By Matthew Pillar, Editor, BioProcess Online
Bert Liang, M.D., Ph.D., stepped into the CEO role at Abcentra earlier this year as the company formerly known as CardioVax found itself at a crossroads. The company bills itself as a clinical-stage bio-pharma company that addresses unmet needs in inflammation by targeting oxidized low-density lipoprotein (oxLDL). When Liang stepped in, Abcentra was trying to develop products that addressed atherosclerosis as an inflammatory disease, as opposed to the ages-old characterization of arterial plaque diseases as those caused by lifestyle choices (i.e. poor diet, no exercise, and smoking).
The company’s assertion is that cardiovascular and inflammatory diseases are inextricably linked, and there’s some sound reasoning behind the theory. The company is founded on research from Chief Scientist, Director, and Founder PK Shah, M.D. (Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center) and Head of Scientific Advisory Board Chairman Jan Nilsson M.D., PhD (Clinical Research Center, Lund University). The pair have spent their lives studying and publishing on heart disease, vascular cell biology, and atherosclerotic research
Liang points to evidence of patients with inflammatory diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis, and SLE (systemic lupus erythematosus) developing accelerated atherosclerosis. “Patients diagnosed with rheumatoid arthritis have a 50 percent greater chance of dying of a heart attack,” he says. Recognizing this link, the company focused on the exploration of active immuno (vaccine-based) and passive immuno (monoclonal antibody) therapies.
Within that context, the CANTOS clinical trial took place. That trial tested the very strong anti-inflammatory monoclonal antibody canakinumab to see whether it, combined with the statins that comprise the current standard of care for cardiovascular disease, would improve a patient's response to adverse cardio events.
“The CANTOS trial found that the monoclonal antibody therapy can knock down inflammation and actually improve patient outcomes by an additional 15 percent over that of the statin alone,” says Liang. “That was powerful, and it suggested that yes, in fact, inflammation matters, and that cardiovascular disease is, at least in part, an inflammatory disease.”
Putting Bioprocess Proficiency Behind The Project
With this data in hand, Liang was charged with setting the company’s path. His first course of action was to shake the idea that Abcentra would pursue an immunization approach. The canakinumab trial looked like a more feasible approach, though Liang recognized that the problem he was setting out to solve isn’t a tidy one. It marries cardiology and rheumatology and hadn’t been approached from that distinct combination of perspectives before. Liang knew the company’s solution would require sophistication beyond simply administering an antibody and waiting to see what happens.
Abcentra’s lead candidate, Orticumab, is a linear pharmacokinetic antibody that’s dosed subcutaneously or intravenously to good effect. It has a favorable safety rating in the 250 subjects tested to date, with the three- to four-week half-life you’d expect of an antibody. The company is moving forward with a trial of the drug for treatment of both psoriasis and the accelerated atherosclerosis that could be associated with psoriasis.
Proactive Process Considerations At The Clinical Stage
Liang’s pedigree is diverse. It includes executive experience at Amgen and Biogen, in addition to a host of smaller biotechs and VC firms. He’s a physician with a Ph.D. in molecular biology and genetics. But he’s also got MIT Sloan School of Management credentials to his name, and he’s as thoroughly interested in the business of biopharma as he is in the science. Perhaps that’s why, even in its early clinical stage days, Liang is hyper aware of the bioprocess challenges his company faces today—and will face at scale tomorrow—and the implications of those challenges on his business.
“I think about bioprocess manufacturing challenges all the time,” says Liang. New to the company and in advance of its phase two clinical trial of orticumab, he had good cause to. The company had its master cell bank and about ten vials of its reference standard on hand, and those were eight years old. “We had investors who were anxious to begin a clinical trial, and they assumed we could just outsource the production of our antibody and be ready to move forward within a month or so,” he says.
Supply is constantly top of mind for Liang—even at the bench scale stage—because “there are two things you can’t buy,” he says. “The first is a good cell line with a good historical background and the second thing is stability. You can have as much money as you want, but you can't buy it. You have to put the time in and wait that out.”
As such, Liang says it’s in his nature to be constantly thinking about supply and demand. Specifically, thinking about how the company will maintain enough of its stable cell supply to start clinical trials, or have enough product on hand that's been validated through upstream and downstream processing to avoid exceeding the economically viable dose. “These considerations are constant and begin at the outset of any kind of cell line plant,” he says. “How do we look at manufacturing? How do we do this faster, earlier, and cheaper?”
Tactical Approaches To Early-Stage Process Efficiency
It’s not common for science-minded execs like Liang to approach a problem from somewhere in between two seemingly distinct disciplines of medicine (cardiology and rheumatology). Confirmation bias runs rampant in this field. Give a carpenter no tools but a hammer, after all, and everything starts to look like a nail. But Liang is not a common thinker, thus his company’s multidisciplinary approach. That innovative spirit carries over to the process and manufacturing side of his brain. “We're trying to work as smart as we can right now to consider production approaches earlier rather than later, from downstream to process validation,” he says. “To do that, we’re taking production considerations into account on a parallel, rather than serial basis.”
That “think a step forward” philosophy lends itself to the technology trend du jour, platform automation. Liang and company are bullish about it. “We’re looking at technologies that will standardize and automate bioprocess manufacturing, and I think that because large-cap pharmaceutical companies are already moving in that direction, we have to move forward with it too.”
Today’s big tech decisions, Liang explains, aren’t about stainless steel versus disposable tanks. “That’s sort of de rigueur,” he says, “Today’s startups are in the market for technology that will help them bioprocess quickly and cheaply while maintaining sterility and GMP qualifications and transferring production as quickly—and directly—as possible into a fill/finish capability.”
Liang sees plenty of room for improvement in biologics manufacturing, particularly downstream. He believes speed is chief among the opportunities, and he thinks technology will be foundational to growth. “From vaccines to monoclonal antibodies, one of the biggest challenges that we're facing is time. If we can make it faster, we’re going to make both drug development and the value chain shorter and we’re going to make it cheaper,” he says.
Of course, there are barriers to achieving that speed of production, despite the vendor community’s best promises. Analytics, purification, stability, and pre- fill/finish release specification validation take time. Liang understands that it’s hard, costly, and human capital-intensive, especially in constrained space. He exhibits a bit of frustration when he considers the chasm between vendor-created perception and lab floor reality. “How much can we really automate?” he asks rhetorically. “When I ask manufacturers, I get a reassuring nod. But we’re not yet seeing it play out in real life.”
Unorthodox Approach Raises Regulatory Concerns
Asked what he’s most concerned about as he looks beyond clinical trials, Liang points to the education effort Abcentra faces due to its unique, multidisciplinary approach. Treating rheumatological diseases with cardiovascular outcomes is far from standard, and therefore something the regulators aren’t used to seeing. “We're going to need to invest in some significant amount of education around inflammatory diseases as well as psoriasis and dermatologic diseases associated with cardiovascular outcomes,” he says. “That’s all part of the challenge of trying to address an unmet medical need with a new therapy in a regulated environment.”
That unique market position—falling between two seemingly distinct disciplines of therapy—does have some competitive advantages. “There’s a ton of competition among cardiovascular and rheumatological biopharma firms,” Liang admits. “For the most part, those firms are addressing late-stage, condition-specific patients.” Abcentra sees far less competition as it addresses the patient whose disease hasn’t progressed. It doesn’t see competition looking for patients who don't need TNF (tumor necrosis factor)-alpha inhibitors for instance, but still need to get their cardiovascular disease addressed. “We’re at a place where we believe we can fulfill the appropriate solution to address the unmet medical needs that currently exist among a specific patient population,” says Liang.