The blockbuster drug model once reigned supreme. Now it is being succeeded by the precision medicine model. During this transition, the pharmaceutical industry may worry about losing the blockbuster model’s strengths—broad, simple indications and large, steady revenues. Yet the pharmaceutical industry should be reassured by the rise of precision medicine. It represents the sort of change that can, paradoxically, enhance continuity.

Precision medicine is all about customization, or the targeting of ever-smaller subpopulations of patients, so it is unlikely to perpetuate the blockbuster model’s “one size fits all” approach. Precision medicine, however, could reduce development costs while generating many highly profitable drugs. Ideally, such drugs would offer novel benefits from niche to niche, rather than modest improvements for tried-and-true blockbuster categories.

A single niche-oriented drug would likely fall short of traditional blockbuster status—annual sales of at least $1 billion/year. But together, multiple niche-oriented drugs, including orphan drugs, might constitute a new kind of blockbuster, an incremental or a distributed blockbuster. The new blockbuster, it should be emphasized, relies less on direct-to-consumer advertising, and more on cutting-edge molecular medicine.

Redefining the blockbuster

Fouzia Laghrissi-Thode, MD
Fouzia Laghrissi-Thode, MD

“The definition of blockbuster is changing,” Fouzia Laghrissi-Thode, MD, chief executive officer of DalCor Pharmaceuticals, tells GEN. “Now it’s not necessarily just a dollar sign [in front of a revenue figure] that determines a blockbuster.” As drug development and regulatory reviews become more efficient, she suggests, lesser revenues can generate blockbuster-scale returns on investment.

“You don’t need a blockbuster to be successful,” adds Marc Schegerin, MD, senior vice president and head of strategy, finance, and communications for ArQule. “The definition of scientific success has changed from delivering a blockbuster to making a discovery and proving it beyond a shadow of a doubt.” The definition of business success, Schegerin continues, has also changed: “Today, success can be defined as maximizing an individual patient’s therapeutic response by administering the appropriate, targeted therapy.” (This definition doesn’t mention reimbursement, but perhaps the need for reimbursement goes without saying.)

Marc Schegerin, MD
Marc Schegerin, MD

“Companies today can do more with fewer patients and less money,” Schegerin points out. “That said, some molecular medicines are likely to reach blockbuster status.” Like many biotechs, he says, ArQule is not fixated on generating an arbitrary dollar amount, but on delivering the right therapeutic to patients who can derive the greatest benefit. “This approach,” he insists, “confers the highest probably of success.”

Such an approach is, essentially, a precision medicine approach, and so it targets a narrow, well-defined patient population. Presumably, the scale of the target could be commensurate with the scale of the drug development program. “I don’t think a large program would be a goal,” comments Laghrissi-Thode.

Precision blockbusters are looming

DalCor thinks that its lead compound, a cholesterol ester transfer protein (CETP) inhibitor that takes a precision medicine approach to coronary disease, has the potential to become one of the first precision medicine blockbusters. The compound, a rescue drug called dalcetrapib (dal-GenE), is in Phase III trials involving 6000 patients at 680 sites in 32 countries. It targets the 20% of cardiovascular patients who have an allelic polymorphism in the adenylate cyclase type 9 (ADCY9) gene.

“Roche took the drug into Phase III trials, which failed”, Dr. Laghrissi-Thode says. When Roche looked at results through the lens of DNA, “We found one SNP that predicts a different response than the overall study.” Specifically, patients with the ADCY9 AA genotype experienced significant benefits from the therapy, but those with the GG genotype actually worsened. The AG genotype was neutral, she says: “DalCor is rerunning the Phase III trial, but just on patients with ADCY9 AA genotype.”

Like DalCor, ArQule is a young company. ArQule, however, is focused on small molecules targeted to either solid or hematological tumors. The company’s most visible program is a reversible Bruton’s tyrosine kinase (BTK) inhibitor that inhibits both wild-type and C481S-mutant BTK. “Some chronic lymphocytic lymphoma patients do very well on ibrutinib until they develop the C481S mutation,” Schegerin says. “Our drug, ARQ 531, functions as if it’s unaware of that mutation.” The drug is likely to enter Phase II trials soon.

“Ibrutinib is a multi-blockbuster drug, but it isn’t a direct competitor of ours,” he continues. “Rather, ARQ 531 follows in the wake of its success.”

What you need to build a blockbuster today

“Many of yesterday’s blockbusters were not innovative enough to be blockbusters today,” noted Stephen R. Davis, chief executive officer, Acadia Pharmaceuticals, when he spoke at a breakfast panel (“How to Build a Blockbuster”) that was sponsored by Endpoints News and held at the 37th annual J.P. Morgan Healthcare Conference. For a drug to be a blockbuster today, he continued, it must embody “true innovation that brings a high level of value to the disease and patient communities.”

As Laghrissi-Thode points out, that means ever-greater levels of innovation that bring real value to patients, payers, and providers as well as the ability to gain widespread reimbursement so patients can access that innovation. To put this in perspective, she says, “in cardiovascular disease, products demonstrating a 12% percent risk reduction (over previous therapies) already are out there, so payers need to see greater risk reduction for a new therapy to be relevant.”

“You also need a durable franchise,” Andrew Plump, chief medical and scientific officer, Takeda Pharmaceutical, said when he participated in the Blockbuster panel. The fast-changing nature of genetic therapies doesn’t provide the IP foundation to sustain any given therapeutic for the long time needed for it to become a blockbuster, he argued, but it does spur continued innovation.

Regulators get involved, too

The FDA really doesn’t care whether a drug has blockbuster potential as long as the drug is safe and effective. Payers don’t care, as long as the drug is substantially better than existing therapeutics and meets reimbursement guidelines. Developers care, however, and they can help a drug achieve its blockbuster potential more expeditiously if they anticipate the FDA’s requirements.

Specifically, blockbusters are more probable when R&D operates efficiently. New regulatory guidances that align regulatory reasoning with current scientific and clinical thought, and the acceptance of modern technologies and practices—like using real-world evidence for control arms—are boosting efficiency within the FDA and within drug companies. As a result, drug developers can apply more of their resources where they can have the greatest impact.

The use of digital medicine tools can cut costs and development time. Rather than conduct a clinical trial of a new flu vaccine, Sanofi teamed with Kaiser Permanente to test either the new vaccine or the standard vaccine on 10,000 patients. It then used those patients’ medical records to determine which patients, if any, contracted the flu. According to John Reed, MD, PhD, executive vice president, global head of R&D, Sanofi, this investigation cost only $5 million—only $500 per patient—and outcomes were evident within a few months.

Data mining is offering new ways to look at data, and access to electronic health records is creating new ways to conduct clinical studies. By coupling artificial intelligence (AI) and machine learning, researchers can identify patterns and select patients most likely to benefit from prospective drugs. “We’re incorporating wearables and smartphone apps, which is giving richer, more quantifiable data and more timely feedback,” Reed says.

Among regulators and life sciences companies, Plump says, “there’s a willingness to think differently about how to bring speed and efficacy to drug development. If a drug has transformative potential today, it’s typically in a more targeted population. Trials can be smaller, and regulators can streamline phases.” The bottom line, he insists, is that, “the definition of blockbuster can change because your ROI can change.”

Blockbusters are still possible

“The blockbuster, one-size-fits-all approach is not the right approach today. The science has advanced,” Laghrissi-Thode says, “so aspiring to blockbuster status is falling out of grace.”

Even if conventional blockbuster status is beyond reach, it may still be possible to achieve an updated kind of blockbuster status. “The genotype we’re working on is present in about 20% of cardiovascular patients, but 20% of that population, worldwide, is still a huge number,” she points out.

Given the rapid pace of science and the continual stratification of patients and diseases, Schegerin’s assessment of the pharmaceutical environment may prove most accurate for the majority of biotech companies. Today’s blockbusters, he says, are more likely to be replaced not by any one drug, but by many, tightly targeted therapies.

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