Navigating Genomic Therapy Development

Genomic medicine research is advancing quickly, bringing with it questions about clinical trial design, regulatory pathways, manufacturing and pricing. In this article, Sandy Macrae, Chief Executive Officer of Sangamo Therapeutics, Inc., will discuss this new wave of medicine and navigating challenges to change the treatment of genetic diseases.

Moe Alsumidaie: What challenges have you experienced running gene therapy studies? For example, how do patients and physicians respond to the concept of gene therapy?

Sandy Macrae

Sandy Macrae: Gene therapy studies are part of a complex ecosystem that we, along with regulatory agencies, need to manage very responsibly. In pharma, you're usually dealing with trials of several hundred or maybe many thousands of patients. In gene therapy, studies often only have 10 or 20 patients.

Patients go directly to investigators, so our relationship with those investigators has to be managed carefully. We often work with patient communities to make sure they have the support of people who understand their disease and available treatments and help them think through whether they should be part of a trial.

We have to think through those nuances, and then get through the IRB, because sometimes the hospital IRB has never done a trial with us, and they need to understand what we’re trying to do. In addition, the first dosing of a genomic medicine almost always takes longer, due to the “first patient” phenomenon, which happens when we’re working on a novel therapy. The patient may be a little unsure about what happens, and they know it's a big decision they're making.

MA: Do you involve patients in the design of the trials?

SM: Every trial we do has patient input. When I worked in big pharma, that is something we always talked about and tried to do. At Sangamo, the patient is at the start and center of every conversation. We make sure that patient groups see our clinical protocols and we listen to their feedback.

I think it's important to understand the patient journey -- what it feels like to drive 500 miles across California to find parking at the hospital, and then wait in a waiting room, receive numerous tests, and then stay in a hotel overnight. We're trying things like working with investigators to look at how we house patients in the clinical trial, even bringing them near the investigator for a period of time. It's costly, but if it means the patient doesn't have to make that journey, it’s worth it.

We have pictures of patients on our walls, and we do it for several reasons: primarily because patients inspire us all, from people who work directly with patients to people who work in the packing department or the manufacturing group. There's a sense of urgency - you know that patient depends on you and you’d better get it right.

MA:How do the differences of developing one-time gene therapies impact clinical trials, and what different responsibilities do you have during studies and post-marketing?

SM: We hope that gene therapies are going to work inside the body for five to 10 years; with gene editing, we hope it's going to be effective for the patient's entire lifetime. Because of that, we need to understand and talk about risk in a way people can understand. We're working with ethicists and discussing how to manage consent better, and about what our obligations are for the long-term.

We feel a responsibility to follow these patients over time. Drug companies often get sold, patients move geographically, or doctors move on to their next job, and there isn't a single place where that patient is followed throughout their lives. We need to find a way to do that. One way would be a national authority because, in countries such as the UK, there's a National Health Service that follows the patient wherever they go. In America, there isn’t a parallel, and I think we need to be thoughtful about that.

MA: Have you considered digital health as an option to follow the patients?

SM: Incorporating novel methods for tracking patients requires a full evaluation. If it’s digital, that takes you into all of the realms of privacy, and who owns the data. We have to consider whether it’s the government, or a body like the NIH or the FDA, that follows these patients long-term; the way it’s currently done with a small molecule is by submitting an annual safety report each year on the population. We can’t take that approach with gene therapy because, in theory, the patients no longer need therapy, and therefore don’t need to continue to see doctors. It is an interesting challenge we are focusing on solving.

MA: Can you describe the regulatory pathways that have changed with gene therapy clinical trial execution?

SM: Sangamo is the longest-established gene editing and gene therapy company, and we've grown with the regulations. In our interactions with the FDA, we sense that they want to be part of the ecosystem. They ask questions that suggest they want to learn and understand. More and more, the FDA comes to us with questions that reflect a broader experience that we now have as other companies are starting to go through the same process we did. We cannot speak kindly enough of the regulatory process, I think it protects patients, and it is thoughtful and reliable.

MA: There's a lot of talk about pricing. With genomic therapies, you’re aiming to treat or cure severe genetic diseases. How has that impacted questions you get about pricing strategies?

SM: It's about access to medicine. Patients are precious, and it needs to be about what we bring to the patient with this new treatment. The drug has to be reimbursed so patients can access it. For a patient with hemophilia, for example, the lifetime cost factor is an average of $6.5 million. That doesn't include ancillary costs, such as treatment visits for the bleed in their knee, or an X-ray or hospitalization.

Beyond that is the time that the patient couldn't work, or the time their mother or father couldn't work. It's crucial that patients can access the treatment and that insurers will make it reimbursable. We have to balance that with the cost of developing these medicines and running the clinical trials.  

MA: What's your top guidance to trial management teams for setting up success in studies?

SM: Don't change what you're doing between phases I and II; that's the golden rule of research. Confirmatory or pivotal study results tend to go awry when you change the dose, the patient population, or something else. If you achieved a specific result with the patient population in earlier phase studies, go back to this population so you can still get the same result. We have a responsibility to patients to design studies well and make it available as a medicine; that’s at the center of everything we do to advance genomic medicine.