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As Pharmas Track Blockbuster Deathwatch, PGx Technologies Begin Playing Larger Role

PHILADELPHIA – Is the blockbuster model dying?
A Novartis official thinks so, and has put a 10-year life expectancy on pharma’s bread-and-butter drug-development model. The belief, echoed by other drug makers, has increased the amount of pharmacogenomics-based R&D performed by big pharma.
“It’s our current position that the blockbuster approach … is not sustainable,” Robert Schmouder, executive director of translational medicine at Novartis, said here during a Cambridge Healthtech Institute conference. “We expect that at most it will be 10 more years for that paradigm, and then either companies will evolve into more focused approaches or fail based on that.”
“It is, I think, a fairly bleak view right now,” he added.
Industry observers have often viewed biomarkers and pharmacogenomics as a death sentence for the blockbuster model. However, with drug-development costs soaring above $800 million for a single product and recent high-profile failures of investigational drugs, such as Pfizer’s cardiovascular therapy torcetrapib [see PGx Reporter 12-06-06], the industry is facing increasing pressure from investors, the public, and health authorities to embrace alternative R&D strategies to improve its record.
That Novartis has taken this prognosis seriously is evident in the fact that the pharmaceutical giant is in the midst of shifting its entire drug-development approach from a system structured to yield drugs that are efficacious for broad populations, to a process designed to target early and quickly the specific subset of people that will most likely benefit from a drug.
In May 2005, Novartis announced that it was “redefining research-to-development transition through fast and rigorous ‘proof-of-concept’ trials.”
Specifically, Novartis’ strategy is to use a single biological target to capture small pieces of many disease markets.
At the meeting, Schmouder said the company has altered the traditional three-phase drug-development model for a “learn and confirm”-type protocol that will allow for earlier proof-of-concept studies in humans.
Only when Novartis has sufficient confidence in an investigational product’s efficacy and safety in the exploratory phase will the company move the drug into larger confirmatory studies.
Although this new model is not a guarantee that all investigational candidates will garner approval from the US Food and Drug Administration, it “is moving the probability in our favor,” Schmouder said.
At Novartis, the new system has resulted in broad management changes, changed the way the firm conducts clinical trials, and modified how its R&D teams interacts, Schmouder said.  
He highlighted one recent example of a successful proof-of-concept trial at Novartis for ACZ-885, an antibody to treat a rare inflammatory condition called Muckle-Wells syndrome. In the proof-of-concept study, disease symptoms such as rash, joint aches, fevers, and migraines were relieved after a single shot of ACZ-885, which targets the inflammatory signal IL-1 beta. 

“Even if that may be a smaller market, we may be able to charge a premium price for that.”

According to Schmouder, based on these results Novartis now plans to study the efficacy of the IL-1 signal in other disease areas, such as rheumatoid arthritis, asthma, type-1 diabetes, and psoriasis.
“Not all patients in these disease populations will benefit, but subsets of patients will,” Schmouder said, adding that the earlier proof-of-concept model may allow the company to target the proportion of these disparate disease populations that might benefit as a result of this one signal.
If ACZ-885 is commercialized, Novartis will also make a kit available to help physicians determine which patients should be prescribed the drug, Schmouder noted.
“More and more health authorities will respond favorably if they think we can discriminate between [the responders and the non-responders], and focus the drug on those who will get the most benefit,” he said. “Even if that may be a smaller market, we may be able to charge a premium price for that.”
Magic Markers
Novartis’ strategy is similar to Bristol-Myers Squibb’s model of expanding the indications for existing oncologics by using biomarkers and pharmacogenomics [see PGx Reporter 01-10-07].
Some industry observers believe that big pharma will not abandon its pursuit of the blockbuster, but simply change the pathway by using biomarkers and pharmacogenomics opportunistically to arrive more efficiently at cash-cow drugs.

Pharmaceutical companies will eventually warm up to pharmacogenomics in their own way, they say, using molecular tools to reduce drug-discovery timelines, quicken regulatory reviews, and remove unpromising or unsafe drugs from the pipeline earlier [see PGx Reporter 09-15-05].
Pharma’s blockbuster model thrives in markets such as hyperlipidemia and hypertension, yielding medicines for chronic ailments that impact large populations. However, as Hugo Stephenson, president of strategic research and safety at Quintiles, pointed out, even mega-blockbusters like Pfizer’s Lipitor are essentially based on a biomarker: LDL level.
The use of biomarkers to predict for degenerative diseases has blockbuster potential, Stephenson observed.
By using biomarkers for long-term disease processes, “We are able to say, ‘With this much family history, and this much risk of developing Alzheimer’s disease … here is a product you can take and it’s going to delay your onset of disease by five or 10 years.’ I can guarantee you that is a product that’s going to be selling $5 billion in its first year on the market,” Stephenson said.
“We can be preventing Alzheimer’s; we can be preventing osteoarthritis; we can be preventing COPD. There are lots of degenerative diseases where we can begin to start treating people early on,” he said. “I’m personally optimistic given some of the programs I’ve seen at the biotech level.”
Novartis’ Schmouder isn’t so optimistic: “I have to say we take a bit of a pessimistic view on that,” he said. “In my heart of hearts I hope that the blockbuster isn’t dead. But time will tell.”

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