Guest Column | January 3, 2020

4 Top Challenges Facing Gene Therapy

By Holly May, Chief Commercial Officer, AVROBIO

How To Fix The Patient Diversity Problem

It’s never too early to start thinking about the end goal. That’s been my philosophy throughout my career, and in the rapidly maturing field of gene therapy, it’s non-negotiable.

After all, even after we as an industry nail the science, we will face substantial clinical, regulatory, and logistical challenges in bringing these therapies to market. Those are not issues you can resolve on short notice. Indeed, this long-lead work is precisely why I recently joined AVROBIO’s leadership team as chief commercial officer — at a time when we are still quite a way from commercialization.

Here are the challenges I’m thinking about now:

Working Toward an Ideal Label

We all want approved therapies to be available to every patient who can benefit. I believe that goal is best served by a broad label when the product comes to market. And the time to start thinking about the label is years earlier, during the design of clinical trials.

There’s a natural tension here: The clinical team may want to tighten trial eligibility to a more homogeneous set of patients who are more likely to show strong benefits. Yet that approach could lead to an overly restrictive label and crimp access. This is a challenge for every modality, of course, but it’s especially critical for gene therapy, where we have to make decisions early on about whether to include patients with genetic variants in clinical trials — and understand what that might mean for the biomarkers we use to measure efficacy.

Beyond eligibility, considering the final patient experience is crucial in protocol design. Again, this is especially pertinent for a multi-step therapy such as the ex vivo, lentiviral therapies we’re developing for lysosomal storage disorders. Will patients ultimately want to have choices at certain stages, such as the flexibility to choose from among several conditioning regimens? Or, do we expect that every patient will follow precisely the same protocol? These questions are important to think through early, as the answers can help shape trial design.

To get people thinking about these issues, I like to run a thought exercise with each program team. First, we talk through the ideal, mediocre, and restrictive labels for our investigational therapy. Then, we work backward to identify how we might arrive at each of those outcomes. The goal is to ensure we are all aware of the future ramifications of every decision we make now. As I tell my teams, you only get one chance to launch, and at launch, you are your label — so it’s essential to get it right.

Securing the Supply Chain

We all know that the supply chain for these therapies is long and complex. Every step along the way needs to be carefully planned.

That means not just securing reliable partners, but making sure that within those partners’ teams, all who touch components of the therapy are impeccably trained. It means implementing rigorous quality assurance protocols, starting with the apheresis centers that collect the patient’s blood products and continuing through every step of vector manufacturing, cell transduction, cryopreservation, and infusion. It even means thinking through and planning for crisis scenarios, such as a natural disaster that might disrupt shipping of a therapy during a crucial window for delivery.

At AVROBIO, we’ve sought to build strong supply chains for clinical trials, and we’ve sought to give patients more flexibility in scheduling with innovations such as improved cryopreservation to extend drug product shelf life. We’re proud of this work. But we know that expanding the supply chain to a global, commercial scale — even in rare diseases with relatively small patient populations — is very different. It is important to pressure test your clinical trial supply chains early, probing the capabilities of existing and potential partners and systematically working through all the implications of scaling the process.

Confronting the Challenges of Reimbursement

With just a tiny number of gene therapies approved globally, we don’t have much precedent here. That’s why it is vital to start talking about reimbursement, not just at leadership and board meetings, but more broadly among potential stakeholders.

As my first hire, I plan to bring on a specialist in global market access. Again, this may seem early for a company at AVROBIO’s stage. It’s not. We need to start having discussions now with commercial and government payers and with the external voices who help shape public policy on pricing.

These conversations involve post-approval hypotheticals, but they do not involve promoting investigational products. The rules of engagement in the gene therapy space allow for this type of early conversation because this modality is so new and — let’s face it — because the high prices for the early-to-market gene therapies have payers searching hard for solutions. High prices, of course, are relative; these are also potentially extremely high value therapies, both for individual patients and for the health care system as a whole. At AVROBIO, for instance, we expect our gene therapies, if approved, potentially could save many millions for each patient treated by comparison with lifetime costs for the standard of care in indications such as Fabry disease, Gaucher disease, Pompe disease and cystinosis.

We therefore want to put our collective brain trust to work early to think through innovative models for reimbursement. Other gene therapy pioneers have tested pay-for-performance and value-based models; these may well be successful, but it’s still too early to declare them the definitive answer for all gene and cell therapies, especially as the range of approved indications and technologies broadens. We have the opportunity to pioneer our own model to best reflect the value proposition we expect to offer, the cost savings we hope to deliver and the core goal of reaching as many patients as stand to benefit from our therapies.

Understanding the Patient Journey

Underlying all the elements I’ve discussed here is the need to understand the patient journey. This is a foundational element for all our work.

We need to appreciate at a very deep level what it means for patients to live with these genetic diseases, day in and day out. We need to learn more — from them, not from textbooks — about the strengths, limitations, and burdens of the standard of care. We need to understand what might motivate them to take a leap of faith and enroll in a clinical trial for an investigational gene therapy. And we need to understand who among them would be ideal candidates for the therapy if approved, and how to address the many questions that are bound to arise.

We need to understand, too, the hopes and the hesitations of their loved ones, their physicians, their trusted advocates, and everyone else who might play a role in the anticipated success of our mission.

Perhaps most important, we need to train world-class field teams to work closely with all these stakeholders. To be clear, this is not just a sales force — not in the traditional sense, at least. Their job is more than promoting a pharma product. In the gene therapy realm, we need all our field teams to be creative, empathetic, and mission-driven problem solvers. They must truly understand what patients need and move heaven and earth to make that happen — all in an environment where compliance is fundamental.

As I look back at these recommendations, I must admit, they seem staggering. In truth, though, this is just the beginning. I am adding to my priority “to do” list as I continue to think through the steps we need to take now to ensure we have the capabilities to deliver what we anticipate to be transformational therapies in the future.