Early results indicate that Medivation Inc. MDV3100 may reach the market with, among other advantages, a strong survival benefit that will position the androgen receptor signaling blocker to make considerable waves in the volatile and lucrative castrate-resistant prostate cancer market.

On Nov. 3, San Francisco-based Medivation released interim data from a pivotal trial of MDV3100 in men with metastatic castration-resistant prostate cancer who had failed prior chemotherapy. The trial was stopped by the Independent Data Monitoring Committee after it demonstrated a dramatic improvement in overall survival (OS), reducing the risk of death in this population by 37%.

MDV3100 produced a 4.8-month advantage in median OS at the interim compared to placebo, beating the survival benefit of the current market leader, Johnson & Johnson’s Zytiga (abiraterone), by nearly a month on the basis of its interim result (3.9 months) – but was roughly equivalent based on Zytiga’s full survival analysis (4.6 months, a 36% reduction in risk). However, MDV3100 offers another key advantage over Zytiga: it does not need to be taken with prednisone, and so may be more easily sequenced with other treatments.

Though J&J’s launch of Zytiga has been near flawless, the MDV3100 results appear to have it beat.

Launched in April, Zytiga had been making waves recently in the same mCRPC indication, which in the past year-and-a-half has become one of the most volatile and lucrative cancer markets. Zytiga quickly rose to dominate the setting, capturing nearly a quarter of new patient starts. In the past month, analysts had been predicting peak sales of $2 billion once abiraterone launched in Europe and won approval in a key earlier disease setting. [Editor’s note: “J&J’s Zytiga: The Anatomy Of A Cancer Launch” will appear in the November issue of IN VIVO. Please contact customer care at 800-332-2181 or custcare@elsevier.com for more information.]

But in a sign of how mercurial and unforgiving certain cancer markets are becoming, the new data indicate that MDV3100 may be in a position to leapfrog Zytiga, just as Zytiga launched on the backs of two recently launched predecessors.

Increasingly Competitive Dynamics Of mCRPC

Men with mCRPC have received androgen deprivation therapy but have nonetheless progressed to a point where the disease has spread to the bone. ADT therapy typically consists of luteinizing hormone-releasing hormone analogues like Lupron (leuprolide) or anti-androgen therapy such as Casodex (bicalutamide). In the past, these patients were usually started on chemotherapy such as docetaxel (a generic version of Sanofi’s Taxotere). In recent years, however, it’s been determined that patients who appeared to show resistance to hormone therapy, who were “chemically castrate,” in fact had tumors that were still dependent on androgen. “These tumors are not hormone refractory,” said Howard Scher of Memorial Sloan Kettering Cancer Center and a principal investigator on trials for Zytiga and MDV3100.

This insight, that resistance to one kind of hormonal therapy doesn’t mean these men can’t be treated with other types of hormonal treatment, gave rise to J&J’s Zytiga, which blocks androgen production at three sites, including the tumor microenvironment, and to Medivation’s MDV3100, which works through the androgen receptor signaling pathway to shut down androgen.

But in the year before the introduction of Zytiga, therapeutic approaches to mCRPC had taken a detour. In the summer of 2010, Sanofi took a run at the mCRPC post-chemo population with Jevtana, a second-generation taxane given by infusion in combination with prednisone. Although the drug was a cytotoxic and carried a “black box” warning for neutropenia, it was the first new entrant to show a survival benefit over earlier chemo standbys mitoxantrone and docetaxel. Sanofi mounted an aggressive promotional campaign, and because it had the field to itself for nearly a year, oncologists embraced it. But its success was short-lived.

Meanwhile, in April 2010, Seattle-based Dendreon Corp. had launched Provenge (sipuleucel-T), the first FDA-approved active cellular immunotherapy for treating cancer. Because Provenge’s launch indication of mCRPC in men who were chemo-naïve was upstream of Zytiga’s chemo-resistant population, the two drugs theoretically didn’t compete. Also, the prescriber base was different for each drug, with Zytiga targeting medical oncologists who treated the more advanced, chemo-resistant patients, and Provenge targeting urologists who traditionally lacked the infrastructure to administer chemo infusions.

But as Provenge encountered product acceptance issues among community urologists, for whom its high price ($93,000) and short treatment timeframe created reimbursement uncertainty Also see "Disappointing Provenge Sales Stir Doubts About Demand" - Pink Sheet, 4 August, 2011., urologists started looking for other treatment options. Provenge launched at a time when urologists were looking for ways, short of chemo, to treat more advanced prostate cancer patients who were no longer responding to hormone therapy. That was why they were receptive to Provenge – a safe, effective therapy that offered the possibility of making some extra money through the practice of buy-and-bill.

So, although Zytiga launched into the chemo-resistant mCRPC market and rapidly stole share from Jevtana, it also benefited from Dendreon’s stumble in the market, and began poaching off-label share from the chemo-naïve population. Baird Equity Research released the results of an oncologist survey fielded in July 2011 showing extremely high awareness of Zytiga early in its launch cycle, and more tellingly, significant off-label use of Zytiga in the chemo-naïve setting. In a sample of 44 oncologists who had started at least one CRPC patient on Zytiga in the prior 90 days, 71% of patients had failed chemotherapy (Zytiga’s approved indication), and 22% of patients were pre-chemo.

This all worked to Zytiga’s advantage, raising interest and some usage among urologists in advance of the results of its Phase III trial in mCRPC chemo-naïve patients (full data will be released in the first half of 2012).

Enter Medivation And MDV3100

Although J&J had executed a near flawless launch of Zytiga, it was entering a complex and fluid landscape. Medivation’s release of the interim results from the AFFIRM trial comes about seven months after Zytiga launched, and analysts are once again busy revising their models and drug sequencing predictions.

Medivation made a name for itself in September 2008 when Pfizer Inc. r in-licensed the biotech’s Phase II dimebon for Alzheimer ’s disease, paying $225 million in upfront cash plus milestones and assuming 60% of the development costs in exchange for a 60% share of the profits. But in March 2010, the drug failed to meet its endpoints in two Phase III trials, and Medivation’s future seemed in doubt Also see "Prospects For Pfizer/Medivation's Dimebon Dashed By Phase III Flop" - Pink Sheet, 3 March, 2010..

Then, in October 2010, Astellas Pharma Inc. and Medivation announced a worldwide co-development and co-commercialization deal for MDV3100, which at the time was in one Phase III trial for mCRPC in post-chemo patients, and in earlier trials for upstream mCRPC indications. Medivation got $110 million in upfront cash, pre-launch milestones totaling $335 million and post-launch milestones totaling $320 million. Similar to the dimebon deal with Pfizer, Astellas will pick up two-thirds of development costs in the U.S. and Europe. Medivation will retain 50% of profits in the U.S. and will realize tiered, double-digit royalties in ex-U.S. territories.

CEO David Hung told “The Pink Sheet” that the company has decided to exercise its option to co-promote MDV3100 in the U.S. with Astellas, providing 50% of the sales force and medical support resources. That extension of the company’s business model into commercial activity, plus the recent establishment of a “discovery arm,” marks Medivation’s transition from a pure development company to a fully integrated commercial organization.

In addition to the interim readout from the AFFIRM trial, Medivation is enrolling patients in another Phase III trial, called PREVAIL, testing MDV3100 in earlier-stage mCRPC patients who are chemo naïve. PREVAIL will enroll 1,700 patients and its co-primary endpoints are PFS and OS. In contrast, J&J’s Phase III for Zytiga in the same population has enrolled only about 1,000 patients, putting the robustness of its dataset at a disadvantage with respect to payers, assuming that both companies file on the OS endpoint.

MDV3100 is also in a Phase II trial called TERRAIN, comparing the effect of MDV3100 versus bicalutamide, the most commonly used anti-androgen, in 370 advanced prostate cancer patients who have progressed following medical castration with LHRH-analog therapy or surgical castration.

CEO Hung added at a Nov. 9 third quarter earnings call that “Moving even earlier in the disease progression, we’re conducting a Phase II open-label study in 60 men with advanced prostate cancer who have not yet undergone chemical castration with LHRH-analogs.” The idea behind this trial is to “see if MDV3100 can achieve comparable tumor control to LHRH-analogs while avoiding the negative impacts of chemical castration.”

What It Means For The mCRPC Market

Medivation’s ambitious clinical strategy – four concurrent trials – is clearly to make a clean sweep of all settings within mCRPC, from early stage, pre-ADT castrated patients to the most advanced patients who have failed docetaxel. The company’s clinical plans span a greater swath of the prostate cancer market than any other contender, with the possible exception of Takeda Oncology’s TAK700. “We are developing MDV3100 in as broad a spectrum of the disease as possible. We know that androgen receptor signaling is relevant to all these disease states.” Scher says that MDV3100 and other improved anti-androgens may even find use in non-metastatic prostate cancer.

Medivation recognizes that the largest addressable patient population, and therefore the greatest commercial opportunity, lies upstream in these early disease settings.

Hung recognizes that the largest addressable patient population, and therefore the greatest commercial opportunity, lies upstream in these early disease settings, where urologists are the primary prescribers. Urologists are comfortable prescribing hormonal therapy; MDV3100, like Zytiga, is an extension of ADT therapy.

If approved, it will enter the post-chemo mCRPC market a little under two years after Zytiga. If it gets priority review, Sanford Bernstein analysts predicted in a Nov. 10 note that this could put the filing in third quarter 2012 and approval in first quarter 2013. The PREVAIL trial, which is still enrolling, is about a year behind Zytiga’s Phase III trial in the same chemo-naïve study population. And although J&J has announced its intention to test Zytiga in earlier-stage patients, it does not appear to have initiated a study yet in the indications targeted in Medivation’s TERRAIN trial or in its unnamed trial in patients who have not yet undergone chemical castration with LHRH-analogs.

Therefore, assuming another competitor doesn’t spring onto the mCRPC stage in the near term, MDV3100 has a shot at becoming the standard-of-care over the next five years in each of four different settings within the disease, with the current drugs in the market falling behind in sequence.

Of course, there are still hurdles. Apart from needing to meet its endpoints and be approved by FDA and other regulatory bodies, two issues still cloud its future.

An analyst on Medivation’s third quarter call asked Chief Financial Officer Clarence Machado about a legal issue with the University of California at Los Angeles (UCLA) over ownership of MDV3100. Medivation licensed exclusive worldwide rights to the MDV300 series of compounds from UCLA; the company pays UCLA 10% of all upfronts and milestones in connection with MDV3100. Medivation’s failure to meet agreed upon diligence requirements or milestones would allow UCLA to terminate the agreement. Machado responded that Medivation filed a lawsuit against UCLA in the second quarter of 2011. He noted that the courts are busy, and “the estimated trial day would probably be three years out.” The substance of the dispute was not discussed.

A more near-term issue is that of safety. The AFFIRM safety data won’t be available until the trial is unblinded. The data monitoring committee has reviewed the data, and “we did not hear of any safety signals that would jeopardize the results of the trial,” Hung added. But aside from serious adverse events that would have prompted an intervention by the IDMC, the dropout rates are another safety question that will be scrutinized by payers.

Apart from safety issues, if approved, MDV3100 would enter into competition with Zytiga, bringing with it the seemingly unstoppable advantages of superior survival data and no need for concomitant use of prednisone. Some analysts believe that prednisone complicates the sequencing options available to Zytiga.

The only other factor that could hobble MDV3100 in competition with Zytiga is price, which neither Medivation nor its partner Astellas have discussed. Zytiga costs $5,000 a month or approximately $40,000 for a median eight-month treatment duration. The cost is a little lower than Jevtana ($8,000/cycle, median six cycles) and well under Dendreon’s Provenge ($93,000 for a course of treatment). The prostate cancer market appears to be swinging toward the use of improved anti-androgens. MDV3100 will likely be reference priced to its nearest competitor and fellow ADT, Zytiga.

Meanwhile Millennium’s TAK-700 is in two Phase III trials for mCRPC (pre- and post-chemo), and also in a Phase II trial for the earliest setting of non-metastatic CRPC. The Phase III trials will be completed in 2014, with likely approval in 2015. TAK-700 targets the same enzyme as Zytiga. Further back in development is another anti-androgen, Aragon Pharmaceuticals’ ARN-509, in Phase I/II. Scher speculates that the next generation of mCRPC treatments may be biologicals, and cites Bavarian Nordic’s PROSTVAC, a therapeutic vaccine in Phase II, and Bristol-Myers Squibb’s CTLA-4 antibody ipilimumab, in Phase III against chemo-naïve mCRPC.

But Medivation has set the efficacy bar high. If MDV3100 is approved, the mCRPC market may settle into something like stability for the foreseeable future as the drug begins its steady rise to the frontline in each of its settings.

Beyond the prostate cancer setting, MDV3100 is in a preclinical trial for breast cancer. Hung said that, as expected, MDV3100 inhibited testosterone-mediated androgen, which drives about one third of breast cancers; but in a surprise finding, researchers at the University of Colorado at Denver found that it also blocked breast tumor growth fueled by estrogen. “MDV3100 appears to bind to the estrogen receptor as well,” Hung noted.

Medivation is sitting on about $180 million in cash as of last quarter. Hung is confident that available cash, plus expected pre- and post-launch milestones in the U.S. and elsewhere, will enable the company to meet its R&D obligations and the cost of fielding a sales force to co-promote MDV3100 – quite a position for a company that came close to shutting its doors a few years ago.

Medivation Aims To Capture Prostate Cancer Market, One Trial At A Time

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