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Big Pharmas Show How They Use PGx Tools To Develop Better Blockbusters, Niche Rxs

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As many in the drug industry claim that the blockbuster model is on its last legs, some large pharmas maintain that even though they employ pharmacogenomic tools, which by design are meant to shrink patient populations in exchange for greater safety and efficacy, they continue chasing the blockbuster homerun, using personalized medicine tools and techniques to help them.
 
Although pharmacogenomic techniques would ensure greater efficacy and safety for a smaller subset of patients, industry observers have been characterizing pharmacogenomics as the poison pill that could eventually kill pharma’s profitable blockbuster model. Still, it seems that some pharmas are attempting to make the science work in concert with that blockbuster model.
 
“Pfizer’s in the business of selling medicine. So [for] every … compound that we move to clinical development and launch on the market, the aim is to sell and [impact] patients as much as possible,” Andy Williams, Pfizer’s head of molecular medicine within its angiogenesis programs, said at a conference on personalized medicine earlier this month in San Francisco, hosted by Burrill & Company.
 
As an example of the mutually exclusive development paths his company sometimes encounters, Williams cited the findings from a 5,000-patient study looking at 16 genes thought to affect the efficacy of some statins, including its own uber-blockbuster Lipitor. In the study, investigators identified “only one [gene that] had any impact on the efficacy” of statins, but also found that “that effect was overshadowed” by the more traditional factors such as age and gender, Williams said.
 
“So you may have a blockbuster drug, and you might have the knowledge, opportunity, and potential to see whether you could improve efficacy [in] a subset [of patients], but for that example, you just aren’t there,” he added. 
 
Williams previously worked with Pfizer’s pharmacokinetic and metabolism group on cash-cow drugs like Lipitor and the targeted oncologic Sutent. But “it’s only after you’re successful [launching a blockbuster] that you stop talking about blockbusters,” he said.
 
According to Williams, Pfizer uses PGx tools and strategies to run its clinical trials more efficiently, specifically to understand the molecular underpinnings for disease and patient response.
 
At the conference, Burrill & Company CEO Steven Burrill said that in the coming age of personalized medicine, “business models will have to change dramatically.” He added that as the big pharma model “disintegrates [and] disaggregates,” the industry will buy innovation — not only validated compounds but also PGx tools and know-how — from smaller life sciences companies and leverage their marketing prowess to play the role of large Wal-Mart-like distributors [see PGx Reporter 11-21-2007]. 
 
Other drug companies at the conference similarly acknowledged that the industry is changing and that pharma is increasingly interested in the technologies and strategies that help them understand the nature of disease and patient response as they pursue safer and more efficacious blockbusters.
 
For instance, Lilly is using PGx to improve patient outcomes and patient compliance in using its products, and Novartis is using genomic tools to better characterize patient populations for diseases in which the genetic mechanisms are well known.
 
Although pharmaceutical companies like Novartis have already mourned the death of the traditional blockbuster [see PGx Reporter 03-07-2007], today’s environment of increasing competition from generics, weak innovation, and slow regulatory environment means that the industry cannot afford to shift its focus away from pursuing blockbusters.
 
Indeed, between Jan. 1 and Oct. 31 the FDA approved just 15 NMEs. At this rate, the agency stands to approve fewer NMEs than the 22 projects it approved in 2006, the 20 it green-lighted in 2005, or the 36 it cleared in 2004. In addition, $23 billion worth of brand name drugs worldwide last year went off patent.
 
“In the drug industry we need more successes,” Pfizer’s Williams said at the conference. “After that success we can build from there” using genomic strategies to hone in on a subset of patients most likely to benefit. Without this strategy, “we’re just trying to get the biggest sale and not actually thinking about the actual incentives of the drug being developed, and we’re going to end up with a whole bunch of failures,” he added. And “that’s not going to be good for the drug or diagnostic industry.”
 
According to Eiry Roberts, vice president of medical projects and programs at Lilly, pharma companies wanting to maintain their previous pace of success in the face of technological advances must embrace new economic models and be more collaborative.
 
Pfizer’s PGx ‘Opportunities’
 
According to Williams, Pfizer is mainly using PGx strategies to improve the efficiency of its clinical trials for drugs intended for the global market.
 
Pharmacogenomics results of one recently completed academic study looking at healthy volunteers from East Asian countries and Caucasians yielded “very interesting results with regard to how similar Korean, Japanese, Chinese are in their phenotype,” Williams said.
 
That 600-person study, comparing East Asians and Caucasians, found that Koreans, Chinese, and Japanese are phenotypically similar to one another, and that third-generation Japanese living in the US are phenotypically similar to those living in Japan.
 
These findings may ultimately enable Pfizer to be more flexible in how it registers and develops drugs for the global market. For instance, results from that study will prompt Pfizer to enroll Korean, Chinese, and Japanese patients in clinical trials for drugs intended for a broad swath of the East Asian market. Or the company can run a clinical trial for a particular drug on Japanese subjects in America and then safely launch the drug for Japanese patients in Japan.
 
Given the results of this study, Pfizer is “pretty excited about the opportunity for [using pharmacogenomic tools to] improve the efficiency of global clinical protocols,” Williams said.
 
Additionally, Williams noted that there are “opportunities for the company to use PGx strategies to recruit patients for clinical trials for certain cancer drugs.”
 
Outside of cancer, in January, Genizon BioSciences granted Pfizer diagnostic rights to its discovery programs in Alzheimer's disease, attention deficit/hyperactivity disorder, and endometriosis. The collaboration will enable Pfizer to use Genizon’s technology to discover diagnostic markers linked to these disorders from ongoing genome-wide association studies using DNA samples from the Quebec Founder Population [see PGx Reporter 01-17-2007]. 
 
Pfizer also dabbles in traditional pharmacogenomic research models that by design constrict a potential patient population for a particular drug.
 
Last year, the company used an assay made by Monogram to determine which patients to enroll in a clinical trial of its HIV drug Selzentry. The drug, more commonly called maraviroc, was eventually approved by the FDA and will be marketed worldwide with the test, called the Trofile assay, to ensure that the right patients are administered the drug [see PGx Reporter 08-08-2007]. 
 
Overall, Williams concluded that at Pfizer, PGx “technology is being used to understand the nature of diseases, so we can see … more successes.”
 
Lilly’s ‘Personalized Fashion’
 
For Lilly, pharmacogenomics is merely one tool in a host of strategies the company uses today to improve patient adherence to its drugs.
 
Clinical researchers estimate that for most prescribed drugs, compliance hovers between 50 percent and 60 percent. Industry observers have noted that by improving patient compliance for drugs, drug companies can increase drug sales of its products, as well.
 
Lilly’s Roberts said her company is using pharmacogenomics technologies along with “more established” strategies and tools to improve patient outcomes and, in turn, increase the likelihood that patients will adhere to treatments.
 
“I think in our traditional one-size-fits-all medicine environment … any given medicine achieves a very small market share within a very large market opportunity,” Roberts told Pharmacogenomics Reporter last week. “Lilly’s belief and our work in this area focus on improving patient outcomes and delivering a better value proposition to patients in a more personalized fashion.”
 
At the Burrill conference, Roberts noted that Lilly’s focus on personalization is to improve patients’ adherence to therapies for chronic disorders, such as insulin.
 

“Where appropriate, [Lilly is] investing in pharmacogenomic approaches focused on trying to understand within a particular disease area, and in support of a particular medicine, how we can optimize patient outcomes in that area.”

She noted that finding a subset of patients who are genetically more likely to respond better to a drug, and thereby remain on the therapy, would “change in a favorable fashion and would ultimately result in a favorable environment with respect to market share and sales.”
 
“Where appropriate, we are investing pharmacogenomic approaches focused on trying to understand within a particular disease area, and in support of a particular medicine, how we can optimize patient outcomes in that area,” Roberts explained.
 
She gave two examples in this area: a diagnostic the company is developing with ParAllele and Affymetrix to understand the variability in patient response in early clinical trials; and a collaboration with BioSite to optimize the patient population for a sepsis drug called Xigris.
 
In the first example, Roberts said Lilly has been working over the last two years with ParAllele, using a transporter chip based on Affy’s GeneChip technology to broadly genotype patients in its clinical trials and help it understand “a broad spectrum [of] drug-metabolizing enzymes.
 
“We’re using that chip technology very extensively in all phases of clinical development within the organization in order to help us understand variability of exposure and response in our patient populations in those trials,” Roberts said. “We’ve also had several meetings with the [US Food and Drug Administration] in the context of trying to understand how to make that type of technology more broadly available in the health care environment.”
 
ParAllele will take the lead, with Lilly’s support, in taking any resulting diagnostic through the FDA regulatory process. Lilly would not say when it intends to submit its application for such a diagnostic to the agency.
 
“Personally, I believe that this is going to be one of the most important areas, in the short term, in terms of a breakthrough in how we use pharmacogenomic technology to support drug-prescribing or generally,” Roberts added.
 
The second example of how Lilly is using PGx, involves the approved sepsis drug Xigris. “We’re still working on identifying patients who do best with Xigris therapy: how we optimize the timing of when we start that therapy, and how we provide that information to providers,” Roberts said.
 
Lilly entered into a collaboration last year with BioSite to provide bedside testing of serum markers of activated protein C, which Lilly hopes will help identify patients that should receive Xigris. “And obviously, it’s a very important outcome, because we’re obviously focused on mortality in this patient population,” Roberts added.  
 
Xigris is a recombinant version of human activated protein C that manages microvascular function by decreasing inflammation and coagulation and increasing fibrinolysis. In 2005, Lilly updated the label for the drug to warn of an increased risk of mortality with the drug in patients with single organ dysfunction and following recent surgery.
Lilly is also using PGx to develop diagnostics for cancer treatments. Lilly and the Phoenix-based non-profit Translational Genomics Research Institute announced in July that researchers had identified an altered form of AKT1 that appears to play a role in tumor cell proliferation and cell resistance to certain therapies.
 
The finding may lead to the development of a diagnostic in breast, colorectal, and ovarian cancer if additional research shows that a therapy targeting this polymorphism will confer a survival advantage in patients [see PGx Reporter 07-11-2007]. 
 
Swiss Resistance
 
Novartis has been one of the few companies in the industry that has openly acknowledged that the blockbuster model is dying. At a conference earlier this year, Robert Schmouder, executive director of translational medicine at Novartis, predicted that pharma’s bread-and-butter drug-development model will draw its last breath around 2017 [see PGx Reporter 03-07-2007].
 
In many ways, Novartis has set itself apart from the rest of the big pharmas in how it is employing PGx strategies. Unlike its counterparts pursuing drug development initially in the broadest populations and then employing PGx strategies to hone in on a subset of patients, Novartis claims its strategy is to first genetically characterize populations in “narrow diseases whose precise genetic mechanisms are well known.” The company has said it is using PGx to help make go/no go decisions for investigational candidates early in their development [see PGx Reporter 03-14-07].
 
“By doing this, researchers can rapidly prove their drug is hitting its intended target in trials of a few dozen people, then move into large and costly trials in more common diseases,” a Novartis spokesperson told Pharmacogenomics Reporter.
 
For instance, the Swiss drug maker recently conducted a successful proof-of-concept study for ACZ-885, an antibody that targets the IL-1 beta signal to treat a rare inflammatory condition called Muckle-Wells syndrome.
 
From there, the company plans to use the learn-and-confirm strategy to identify biological targets with broad applicability in multiple disease markets. According to the company, the IL-1 beta signal may also be meaningful for certain populations with rheumatoid arthritis, asthma, type-1 diabetes, and psoriasis.
 
Novartis’ primary focus for PGx projects has been oncology, with the development of Gleevec for chronic myeloid leukemia and gastrointestinal stromal tumors, and an investigational drug, Tasigna, also know as AMN107, for patients resistant to Gleevec. 
 
In terms of diagnostics development, Novartis is drawing on the work of its own vaccines and diagnostics division as well as pursuing external partnerships, the company said.
 
Back to Basics’
 
While pharma companies are internally using genomics tools and strategies to learn more about diseases and patients’ response to drugs, if the industry wants to get out of its current doldrums, companies need to collaborate with each other around emerging technologies, according to Lilly’s Roberts.
 
“We’re now in an era where technology and our molecular understanding of disease and how to use therapies is exploding, but we need to go back to basics in terms of describing the same relationships between what these technologies are telling us, what it means to patients and what the relevant outcomes are,” Lilly’s Roberts said at the Burrill conference.
 
“And that’s going to require very extensive collaboration from many groups, including academia, the industry, the diagnostic and pharmaceutical companies, the regulators, the payors, and patients,” she added.

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