Gene Therapy Drug Development is a Team Sport

Emily Walsh Martin, Ph.D. - January 26, 2021

In drug development, scientific progression was never a solo effort, writes Emily Walsh Martin, Ph.D.   

When I was in my PhD program at the University of California at San Francisco, many moons ago, the highest achievement one could have would be a two-author paper. Just you and your graduate advisor alone on the masthead, sharing important science with the world. During my post-doc at the Broad Institute with Eric Lander, I found that in the genomic sciences the list of authors was often an inch or more deep in 11-point font. However, even on those papers, in my experience, the lead author is the driver of the work, and often, the decider for strategy. Sometimes that was performed in collaboration with their advisor or a close collaborator, but many times, not so much. And so, I was honestly not prepared by that effort to understand what to expect when I went to industry to help develop novel therapeutics. In drug development, scientific progression was never a solo effort. Rather, to advance new therapies, particularly cell and gene therapies, drug development is a team sport.

Why is the team so important?

Oftentimes when one tests novel cell and gene therapies in the clinic for the first time, one is treading completely new ground. The unknowns (and the unknown unknowns) prior to that first patient-volunteer being dosed are usually much greater than the knowns. The argument to continue to progress a therapy in the clinic is often based on a “totality of data” assessment and the implications for the patient risk-benefit. To assess the potential benefits and risks, a comparison is performed of the drug’s merits to historical programs across a range of disciplines including manufacturing, analytics, toxicology, pharmacology, pharmacokinetics, medicine, and regulation. While many drug development scientists are deeply expert in their corner of the work, the rationale for progression to test a new therapy in human volunteers is by definition cross-functional.

For instance, even what might seem to be a simple decision, e.g. the starting clinical dose for a viral gene therapy, must be interrogated cross functionally. Teams making this decision must wrestle with the question from many different vantage points including (but not limited to):

  • Deep understanding of the preclinical model’s biology relative to the human disorder (e.g. does it reproduce the disease as well as the therapeutic intervention timing expected clinically relative to diagnosis?)
  • Sufficient understanding of the relative transduction efficiency, tropism, payload potency, etc., in the animal model species compared to the human species
  • Examination into whether the manufacturing process used is representative of what will be used clinically and that the analytical release testing is also reproducible, reliable, and representative of what will be used for clinical batches
  • Thorough consideration that the therapeutic mechanism is well-assessed by analytical testing as it pertains to efficacy, safety, and durability
  • Thoughtful understanding of what other options patients have, and whether the gene therapy under study provides a distinct benefit, given the risks and unknowns
  • And particularly for viral vectors, for which we currently have no means of re-dosing, there is the question of whether the selected dose is not only safe, but also offers some benefit directly to the patient as you may be taking away that patient’s shot for a therapy (at least of the same serotype)

And while program leaders in gene therapy drug development have a general framework for these big-picture questions, every new program presents new challenges which can change the risk-benefit considerations. Some of the novelty may come from specifics about the vector or disease, and some arise from emerging science. Perhaps it’s obvious, but there simply is not enough time in a day (or years in a career) to be a cutting-edge expert across all these disparate disciplines. Therefore, the only way for a program to faithfully pursue an understanding of their product is as a cross-functional team.

Who makes up a drug development team in gene and cell therapy?

Successful team building starts with ensuring the correct disciplines are in the room. For programs where a development candidate has been identified but has not yet entered clinical testing, most high-functioning core teams include the following members from the following disciplines:

  • Manufacturing – the folks who will take the research production process for the therapy and scale it up for IND enabling and clinical studies, while also keeping current with the science of the product and current GMP regulations
  • Analytical – experts who ensure the correct testing for manufacturing is performed and is performed at a quality that can ensure batch to batch consistency
  • Biology – the vector experts who understand the mechanism and disease modification hypothesis and who provide key inputs into how to test the product prior to advancing into the clinic
  • Pharmacology – animal model specialists who help ensure IND enabling designs incorporate considerations that allow for interpretations of efficacy (and often safety) relative to species differences
  • Toxicology – similar to pharmacology above but with a safety focus as well as a focus on interpreting the implications of the results of the IND studies relative to other similar therapies
  • Pharmacokinetics – folks who work to ensure that the right data are generated preclinically and clinically to inform the biodistribution of the drug product and payloads, which allows for a thoughtful understanding of the safety and efficacy of the therapy
  • Medical – specialists who design the clinical trials based on the therapeutic hypothesis and considerations/limitations of clinical inquiry in the specific disease understudy
  • Biomarker – folks who help to add molecular endpoints to the design of animal and clinical studies which can help to elucidate not just efficacy but also confirmation of therapeutic mechanistic proof of concept
  • Regulatory – individuals who play the interface role with regulatory agencies such as the FDA. Part historian, part reader-between-the-lines, and part strategist.
  • Program Lead – this is often a role that changes depending on the stage of the program. Can be a Ph.D. or M.D. depending on the company and stage of development. Certainly, sets the direction of the ship, but only after soliciting input from the rest of the team (and management!)
  • Program Manager – “air-traffic-control” person who ensures that the right team members have given the needed input into the key decisions the program has to take. Sometimes this person also oversees that the science is done in alignment with the budget for the program as well.

This is a long list. But, importantly, this is not the full team responsible for development. Often each of these disciplines works as part of a function or subteam. And their role at the core team level is to provide input not only for themselves but on behalf of others. As a result, the core team is basically a team-of-teams, where all disciplines are critical, and some are more crucial than others depending on the phase of the program or the challenges faced.

What qualities of the core team make a program successful?

This is bit of a nebulous question. Certainly, the qualities of the product under development play a role. However, in many cases it is the way the team comes together around the product that makes all the difference. The list of key attributes is long, however some of the key qualities are:

  • Communication, communication, communication
  • Shared contribution to decision making
  • Accountability for delivering against the program plan
  • Ability to understand when past experience is a useful guide
  • And, on the other hand, ability to recognize when past experience has limited utility because the team is forging new ground

But at the core, most successful teams have a deep understanding that no one person on the team alone has the answers, even for questions that might seem to fall squarely in a single discipline. An equally important counterpart to that quality is that the teams also understand that ultimately, they will be unable to answer all the open questions prior to use in that first patient volunteer.

Teams that can hold both concepts in their minds—acceptance of the unknowns along with a drive to fully elucidate the knowable—are key in advancing novel gene and cell therapies to address unmet medical need.

Dr. Walsh Martin is a principal at Tremont Therapeutics and a member of the ASGCT Communications Committee.

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