At Astellas R&D Day, Enzalutamide And In-house Tech In The Spotlight

Astellas has tried to build oncology knowhow in the past six years, and while licensed compounds approach approval, Phase II in-house compounds may show whether it can be a global leader.

TOKYO - Astellas Pharma Inc.reorganized company priorities in 2006 to include oncology as a key therapeutic area. Since then, the acquisitions of Agensys Inc. and OSI Pharmaceuticals LLC have bolstered Astellas' technical capabilities. But it's still too early to tell whether the firm's in-house capabilities can match its licensing appetite.

Astellas' current business plan is built around becoming a "global category leader" in five therapeutic areas. Having already established itself in urology and transplantation, Astellas expects to extend its presence into oncology, neuroscience and diabetes/kidney disease by 2015 (Also see "2012 A Key Year For Astellas, Says New CEO Yoshihiko Hatanaka" - Scrip, 31 Jan, 2012.).

With the recent filing of enzalutamide – formally known as MDV3100 – in the U.S. and EU, Astellas devoted an R&D Day meeting to oncology.

In June 2008, Astellas brought on Wayne Klohs, former senior director of medical oncology at Takeda Pharmaceutical Co. Ltd., as senior vice president and oncology therapeutic head. Klohs was tasked with leading a cross-functional therapeutic team that brought together staff from R&D, product strategy and marketing units, Drug Discovery Research Senior VP Shinichi Tsukamoto said during the July 11 meeting.

In part, Klohs has to promote cross-site collaboration within Astellas. The firm's primary oncology research takes place at OSI in Farmingdale, NY, Agensys in Santa Monica, CA and Astellas' in-house research site, Tsukubua Research Center outside of Tokyo.

Precision Medicine Pipeline Focus

The companies that merged to create Astellas – Yamanouchi and Fujisawa – did not have extensive experience in novel oncology R&D, but partnering has helped Astellas accelerate its activity. Tsukamoto emphasized the importance of "precision medicine" for Astellas' oncology candidates. Of the 16 candidates disclosed in Astellas' oncology pipeline, seven compounds also have companion diagnostics being developed, and four of those diagnostics are being developed with the help of partners.

Asked about the 2011 U.S. FDA guidance for drugs and companion diagnostics, Astellas Pharma Global Development, Inc. President Steve Ryder said, "We're aware of the guidance and certainly we'll take that into consideration as future plans for some of these early agents. For an agent like Tarceva where you're talking about identifying an EGFR mutant, the guidance doesn't apply because Tarceva was approved well before the guidance, but for all the new agents, we're aware of it and as future plans evolve, it'll certainly be considered."

But Tsukamoto also boasted about Astellas' in-house capabilities, including a bioimaging research laboratory. According to Tsukamoto, no other Japanese company has a similar facility, which includes a PET scanner for large animals co-developed with Hamamatsu Photonics KK. Tsukamoto points to the facility as a competitive advantage for Astellas among local competition, many of which are pursuing oncology.

Agensys is currently constructing a new research facility, with an expected completion date in early 2013. It is the success of products developed from Agensys, OSI and the Tsukuba that will clarify Astellas' in-house capabilities.

Agensys, originally an early CMC and development operation, in-licensed an antibody drug conjugate (ADC) platform from Seattle Genetics Inc. Astellas has three compounds in Phase I utilizing ADC for renal, prostate, pancreatic cancers and solid tumors. Agensys also advanced in-house compound AGS-1C4D4 to Phase II, marking Agensys' first naked antibody – as opposed to a conjugate – to advance to Phase II.

"There have been technological improvements in linker technology. Seattle Genetics has been at the forefront of that. … We believe that the team at Agensys is literally the cutting edge in terms of linker technology and the use of antibodies and antibody drug conjugates or cancer chemotherapy," Ryder said at the meeting.

AGS-1C4D4, which targets the prostate stem cell antigen (PSCA), is being developed for pancreatic and prostate cancer. But as Klohs noted during the R&D meeting, the compound may have a long road ahead. "To be very honest, PSCA as a target is not really understood. It's thought to be involved in metastasis. It's thought to be involved in self-signaling. It's possible, and in fact, we have data that shows that AGS-1C4D4 has ADCC activity but this is not a target that's completely understood," Klohs said

MDV3100's Entrance

MDV3100, now known as enzalutamide, is the current star of Astellas' pipeline. Astellas is co-developing the compound – the first androgen receptor signaling inhibitor – globally with Medivation Inc. for prostate and breast cancer.

In May, the partners filed an NDA in the U.S. for post-chemo prostate cancer, and quickly followed by a filing in the EU, based on robust data from the Phase III AFFIRM study. Data presented in February showed enzalutamide prolonged overall survival by a median time of 4.8 months compared to placebo, and the trial was stopped early because of the positive results to allow patients on placebo to take the drug. Enzalutamide met all secondary endpoints and was well-tolerated, particularly in compared to placebo in ≥3 adverse events. A Phase I/II trial for the same indication completed enrollment in Japan in April.

According to Klohs, enzalutamide binds to the androgen receptor "more potently than bicalutamide," and analysts expect enzalutamide to take share from Johnson & Johnson prostate cancer therapy Zytiga (abirateron acetate) if it reaches the market. If U.S. FDA grants priority review for the drug, it could hit the market before the end of the year (Also see "More Competition In Prostate Cancer? Medivation’s Enzalutamide Now With FDA" - Pink Sheet, 22 May, 2012.).

Astellas' expectations for enzalutamide run deep. Klohs said Medivation and Astellas believe the compound is well-suited for both late-stage and early-stage prostate cancer. The companies completed enrollment in June for PREVAIL, a 1,680 patient study for chemo-naïve patients. Klohs noted that selected sites in Asia will remain open for filing requirements in key Asian markets. "We're just ticking the boxes," Ryder, told PharmAsia News on the sidelines of the meeting. Two other Phase II trials completed enrollment in the EU this year, and the first patient entered a U.S. Phase I breast cancer trial in April.

Asked whether Astellas is pursuing combination therapies with enzalutamide, particularly with a product like Dendreon Corp. personalized immunotherapy Provenge (sipuleucel-T), Klohs replied: "Absolutely. I see no reason why an immune-modulator plus enzalutamide that does not affect the immune system would not be very combinable. … I think there are other opportunities as well and, without commenting on specific opportunities, the combined team of Medivation and Astellas are looking at all of those opportunities."

Tivozanib Going Head-To-Head With Pfizer Inc.’s Sunitinib

Tivozanib, which Klohs called Astellas' next most important drug, obtained top line results in January for a Phase III renal cell carcinoma trial, and Astellas is preparing U.S. and EU submissions.

Klohs called tivozanib "the most potent…and the most selective VEGFR inhibitor in development or approved, and we believe that this selectivity and potency will result in less off-target toxicity versus other VEGFR tyrosine kinase inhibitors,"

But analysts weren't enthusiastic about the gap with which tivozanib – co-developed with Aveo Pharmaceuticals Inc. – bested Onyx Pharmaceuticals Inc./Bayer HealthCare LLCNexavar (sorafenib) (Also see "Aveo/Astellas’ Tivozanib Bests Nexavar, Barely, In Advanced Kidney Cancer" - Pink Sheet, 3 Jan, 2012.).

Notably, Aveo and Astellas initiated the TAURUS patient preference trial in June to compare tivozanib with sunitinib in first-line renal cell carcinoma. Pfizer Inc.'s Sutent (sunitinib) is the current VEGF leader for first-line advanced RCC, and Astellas hopes to show patient preference for its product in the trial. The double-blind, crossover controlled Phase II trial will compare patient preference in 160 patients after receiving tivozanib and sunitinib in sequence. Klohs noted the trial design is very similar to GlaxoSmithKline PLC's PISCES trial, which evaluated patient preference between Votrient (pazopanib) and sunitinib.

Klohs was optimistic, noting tivozanib demonstrated in the TIVO-1 study the longest progression-free survival recorded in a treatment-naïve metastatic RCC population. "RCC while that's a very crowded space, I believe that we have a very good opportunity to be a first line therapy," Klohs said.

Aveo and Astellas have a Phase II head-to-head trial with tivozanib and Avastin (bevacizumab) for metastatic colorectal cancer.

Phase II Interests

Klohs also highlighted a few Phase II compounds working their way through development.

Quizartinib, a second-generation FLT3 kinase inhibitor, is the first new treatment for acute myeloid leukemia in 25 years, Klohs said, noting quizartinib the most selective FLT3 inhibitor in development, particularly since Takeda Oncology withdrew development of MLN-518.

All trials are ongoing, leading with a dose-ranging Phase IIb monotherapy trial that enrolled its first patient in May 2012.

Astellas is also developing a truly in-house breast cancer and lymphoma therapy. Sepantronium bromide is a first-in-class surviving suppressant discovered at the company's research facility at Tsukuba. Astellas completed enrollment for a EU/U.S. Phase II breast cancer trial for first-line HER2 negative metastatic breast cancer in combination with docetaxel.