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By George Dimopoulos, Ph.D., Ning Yang, Ph.D.

This is the second article in a two part series about ongoing changes that will shape the prostate cancer treatment market going forward. In Part 1 we examined new, recently approved therapies that are already reshaping the market. Part 1 can be found here. In this second part we turn to the future and examine the most promising clinical candidates being developed to treat prostate cancer, as well as the prospects for the companies that are developing these treatments.

According to ClinicalTrials.gov, hundreds of prostate cancer clinical trials are underway to investigate drug, device, biological, preventive behavioral, and nutritional interventions, underscoring the market potential for effective prostate cancer treatments. Among drugs, a handful of therapies merit recognition due to their potential impact on the prostate cancer market, though a plethora are in early-to-mid clinical trials. The majority of the drugs in clinical development are focused on hormone resistant prostate cancer. Table 1, at the end of this article, lists the major pharmacological development programs for prostate cancer.

Takeda's (OTCPK:TKPHF) Tak-700 (orteronel), a selective inhibitor of 17,20 lyase, is being evaluated in Phase II and Phase III clinical trials. Ongoing Phase II trials are evaluating Tak-700 safety and efficacy in hormone responsive prostate cancer patients. Safety data have revealed that common side effects were fatigue, nausea, and constipation. The primary objective of the efficacy studies is to evaluate PSA levels. Tak-700 has allowed all patients to achieve a 50% or greater decline in PSA levels at doses of 300 mg, 400 mg, and 600 mg, however it is important to note that decline in PSA has not historically correlated with an extension of overall survival. The success of Tak-700 will ultimately hinge on improvements in progression free survival and overall survival. One Phase III clinical trial is evaluating the drug's effectiveness in chemotherapy-naïve mCRPC patients, while the concurrent second trial is evaluating it in mCRPC patients who are refractory to Taxotere. The results of these studies will weigh in heavily on Tak700's likely position in the prostate cancer market.

OncoGenex Pharmaceuticals (NASDAQ:OGXI), in partnership with Teva Pharmaceuticals (NYSE:TEVA), has two Phase III studies underway to evaluate custirsen (OGX-011), an mRNA oligonucleotide antisense therapeutic agent targeting clusterin, as a treatment for patients with mCRPC. Clusterin, the target protein, is over expressed in tumor cells, and plays an important role in treatment resistance, including chemoresistance. The first study (Synergy) will examine efficacy of custirsen in combination with Taxotere in patients who are hormone refractory but have not been treated with chemotherapy. Patients will be treated with Taxotere q3 weeks in combination with prednisone (5mg qd) and weekly infusions of custirsen (640 mg) or with Taxotere and prednisone alone. The primary outcome for the trial is overall survival and the secondary outcome is progression free survival at day 140. Other outcomes are progression free survival at day 225, PSA measurements, and safety. The study has completed enrollment and results are expected by end of 2013.

The second study (Affinity) will investigate the effect of custirsen in combination with Jevtana in mCRPC patients whose disease progressed after receiving Taxotere treatment. Patients will receive Jevtana (25 mg/m2 q3 weeks) and prednisone (5mg qd) with weekly infusions of custirsen (640 mg) or will receive Jevtana/prednisone alone. The primary outcome is overall survival while the secondary outcome is progression free survival measured at day 140. The results are expected by late 2015/early 2016. If shown to improve the efficacy of Taxotere and Jevtana in extending the survival rates in patients, custirsen may become a profitable drug once it is approved.

Additionally, OncoGenex is evaluating an antisense therapeutic, OGX-427, and has reported Phase II clinical data for the treatment of chemotherapy-naïve metastatic hormone refractory prostate cancer patients. Preliminary results show that patients co-treated with OGX-427 and prednisone had declining PSA levels and less disease progression at 12 weeks when compared to the prednisone arm. Furthermore, the company is intending to initiate an additional randomized Phase II study evaluating OGX-427 in combination with Zytiga and prednisone compared to Zytiga and prednisone alone. Though the Phase II OGX-427 data seems encouraging, with only PSA data available it is too soon to value it as a potential market mover.

Aragon Pharmaceutical's ARN-509, an androgen antagonist, is currently in a Phase II clinical trial. The study is investigating the drug's efficacy in CRPC patients, in treatment-naïve mCRPC patients, and in failed, Zytiga-treated mCRPC patients. These three patient groups were given ARN-509 (240mg qd) for 12 weeks. The primary outcome measure was to determine the percentage of patients in each arm who had a 50% or greater decline in PSA levels from baseline. Preliminary results showed that 88% of the treatment-naïve mCRPC patients, 29% of the failed, Zytiga-treated mCRPC patients, and 91% of CRPC patients had a 50% or more decline in PSA levels. The final data collection date for this trial is set for June 2013.

The Exelixis (NASDAQ:EXEL) drug cabozantinib is designed to block MET and VEGF signaling pathways, which are associated with proliferation and invasiveness of tumor cells. Cabozantinib is being evaluated in two Phase III clinical trials, dubbed COMET-1 and COMET-2. The COMET-1 study is enrolling 960 patients with mCRPC who have been treated with Taxotere and Zytiga and/or Xtandi. The trial will compare cabozantinib (60mg qd) to prednisone (5mg bid) and each arm will receive a placebo version of one or the other drug. The primary endpoint is overall survival, while the secondary endpoint will evaluate bone scan responses.

The COMET-2 trial is focused on men with previously treated, symptomatic mCRPC. Patients will be given either cabozantinib (60mg qd) or intravenous mitoxantrone (q3 weeks) with prednisone (5mg bid). The primary endpoint of the trial is pain response and secondary endpoints include overall survival and bone scan response. These trials are expected to report data by early 2013 (COMET-1) and by mid 2014 (COMET-2). Unless Phase III trials demonstrate exemplary early outcomes, it is likely to be three years before cabozantinib can be marketed, making it a laggard in the prostate cancer market.

Tasquinimod, an inhibitor of angiogenesis and metastasis, is Active Biotech's (OTC:ATVBF) lead drug in clinical development. The company recently presented results from a Phase II study that investigated progression-free survival in approximately 200 men with asymptomatic mCRPC. Patients were administered 0.25mg for 2 weeks, 0.5mg for 2 weeks, 1.0 mg for 5 months or were given placebo. The primary endpoint in the trial was disease progression-free survival after six months. The company reported that 69% of tasquinimod treated patients were progression-free after six months compared with 37% for patients on placebo (p<0.001). The median progression-free survival was 7.6 months for the tasquinimod arm and 3.3 months for placebo (p=0.0042). A Phase III trial is currently recruiting 1200 asymptomatic to mildly symptomatic mCRPC patients to confirm the results from the Phase II trial. If successfully approved, tasquinimod may potentially be used to treat mCRPC in the pre-chemotherapy setting. Results are anticipated for late 2013

In addition to Provenge, Dendreon (NASDAQ:DNDN) has early Phase I clinical trials underway evaluating a small molecule agonist which activates the calcium ion channel TRPM8. TRPM is highly expressed in solid tumors, especially in advanced prostate cancer tumors, and once activated can allow calcium to enter tumor cells, causing apoptosis. Since the drug is in Phase I clinical trials, it is too soon to tell whether the Dendreon drug will be a market changer.

Bristol-Myer Squib's (NYSE:BMY) Sprycel (dasatinib), approved for acute lymphoblastic leukemia and chronic myeloid leukemia, is currently in a Phase III clinical trial for mCRPC. Patients are administered Sprycel 100mg daily with docetaxel 75mg/m3 every three weeks combined with prednisone 5mg twice daily or placebo with docetaxel 75mg/m3 every three weeks combined with prednisone 5mg twice daily. The results are due in late November/early December of 2012. Sprycel, a potent tyrosine kinase inhibitor, combating both soft tissue and bone tumors, may become an add-on treatment for mCRPC patients undergoing chemotherapy.

Algeta's (OTCPK:ALGZF) lead candidate Alpharadin (radium-223 chloride) is an alpha particle emitting radiotherapeutic agent selectively targeting tumor cells in bone. It has a successful track record in all three clinical trial phases, and may be approved by mid-to-late 2013. In the Phase III trial, called ALSYMPCA, mCRPC patients with radiographic evidence of at least two skeletal metastases received treatment with intravenous Alpharadin (50kBq/kg) or placebo infusions every four weeks for six cycles. The primary endpoint of the study was overall survival, while secondary endpoints included time to occurrence of skeletal events, changes in PSA, and time to PSA progression. Due to strong efficacy, the trial was halted before the intended completion year of 2013. Interim analysis of the results for the primary endpoint showed a median overall survival of 14 months for treated patients compared to 11.2 months for the placebo arm ( p=0.0185).

Although the Alpharadin arm had fewer skeletal related events than the placebo arm, statistical significance was not achieved. However, the study showed that the time to first skeletal related event was statistically longer in the Alpharadin arm than in the placebo arm (13.6 months vs. 8.4 months, p=0.00046) Recent updated results of this study point to an improved overall survival by 44%, resulting in a 30% reduction in the risk of death compared to placebo (p=0.0007, hr=0.695). The median overall survival for treated patients was reported to be 14.9 months versus 11.3 months for the placebo arm. Frequent side effects were consistent with earlier studies, which include anemia, neutropenia, and thrombocytopenia and other non-hematologic side effects include grade 1/2 nausea, diarrhea, and vomiting.

Alpharadin is the first treatment that may successfully treat bone metastases without severe adverse events and can be potentially used in combination with other prostate cancer treatments in pre- and post-chemotherapy mCRPC patient populations. It may therefore command an enormous portion of the market which may elevate it to blockbuster status with sales peaking at $1.7 billion annually. Additionally, Alpharadin may be used potentially with other types of cancers which have metastasized to bone.

Valuations: Algeta

Algeta announced Q3 results on November 15, 2012. At the end of the quarter, the company had a total cash and cash equivalent of $74.2M. With a quarterly cash burn rate of about $7M, we project a $18-22M burn rate for the year. Algeta has no long term obligations, and with a partnership with Bayer, the company may have the appropriate financial backing to take its lead radiopharmaceutical, Alpharadin, through the approval process without further fundraising. With a total diluted share count of 42.53M shares and a stock price of $27.92, the company has a market cap of $1.19B and an enterprise value (EV) of $1.13B. Alpharadin may be used in more than one cancer indication due to the fact that many cancer types metastasize to bone. Given its efficacy and safety, it has the potential to become a blockbuster by 2015-2020. Sales of Alphradin are expected to reach $662 M by 2015, but its collaborative sales agreement with Bayer will cut into Algeta's revenue stream. When considering a 40% profit margin and P/E multiple of 20, we arrived at a stock value of $39.78 using a DCF model.

Exelixis

Exelixis recently announced Q3 results. The company reported a total cash and cash equivalent of $309 M and $163.5 M in short term investments at the end of the quarter. With a quarterly cash burn rate of approximately $30M, we project a $100-120 M burn rate for the upcoming year. Exelixis raised $416.1M in Q3 through concurrent stock offerings and a convertible senior subordinate note due in 2019, and we believe the company will have sufficient funding to meet financial obligations related to the clinical development of cabozantinib for prostate cancer. The company is expecting an imminent approval decision for the drug as a treatment for medullary thyroid cancer. Potential FDA approval and marketing of the drug in 2013 for this cancer may provide added funding, reducing the burn-rate, for its clinical development in prostate cancer and in other cancer types. With a total diluted share count of 183.6M shares and a stock price of $5.03, the company has a market cap of $920M and an enterprise value of $786M. Given cabozantinib's anticipated late entry in the prostate cancer market as well as fierce competition by other therapeutics such as, Johnson and Johnson's (NYSE:JNJ) Zytiga and Medivation's (NASDAQ:MDVN) Xtandi, we believe potential sales for the drug will peak at $380M in the prostate cancer indication. Our DCF calculations, taking into consideration of a 40% profit margin and P/E multiple of 20, places the stock value at $5.85. Cabozantinib is being developed for other large market cancer including breast and lung cancers, and each of these provides significant potential upside for EXEL investors.

OncoGenex

OncoGenex announced Q3 financial results on November 8, 2012. By quarter's end, the company had total cash and cash equivalents of $11.36M and $73.74M in short term investments. With a quarterly cash burn rate of approximately $12M, we project a $45-55M burn rate for the upcoming year. OncoGenex's global collaboration and license agreement with Teva Pharmaceutical Industries Ltd. to develop and commercialize custirsen, may provide ample financial support without relying on future fundraising activities for clinical trials. With a total diluted share count of 14.65M shares and a stock price of $11.75, the company has a market cap of $172.2M and an enterprise value of $94.37M. With the expectation that custirsen will be approved by 2014, our sales forecast for the drug is $160-200M in 2017. The sales projection for custirsen is on the conservative side, though, due to uncertainty with the Phase III outcomes. Taking into consideration of a sales multiple of 5 and a discount rate of 30%, our DCF calculations show a stock price valuation of $24.83. With a significant asset in Phase III trials and a large pharmaceutical partner, OncoGenex' valuation seems low, which is likely due to past problems and many investors' view that antisense therapies are not yet proven in the market. However, custirsen is also being tested in Phase III in lung cancer and OncoGenex has multiple promising programs in earlier stages of development. Success in any one of these programs would justify a much higher share price for OncoGenex. If custirsen meets the primary endpoint in ongoing prostate cancer trials, it could be the first of many steps up for the stock.

Table 1: Clinical Stage Drugs for Prostate Cancer

Drug

Sponsor

Mechanism of Action

Safety/Efficacy

Phase

Indication

Alpharadin

Algeta

Alpha -particle emitter which targets bone tumors

Efficacy: median overall survival of 14.0 months compared to 11.2 months in placebo arm p=0.0185

Safety: Well tolerated for the most part. Side effects include anemia, neutropenia, thrombocytopenia, Grade 1/2 nausea, diarrhea, vomiting

Phase III

mCRPC

Custirsen

(OGX-011)

OncoGenex

Antisense oligonucleotide

Efficacy: Phase II studies ,evaluating custirsen in metastatic hormone resistant prostate cancer patients, showed that custirsen + docetaxel arm had progression free survival of 7.26 months compared to the docetaxel arm progression free survival of 6.4 months. The overall survival for the custirsen + docetaxel arm was 23.82 months, while the docetaxel arm was 16.89 months p=0.06

Safety: Custirsen in combination with docetaxel caused the following most common side effects: fatigue, anemia, neutropenia, lymphopenia, sensory neuropathy, chills, and diarrhea.

Phase III

CRPC

Dasatinib

Bristol-Myers Squibb

Tyrosine kinase inhibitor

Efficacy: Phase III study underway to investigate overall survival in mCRPC patients. The comparators include 1)dasatinib 100mg and docetaxel/prednisone daily and 2) placebo and docetaxel/prednisone daily. Results are pending.

Safety: Phase II study determined that 100 mg is well tolerated in mCRPC patients. Side effects include diarrhea, nausea, and fatigue

Phase III

mCRPC

TAK-700

Takeda

Steroid hormone synthesis inhibitor

Efficacy: Phase II studies evaluated reductions in PSA levels and freedom from metastasis in hormone resistant prostate cancer. 16% of patients obtained PSA levels lower than 0.2 ng at three months of treatment. Freedom from metastasis was 97% at months 6 and 12.

Safety: Side effects include fatigue, diarrhea, and hypertension.

Phase III

mCRPC

EMD 525797

Merck KgaA (OTC:MKGAF)

Alpha integrin alpha monoclonal antibody

Efficacy: Patient infusions of EMD 525797 consisted of 250, 500, 1000, or 1500mg. Two patients treated with 500 mg of EMD 525797 had a significant decrease in PSA, and an additional patient treated with same dose had marked tumor shrinkage and normalization of lymph nodes.

Safety: Side effects include generalized pruritus, erythemia and rash.

Phase2/3

CRPC

PROSTVAC

Bavarian Nordic

(BAVA.CO)

Vaccine against PSA

Efficacy: Phase II results evaluated overall survival in patients. The PROSTVAC arm had a significant longer median overall survival by 8.5 months compared to control arm p=0.006

Safety: Very well tolerated. A few lower grade side effects include fatigue, fever, and nausea.

Phase II/3

CRPC

ARN-509

Aragon Pharmaceuticals

Androgen antagonist

Efficacy: The Phase II study is investigating the drug's efficacy in CRPC patients, in treatment-naïve mCRPC patients, and in failed Zytiga-treated mCRPC patients. These three patient groups were given ARN-509 240mg daily for 12 weeks. Preliminary results showed that 88% of the treatment-naïve mCRPC patients, 29% of the failed Zytiga-treated mCRPC patients and 91% of CRPC patients had a 50% or more decline in PSA levels.

Safety: Well tolerated. Adverse effects include fatigue, nausea, and pain.

Phase II

CRPC

Eribulin

(E-7389)

Eisai (OTC:ESALF)

Tubulin polymerization inhibitor

Efficacy: Phase II studies have shown significant reduction in PSA levels in patients who had failed Taxotere treatments.

Safety: Well tolerated. Side effects include fatigue, asthenia, diarrhea and neutropenia.

Phase II

CRPC

GTI-2501

Lorus Therapeutics

(LRUSF.PK)

Ribonucleotide reductase inhibitor (antisense)

Efficacy: Phase II studies in chemo-naïve castrate resistant prostate cancer treated with GTI 2501, docetaxel and prednisone showed a confirmed PSA decline in 41% of patients, compared to controls.

Safety: Most common side effects include anemia, fatigue, lymphopenia, leucopenia, and neutropenia.

Phase II

CRPC

Ipilimumab (BMB 734016)

Bristol-Myers Squibb /

Medarex

Anti-CTLA-4-monoclonal antibody

Efficacy: Phase II studies are evaluating ipilimumab in hormone resistant metastatic prostate cancer. Preliminary results are 21% of patients have experienced a reduction in PSA over 50%.

Safety: Side effects include diarrhea/colitis, rash, and elevated liver enzymes.

Phase II

mCRPC

Ixabepilone

(BMS 247550)

Bristol-Myers Squibb

An epothilone B analogue, which inhibits mitosis

Efficacy: Phase II studies in progress have shown that ixabepilone alone produced reductions in PSA>50% in 17% in patients with hormone-and taxane refractory prostate cancer, with a median survival time of 10.4 months.

Safety: Common side effects include neutropenia, sensory neuropathy, fatigue, mylagias, and stomatitis

Phase II

CRPC

ISIS elF4ERx

Isis Pharma

(NASDAQ:ISIS)

Initiation factor-4 blocker

(antisense)

Efficacy: Phase I studies confirmed the antisense blocker's ability to shrink tumors which express initiation factor-4. Ongoing Phase II studies are evaluating safety and efficacy of ISIS elf4ERx with docetaxel and prednisone in prostate cancer patients.

Safety: Phase I studies have shown that it is well tolerated with common side effects such as nausea, fatigue, anemia, and neutropenia.

Phase II

CRPC

OGX-427

OncoGenex

Antisense oligonucleotide which blocks the expression of HSP27.

Efficacy: Randomized Phase II studies have shown in hormone resistant patients taking OGX-427 and prednisone, a significant reduction in PSA levels and disease free progression events at 12 weeks, compared to patients on prednisone alone.

Safe: Well tolerated with mainly grade 1 and 2 adverse events: most common side effects associated with infusion were chill, diarrhea, fatigue and nausea. Grade 3 or 4 laboratory adverse events included, lymphopenia, hyperglycemia, and elevated creatinine.

Phase II

CRPC

Tasquinimod

Active Biotech

Angiogenesis/ metastasis inhibitor

Efficacy: Phase II results show that the median progression -free survival was 7.6 months for the tasquinimod arm and 3.3 months for the placebo group (p=0.0042).

Safety: Well tolerated. Side effects include fatigue and diarrhea.

Phase II

CRPC

TKI-258

Norvartis (NYSE:NVS)

Tyrosine kinase inhibitor

Efficacy: Actively recruiting prostate cancer patients for Phase II No data can be located, specifically for prostate cancer.

Safety: Phase I studies, examining four intermittent 25-100mg/d arms and three continuous 100-175 mg/d arms, determined the maximum tolerated dose will be 125 mg/d. side effects included nausea and vomiting, fatigue, headache, anorexia, and diarrhea.

Phase II

CRPC

Apoptone

Harbor Biosciences

(OTCPK:HRBR)

Synthetic steroid hormone analog

Efficacy: Data from ongoing Phase I studies, examining Apoptone in hormone resistant prostate cancer patients, highlighted significant declines in PSA levels of equal to or greater than 50% in 33% of patients.

Safety: Well tolerated, and common side effects include fatigue and nausea.

Phase I/2a

CRPC

Gossypol (AT 101)

Ascenta Therapeutic

Oral Bcl-2-inhibitor

(promotes apoptosis)

Efficacy: Thirty eight percent of docetaxel failed hormone resistant prostate patients treated with AT-101 in combination with docetaxel and prednisone had at least a 30% decline in PSA compared to the docetaxel/prednisone arm. Nineteen percent of these patients had a 50% or greater decline in PSA levels compared to control arm.

Safety: Most common side effects were fatigue, diarrhea, nausea, anorexia, neuropenia, vomiting and dizziness.

Phase1

/2

CRPC

PHA 739358

Nerviano Medical Sciences

Aurora kinase

inhibitor

Efficacy: Phase I studies have revealed stable disease in 23.7 percent of metastatic hormone resistant prostate cancer patients. Biomarker analysis of histone H3 phosphorylation showed an inhibition in aurora kinase inhibition in patients taking 190mg.

Safety: Main side effects include neutropenia, nausea, anorexia, fatique, and diarrhea

Phase I/2

CRPC

TOK-001

Tokai Pharma (OTCPK:TOKTY)

Steroid hormone synthesis inhibitor (inhibits cyp17 lyase), androgen receptor blocker, and decreases androgen receptors in prostate cancer cells

Efficacy: Phase I studies evaluating TOK-001 in chemotherapy naïve hormone resistant patients showed that 49 percent of patients had PSA reductions of 30 percent and 11 of these patients had reductions of 50% or more. CT scans revealed significant decreases in tumor size.

Safety: Very well tolerated. Minor common side effects include fatigue, nausea, and diarrhea.

Phase I/2

CRPC

TRPM8-D-3263

Dendreon

TRPM8 calcium channel agonist; promotes apoptosis

Efficacy: n/a

Safety: n/a

Phase I

CRPC

Source: LifeSci Advisors

Source: Prostate Cancer Market Takes Shape - Part 2: Treatments In Clinical Development