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Prostate Cancer - Newer Antiandrogens & Emerging Therapies Targeting a “Watchful Waiting” and Resistance Population

Date: Feb 01 2017
MP Advisors
Number of Pages: 200
Category: Healthcare

Xtandi – Replacing competitor from Zytiga to Casodex (Bicalutamide) for a
bigger pie in Prostate cancer & Finding its niche in crowded BC market
Xtandi + Zytiga vs. ARN-509 + Zytiga - Who will win the race?
Rising star Anti Androgens – Third generation Antiandrogens- What left for AR-V7 mutants after TOK-001 failure?
Late Stage Prostate Cancer Pipeline drugs – AKT inhibitors or PARP inhibitors or a new MoA combination with Antiandrogen or IO combo - Competing to Xtandi/Zytiga or targeting Xtandi/Zytiga Resistance Population?
Increase in prevalence of Prostate cancer and availability of new treatment options (Zytiga, Xtandi, Cabazitaxel and Xofigo) in last few years has extended role of newer oral Antiandrogens to treat metastatic CRPC patient populations where the unmet need was high. This has expanded WW market size of Prostate cancer drugs to $7b in 2016 from $2.5b in 2011. Now nmCRPC, HSPC and Xtandi/Zytiga resistance population are the markets where in new pipeline drugs are under development.
Reported PhII clinical data of Xtandi, ARN-509 and ODM-201 in nmCRPC when indirectly compared demonstrate the bar is high for ARN-509 to compete against Xtandi in nmCRPC market and while ODM-201 is few years behind in clinical development. While in mHSPC reported clinical results of STAMPEDE study opens door for docetaxel combination approach as standard of care in first line setting.

Around 8 plus drugs are in PhIII development for Prostate cancer treatment and 26 plus drugs are in PhII development (21 small molecules) - success of a few (ARN-509, ODM-201, AZD 5363, GX301) in coming years will expand nmCRPC ($3.5be), mHSPC market ($1be) and Xtandi/Zytiga resistant population ($1be) market by 2023. Longer duration of therapy and high prevalence makes earlier setting market more attractive and bigger for newer options than the late stage if they succeed.

For drugs targeting through androgen pathway - Now trials and clinical development is underway for second and third generation androgen receptor inhibitors (ARN-509, ODM-201, ODM-204, EPI-506, VT-464, TAS-3681 and DR103). While androgen synthesis inhibitors still needs a proof of concept in clinic due to failure of TAK-700 & TOK-001. Expected data from VT-464 (Apr 2017) & ASN-001 will be important to watch to taste the success for this class. Androgen receptor degrader is another MoA in development from a decade and success of in clinic compound GTX-758 (Data expected anytime from now as study completed in March 2016- less likely to succeed) will decide the proof of concept.

Other than pipeline drugs targeting androgen pathway, NCE targeting AKT pathway (AZD5363, Ipatasertib) appears to be more promising to succeed in late stage, while drugs acting through PARP inhibition (Olaparib, Niraparib) still needs a taste of success. Other interesting pipeline asset is LHRH agonist LMIS 50 mg, which is designed to overcome the drawbacks of the commercial depot products containing GnRH agonists by using a proprietary delivery system.

Also 6 therapeutic vaccines are in clinical development to treat prostate cancer. Recently launched PD-L1 IO therapy has increased hope of treating cancer in much safer way. Current ongoing studies of late stage IO mab are in Ph I/II clinical development and would be able to answer of PTEN hypothesis for role of PD-1, PD-L1 inhibitor to treat prostate cancer in coming years.

Resistant development is another challenge with long term use of Xtandi/Zytiga and needs to be addressed by pipeline second/third generation Antiandrogens/ combination approach with IO/PARP/AKT inhibitors to treat mCRPC. Increase in pricing pressure in developed market again put inference on Combination approach unless the advantage is significant and improve the Q0L in earlier setting. Due to that, drugs targeting adjuvant setting has high bar to deliver (Atezolizumab, GX301, Mipsagargin and Olaparib) in the clinical development to add significant value.

This report details current unmet need, changing regulatory requirement, reimbursement challenges & market dynamics of Prostate Cancer drugs. Report mention pipeline Antiandrogens, late stage prostate cancer pipeline drugs/new Mechanism of action & major companies developing Prostate cancer drugs. It also provides insight on clinical development strategy of combination pipeline/marketed drugs & therapeutic competitive landscape to find treatment paradigm fit & market potential of new drugs for treatment of Prostate Cancer

1. Executive Summary

Antiandrogens- Expanding Role of new Oral Antiandrogens in early treatment armamentarium of Prostate Cancer and Other indications-
 Current Role of Oral antiandrogen therapy and its limitations
o nmCRPC and HSPC- Next growth driver of New Oral Antiandrogens – ARN-509 or Xtandi or ODM-201- Who will win the race?
o WW Targeted Patient population and expected Market size expansion of Anti androgens in each stage
o Zytiga patent expiry – Game Changer in Antiandrogen Class
o New Pipeline early stage Antiandrogens
 Targeting Xtandi and Zytiga Resistance population- A way to Fast track drug development?
Immuno-Oncology drug –Potential in Prostate Cancer and ongoing combination studies with Antiandrogens & with Pipeline Prostate Cancer drugs
Other Late stage Pipeline drugs for treatment of Prostate Cancer- AKT inhibitors or PARP inhibitors or a new MoA combination with Antiandrogen- Competing to Xtandi/Zytiga or targeting Xtandi/Zytiga Resistance Population?
2. Prostate Cancer

 Stages of prostate cancer
 Signs and symptoms of prostate cancer
 Causes of prostate cancer
 Treatment of prostate cancer
 Unmet need of prostate cancer
 Current market size of prostate cancer
3. Xtandi

 Xtandi – current uptake
o Xtandi current US prescription trend and its uptake
 Xtandi Price issue
o Xtandi uptake in Europe
o Xtandi uptake in Japan
 Xtandi- additional opportunities in Prostate Cancer
o Xtandi in nmCRPC- PROSPER study
 Urology opportunity / Xtandi as a preferred urology drug
 Xtandi Market Potential in nmCRPC
• Xtandi Price Issue in nmCRPC
• Xtandi duration of therapy in nmCRPC
o Xtandi – additional clinical trials in Prostate Cancer
 Xtandi in M1 Hormone Sensitive patients
 Xtandi in Mo Hormone Sensitive patients
 Xtandi other ongoing clinical studies
o Xtandi with Pfizer early stage Prostate cancer Pipeline drug
 Xtandi in Other Indications
o Xtandi Potential in Breast Cancer
o Xtandi in Hepatocellular Carcinoma
 Xtandi in combination with New pipeline drugs
 Xtandi with IO combo- please refer chapter no. 7
4. Zytiga +ARN-509- How big is it has potential to change the treatment paradigm of Prostate Cancer? A competitive threat post Zytiga patent expiry for Xtandi?

 Zytiga generic entry: An opportunity for ARN-509 or A threat for JNJ?
 Zytiga patent Expiry- more worries for early entry in US market than Ex-US
 Use patents of Zytiga : the 438 Patent
 Ongoing clinical trial of Zytiga with ARN-509
 Ongoing clinical trials of Zytiga with Xtandi
 New formulation under development for Zytiga/Xtandi
 Combination studies of Zytiga with other targeted therapy vs. combination study of Xtandi with other targeted therapies, Ongoing Clinical trials
 Combination of Zytiga with Onapristone
5. Pipeline Antiandrogens: Androgen Receptor Inhibitors vs. Androgen Synthesis inhibitors-

 Androgen Receptor inhibitors: Who could be the major threat to Xtandi?
• ARN-509- A better Xtandi is in making
o Ongoing Clinical trials of ARN-509 and our expectations
o ARN-509- Clinical data comparison vs. Xtandi and other pipeline candidates
• ODM-201- Does its safety differentiate it against ARN-509/Xtandi?
• ODM-201 and ODM-204 has potential to challenge current leader Xtandi and Zytiga
• EPI-001 and EPI-506
• SHR3680
• GT0918 (Proxalutamide)
• ONC1-13B
 Other early stage pipeline Antiandrogens and our view –
• DR103
• AZD3514
• HE3232 (Apoptone)
• BMS-641988
 Androgen Synthesis inhibitors: TAK-700 and TOK-001 Failure in clinical trials creates “No hope” for VT-464 & other Cyp17 lyase inhibitor?
• TAK-700- How it is different from Zytiga?
• VT-464
• ASN001
 Selective Androgen Receptor Degraders
• GTX-758
 Indirect near term key competitors to Zytiga/Xtandi in Post chemo setting:
• OGX-011
• TAS-3681
• ARV-330
• PROTAC (Proteolysis Targeting chimera) platform of ARVINAS pharmaceutical
6. Targeting Xtandi and Zytiga Non Responder and Resistant population

 Causes of resistance -Emerging mechanisms of Resistance to Xtandi/Zytiga
 How do the Mechanism of resistance to the Zytiga and Xtandi differ and do some of them overlap?
 Can AR-V7 splice biomarker be used to determine whether Xtandi and Zytiga will work??
 What other studies are looking at different ways to overcome resistance??
 Who will win the race for AR-V7 variant mCRPC??
7. Combination of drugs with IO therapy

 Pembrolizumab
 Durvalumab with or without Tremelimumab
 Atezolizumab (Tecentriq)
 Nivolumab
8. New pipeline drugs

 AZD 5363
 ADXS31-142 (ADX-PSA)
 [68Ga]RM2 or Ga-bombesin
 Recombinant adenovirus (Ad5-SGE-REIC/Dkk3)
 SM-88
 Mobilan (M-VM3)
 Dendritic cells DCVAC
 LMIS 50 mg
 Niraparib
 GX301
 ODX (Osteodex)
 BHR-200 (transdermal estradiol gel)
 Mipsagargin (G-202)
 ProstAtakÂ
 99mTc-MIP-1404 injection
 PectaSol –C Modified Citrus Pectin
 ATL-101
 MVI-816
 Olaparib (Lynparza)
 TAK-385 (Relugolix)
 Ipatasertib (GDC-0068, RG7440)
 LY3023414
 Zoptrex (Zoptarelin doxorubicin)
Companies mentioned:
• Pfizer
• Medivation
• Astellas
• Valeant pharmaceuticals
• Turing pharmaceuticals
• Abbott
• Johnson & Johnson
• Tokai pharmaceuticals
• Bayer pharmaceuticals
• AstraZeneca
• Teva pharmaceuticals
• Mylan
• Bind therapeutics
• NanoString Technologies
• Zenith Technologies
• Actavis
• Apotex
• Par pharmaceuticals
• Citron pharma
• Dr. Reddy’s Laboratories
• Sun pharma
• Wockhardt
• Amneal pharmaceuticals
• West-ward pharmaceuticals (Hikma pharmaceuticals)
• Hetero Labs.
• BTG International Ltd.
• Janssen pharmaceuticals
• Amerigen pharmaceuticals
• Aragon pharmaceuticals
• Sanofi
• Arno Therapeutics
• Invivis pharmaceuticals
• Orion pharmaceuticals
• Endo pharma
• ESSA pharma
• Jiangsu Hengrui Medicine Co.
• Suzhou Kintor pharmaceuticals Inc.
• Allchem pharma
• Harbor Bioscience
• Bristol-Myers Squibb pharma
• Takeda pharma
• Viamet pharmaceuticals
• Innocrin pharmaceuticals
• Asana Bioscience
• GTx pharma
• OncoGenex pharmaceuticals
• Taiho Oncology
• Arvinas pharmaceuticals
• Roche pharmaceuticals
• Merck pharmaceuticals
• Sotio pharma
• Foresee pharmaceuticals
• Advantagene
• Progenics pharmaceuticals
• Econugenics
• Bavarian Nordic
• Mediolanum S.p.A
• Piramal Imaging S.A
• Panacela Labs
• BHR pharma
• DexTech Medical AB
• ATLAB pharma
• Madison Vaccines
• Millennium pharmaceuticals
• Genetech
• Eli Lilly Company
• Inspyr Therapeutics
• Momotaro-Gene Inc.
• Tyme Technology
• Advaxis
• Aeterna Zentaris Inc.
• Nanobiotix

Table 1: Competitive landscape of phase I/II clinical data comparison of ARN-509 vs.
Enzalutamide vs. ODM-201
Table 2: Non metastatic CRPC- phase I/II clinical data comparison of ARN-508 vs. Enzalutamide vs. ODM-201- long term safety profile in Ph III is key to watch
Table 3: Competitive landscape of mHSPC- STAMPEDE study data raise bar for newer
Table 4: Key study status of IO combination studies for prostate cancer
Table 5: Stages of prostate cancer and its therapeutic options with drugs
Table 6: Calculation of Targeted patient population Prechemo/Postchemo-US geography
Table 7: Reported sales of Xtandi/ Zytiga
Table 8: Sales of drugs in 2014 and 2015
Table 9: Reported sales of Xtandi
Table 10: Completed study of Xtandi in prostate cancer
Table 11: Subgroup analysis shows benefit in MO
Table 12: Ongoing study of Xtandi in prostate cancer
Table 13: Xtandi market potential
Table 14: Price related Petition in US
Table 15: Treatment to rPFS would extend duration in TERRAIN study
Table 16: Xtandi ongoing clinical trials in breast cancer
Table 17: Xtandi ongoing clinical trials in other indication
Table 18: Reported sales of Zytiga
Table 19: List of companies who filed PARA IV
Table 20: Ongoing clinical trials of Zytiga
Table 21: Prostate cancer Xtandi vs. Zytiga in post chemo patients
Table 22: Pipeline androgen receptor inhibitor
Table 23: Upregulated GR protein expression
Table 24: Ongoing clinical trials of ARN-509
Table 25: AR affinity of newer antiandrogen
Table 26: Ongoing clinical trials of ODM-201
Table 27: ODM-201 clinical studies
Table 28: ODM-201 patient type in dualides study
Table 29: Ongoing clinical trials of ODM-204
Table 30: Targeted product profile in mCRPC
Table 31: Ongoing clinical trials of EPI-506
Table 32: AZD3514 Ph I clinical data in prostate cancer
Table 33: Clinical trial status of TOK-001
Table 34: Ongoing clinical trials of VT-464
Table 35: List of androgen receptor inhibitor discontinued or on hold due to various reasons
Table 36: AR-V7+ had poor responses regardless of therapy
Table 37: Possible MOA of resistance with Xtandi and Zytiga
Table 38: Pipeline drugs for Prostate cancer treatment in combination with IO therapy
Table 39: New pipeline drugs for Prostate cancer
Table 40: Clinical trial study design of ADXS 31-1-42+ Pembrolizumab
Chart 1: Zytiga and Xtandi weekly TRx since Oct 2013
Chart 2: Zytiga and Xtandi weekly NBRx since Oct 2013
Chart 3: Prostate Cancer Current and Future Treatment Options
Chart 4: Natural history of Prostate cancer
Chart 5: Difference in Scrips given by Urology and Oncology
Chart 6: Comparison of recent TRx share trends
Chart 7: Ongoing Xtandi trials targeting earlier stage prostate cancer patients and
Market size
Chart 8: Quarterly net sales of novel hormonal therapies
Chart 9: Xtandi- Duration of Therapy in Various Study
Chart 10: Distribution of various breast cancer subtypes
Chart 11: Xtandi Addressable Patient Population in US to treat Breast Cancer
Chart 12: ODM-201- Permeability to Blood Brain Barrier
Chart 13: Efficacy Results from Phase 1 study of ODM-201
Chart 14: ODM-201-how it is different from Xtandi and ARN-509
Chart 15: ODM-204- A derived structure from Zytiga and Xtandi
Chart 16: Positioning of ODM-204
Chart 17: Target product profile in mCRPC
Chart 18: EPI-506- Androgen Receptor Binding Site
Chart 19: Trial designee of EPI 506
Chart 20: EPI-506- Target Prostate Cancer Patient
Chart 21: APOPTONE in preclinical model in CRPC
Chart 22: Phase 3 study size for TOK-001 vs. Xtandi/Zytiga
Chart 23: OncoGenex – Mechanism of Action
Chart 24: ARV-330 – Mechanism of Action
Chart 25: PROTAC Platform of Arvinas Pharmaceuticals
Chart 26: Emerging mechanisms of Resistance to Xtandi/Zytiga
Chart 27: Xtandi/Zytiga- Shorter rPFS of AR-V7+ Patients
Chart 28: MOA of Action of ADX- PSA
Chart 29: Recognized Prostate Cancer Cells by ADX-PSA
Chart 30: Killed cancer cells by ADX- PSA
Chart 31: Step by Step Lm-LLo Immuno modulation of Pembrolizumab
Chart 32: REIC/ Dkk-3 – Western Blot Analysis
Chart 33: Dendritic Cells
Chart 34: Clinical Trial study design of NBTXR3 in Prostate Cancer
Chart 35: Preliminary Efficacy of Osteodex in Cancer
Chart 36: MOA of Mipsagargin
Chart 37: MVI-816 (pTVG-HP) Plasmid DNA Vaccine Targeting PAP
Chart 38: MOA of AKT inhibitor –Ipatasertib
Chart 39: MOA of AKT inhibitor –LY3023414 (PH II)

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