Blog | December 10, 2021

Scott Gottlieb: Plotting The Trajectory Of Cell & Gene Therapy CMC

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By Anna Rose Welch, Editorial & Community Director, Advancing RNA

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When I transitioned from the biosimilar industry into the cell and gene therapy (CGT) space, the irony of such a transition wasn’t lost to me. I was making a leap from one end of the innovation and patient access spectrum to the other. On the one hand, biosimilars are a celebration of what is possible when we know the analytical and clinical profile of a molecule so well that we can replicate it, manufacture it at a large scale, and sell it at a discount. Such a development expands patient access and frees up healthcare funds to cover innovative treatments — including CGT treatments.

The same is not even close to being said on the CGT side. In addition to the striking differences between CGTs and biologics in terms of cost, patient access, and market tenure, we also know infinitely less about what’s going on structurally inside the black box of CGTs.

Many of the articles I’ve written in the past year have explored why the CGT manufacturing paradigm — from a scientific and economic standpoint — is keeping many of us up at night. But it took a quick 10-minute conversation with former FDA commissioner Scott Gottlieb on a dark and stormy Thursday night to find the biosimilar and CGT manufacturing world colliding. And suddenly, my two beloved worlds didn’t seem nearly as far apart as they currently are, scientifically and economically.

In mid-November, I had the immense fortune (thanks to a little help from some friends) to be one of three editors/journalists to meet with Dr. Gottlieb at a press junket prior to his public presentation on the campus of Penn State Erie, The Behrend College. Though he has become one of the most trusted voices through the COVID pandemic, I wanted to hear how his thoughts on the advanced therapies development paradigm have evolved in the past few years, and how he sees the world of CGT CMC changing in the future.

Cell & Gene Therapy CMC In 2021: Are We Stuck In A Time Loop?

The FDA’s Peter Marks may be the current face of cell and gene therapy regulation, but Dr. Gottlieb made an indelible impression on the industry. Not only did he bring the oft-mysterious workings of the FDA to the general populace, he also went down in history for his quote on how CGTs have challenged the industry and regulators alike. Everyone knows the quote I’m talking about (from 2018):

In contrast to the traditional drug review, where 80 percent of the review is focused on the clinical portion of that process, and maybe 20 percent is focused on the product issues, I’d say that this general principal is almost completely inverted when it comes to cell and gene therapy…. The more challenging questions relate to product manufacturing and quality…

I’ve heard it time and time again from a number of manufacturing experts, many of whom have made the leap from the world of antibodies into the kingdom of advanced therapies: it often feels as though the clock has been rewound and we’re (sort of) back at the beginning of the monoclonal antibodies market. Even Dr. Gottlieb himself sees history repeating itself in the CMC-related challenges the CGT industry is facing today. Pharma’s general inability to fully characterize monoclonal antibodies in the earliest days of their development was a significant limiting factor in understanding and improving a product’s clinical profile. Hence why it took upwards of 20-plus years for the arrival of biosimilars — a feat some even argued would forever be impossible. (And, if you can even believe it, even 30 years later, there are still some pretty impassioned regulatory debates about how much we can know clinically about these CQAs and what advanced analytical approaches can tell us.)

The CGT space has found itself on similar footing the past few years. As CMC continues to throw companies for a loop, it’s only natural that there would remain some critical clinical questions. The overall durability and toxicity of these therapies remain big question marks hanging over the industry and healthcare system. How the industry can engineer these products to reach the necessary targets without causing deleterious off-target effects is on many bucket lists. But a product’s safety and clinical profile is dependent upon its (fully characterized!) structure-function relationship.

“There is a nexus between how you make a product and what the clinical characteristics of the products could be,” Dr. Gottlieb explained. “Much of the clinical uncertainty today ties back to uncertainties within the manufacturing process, particularly as it relates to achieving overall manufacturing consistency and/or fully understanding and characterizing the principles of your cells. We were better able to improve a biologic’s clinical characteristics only as we were able to better characterize the biologics themselves. I think the CGT space is going to follow a similar trajectory.”

Despite the fact that characterization was a forefront issue for the biologics industry of yore, Gottlieb wouldn’t go so far as to say that the rise of antibodies in the 1980s/90s “flipped the development paradigm on its head.” The 80 percent CMC/20 percent clinical ratio is unique to CGTs. (You’re welcome, I guess?) Though biologics as we know them today have revolutionized the oncology and autoimmune disease treatment paradigms, it was unclear back at the start of the market just how impactful the earliest antibodies would be clinically for patients and treatment regimens. For example, in its initial registration studies, blockbuster rituximab (Rituxan) only demonstrated marginal benefit for the studied population. It has since gone on to become a standard of care for several hematological malignancies and autoimmune diseases and has a number of biosimilar competitors on the U.S./EU market to boot.

Early clinical data in the CGT space, on the other hand, has suggested these therapies’ transformative potential. Hence, the revamped 80/20 development ratio. The immediate challenge — given their intriguing clinical potential in small patient populations — is to figure out how to reliably and consistently manufacture these therapies, both at small and large scale. (That latter part is where we’re currently stuck.) We also have to clearly demonstrate each product’s consistency to regulators, not only throughout clinical development but also after commercialization, through which routine adjustments and advancements in manufacturing processes and technologies occur.  

A Prediction On The Future Of Cell & Gene Therapy CMC Innovation

The catalyst for industry advancement is often a single event. The advent of the fully humanized antibody unleashed the monoclonal antibodies space. For CGT, the rise of AAV as a delivery tool paved the way for the industry as we know it today. However, though the industry’s most recent wave of progress may have been kickstarted by AAV, it certainly doesn’t end there. In fact, Gottlieb is most excited by the ongoing work to improve gene therapy delivery. The goal is to move away from only being able to address the “low-hanging fruit” targets (i.e., those reached using needle-based administration) to those that are currently harder to reach using systemic (IV) delivery. Whether this means improving upon current viral vectors or exploring nonviral vectors, he anticipates much more innovation in receptor-mediated delivery.

Making such strides in delivery will ultimately broaden the therapeutic possibilities for gene therapy. Though it may seem farfetched that today’s pricy gene therapies will be used to treat a more routine condition, Dr. Gottlieb is optimistic they will become a more mainstream form of treatment. (Never in Dr. Gottlieb’s wildest dreams would he have ever thought biologics would be used as primary care drugs to treat something as common as high cholesterol. “I would’ve said you were crazy,” he joked — but here we are.) Not only will the economics improve as manufacturing becomes more standardized, but there are also a number of forthcoming manufacturing innovations — whether they be allogeneic cell therapies or nonviral therapy delivery — that will reshape the economics of these therapies.

Little did Dr. Gottlieb know when we sat down and started our conversation that I had lofty goals of offering my readers a new quote with which they could arm themselves as they leave 2021 and enter 2022 (and beyond). His statement from 2018 remains — and likely will remain — relevant for the years to come. But it’s always good to have an optimistic take on what’s to come from each and every day of what can feel like painstaking labor and slow progress. And I daresay, Dr. Gottlieb delivered.

“The 80/20 ratio will shift,” he offered when I asked if this would be our status quo forever. “The complexity of the drug review today is a result of current manufacturing and product features.  This will be reduced as we understand these factors better, as was the case with antibodies. We now have all kinds of tools that allow us to characterize antibodies. It’s no longer a mystery of ‘What’s in the soup.’ That’s what’s going to happen for cell and gene therapies, too."