Suppliers Pushing Novel Analytical Methods Testing Forward
By Matthew Pillar, Editor, Bioprocess Online
Lexeo Therapeutics VP of Analytical Development & Quality Timothy Fenn, Ph.D. took the stage at the ribbon cutting ceremony for MilliporeSigma’s new $285 million biosafety testing facility in Rockville, Maryland last week. His presentation got into the weeds of the analytical methods challenges Lexeo has faced over the course of his three-and-a-half-year tenure there, time spent developing AAV gene therapies for cardiovascular and CNS indications, including Alzheimer’s Disease. While he spoke at length on Lexeo’s approach to analytical science, it was his characterization of gene therapy testing protocols as the “wild west” that caught my attention.
With three candidates in Phase 1/2, two pre-clinical, and two in discovery, Lexeo, founded in 2017, isn’t unlike other early-stage biotechs in its quest for speed. Alzheimer’s and cardiomyopathy are giant indications, their patient needs are unmet, and collectively, patient populations number in the millions in the United States alone. There is quite literally a race to develop treatments for these diseases, a race run by competitors across multiple therapeutic modalities. The hope for a viable gene therapy approach, and its unique potential to be not just therapeutic, but potentially curative, creates an extra layer of urgency for Lexeo. The safety of experimental gene therapies is scrutinized by regulators, patients, payers, and caregivers alike, and that scrutiny has only intensified in the wake of news that 7 of the 67 patients treated with bluebird bio's elivaldogene autotemcel (eli-cel, marketed as Skysona) gene therapy product for cerebral adrenoleukodystrophy have developed hematologic malignancies. While an investigation into the potential of a causal relationship in those cases is ongoing, and despite an 81% 4-year survival rate free of major functional disabilities and hematologic cancer among Skysona patients, the specter has been raised.
In Pursuit Of ATMP Testing Protocol Maturity
That urgency, however, must be balanced by rigorous safety testing, and as Dr. Fenn pointedly stated, gene therapy testing protocols, of which there are many, have to date been neither standard nor quick. The FDAs safety testing expectations include documentation and reporting on sterility, mycoplasma, endotoxin, potency, and viral tests, vector characterization, and risk assessment. While the agency released guidance on the matter most recently in April 2024, standard protocols have yet to be established.
With help from multiple corners of the industry, beginning with therapeutic innovators like Lexeo, led by conscientious professionals like Fenn, and aided by analytical method technology and outsourced service providers like MilliporeSigma, the acceleration of thorough and replicable testing methodologies is in effect. The effort took a measurable leap forward last week, when the latter opened its new biosafety testing facility in Rockville, Maryland. I was there for the ribbon-cutting ceremony, followed by a tour of the shiny new 250,000 square-foot building that will house biosafety testing, analytical development, and cell banking manufacturing services.
The facility will consolidate equipment, services, and people that are currently spread across four buildings in the Rockville area, a move that the company expects to foster increased collaboration among the analytical development scientists who staff it, as well as enable automation gains. In fact, the facility will offer a rapid methods package, designed to accelerate virus testing of bulk harvest material, the first offering to include the company’s Blazar CHO Animal Origin Free (AOF) panel. That’s a targeted molecular method for detecting virus families, and by combining it with assays for mycoplasma, sterility, and retrovirus-like particle detection, Head of Life Science Services, Life Science business of Merck KGaA, Darmstadt, Germany’s Benjamin Hein says test results can be obtained in 14 days, compared to 35 days with traditional assay methods.
Analytical Speed, Redundant Supply At The Forefront
While in Rockville, I had the opportunity to sit down for a chat with Hein, in addition to SVP, Head of Contract Testing Services Heather Ahlborn, Ph.D. and Chief Technology Officer Karen Madden, Ph.D. Here at Bioprocess Online, we rarely publish interviews with execs from the supplier community. That said, I drove five hours to see the place firsthand. They fed me a nice lunch. I got to rub elbows with Congressman Jamie Raskin, who was in attendance for the ribbon cutting. I’m making an exception here.
Biologics testing is high-stakes work, and it’s work that’s rife with obstacles. Supply and transportation challenges, competitive pressure, geopolitical concerns around outsourced manufacturing partner selection, and cost are but a few of them. I asked Dr. Ahlborn which of these, or other, challenges she expected the commissioning of this new testing facility to most directly address for the biopharmaceutical industry at large. She didn’t hesitate to respond with “speed.”
“We’re heavily investing technologies like next-gen sequencing in our Blazar platform, the molecular methods that result in better specificity, sensitivity and faster turnaround,” she says. “The pressure on the industry is to keep getting faster, and that requires getting to those answers faster. That's not going to let up, it’s always been the case, and it continues to be the case,” she says, pointing to automation, better use of data, and tech advances converging to make testing both faster and more sensitive. “No matter what characterization you need, for whatever your modality of choice, you're going to need to make sure that it is what it says it is, and that it's free from adventitious agents.” Doing that quickly is the task at hand, she says, because quicker turnaround time is what sponsor clients are demanding.
Hein agrees and qualifies that the demand for speed is decidedly more intent from developers on the cell and gene therapy side of the business. “These customers are very demanding, because speed is much more important in these novel modalities than it is in monoclonal antibodies, for instance,” he says. “What we measure is vein-to-vein time—how long it takes to remove cells from a patient’s body and inject the therapy back into the patient’s body. Clients want that to happen in seven to maybe fourteen days.” It’s easy to understand the desire to reduce the time required for critical analytics from days to hours on a production timeline that measures under two weeks. Combine that with a regulatory environment that’s in the process of sorting itself out, and Fenn’s “wild west” characterization seems spot-on. “Much of this is such groundbreaking science and technology, our clients haven’t yet figured out how to quickly and precisely test technologies and therapies. We’re figuring this out together,” says Hein.
ADC Analytical Services Capacity
Dr. Madden was quick to chime in here to acknowledge that, in addition to the lofty demands of the cell and gene therapy space, monoclonal antibodies remain the bulwark and represent the highest volume of the biologics work the facility will test. “Great therapies are going to come out of the antibody space for a long time to come, and the incremental innovation next to it is of course ADCs (antibody-drug conjugates),” she says. She points to the number of late-stage clinical trials, approvals, and the merger and acquisition activity in that space as proof. “We’ll continue to address the risk in the populations that those therapies treat from a drug company's perspective, but the science there is better-known, and the regulatory expectation is locked down. In the novel modalities, it’s a bit like changing the tires out while driving the car.”
Madden’s comments on ADCs evoked some recent conversations I’ve had with ADC developers who expressed concern about transfer and manufacture of their assets to qualified outsourced manufacturing partners, given that there were few to begin with, and the implications of the Biosecure Act only threaten to tighten that market. I asked Hein, as an outsourced partner to ADC sponsor companies, for his take on the situation. He made no bones about his company’s position as an advocate for globalization and free trade.
“This industry, just like a lot of other industries, has been built on the premises of free trade. We are strong believers in globalization. We're a strong believer in the free movement of goods and services from one country to the other because it is a global industry,” says Hein. “At the same time, we assess and monitor governmental developments that happen very closely. What we're seeing in the market, and I wouldn't ascribe this solely to the Biosecure Act—you could also take Covid as an example—is that biotech companies large and small are looking much more closely at supply security. So, they're more carefully assessing supply chain risk.” As a result, Hein says he’s seeing more supply chain redundancy measures being put in place by all supply-dependent players in the ecosystem, from biotechs to product and service providers like MilliporeSigma. “This might mean regional redundancy, or supply chain security, or integration of partners within a certain geography, for instance, because the logistics, cost, and paperwork associated with the shipment of biologic samples across different continents is incredibly challenging.”
Ahlborn says that regardless of intercontinental logistics, the company supports the advance of analytical methods standardization and scale-up accuracy because its global footprint of testing centers all work in harmony, applying the same processes from one to the next to reduce risks in transfer and scale-up. The glistening new facility in Rockville is the latest, and with apologies to its counterparts in Glasgow, Shanghai, and elsewhere, the greatest among them.