumulates real data, real regulatory milestones and stories of real patients’ lives dramatically changed.

In the clinic for example, the dramatic potential of gene therapy is turning into reality as patients go months and then years without needing the chronic treatments they once relied upon to help manage their disease. We have seen and heard more case studies of gene therapies slowing or stopping the course of progressive, fatal genetic diseases, leading to talk of “functional cures.” And importantly, while there have been some exceptions, the overall safety profile of gene therapies has advanced to be generally more predictable and understood.

The chemistry, manufacturing and controls (CMC) side of gene therapy has advanced too, with manufacturing no longer the showstopper it was once feared to be. When Spark Therapeutics developed LUXTURNA®, the first gene therapy approved in the United States, it had to create virtually everything from scratch. Assays, manufacturing, clinical and regulatory pathways all had to be invented, the company’s former head of technical operations, Diane Blumenthal, once wrote. But five years down the road, those trails through the wilderness have become familiar terrain. Innovations like AVROBIO’s plato® platform, an automated process that is designed to incorporate everything from vector design to manufacturing, from drug product testing to delivery, have been built to be scalable to support late-stage clinical development and future commercialization for successive gene therapy programs.

These clinical and technical advances have been matched on the regulatory side by a clearer path to approval for more patients. Feedback from regulators has been consistent, and a pattern around how regulators will evaluate the risk/benefit of gene therapies has started to emerge. In the face of urgent unmet needs among patients, this insight is giving more companies the confidence to request creatively designed accelerated approval pathways, including Sarepta Therapeutics for their Duchenne gene therapy and REGENXBIO for their Hunter syndrome gene therapy.

We have also seen increasing acceptance of the economic and healthcare system value of these gene therapies. For example, in August 2021, bluebird bio announced it was exiting the European market over difficult price negotiations around its beta thalassemia gene therapy, Zynteglo. Eight months later in the U.S., the nonprofit Institute for Clinical and Economic Review reported that the same therapy would be cost effective at a price of up to $2.77 million, opening the door to a small but promising market in the United States. The gene therapy has since been approved by the U.S. Food and Drug Administration (FDA) and is priced at $2.8 million.

There is increasing recognition that this price is well below the typical cost of treating beta thalassemia over a patient’s lifetime (which according to bluebird can reach $6.4 million) for a one-time treatment that directly addresses the root cause of a serious disease, potentially halting its symptoms, progression and lifelong current treatment burden for good. The same is true for BioMarin’s hemophilia A gene therapy: ICER said it would be cost effective up to $2.5 million. When it was approved in the European Union this summer, BioMarin announced a price of around $1.5 million euro. The healthcare system, unaccustomed to applying such powerful tools, will naturally take time to adjust to the advent of this new technology. But gene therapies have already begun to spur that transformation.

The Gartner curve settles into a period called the “plateau of productivity,” which is when a new product starts to go mainstream, seeing widespread adoption and has a clear value proposition. We are not yet there when it comes to gene therapy, but I think we are building the momentum we need to get to that stage over the next few years. The opportunity to dramatically transform the lives of more patients and families, as well as to dramatically change our entire healthcare system, is in our sights.

At the same time, there are more gene therapies in development overall than antibodies, with 39 Phase 3 trials ongoing and several companies expected to file for approvals over the next 12 months. The FDA’s Office of Therapeutic Products (formerly known as the Office of Tissues and Advanced Therapies until September) recently reported that it was overwhelmed with more than 3,000 IND applications for cell and gene therapies and plans to hire another 100 people over the next four to five years.  It may be a safe assumption that OTAT’s transformation into OTP, a so-called “super office,” was prompted in part by this burgeoning gene therapy wave.

I believe we’re seeing this level of activity because gene therapy has reached a tipping point. A range of questions and technical obstacles that once bedeviled the industry, from manufacturing and safety to durability and pricing, have gradually receded as companies have developed solutions and worked through issues with regulators, payors and other stakeholders. We now have an accumulation of data, regulatory milestones and patients whose lives have been dramatically changed to show that gene therapy is here, and here to stay.

The sector faces financial headwinds to be sure, but with this progress the opportunity exists for gene therapy to capture markets across an array of genetic diseases, as well as potential blockbuster indications like GBA-Parkinson’s and wet AMD. If you are a biopharma or large biotech company, and you do not currently have a gene therapy strategy or the internal know-how and capabilities to drive it forward, you are already in danger of never reaching – or worse, losing – your leadership position across a range of therapeutic areas. Now is the time to invest in this space — here are several factors to consider as you weigh your options.

Ingredients for success

When you think about it, success in gene therapy is not really dependent on patents and traditional drug development methodologies and functions. Success in gene therapy is much more dependent on know-how and speed to market. Because each patient treated is potentially functionally ‘cured,’ or as envisioned is treated only once, and, thus, no longer a candidate for treatment, the target population decreases with each patient dosed. This means whoever gets to market first starts depleting the number of patients available, which quickly makes the remaining market unattractive for potential competitors. In other words, the first company to market gains a tremendous market advantage. For rare diseases, whichever company gets to market first will also likely get orphan drug exclusivity, another important form of protection. This puts a premium on companies with a critical mass of know-how today and with real platforms that can more easily and quickly enable programs in different diseases by switching out the DNA construct.

This know-how and the assets and capabilities that come out of it cannot be built overnight. Gene therapy companies have spent the past five to 10 years developing the expertise and processes necessary to deliver their products to patients efficiently and effectively. Interestingly, one vendor recently told us that every single person they hired with ‘biologics’ capabilities eventually turned out not to have the right skill set for gene therapy. Because speed is the secret to success in this sector, it would not surprise me to see a flurry of partnerships and acquisitions as pharma and large biotech players position themselves to reap the benefits of gene therapy’s emergence. Certainly, the sector’s recent positive regulatory signals and robust pipeline are important parts of the equation, but there is also an important business distinction that sets gene therapy (and other one-time genomic medicines) apart from other products.

The revenue tsunami

If you are first to market with a gene therapy product, you don’t just have an edge on the competition – you quite possibly wipe out the competition. It’s a potential “winner take all” situation, and on top of that the majority of your revenues will be made quickly, in the first three to five years on the market, because each patient treated results in a one-time payment representing a substantial fraction of the lifetime value of the treatment. Rather than collecting incremental revenue with each dose delivered over a patient’s lifetime, gene therapy revenue essentially comes all at once.

Take Zynteglo (beti-cel), recently approved in the United States for the treatment of beta thalassemia. With a price tag of $2.8 million, it was the most expensive drug in history for just a few weeks before another gene therapy made by the same company entered the market at $3 million. But those figures pale when compared with the lifetime cost of treating a patient with a serious rare disease like beta thalassemia, which can easily exceed $6 million, or for Fabry disease, where it has been reported to exceed $14 million (Rombach S et al. OJRD. 2013). After making such comparisons in a report issued earlier this year, the nonprofit Institute for Clinical and Economic Review concluded that Zynteglo would be cost-effective for payors at its $2.8 million price.

Skeptics have correctly pointed out that once you have treated the majority of the patient population in a given indication, revenue from that particular product will fall substantially. But as I’ve explained in an earlier post, that’s not as big a problem as one might think. For one thing, even treating 400 patients at a price of $2.5 million yields $1 billion in revenue. But beyond that, the key to ongoing success is to have the expertise and platform, developed over long experience, which enable you potentially to move from one indication to the next. With each new indication, you have the potential to collect revenues on the scale of the total lifetime treatment cost of the majority of the patient population within a matter of years. Revenue opportunities like this have never existed in the history of the pharmaceutical world — until now. What pharmaceutical company executive wouldn’t want that opportunity?

When you look into the details, there are additional benefits to be had. In many cases, rare disease gene therapies are in development for diseases that are currently treated using a chronic regimen that has already saturated the market. That means patients may be easier to identify, and with clear gene therapy benefits such as reduced treatment burden and potentially more systemic symptom relief, the decision to switch from a chronic regimen to gene therapy will likely come down to familiarity and safety. Both of those issues can be expected to diminish as barriers as gene therapy becomes more common, which may not take long. All of these factors may mean less investment in sales and marketing will be needed to maximize gene therapy revenue.

No late entries

But I can’t say it enough: The key is having an experienced team and mature platform in place when the gene therapy era comes. Even if you were to start building a program from scratch today, existing players will have reaped the rewards of first-generation genetic disease indications and moved on to more common and, thus, potentially more lucrative applications before it had a chance to bear fruit. Gene therapy companies, and academic researchers before them, have spent decades developing the vectors, assays, manufacturing and other technology needed to deliver these treatments, as well as the expertise to keep moving forward as the field progresses. That accumulated know-how should not be discounted.

Today gene therapy stands on a strong foundation, with a recent wave of regulatory approvals and potentially more in the near future as positive clinical data accumulates across multiple programs. A growing number of patients’ lives have been forever changed by this technology, especially those who are able to be treated early in childhood, as that creates the opportunity to have potentially an entire lifetime freed from the consequences of genetic disease. The opportunity to dramatically transform the lives of more patients and families, as well as to dramatically change our healthcare system, is in our sights. The window is now open for pharma and biopharma to consolidate gene therapy expertise and capabilities through partnerships and acquisitions in order to propel themselves to leadership positions and drive this revolution forward, and to benefit from it as well.

Gene therapy is here to stay.  Speed matters.

A vector comprises multiple elements designed to provide the therapeutic gene that is integrated into a patient’s hematopoietic stem cells (HSCs). One key element in a vector is the promotor, which influences how strongly a gene is expressed. Strong gene expression can be critical for sufficient efficacy, but vectors with a powerful promoter are at risk of activating genes close to the integration site, which can lead to safety concerns. It is important to try to reduce the risk of activating proto-oncogenes, or genes that may lead to cancer.

In collaboration with Professor Axel Schambach, Ph.D., Institute of Experimental Hematology, Hannover Medical School, Germany, AVROBIO is researching two preclinical cell-based assays — in vitro immortalization (IVIM) assay and the novel surrogate assay for genotoxicity assessment (SAGA) — to evaluate viral vectors in a preclinical setting. Together these assays are designed to assess a vector’s likelihood to exhibit genotoxic behavior and to monitor if these vectors activate proto-oncogenes. The Hannover Medical School team working with Professor Schambach and Michael Rothe, Ph.D., has previously published its data in Molecular Therapy.

The IVIM assay is designed to estimate the risk of vector-induced cellular transformation. The technique assesses genotoxicity by determining how likely a vector is to insert near and activate proto-oncogenes and lead to an over-proliferation of cells. To evaluate the risk of vector-induced cellular transformation, mouse hematopoietic and stem progenitor cells (HSPCs) were transduced with a panel of vectors and resulting cell growth was compared to a non-transforming mock control and a positive mutagenic control.

The newer SAGA assay assesses genotoxicity more directly. SAGA relies on the observation that genotoxic vectors induce a unique gene expression signature that has been linked to stemness and oncogenesis in mouse HSPCs. Machine learning algorithms developed from transcriptional data of known genotoxic vectors are used to estimate the transformational potential of candidate vectors. On a set of benchmark vectors with known genotoxic potential, the SAGA assay achieved an accuracy of 90.9%, making it more sensitive than previous assays.

In the research presented at ESGCT, the IVIM and SAGA assays were used to evaluate the mutagenic and genotoxic risk potential of lentiviral vectors containing two promoters – the EF1 α short promoter (EFS) and the murine myeloproliferative sarcoma virus promoter (MND). Growth of cells transduced with vectors containing the EFS promoter was statistically different from the mutagenic positive control, whereas growth of cells with the MND promoter was not significantly different from the positive control, suggesting the potential for insertional transformation. Similarly, SAGA analysis of these vectors found the EFS vectors had low normalized enrichment scores of < 1, indicating low mutagenic risk, whereas the MND vector showed a gene enrichment score associated with insertional oncogenesis.

By continually looking at research designed to evaluate and understand the vectors used in gene therapy and using assays in the development process to better assess vector behavior, we have the potential to pave the way for safer gene therapy vectors used in clinical trials.

The clinical data presented, and the testimonials of patients, caregivers, physicians, and the sponsor, all emphasized the transformative potential that hematopoietic stem cell (HSC) gene therapy using lentiviral vectors can have for patients living with serious conditions. For those of us working to develop new gene therapies, these testimonials are always a humbling reminder of the importance of the work taking place across the industry. Additionally, the committee made no requests for longer efficacy follow-up data. I believe these recent developments further support the value of HSC gene therapy using lentiviral vectors, especially in rare diseases with CNS manifestations and for diseases where early treatment is needed.

But at the same time, the hearing may signal a long-term challenge. If we do not accelerate the development of gene therapy and expand our disease focus beyond ultra-rare diseases, we could miss a valuable opportunity to deploy this technology against other diseases that cause significant disability and mortality in our society.

The recommendations made by the advisory committee demonstrate the valuable progress that has been made in cerebral adrenoleukodystrophy (CALD) and beta thalassemia, both life-shortening and life-limiting conditions. As an industry we need positive milestones like the advisory committee’s unanimous recommendations to continue to build our scientific knowledge and to secure the capital resources to keep moving forward, and we are beholden to the patients, clinicians, sponsors, and investors who make that possible. But throughout the committee’s discussions, I heard several themes that underscore gene therapy’s long-term potential to address more common genetic diseases:

• No new safety signals of broad significance – The safety issues discussed last week have not been observed in the hundreds of people who have been treated to date with other gene therapies using lentiviral vectors. The committee appeared to be constructive in their approach to assessing HSC gene therapy and evaluated each gene therapy based on its own unique risk-benefit analysis. Their post marketing surveillance (PMS) requests were pragmatic and reasonable. Risk is inevitable in the treatment of any serious genetic disease, even in the current standard of care, but those surrounding gene therapy are much better understood and characterized now than in the past. Importantly, the emerging clinical data from HSC gene therapy trials have made the risks more predictable and thus potentially more manageable.
• Not all lentiviral vectors are designed the same – Vectors have a starring role in gene therapy, as they deliver the required therapeutic gene to modify the cell’s genome. But the hearing repeatedly highlighted the differences between vectors and how they are each designed to specifically target the type of disorder being treated. Just as there are different types of adeno-associated viral (AAV) vectors – mostly designed to extend reach in particular tissues – there are also distinct differences between the lentiviral vectors used in HSC gene therapy that calibrate their properties in different contexts. Different companies use different versions of the lentiviral vector, different promoters, different transgenes and different manufacturing processes based on the disease they are targeting. This flexibility and adaptability offers possibilities that we have only just begun to explore.
• Ability to treat babies and young children with head-to-toe reach – We heard several times during the testimony that “Time = Brain,” when discussing the urgency to treat CALD. That statement gets at the root of our belief in how important it is that we develop gene therapies that can be dosed early in a child’s life, before their disease causes irreversible damage, and that can reach the entire body, including the brain. Both the ability to treat early and reach the brain are unique features of HSC gene therapies. Sometimes referred to as the “last frontier” of medicine, the brain is where some of our most difficult and long-standing therapeutic challenges lie.
• Better scientific tools – After decades of working on HSC gene therapy, the industry has refined the systems used to modify cells, the processes used to treat patients and the analytical methods used to measure success. During the hearing, scientists were able to discuss in detail, for example, not only whether inserted genes were being expressed but precisely where in the genome they had taken up residence. Standardizing these tools and processes is essential to accelerating the development, regulatory review, as well as delivery of gene therapies to patients.

The learnings from the hearings are further building blocks that could help create a pathway to taking gene therapies mainstream, rather than keeping them sectioned off for ultra-rare diseases. If the FDA approves these two gene therapies later this year, it will bring us to four gene therapies approved in the U.S. in five years. Europe is setting the pace for regulatory approvals of gene therapies, with six gene therapies approved to date.ⁱ And there are a couple of additional gene therapies that either have been submitted, or are expected to be submitted by year end, for FDA consideration.

This progress is further reason for celebration, for sure. But as an industry, we need to keep pushing for more. In the development of game-changing monoclonal antibodies, it has taken more than 30 years of blood, sweat and tears to test, modify and switch out elements to build an industry with dozens of approved therapies and an annual global sales revenue of $163 billion, representing about 70% of the total sales for all biopharmaceutical products.ⁱⁱ

I hope my industry colleagues agree that we need to do more, and faster, to emulate that progress and increase the number of patients and families who can potentially benefit from gene therapy.

[i] Gene Therapy Medicinal Products with a valid marketing authorisation – Paul-Ehrlich-Institut (pei.de)

[ii] MAb Products: Market Trends and Projections – BioProcess InternationalBioProcess International (bioprocessintl.com)

I recently caught up with friend and fellow Canadian, Christine White, president of the National Gaucher Foundation of Canada. Even in a virtual meeting, it’s hard not to feel energized talking to Christine. I’ve long admired Christine’s dedication to improving the health and well-being of Canadians living with Gaucher disease. She is an empowering force and a terrific advocate for people with Gaucher disease around the world. Her work closely intersects with what we strive to do at AVROBIO – bring potentially life-changing gene therapy to the world so individuals with lysosomal disorders such as Gaucher disease can live free from disease progression, painful and debilitating symptoms and the burden of chronic treatment regimens.

Christine’s involvement with the Gaucher disease community began when her two daughters, Meghan and Kate, were diagnosed with Gaucher disease type 1 in 1991. Her son was later identified as a carrier of the condition. Like many other families at that time, Christine and her family were completely unfamiliar with the condition and felt isolated and uncertain about the future.

It wasn’t until Christine and her family met a fellow person with Gaucher disease that she realized they were part of a larger community fueled by a great desire to find better support and treatments. Determined to create change for people living with Gaucher disease in Canada, Christine met with patients, family members and health professionals and eventually helped form the National Gaucher Foundation of Canada. For more than 30 years, the Foundation has worked to improve the health and well-being of Canadians living with Gaucher disease.

From its inception, the Foundation worked on educating and speaking with members of the Canadian government about access to new therapies that had become available for Gaucher disease outside of Canada.

In 1991, the U.S. Food and Drug Administration (FDA) approved the first enzyme replacement therapy (ERT) for Gaucher disease, offering a significant improvement in treating Gaucher disease. ERT works by replacing the missing enzymes that people with Gaucher disease are not able to produce that are needed for the body to break down fatty chemicals that would otherwise build up in bones and organs.

Christine and her fellow advocates worked tirelessly to research and develop a case to demonstrate why access to this therapy was vital and viable for Canadians living with Gaucher disease.

The Foundation helped secure broad access to ERT after meeting with the Canadian Minister of Health. However, ERT was just the first step for Christine. She continually works to ensure that treatments and new solutions are moving forward for her children and others just like them. The Foundation recognizes that even patients with access to current therapies may still have significant unmet needs.

In addition to raising awareness of new therapies, Christine and the Foundation also push to help provide access to these novel treatments. Canada’s healthcare delivery mode is unique and provinces act independently, which may lead to inconsistency in therapy availability across Canada. In her role on the Board of Directors for the Canadian Organization for Rare Disorders (CORD), Christine is working with other leaders on a Rare Disease Drug Framework, which aims to ensure all those living with a rare disease have access to therapy regardless of where they live.

Speaking with Christine, and hearing about her own experiences and the work she does for the Candadian Gaucher disease community, the need for new treatments that can address the various types of Gaucher disease and the wide range of symptoms is clear. Gaucher disease is typically categorized across three types. While Gaucher disease type 1 and type 3 can be managed with ERT, people receiving treatment may not meet the predefined disease parameters for treatment, and still have a significant burden of disease and limited quality of life. There are no therapies for Gaucher disease type 2 and relatively few specialists to care for people living with this type of Gaucher disease in Canada.

Thank you, Christine, for the opportunity to catch up about the issues that matter to people living with Gaucher disease.

Conversations with advocates like Christine help keep these priorities on our radar at AVROBIO, including the importance of collaborating with communities to inform clinical research, listening to people living with and caring for people with genetic diseases to ensure we understand which study outcomes matter to patients, as well as better understanding the unmet needs in the community.

Christine and the many other advocates of the patient communities inspire us at AVROBIO to keep working toward our purpose of freeing people from a lifetime of genetic disease.

Imagine yourself setting out to do business in Japan. You step off the plane, check into your hotel, take a quick nap and then head to a restaurant to meet your potential new Japanese colleagues. You shake hands, sit down, enjoy a delicious meal, talk business – get straight to the deal – and then graciously pick up the check when it arrives at the table. It’s the beginning of a beautiful relationship.

Except that isn’t even close to how things are done in Japan …

While there are many important elements to business negotiation (including basic deal making tactics and strategies), partnerships that extend across international waters can come with a unique set of rules and nuances. A handshake to introduce yourself to someone you do not know is generally viewed as far too forward in Japan. You should know someone’s name before you touch them, which is one reason for the well-known Japanese emphasis on the exchange of business cards – cards essentially introduce your identity. And if you host a business dinner in Japan, don’t expect to talk about business, don’t settle the bill at the table and don’t tip — it’s considered demeaning.

As the third-largest pharmaceutical market in the world, Japan is a prime target for U.S. partnerships. It has similarities to the U.S. biopharma market; for example, Japan has a form of the Orphan Drug Act, as well as an accelerated approval process called Sakigake. But there are important differences, too. Drug approval is more of a two-step process, with marketing approval by the Pharmaceuticals and Medical Devices Agency followed by a reimbursement pricing process governed by the National Health Insurance system. There are also strict shipping rules on biological material which may make it more economical to manufacture drug product on the ground in Japan.

While there are many important factors to consider before journeying down the partnering path with a Japanese company, understanding a little bit about the country’s unique culture is a valuable prerequisite for doing business there.

Five basic rules for engagement in Japan

One: Mirror the culture of politeness and formality

You may sometimes be tempted to break the ice with a joke or casual remark, but in the context of a business meeting, slang and humor may be viewed as a lack of seriousness. While business negotiations can get stressful and contentious no matter where they take place, it is also vital in Japan to avoid confrontation, visible irritation, verbal explicitness or raised voices. The Japanese often try to avoid awkwardness or even a friendly dispute, which is why, at the hypothetical business meal we imagined at the outset, the bill would never come to the table. When hosting dinner for your Japanese business counterpart, you will discreetly pay the bill with the cashier at the front of the restaurant before the meal winds down.

First meetings are more formal, too. Instead of shaking hands, you first introduce yourself using your last name and then present your business card with both hands so that it is readable to the recipient. Again, the business card is a formal representation of a person’s identity. So that means when accepting another’s business card, avoid writing on it and treat it with respect. Do not just fling it into your purse or briefcase, and definitely do not leave it behind, as that is seen as disrespectful. And if you really want to impress your Japanese colleagues with your understanding of their culture and customs, after you exchange business cards then immediately bow for about three seconds and do not extend an American style handshake.

Long after introductions are over, Japanese business culture continues to emphasize formality to express politeness and respect and help build relationships and trust. In more traditional settings, colleagues from different companies never use first names unless invited to do so – it is too personal. Instead, use a person’s last name with the honorific phrase “San” following it to show respect. If someone’s last name was Tanaka, it would be “Tanaka-San.”

The Japanese are courteous to the point that they may not even reject a deal with an outright “no,” and will avoid a negative response, if possible. And if that moment does come, expect the utmost politeness. One U.S. biotech executive of our acquaintance had the experience of flying to Japan with the intention of coming to a mutual agreement with a Japanese company only to discover that no meeting would occur – the deal was off. The Japanese negotiators felt they owed the executive the courtesy of a face-to-face rejection, even at the cost and inconvenience of two trans-Pacific flights.

Ultimately, going the extra mile to learn specific local customs and etiquette can help build trust early in the establishment of a successful partnership. Demonstrating this knowledge also signals an attention to detail – even small things like writing out dates (year-month-day, all in numerical form) and addresses in the Japanese manner (start with the postal code, then state, city, district name, etc.). Such thoughtfulness will not go unnoticed.

Two: Recognize that Japan is a consensus-driven, risk-averse society where decisions take time

Japan is a society where decisions are made through consensus and where all interactions are defined by respect. It is thought that having more minds focused on a decision is better than having one champion or leader who has the final say. As a result, deals may take time and cannot be rushed. In our experience, there is no such thing as a quick deal in Japan.

Never expect to reach agreement in the conference room in Japan, as private discussions are needed before any decision is made. And if you do pressure the Japanese for a decision, they are more likely to slow down than pick up the pace, sensing your urgency as a sign that something may not be right. Quick decisions leave more room for error: the Japanese are risk-averse and apply due diligence to every action they take to ensure important details are not missed. In a business culture where employees often stay with the same company for 30 years, people have an innate understanding they will have to live with their decisions for the long run.

Three: Know your audience

Slow decisions also make sense if you consider your audience: the Japanese party you are courting is likely a manufacturer, whereas you are likely to be in the business of R&D. After signing a contract with a U.S. company, a Japanese firm may need to pull a salesforce and facilities together and sell the product for the lifetime of the patent, which could be a 20-year commitment.

Additionally, in Japanese biotech deals, targeting both the business development and the R&D team is important. First, any proposal to a potential partner will require going through a Japanese company’s business development and licensing department, which likely includes license evaluation, license negotiation and license management. After a license agreement is signed, the last group will become the permanent team assigned to implementing and managing the signed contract – another example of how your counterparts are in it for the long haul.

But BD teams cannot do their job without R&D in their court. While Japanese BD teams will be more familiar with U.S. customs, it’s even more important to exercise Japanese etiquette with their R&D teams, who may not be as familiar with American business practices. Their exposure to your language may also be more limited. In many companies, R&D technical experts will know your technology by reading English material but will not understand it in live conversation – consider discussing whether an experienced, technical translator is needed during the meeting. Only companies in a full-time international business will be fluent in English – domestic companies, even in the largest cities, often will not have many fluent speakers.

Given the language barrier, it is in a presenter’s best interest to avoid confusion by following agendas and slides to a tee. Ensure verbal communications are precisely aligned with written materials and place more emphasis on diagrams and handouts over conversation when relaying complex concepts. And because Japanese businesses tend to make decisions based on a historical lens, compare your data to the current standard of care instead of sharing forward-looking projections, which will be less valued.

Finally, keep your mind open to meeting with Japanese counterparts outside a formal setting or dinner – an international conference is a great opportunity to connect with a peer from a Japanese company of interest.

Four: Business is built on relationships

It’s true anywhere in the world that relationships are essential to business success. But in Japan, those relationships are deeper, more complex and more personal than in other parts of the world. For example, the Japanese are gracious hosts, and if you have advanced your negotiations to the more detailed, advanced stage, long, late and delicious dinners are part of the process. It is important for you to also invite your counterparts to lunches or dinners after your business meetings to further deepen your engagement with your potential partners – reciprocating at the right time throughout negotiations is vital. In Japan, time spent at meals is just as important as time spent in conference rooms – people do deals with people they like. But again, contrary to our imaginary opening anecdote, meals are not for business discussion; they are purely for relationship building. Meetings are not where decisions are made – it is where information is gathered. Strong, personal relationships better round out people on both sides of the license agreement.

If you really want to be on your A-game, participate in the gift-exchange culture of Japan, which is shared with other parts of East Asia. In the United States, you may give a gift to a business colleague to mark a special occasion or celebrate a shared accomplishment, but in Japan gifts are seen as a way to build, not just recognize, relationships. So be thoughtful in the selection of your gift and ratchet up the thoughtfulness of the gift as the relationship deepens. For example, initially bring a gift that reflects where you come from – maybe it’s baseball caps from your home team or a regional food product like maple syrup. As you get to know your counterpart across the table, make the gifts more personal. A well accepted and appreciated gift-giving option is to have a seasonal fresh fruit basket (carefully gift-wrapped) delivered from a local market about an hour before your meeting. Whatever it is, gift-giving is seen as another great relationship-building tool.

Five: Don’t go it alone

Finally, no matter how strong your BD team is, know when you need to bring in a local consultant who can help you navigate the Japanese market. I (Deanna) have traveled to Japan 4-5 times over the years…including Tokyo, Osaka and Kyoto…and have always utilized a consultant to help make business development connections and organize the trips.  Along the way I’ve tried to implement the Japanese training and tips I’ve received, and it has been very much appreciated by my Japanese counterparts who are genuinely grateful to interact with a Westerner who has learned and respects their customs and ways of doing business.  Depending on your own company’s needs, local expertise might come in the form of a single expert or an entire company that has experience getting drugs approved in their respective market. If the deal eventually requires a company entity or manufacturing facility to be set up, those consulting relationships will also facilitate the hiring of local experts to run it.

Biotech is a complex business, and often these sorts of arrangements allow a biotech company to focus on what it does best – discover and develop new solutions for unmet medical needs. International partnerships can help more patients benefit from those innovations, expand a growing company’s commercial horizons and often provide a useful source of funding, as well. If you end up partnering with a Japanese company, it might just be the best corporate relationship of your career.

Originally published on Life Sci VC. 

This work is incredibly important as a foundation for our ongoing clinical programs in lysosomal disorders, where the systemic and cognitive effects of these diseases often are not addressed adequately by the current standard of care. For example, enzyme replacement therapy (ERT) can slow the progression of disease, but it cannot cross the blood-brain barrier to arrest the declines in common CNS manifestations such as visual motor integration, motor coordination and visual perception that are often observed in people with cystinosis.

AVROBIO was founded in 2015 with the goal to harness the curative potential of genetic modification with the regenerative benefits of HSCs, leveraging HSCs’ natural properties that potentially can pass genetic modifications on to their cellular progeny and distribute them throughout the body, from head to toe. HSCs are found in the bone marrow, where they differentiate to produce every kind of blood cell – macrophages, T cells, B cells, erythrocytes (aka red blood cells) and many others.

In fact, although AVROBIO has traditionally referred to itself as a lentiviral gene therapy company, we might be more fairly characterized as an HSC company. Although we of course use next-generation lentiviral vectors to genetically modify HSCs, the vectors themselves never enter the patient’s body. It is the patient’s own cells, augmented with a missing gene intended to produce a necessary protein, that constitute our drug product.

The power of HSCs

Their primordial role gives HSCs multiple properties that make them well-suited to address genetic disease at its root. First, they can be removed from the body, modified and re-infused. In fact, donor bone marrow transplants have been conducted for more than 60 years in over 1.5 million patients worldwide.[i] Second, because HSCs are precursor cells that give rise to all blood cells, their progeny have access to every tissue in the body, including the brain and spinal cord. And finally, the presence of a stable HSC population in the bone marrow means that any genetic modification should continue to be passed on to daughter cells, potentially for the lifetime of the patient.

Today, more than 400 people have received some type of gene therapy designed to genetically modify their HSCs. One recent study[ii] found that in clinical trials using lentiviral vectors to insert the modified genes into the HSC genome, engraftment rates have been 99%. And because the HSCs are a patient’s own, they do not pose the risk of provoking an immune response, which may have caused potential safety issues in some other types of gene therapy.

Broad applications

These properties make genetically modified HSCs potentially well-suited across a broad spectrum of genetic diseases where there is urgent unmet medical need. They are obvious candidates for the treatment of genetic diseases that directly affect HSC daughter cells, such as sickle cell disease (SCD) and beta thalassemia. In these conditions, mutations in a gene encoding part of the hemoglobin protein affect the function of red blood cells. Investigational HSC gene therapies currently in development have the potential to free people with these conditions from a regimen of frequent blood transfusions and drugs that often come with substantial side effects, along with the potential to live with less pain and pursue more physical activities. One HSC gene therapy for beta thalassemia and one for SCD have been approved for use in Europe and are currently under consideration by the U.S. Food and Drug Administration.

More rare, but similarly promising as a potential application for HSCs, are the primary immunodeficiency disorders (PIDs), which result from a wide variety of mutations affecting different components of the immune system.[iii] Children born with these conditions can be particularly susceptible to infections, sometimes requiring extreme protective measures such as isolation in sealed chambers with controlled air flow. Because HSCs give rise to every type of blood cell affected by this family of disorders, these gene therapies have the potential to address a wide variety of PIDs at their root, and children have been successfully treated using this approach since the 1990s.

The third major area in which HSCs potentially offer a major advantage is in the treatment of metabolic diseases. While HSC-based treatments for hemoglobinopathies and PIDs aim to make repairs to cells that ultimately derive from hematopoietic progenitors in the bone marrow, this technology can also be used to treat inherited deficiencies in other cells. In these cases, correct copies of affected genes are engineered into HSCs so that their descendants produce a working copy of a protein that is otherwise flawed or missing across all of a person’s cell populations. One gene therapy for the rare metabolic disease metachromatic leukodystropy has been approved for use in Europe.

At AVROBIO, we concentrate on a family of inherited metabolic diseases called lysosomal disorders. Lysosomal disorders are a family of genetic conditions, each caused by changes in a particular gene involved in helping subcellular organelles called lysosomes recycle molecular materials. When one of these genes does not function properly, molecular waste products build up to toxic levels inside cells. Depending on the type of material and the rate of accumulation, lysosomal disorders can impact different organs at various degrees of severity.

The current state of care for lysosomal disorders involves regular infusions of enzymes needed to prevent the buildup of cellular waste. For example, people with Gaucher disease receive glucocerebrosidase, while those with Pompe disease get alpha-glucosidase. In cystinosis, the strategy is slightly different, employing regular doses of a compound called cysteamine that breaks down accumulated waste material. All of these treatments have limitations, however. And as I mentioned at the outset of this article, current treatments cannot cross the blood-brain barrier to prevent disease progression in the neurons and other cells of the CNS.

Potential durability of head-to-toe reach

A number of different gene therapies have been proposed, and some have been tried, as a way to overcome the limitations of currently available treatments. But some gene therapy approaches do not reliably reach the brain, which can be severely affected in these disorders and may be overlooked as a site of disease progression in others. In addition, the effectiveness of some gene therapies can diminish over time as treated cells die off without passing on their modified genes, which also makes them poorly suited for pediatric use.

We believe HSCs have neither of those drawbacks. Once resident in the bone marrow, HSCs are designed to be a bottomless well of corrected genetic material. And because HSCs give rise to cells that can circulate everywhere in the body they are expected to cross the blood-brain barrier, creating the potential to extend to every tissue, head to toe.

With HSCs at the core of our technology, we believe that durability and full-body reach potentially can be achieved across a broad spectrum of lysosomal disorders and patient populations. A recent review of gene therapies using HSCs published in Molecular Therapy surveyed clinical progress in the field over the past two decades and concluded that “substantial disease correction was observed in most treated patients.”[iii]

Where does AVROBIO stand? I believe our long-standing application of HSCs puts us at the forefront of an extremely promising and growing sector in cell and gene therapy. This sector includes a growing number of companies that are working to enhance the curative potential of genetic modification with the regenerative potential of HSCs to make sufficient, sustained and, if needed, supraphysiological levels of functional protein, building on industry-wide clinical data that have demonstrated the durability, reach and adaptability of HSCs in a broad spectrum of indications, with the ongoing promise to impact the lives of patients. And that is a pretty exciting place to be.

[i] Granot, N. and R. Storb. History of hematopoietic cell transplantation: history and progress. Haematologica. 2020; 105 (12) 2716-2729.

[ii] Tucci, F. et al. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders. Nature Communications. 2022; 13: 1315.

[iii] Tucci, F. et al. Update on clinical ex vivo hematopoietic stem cell gene therapy for inherited monogenic diseases. Molecular Therapy. 2021; 29(2): 489-504.

The gene therapy industry overall similarly faced challenges in 2021, touching on safety, manufacturing, regulatory and commercialization issues. AVROBIO has not been immune; we recently deprioritized our Fabry disease program due to several factors, including emerging clinical data suggesting variable engraftment coupled with challenging market and regulatory dynamics. While a very difficult decision because of its impact on the patients and families we aim to serve, we believe it was the right step forward for AVROBIO and our stockholders. We have reduced our headcount and streamlined our operations as we aim to extend our cash runway into the first quarter of 2024 to support development of multiple important, and what we believe will be value-driving, clinical programs.

While we have faced headwinds recently, we remain excited about the fundamental promise of our gene therapy. With the steady progress we’ve made across our clinical programs in cystinosis and Gaucher disease type 1, and the path we’ve charted in 2022 as we seek to move multiple programs into late-stage trials, we see great opportunities to move toward our goal of helping free people with lysosomal disorders from disease progression, painful and debilitating symptoms and the burden of chronic treatment regimens. Additionally, in 2021, we received Rare Pediatric Disease Designation for AVR-RD-05, our gene therapy for the treatment of mucopolysaccharidosis type II (MPSII) or Hunter syndrome, a rare and seriously debilitating lysosomal disorder that primarily affects young boys; as well as received Fast Track Designation from the  U.S. Food and Drug Administration and Orphan Drug Designation from the European Commission (EC) for AVR-RD-04, the company’s investigational gene therapy for the treatment of cystinosis. Both of AVROBIO’s investigational gene therapies in the clinic have received Orphan Disease Designations from FDA and EC.

We were also proud to see our industry-leading gene therapy platform, plato®, recognized as the 2021 Technology Innovation winner of the Fierce Innovation Awards: Life Sciences Edition.

So far this year, we reported interim data from the collaborator-sponsored, ongoing Phase 1/2 clinical trial[i] of AVR-RD-04, an investigational gene therapy for cystinosis at the WORLDSymposium® 2022 held in February. This devastating disease causes severe visual impairment, a dramatically shortened lifespan and a kidney transplant in 90% of patients – even on today’s standard of care. The first three patients infused with AVR-RD-04 remain off oral cysteamine, with follow-up durations ranging between 12- and 26-months post-gene therapy infusion. Sustained engraftment, demonstrated by stable vector copy number (VCN) levels, has been observed in each of these patients. A fourth patient was infused in November 2021. No adverse events related to the drug product have been reported in the four patients infused through the most recent safety cut-off date of Dec. 1, 2021.

We strengthened our crew at AVROBIO, including the appointment of three new leaders, including

• Essra Ridha, M.D., MRCP, FFPM, was named chief medical officer in October 2021. She was previously clinical development lead at AVROBIO and has extensive experience in cell and gene therapy development gained at Sangamo Therapeutics and GlaxoSmithKline.
• Azadeh Golipour, Ph.D., was named chief technology officer in January 2022. She has filled multiple roles with increasing responsibility during her five-year career at AVROBIO.
• Sean O’Bryan, was named chief regulatory officer in February 2022. He brings a wealth of experience in regulatory strategy and product development for cell and gene therapies.

Later this year, we anticipate providing a clinical update for our Gaucher disease type 1 program, including data on the first patient who is now more than 18 months post-infusion. We intend to engage with regulatory agencies on the initiation of clinical trials for cystinosis and Gaucher disease type 3 planned to commence in 2023. Additionally, we expect to advance our preclinical programs for Hunter syndrome and Pompe disease by initiating clinical trials in 2023 and to strengthen our industry-leading gene therapy platform, plato®, to ensure that our manufacturing, delivery and analytics are Phase 3 ready.

We’re excited about the many catalysts ahead, and confident that we can meet the various challenges of delivering an investigational therapy to the people who need it. The needs of the lysosomal disorder community we aim to serve are pressing, and the AVROBIO crew works with urgency every day to advance our work and move closer to realizing our vision of freeing people from a lifetime of genetic disease.

Read more about our 2021 performance in the Annual Report. We look forward to updating you on our progress as 2022 unfolds.

[i] Collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04 is funded in part by grants to University of California San Diego from the California Institute for Regenerative Medicine (CIRM), Cystinosis Research Foundation (CRF) and National Institutes of Health (NIH)