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With A Novel Pipeline, Pfizer Tries A New Oncology Business Unit Too

Executive Summary

With a lot of determination and a lot of licensing, Pfizer has managed to pack its oncology pipeline with novel mechanisms. Now the company is trying to innovate its business organization to make the most of what it has

With a lot of determination and a lot of licensing, Pfizer has managed to pack its oncology pipeline with novel mechanisms. Now the company is trying to innovate its business organization to make the most of what it has.

Pfizer continues to ramp up its presence in oncology - thanks to a round of deal-making and a major commitment from the industry's largest research and development organization last year.

Pfizer is now allocating 22 percent of its overall R&D budget on cancer. And there is a commitment to funding the oncology business unit as needed - the company has designated oncology an "invest to win" therapeutic area.

[Editor's note: This is the second in series of profiles on the oncology pipelines of companies with a major presence in the therapeutic area; the first focused on Genentech ( 1 "The Pink Sheet," June 16, 2008 , p. 3) Upcoming profiles include GlaxoSmithKline.]

Pfizer used the American Society of Clinical Oncology annual meeting - the biggest arena out there for oncology - to make a big splash for its new oncology business unit, with a dedicated analyst meeting in Chicago.

If the relatively light attendance at the Pfizer event is any indication, the company still has some work to do if it wants to be known as a cutting edge oncology business.

But Pfizer undeniably has a robust oncology pipeline - and the new business unit at least gives the company the chance to demonstrate that it can succeed in translating those projects into a larger commercial presence.

Pfizer used the analyst meeting at ASCO to introduce the newly created oncology business unit, which "combines commercial, medical and development into a single organization" to "optimize the development and commercialization of our rich oncology portfolio," Alison Ayers, worldwide commercial leader for the business unit, said.

The group got started in March, but the head of it - Senior VP/General Manager Garry Nicholson - was appointed the week before ASCO. Nicholson joined Pfizer from Lilly, where he ran the company's global oncology platform. Nicholson reports to Worldwide Pharmaceutical Operations President Ian Read.

Reporting to Nicholson are Ayers, WW Development Leader Charles Baum, WW Medical Leader Craig Eagle, and U.S. General Manager Pat Andrews. All four were previously with Pfizer and helped drive creation of the new unit. Regional commercial operations are organized under Ayers and regional medical operations are under Eagle.

Pfizer is not the first company to try the focused oncology approach. One model that the company looked at in particular is Novartis, which created five divisions including an oncology business unit eight years ago (2 (Also see "Novartis Rx Exec Changes Include U.S. COO Epstein To Oncology Unit Head" - Pink Sheet, 17 Jul, 2000.), p. 25).

The Pfizer business unit does not have responsibility for discovery - that stays with the discovery research organizations, Ayers explained. "However, the strategy for discovery research is defined by the business unit leaders, so the research organization works toward the strategy that we've identified and the head of research sits on our leadership team."

Ayers explained the philosophy behind the reorganization to the assembled analysts: the goal is an integrated team with the ability to implement plans and manage resources. "We're free to move and we're free to get things done," she said.

She further assured them that with the "invest to win" status, the necessary resources will be there.

"The formation of the business unit underscores the fact that Pfizer has identified oncology as a top priority area based on the high market growth, significant unmet needs and our outstanding portfolio [that] enables used to be first or best in class in many areas."

With that, Ayers rattled off a series of statistics intended to show that Pfizer has numbers to back up the sweeping statements: the number of oncology R&D projects has increased by 400 percent over the past five years; there are 232 oncology clinical trials ongoing or close to starting (including two Phase III studies open and enrolling and five more Phase III starts planned for this year); and there are 22 innovative compounds across four platforms.

Ayers also touted the "robust Phase III program" and "substantial increase" in the Phase I portfolio. "A real benefit of having such a robust portfolio with so many different compounds is that even despite disappointments, we still have many exciting compounds moving forward," she noted.

The Provenance Of The Pipeline

The pipeline accurately reflects Pfizer's history. Pfizer itself did not traditionally have a presence in oncology - most of the segment came as an inheritance from Pharmacia, and Pfizer built the pipeline it has now via merger and acquisition activity.

Ayers acknowledged up front at the analyst meeting that many projects have come from external sources.

"We have such a rich pipeline because of the legacy companies," Ayers noted in an interview. "We have compounds that came from Pharmacia, we have compounds that came from Sugen, which ... Pharmacia had acquired, we have compounds from Agouron, which was acquired by Warner Lambert, we have Parke-Davis compounds which was also part of Warner Lambert." Pfizer's prize oncologic - Sutent (sunitinib) - came from Sugen.

"So the reason that we have so much diversity is because of the legacy companies, in addition to the programs that Pfizer [staff] themselves were working on."

Of the 22 novel compounds in the pipeline, 16 of them have some sort of Pfizer pedigree.

Pfizer has been "very active" on the acquisition and licensing front over the last year. Those deals have been integral to building Pfizer's oncology portfolio into something it could showcase.

The highest profile deal at the moment is with Avant Immunotherapeutics. Pfizer licensed Avant's cancer vaccine CDX-110 in April, in a deal worth up to $440 million, plus royalties.

The roots of the immuno-oncology portfolio go back to the November 2007 acquisition of Coley, which was aimed at developing a vaccine capability. That deal added a vaccine platform, as well as toll-like receptor 7 and 9 programs.

The acquisition of Serenex in March brought in a heat shock protein 90 inhibitor. The Hsp90 mechanism has generated a lot of interest because of its potential to improve the efficacy of other targeted therapies.

"We've also strengthened our anti-angiogenesis portfolio with the addition of two agents from CovX," Ayers said. CovX, a privately held biopharma folded into Pfizer's biologics unit, added a number of oncology compounds that target angiopoietin and thrombospondin, "which represent new ways of inhibiting angiogenesis."

"We hope that they will be complementary to our [vascular endothelial growth factor] inhibitors and that we will be able to develop combinations or sequential therapy that may benefit patients who stop responding to VEGF inhibition."

More recently, Pfizer inked a deal with FivePrime, a protein therapeutics company that will work in conjunction with Pfizer's San Francisco-based bioinnovation center on discovery for oncology and diabetes. The deal was announced May 20.

But now, with 22 drugs in development, licensing has become less important. Ayers said in an interview that "we don't have an urgent need to do licensing deals. We can actually achieve very significant growth based on the compounds that we have in development now."

"If there were some really excellent opportunities we would remain open to them," she explained. But for now, licensing is "not essential. We've got a great pipeline, [so licensing] is not the major focus."

The Strategy Starts With Angiogenesis

Along with the business reorganization, Pfizer has organized its oncology pipeline into four research platforms: anti-angiogenesis, signal transduction inhibitors, immunotherapy and cytotoxics and potentiators.

The first, and most advanced, is anti-angiogenesis, where Pfizer hopes to build on its success with the multi-kinase inhibitor Sutent. "I think we have a really great pipeline there with multiple mechanisms," Ayers said, pointing out that angiogenesis has functionality in early and late stage disease and across many tumor types.

Since Sutent's approval in January 2006 for metastatic renal cell cancer, "we have captured the leading market share in every country where Sutent has been introduced," Ayers reported. U.S. market share, from April 2008 ImpactRx data, was 50 percent of first-line mRCC. Sutent has yielded significant growth quarter-on-quarter, and total sales in 2007 were about $600 million.

Most of Pfizer's presentations at ASCO were on Sutent. There was updated overall survival data from a Phase III study of single-agent sunitinib versus interferon-alfa in first-line metastatic renal cell carcinoma (3 (Also see "Highlights Of The American Society Of Clinical Oncology, In Brief" - Pink Sheet, 9 Jun, 2008.), p. 6), and also a Phase II on safety/tolerability of first-line Sutent with docetaxel and prednisone in metastatic hormone-refractory prostate cancer.

But perhaps more important than Pfizer's own presentations were the number of studies from other sponsors using sunitinib - showing its dominance as comparator of choice. "We are delighted to have so much data presented on Sutent which shows Sutent is becoming a standard of comparison in trials by our competitors," Ayers noted.

"Based on our confidence in Sutent and the evidence that angiogenesis is an important mechanism in many types of cancer and for many patient populations, we've rolled out a substantial development program including 11 Phase III trials," she said.

In the last year, Phase III studies have started in first-line colorectal cancer, second-line non-small cell lung cancer and adjuvant RCC. "And we're planning to initiate Phase III trials in hepatocellular and prostate cancer in the next few months," Ayers added.

Based on a Phase II study showing single-agent activity in refractory NSCLC, and Phase I evidence of tolerability when used with erlotinib, Pfizer initiated the SUN 1087 Phase III study in NSCLC. It compares Sutent plus erlotinib to erlotinib alone in patients previously treated with a platinum-based chemo regimen. "Enrollment is going very well and we expect results from this study next year," Baum, the worldwide development leader, said.

Other Phase III Sutent trials include two in first-line and two in second-line metastatic breast cancer. The Phase II data in breast cancer is very positive, Baum said.

Of the first-line breast cancer Phase III studies, one (SUN 1064) uses docetaxel; the other (SUN 1094) compares Sutent plus paclitaxel to bevacizumab (Genentech's Avastin ) plus paclitaxel. Both are enrolling well. The second-line metastatic breast cancer study SUN 1099, with capecitabine, is well under way. Enrollment is expected to complete this year with results expected in 2009.

Perhaps the most interesting Sutent study coming up is a Phase III in second-line kidney cancer comparing Sutent and sorafenib (Bayer/Onyx's competing Nexavar ) in patients that have failed the first one in initial therapy. Sequential use of the tyrosine kinase inhibitors is a hot area of research (4 , p. 10).

The planned first-line advanced hepatocellular cancer Phase III trial (SUN 1170) will also compare Sutent and Nexavar. The adjuvant RCC trial, called ASSURE, is also against Nexavar. The Phase III randomized, double-blind ECOG study (now enrolling) will compare adjuvant sunitinib versus adjuvant sorafenib versus placebo in patients with resected RCC.

Pfizer's most advanced oncology candidate in pipeline also falls into the angiogenesis category - axitinib, which is a specific inhibitor of vascular endothelial growth factor receptor-1, 2 and 3.

Pfizer has said that the first filing for axitinib will likely be in pancreatic cancer. In a randomized Phase II study with gemcitabine, axitinib produced a median overall survival of 6.9 months compared to 5.6 months for gemcitabine alone. The Phase III study in first-line advanced pancreatic cancer, also using gemcitabine, is recruiting "very well" and should complete enrollment in the next year.

Axitinib is also in Phase III for second-line metastatic renal cell carcinoma, using sorafenib as the comparator. The Phase III AGILE 1032 study, soon to begin enrollment, will use PFS as the primary endpoint. Patients will have had prior treatment with sunitinib, bevacizumab plus IFN-?, temsirolimus or cytokines.

At ASCO, Phase II data was released showing axitinib's anti-tumor activity in mRCC refractory to sunitinib and sorafenib, cytokines and sorafenib or sorafenib alone.

Ayers pointed to this data in patients refractory to Sutent at the analyst meeting to address earlier concerns about how axitinib will fit into the portfolio alongside Sutent. "This demonstrates that there may be a separate role for axitinib in the continuum of treatments," she said. "Axitinib may provide benefit for patients when other angiogenesis agents are no longer working."

In lung cancer, Pfizer is enrolling patients in a Phase II study of axitinib or bevacizumab in combination with paclitaxel and carboplatin in first-line NSCLC (AGILE 1030). The company also is preparing to begin a Phase III study of axitinib with gemcitabine later this year.

Axitinib is being studied in two Phase II trials in colorectal cancer as well.

Pfizer's other anti-angiogenesis compounds include the Phase II SU-14,813, a mRTK from Sugen, and in the Phase I TSP-1 drug CVX-045 and angiogenesis-2 antagonist CVX-060 (both from CovX), the ALK1 monoclonal antibody PF-3446962 and the sVEGFR PF-337,210.

Signal Transduction Is New Platform

The signal transduction platform, the area Ayers is most excited about, is aimed at blocking cancer growth signals. Pfizer's only marketed drug in that area is Aromasin (exemastane).

The insulin-like growth factor-1 monoclonal antibody CP-751,871, a compound created in-house, falls into that category. Ayers reported that Pfizer is leading the pack with IGF-1R development, being the first in clinic, first with published data and first into Phase III.

A Phase II study of '871 in first-line NSCLC in combination with paclitaxel and carboplatin (1002) was presented at ASCO, showing a higher objective response rate for the combination than for chemo alone: 54 percent versus 41 percent. Pfizer also did a subset analysis by histology, and the Phase III program reflects some of that data.

The ADVIGO Phase III global registration program for CP-751,871 will enroll more than 2,000 NSCLC patients worldwide. ADVIGO 1016 is enrolling previously untreated non-adenocarcinoma patients, and will use carboplatin and paclitaxel as the comparators. ADVIGO 1018 compares '871 with erlotinib to erlotinib alone in non-adenocarcinoma patients who have failed prior platinum-based therapy. The final study (1017), planned to start in the fourth quarter, will use gemcitabine and cisplatin and enroll previously untreated patients with all differentiated histologies of NSCLC.

The only Phase II candidate for signal transduction is the Pan-ErbB inhibitor PF-00299804, an orally bioavailable, irreversible small molecule tyrosine kinase inhibitor. The Phase I data presented at ASCO "gives us hope that the irreversible Pan-ErbB mechanism may have further benefit to patients beyond that currently provided by the available EGF inhibitors," Ayers said.

The development plan entails clinical trials in refractory advanced NSCLC (after failure of EGFR TKIs), second/third-line advanced NSCLC (after failure of chemotherapy), "and we also plan to explore this compound for first-line use in specific populations such as non-smokers," Ayers said. The plans include combination trial with chemotherapeutics and targeted agents.

There are several candidates in Phase I: the p-Cad monoclonal antibody PF-3,732,010, the FAK PF-562,271, the C-Met inhibitor PF-2,341,066, the C-Met BU inhibitor PF-4217903 and the Hsp90 inhibitor SNX 5422 from Serenex.

Interest Continues In Cytotoxics

In the most traditional group of cytotoxics and potentiators - where Pfizer intends to "identify the next generation of cytotoxic toxic drugs and potentiators to build on their efficacy while improving their selectivity" - Pfizer has two approved drugs: Camptosar (irinotecan) and Ellence (epirubicin).

There is one Phase II candidate, the PARP inhibitor AG-14,699 from Agouron, and three Phase I candidates: the CDK 4/6 inhibitor PD-332991, the CHK1 agent PF-477,736 and the AUR2 agent PF-3,814,735.

Making Way With Immunotherapy

The smallest platform is immunotherapy, which is also the newest area of research. Pfizer had had two Phase III programs in that area - for the cytotoxic T-lymphocyte associated antigen 4 inhibitor tremelimumab and the TLR-9 compound PF-3,512,676. However, both drugs failed in Phase III and Pfizer has moved the programs back to the drawing boards of Phase II.

Pfizer halted four mid- to late-stage trials of the TLR9 compound in June 2007, after an interim analysis found no difference in efficacy against standard chemotherapy.

The tremelimumab Phase III program was discontinued April 1 after the CTLA-4 inhibitor performed no better than standard chemotherapy in a single agent trial in advanced melanoma.

Pfizer is currently reviewing all of the available data on tremelimumab - including some of the data from the disappointing Phase III trial that was presented at ASCO. In the second attempt at Phase II, Pfizer's plan is to look for biomarkers and immune status data to find the best patient population to move forward with, Baum said.

When asked whether the difficulty in Phase III was due to the dose schedule used in that study, Baum noted that Pfizer had the best tolerated dose with a response. The firm's hypothesis is not that the problems were due to dose selection, but that it was a matter of needing to select a better patient population.

Pfizer intends to try the drug in combination with its cancer vaccines, since the drug should improve immune response. The strategy of combining tremelimumab with a vaccine makes sense, but "we have to figure out how," Baum added. Right now tremelimumab is being looked at in combination with the TLR9 program, and Pfizer is also planning on starting a study with the CDX program "as a way to enhance the efficacy of the vaccine programs."

The company's lead cancer vaccine candidate is CDX-110, licensed from Avant in a deal that closed only two days before ASCO. For Pfizer's first foray into cancer vaccines, the firms are targeting brain cancer. "This vaccine targets the mutated EGFRvIII protein, which is found in a number of other tumors such as breast, ovarian, prostate and colorectal, and we'll evaluate these options with the goal of further expanding the development program into other tumors," Ayers explained.

New data from two Phase II studies in newly diagnosed EGFRvIII-positive glioblastoma multiforme were unveiled at ASCO. CDX-110 was studied with GM-CSF and temozolomide in immune response and time to progression when given with simultaneous standard and continuous temozolomide.

"This data showed an overall survival of 33 months, which is about double the historical rate with a favorable safety profile," Baum said. "The ACT III study is being conducted to confirm and extend these findings. Additional studies of CDX-110 are in the planning stages."

ACT III is a Phase II/III design, where the results of the first phase of the trial will trigger going into the Phase III portion.

At the analyst meeting, Ayers said Pfizer will be working with regulatory authorities to identify the fastest regulatory pathway for this agent. Since the Hart-Scott-Rodino period for the Avant deal closed so recently, "Pfizer has not been in the position to have the discussions with the FDA, they were done by Avant. We're just now getting fully integrated into the program, having enough of a view over the program to have discussions with regulatory authorities," Ayers said in the interview.

Pfizer is confident that it will be able to succeed with cancer vaccine development despite the difficulties that other firms have faced, chiefly because CDX-110 has a specific, known antigen target. "We just feel that that's much more likely to be more successful than the non-specific approaches that just broadly stimulate the immune system without targeting it directly toward the tumor," Ayers explained in the interview.

Rounding out the immunotherapy area is the CD40 antibody CP-870,893.

All in all, there are a lot of reasons for Pfizer to be confident about its new foray into oncology. The firm has bought into a lot of hot areas and created a well-diversified pipeline. Most of the products have unique mechanisms of action, without a lot of overlap, Ayers pointed out.

In terms of investment, the oncology R&D pipeline represents almost a fifth of the company, and there are a lot of promising compounds. The success of Sutent bears some evidence that once it has a good compound in hand, Pfizer can follow through.

And with the new business structure in place, Pfizer should have the resources and organization to follow through and bring out the pipeline's promise.

- Mary Jo Laffler ([email protected])

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