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Wyeth’s Successful R&D Renovation: Neuroscience Shows Early Returns

Executive Summary

Six months after unveiling its "Project Springboard" efficiency initiative, Wyeth is holding up its neurosciences portfolio as an example of the success of the work-in-progress transformation of the company's R&D business

Six months after unveiling its "Project Springboard" efficiency initiative, Wyeth is holding up its neurosciences portfolio as an example of the success of the work-in-progress transformation of the company's R&D business.

Wyeth has built a "large and diverse" neuroscience pipeline with "over 20 drugs in development," R&D President Robert Ruffolo pointed out at the R&D Directions Drug Development Summit Jan. 23 in Phoenix.

"Remember we're a third the size of Pfizer, so this would be the equivalent of Pfizer having 60 drugs in development just in neurosciences," he remarked, "so this is actually quite a substantial development."

The transformation of Wyeth's neurosciences pipeline is the end result of the company's concentrated efforts to overhaul its R&D model. The new Springboard approach started over a year ago and was profiled at the Drug Information Association annual meeting in July 2006.

R&D initiatives have included new goals for each phase of drug development, a reworked approach to clinical trials, a global patient enrollment effort and performance-driven initiatives for R&D staff - all of which have borne fruit in the neuroscience area.

"We've certainly redefined every component of R&D ... from the earliest stages of discovery through clinical development, and we have metrics in place to see what we're doing," Ruffolo said. "We're getting better."

"Getting better" at its business is the aim of Wyeth's Springboard project, an ongoing company-wide effort to improve efficiency that has spurred several initiatives, including the R&D refinements (1 (Also see "Wyeth’s R&D Strategy: Spoonfuls Of Enrollment With A Dash Of Outsourcing" - Pink Sheet, 3 Jul, 2006.), p. 18).

Project Springboard's Next Phase

During Wyeth's fourth quarter earnings call Jan. 30, CEO Robert Essner commented on the impact Springboard has had: "The Springboard project has been a great way within Wyeth of opening the door to a lot of possibilities about what could be done. ... I think it is having a great impact both on our bottom line ... [and] on our relationship with our customers and our top line."

"What we are evolving to now, frankly, is getting away from thinking about Springboard as a centrally run project ... into a basic mentality that every manager in the company has to adopt - which says that every manager's job every year is to find ways to do the work they did last year more efficiently."

"The changes in R&D have been massive," he noted.

What Goes Into The R&D Output

For the R&D improvement initiative, Ruffolo explained that Wyeth started with the goal of delivering two novel drugs every year. "That's something that really hasn't been done by any company on a consistent basis," he noted.

Wyeth is at the head of the big pharma pack in terms of potential NME approvals for 2007 (2 (Also see "2007 NME Prospects Plentiful For Wyeth, Novartis – Other Firms Fall Short" - Pink Sheet, 15 Jan, 2007.), p. 26). It had no NME approvals in 2006. Merck had five novel products approved in 2006. Among Wyeth's currently pending applications at FDA are Pristiq for vasomotor symptoms, Lybrel , Torisel ,bifeprunox, and reformulations of Protonix and BeneFIX .

To reach the goal of two new molecular entities per year, Wyeth used standard industry success rates to determine the number of compounds needed in each stage annually. The process starts with a target of moving 15 drugs into development each year, of which 12 are expected to move into the IND stage and start Phase I trials.

"Here's where most drugs drop out: to get from Phase I to Phase III ... the failure rate is very high," Ruffolo said. "It went even higher in the last several years, and dropped actually from 40 percent to 25 percent in just a couple years across industry, including Wyeth." With the 25 percent success rate, Wyeth plans for three of the 12 drugs that start clinical trials to reach Phase III, and with a 60 percent success rate, two major NDAs will be filed each year.

The current model is a refinement of an earlier R&D productivity model. From 2001 to 2005, Wyeth similarly aimed to have three drugs per year enter Phase III and two NDA submissions, but the earlier stage targets were to have 12 drugs enter development and 8 IND submissions.

The numbers were adjusted last year to reflect increasing difficulties with Phase II. "We're moving more drugs into development to compensate for lower success rates in Phase II. And everybody asks me why not just improve success rates in Phase II? If any of you have a solution to that, let me know, but no one has figured that out," Ruffolo commented.

R&D output has significantly improved with the productivity initiatives. Wyeth is currently on target, whereas from 1990-2000 the firm averaged three development projects a year, with 1.5 INDs and 0.3 Phase III programs. Wyeth had no major NDA filings in 2001, 2002 or 2003 - but the firm met the goal of two in 2005 and exceeded it in 2006 with four filings.

"Last year we had a Phase II problem, [but] that's been repopulated by drugs moving in. Our success rate has actually gone up in Phase II now. We don't exactly know why but we're happy about it. And we ... have a dramatic number of compounds ... at the FDA waiting for approval," Ruffolo reported. "We still have a very large Phase III pipeline - new compounds continue to move in with this system that we have." (see chart: " 3 Putting On The Pressure... ")

The productivity goals are just part of the R&D overhaul. Among Wyeth's highest profile reforms has been the "learn and confirm" approach to clinical trials, replacing the traditional three-phase model with a more streamlined, compressed timeframe (4 (Also see "Wyeth Replacing Three-Phase Development With “Learn And Confirm” Model" - Pink Sheet, 3 Jul, 2006.), p. 19). "It's not totally unique to us," Ruffolo acknowledged. "What's unique is how we're rolling it out." Although the exec did not provide detail on the implementation, he reported that "all learn and confirm teams [are] in place," and that a "pipeline of adaptive studies has been developed."

Bringing New Methods To R&D

"There were about a dozen things that we had to put in place a little bit differently in our paradigm for development," Ruffolo noted. "Every single one of these is in place, including and especially our early clinical development centers that are built in areas of high patient density ... now set up and operational."

Wyeth has focused on patient enrollment as a key to accelerating development; the global patient enrollment initiative was the initial focus of the Springboard project. So far, it appears to be moving ahead and paying off: Wyeth has "end to end improvements deployed in study planning and execution"; it has opened a 24x7 center in Bangalore, India; 10 ECDC sites have been established; and all clinical trials are now "optimized for global patient mix."

"In terms of changing the global patient mix, we've had a dramatic increase in patient enrollment as a result of these - dramatic, nearly 10-fold increases in the number of programs enrolled on time," Ruffolo said.

In line with the new "metrics-based" approach, Wyeth has also applied its innovative strategies to the human resources arena, modeling compensation for its scientific workforce similar to the performance-driven sales teams.

Ruffolo demonstrated how Wyeth's R&D changes have transformed the firm's pipeline and workflow by profiling the neurosciences portfolio. "Our goal was to build a world-class neurosciences [unit]. We had a pretty good group, but it wasn't world-class at the time we started. [With Effexor ], we did have the most prescribed antidepressant in the world and largest revenue ... but it was a single product, and a single product does not make a world-class group."

The Basis Of Wyeth's Neuroscience Expansion

"So we did a major overhaul of neurosciences in 2002, we changed the leadership, we changed the management team, we changed the staff, and we changed basically everything," Ruffolo said. "The development activities ... changed shortly thereafter."

Neuroscience now comprises 30 percent of Wyeth's total pipeline. The company has focused on five major diseases within neuroscience and has over 20 drugs in development.

In fact, Ruffolo reported that Wyeth now is facing the problem of having more compounds that could enter late stage development than it can fund, necessitating a strict prioritization process. One notable outcome of the prioritization analysis was that the factor that mattered most was unmet medical need. "This counted more than anything, more than the commercial value, more than our expertise and so on," he maintained.

Wyeth is taking a diversified approach, with a mix of small molecules, biotech products and vaccines - all areas where the firm has experience and capacity.

The company is also taking a liberal approach to balancing internal and external sourcing. "Probably 90 percent of our pipeline is homegrown," Ruffolo noted. "That's not for any reason, we don't set a target for that. We want the best medicines we can get from all over the world, whether they come from ourselves or not. ... We don't have a 'not grown here' syndrome."

He added that Wyeth "can't compete with Pfizer and GSK, in terms of picking up opportunities. So we have to be a little bit more selective ... but we do look all over. If we find a better opportunity outside, we will bring it in, give our scientists the credit, and take something out of the pipeline if we need to."

Like other companies, Wyeth appears to be put off by the price tags, and success rates, that many acquisitions have hit. At the Morgan Stanley CEOs Unplugged conference Jan. 3, Essner announced that the firm is looking at more partnering deals for early stage compounds in an attempt to mitigate the risk (5 (Also see "Spreading The Risk: Wyeth Seeks Many Partnerships, Rather Than A Few Buys" - Pink Sheet, 8 Jan, 2007.), p. 11).

In neuroscience, Wyeth's strategy is to leverage or license assets in non-core areas, such as multiple sclerosis, sleep, impulse control (not ADHD) and macular degeneration.

Wyeth's Focus Is On Five Neurologic Diseases

In each of the five disease areas in neuroscience, Wyeth is using a combined approach of targeting disease pathophysiology, looking at novel targets and improved models, and taking existing therapies to the "next level."

Depression and anxiety are challenging precisely because they are both "satisfied" areas. "New drugs have to be so much better than existing drugs, [do] something that existing drugs don't do," Ruffolo said. With that in mind, Wyeth is leveraging their existing expertise with serotonin-norepinephrine, using models "and actually looking at drugs that modify the pathophysiology of the disease." Some of the firm's activities include maximizing the value of serotonin equity, moving beyond monoamine and GABA and looking at the role of neurogenesis.

In schizophrenia, Wyeth is trying to improve on tolerability for existing therapies. The firm is developing bipolar disease models; improving models to improve disease relevance and get at cognition and negative symptoms; and trying to modulate glutamate, cholinergic and neuropeptide receptors.

Wyeth is moving into Parkinson's disease at a time when "a lot of companies have left this area. They think you can't make enough money, and most drugs for PD have not been all that successful commercially. But it's an important area, unmet medical need, and we think a drug that truly makes a difference will in fact be worth our investment," Ruffolo said. He noted that Wyeth is not interested in symptomatic therapies like DA agonists or in stem cell or gene therapy. Instead, it is concentrating on neuroprotection, on broad application of targets and multiple mechanistic approaches. Nothing has reached development yet.

In stroke and chronic pain, Wyeth is also trying to move beyond existing therapeutic strategies. For stroke, "we've got to move beyond thrombolytics, which are really not used that often because of the risks, infection and neurodegeneration," Ruffolo said. Although Wyeth is interested in neuroregeneration and developing paradigm-shifting treatments, the firm is determining the potential of an in-licensed novel thrombolytic.

For chronic pain, Wyeth identified opportunity in different types of pain, such as fibromyalgia (desvenlafaxine is in Phase III for the indication). The chronic pain development plan includes incorporating a number of newer technologies and techniques. To identify new pathways and mechanisms, Wyeth is using gene expressing profiling and proteomics. It is also improving on animal models to make them more predictive and disease relevant.

Alzheimer's disease is at the heart of Wyeth's neuroscience portfolio. "We have 11 drugs right now in development just for AD alone. Something will work. I wish I could tell you what, but something will work statistically from that group. That's what the success rates and the attrition rates would predict," Ruffolo asserted.

He described Wyeth's approach to Alzheimer's as "scorched earth." Moving beyond symptomatic treatments, the firm is working on several interventions in the amyloid pathway as they attempt to affect disease modification. Wyeth has two vaccines that they hope will result in plaque removal, as well as trying to prevent plaque formation with a plasminogen activator inhibitor and a gamma secretase inhibitor (6 (Also see "Wyeth Says Portfolio Growth Potential Separates It From Other Big Pharmas" - Pink Sheet, 16 Oct, 2006.), p. 15).

"We also have two biotech products which are antibodies themselves, so we're bypassing the vaccines and making the antibodies directly to A-beta, which will lodge against the plaque in the brain, causing passive immunization," Ruffolo added. "And then of course we have a number of compounds in development that deal with primarily cognition improvement. These happen to be small molecules ... that we believe can be disease modifying."

- Mary Jo Laffler ([email protected])

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