PD1 & PD L1 Targeted Agents - Nivolumab Clinical & Commercial Development (110113)

November 3, 2013

Source: Depiction courtesy of Genentech

By Will Roettger Principal Consultant

20/20 Market Insights, LLC

Page

Introduction/Background 5-‐7

PD-‐1/PD-‐L1 Targeted Agents (Summary, PD-‐L1 Targeted Tumors, Comparison Chart)

8-‐10

PD-‐1/PD-‐L1 Product Profiles (nivolumab, BMS936559, lambrolizumab, MPDL3280A , pidilizumab, nivolumab vs. lambrolizumab, first to market strategy)

11-‐19

Nivolumab Clinical Development (efficacy, development program, phase III clinical trials, development timeline)

20-‐27

Nivolumab Commercial Development (SWOT, Short & Long Term Planning, Issues to Consider, Positioning,

28-‐32

Conclusions 33-‐35

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Will Roettger is an established career professional in the pharmaceutical and biotech industry. Having worked for Novartis, AstraZeneca, Merck, Alexion, and Dendreon he has developed expertise across the therapeutic areas of oncology, hematology, and immunology for pipeline and launch products. He has been instrumental in establishing marketing intelligence as a core capability in support of clinical and commercial new product development, solving the many commercial challenges that high-‐priced specialty products face from a patient, provider, and investor perspective. Additionally he has supported two specialty product launches, providing actionable insights and recommendations by integrating market research findings with competitive intelligence. As a principal for 20/20 Market Insights, LLC, he is dedicated to providing clients with clear vision into competitor landscapes, strategies, and product assessments that drive strategic business decisions in new drug development.

Contact Information:

Will Roettger Principal Consultant

20/20 Market Insights, LLC 908-‐391-‐4362 [email protected]

Positive signal: promotes activation & proliferation

Repressive signal: promotes supression

Source: 1.  Oelke et al. and Schneck Trends in MolecMed (2005) 2.  Keir, Annu Rev Immunol. 2008 26:677-‐704 3.  Ribas, N Engl J Med. 366: 2517-‐2519, 2012 4.  Pardol, Johns Hopkins, Nature Reviews Cancer 12, 252-‐264 (April 2012) 5.  Weber, J Semin Oncol 2010

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Tumor Type Estimated PD-‐L1 Prevalence

NSCLC (SCC) 50%

NSCLC (adeno) 45%

Colon 45%

Melanoma 40%

RCC 20%

As one of the highest prevalent cancers, NSCLC represents a significant opportunity to leverage the effects of PD-‐1/PD-‐L1 blocking agents

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Nivolumab (BMS936558)

Lambrolizumab (MK-‐3475) MPDL3280A Pidilizumab

(CT-‐011)

Company BMS Merck Genentech/Roche CureTech

Target/MOA PD-‐1 (blocks PD-‐L1/PD-‐L2 )

PD-‐1 (blocks PD-‐L1/PD-‐L2 )

PD-‐L1 (blocks PD-‐L1 )

PD-‐1

Antibody Human, IgG4 Humanized, IgG4 Human, IgG1 (effector T-‐cell function)

Humanized, IgG1 (effector T-‐cell function)

Targeted Tumors Melanoma, NSCLC, RCC Melanoma Melanoma, NSCLC, RCC, Colon, Gastric, HNSCC, Lymphoma

Melanoma, pancreatic, lymphoma, CRC, RCC, MM

Latest Clinical Phase Development

Phase III/(melanoma, NSCLC, RCC) [6-‐phase III trials]

Phase III/(melanoma) Phase II (NSCLC)

Phase II (NSCLC) Phase II (CRC, lymphoma, Hep-‐C pancreatic, PCa

Activity/response rates Melanoma: all cohorts (ORR=31%) 3mg/kg Q2W cohort (ORR 41%) NSCLC: (17%), RCC (29%)

Melanoma: all cohorts (ORR>38%) 10mg/kg Q2W cohort (ORR=52%) NSCLC: nscc cohort ORR=23%), scc cohort (ORR=33%)

Melanoma: (ORR 29%, SD 87% , PFS 43%), NSCLC (24%) NSCLC: all cohorts (ORR=23%) RCC: (ORR=13%)

+50% increase in CD4, +40% increase in CD8

Efficacy Melanoma: 3mg/kg Q2W cohort mOS=20.3 mths NSCLC: mOS=9.9 mths

Melanoma: mPFS=>7 mths NSCLC: nscc cohort mPFS=9.1 wks), scc cohort (mPFS=23.5 wks)

All Tumors: 39% vs. 13% NSCLC: 100% vs. 15%

Fast Approval Strategy (w/phase II)

1.  Squamous NSCLC 2.  RCC

1.  Melanoma 1.  NSCLC -‐

ADCC/CDC Toxicity none none none

Pneumonitis 3-‐4% 3-‐4% none none

Grade 3/4 Adverse Events All Grade 3/4 = 14% •  Fatigue 2% •  Diarrhea 1% •  Pruritus 0.3% •  Nausea 0.3% •  Hb decrease 0.3%

All Grades 3/4 = 12.6% •  Fatigue 1.5% •  Rash 2.2% •  Pruritus 0.7%

All Grade 3/4 = 43% •  Hyperglycemia 5% •  Fatigue 4% •  Increased ALT 3% •  Dyspnea 3% •  Hypoxia 3%

Trademark:

Generic Name: nivolumab

Synonyms: BMS-‐936558, MDX-‐1106, ONO-‐4538

MOA: PD-‐1 checkpoint inhibitor, fully human mAb anti-‐PD-‐1 IgG4 receptor blocker. Blocks binding of PD-‐1 to PD-‐L1 and PD-‐L2

Originating Company Ono Pharmaceuticals, Ltd./Medarex

Licensing Company Bristol-‐Myers Squibb

Formulation/Dose IV infusion, 3 mg/kg solution intravenously Q2W, [12 cycles (48 doses), 4-‐doses per cycle]

1st Launch/Indication /Metastatic NSCLC

2nd Launch/Indication /Metastatic RCC or Metastatic melanoma

Patent No./Expiration COM 2027 (US)

Sales Force Size

Cost Not available

Comments Pneumonitis AEs of 3-‐4%, 3-‐deaths to date, 1-‐CRC, 2-‐nsclc. No known Fc function (ADCC, CDC). 6-‐phase III trials are underway in NSCLC, Melanoma, and RCC.

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Trademark:

Generic Name: Not available

Synonyms: BMS-‐936559, MDX-‐1105

MOA: Fully human mAb, PD-‐L1 IgG4 ligand blocker. Blocks binding of PD-‐L1 to PD-‐1 and B7-‐1. Does not block binding of PD-‐L2 to PD-‐1

Originating Company Ono Pharmaceuticals, Ltd./

Licensing Company Bristol-‐Myers Squibb

Formulation/Dose IV infusion/0.1 – 10mg/kg Q2W [phase I, 16 cycles (48 doses), 3-‐doses per cycle]

1st Launch/Indication /Metastatic Melanoma

2nd Launch/Indication /Metastatic NSCLC

Patent No./Expiration

Sales Force Size

Cost Not available

Comments Development was dropped in option to move ahead with nivolumab – a PD-‐1 receptor blocker. No reported pneumonitis in BMS-‐936559.

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Trademark:

Generic Name: lambrolizumab

Synonyms: MK3475, SCH900475

MOA: Humanized mAb anti-‐PD-‐1, IgG4, receptor blocker. Blocks binding of PD-‐1 to PD-‐L1 and PD-‐L2

Originating Company

Licensing Company Merck/Schering

Formulation/Dose IV infusion over 30 minutes, 10 mg/.kg Q2W or 10mg/kg Q3W or 2mg/kg Q2W, [Phase I, 11-‐cycles (34 doses), 3-‐doses per cycle]

1st Launch/Indication /Metastatic Melanoma

2nd Launch/Indication /Metastatic NSCLC

Patent No./Expiration US 20130071403 A1

Sales Force Size

Cost Not available

Comments Pneumonitis AEs of 3-‐4%,

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Trademark:

Generic Name: Not available

Synonyms: MPDL3280A, RG7446

MOA: A human Fc optimized anti-‐PD-‐L1 mAb, IgG1, ligand blocker -‐ binds to PD-‐L1, blocking its binding to and activation of its receptor, PD-‐1. Fc optimization does not induce either antibody-‐dependent cytotoxicity (ADCC) or complement-‐dependent cytotoxicity (CDC).

Originating Company

Licensing Company Genentech/Roche

Formulation/Dose IV Infusion of 1200 mg on Day 1 of 21-‐day cycles for a maximum of 16 cycles, Q3W,

1st Launch/Indication /Metastatic NSCLC

2nd Launch/Indication /Metastatic Melanoma

Patent No./Expiration

Sales Force Size

Cost Not available

Comments 20% clinical benefit in PD-‐L1 negative tumors has been shown. The Fc portion of anti-‐body is engineered to prevent depletion of effector T-‐cells by ADCC thereby allowing PD-‐1 and PD-‐L2 interaction to remain intact in pleural tissues. As a result no pneumonitis has been seen.

Trademark:

Generic Name: pidilizumab

Synonyms: CT-‐011,

MOA: Humanized mAb anti-‐PD-‐1, IgG1, receptor blocker. Blocks binding of PD-‐1 to PD-‐L1 and PD-‐L2 resulting in the attenuation of apoptotic processes in lymphocytes, primarily effector/memory T cells, and the augmentation of the anti-‐tumor activities of NK cells.

Originating Company CureTech

Licensing Company

Formulation/Dose IV infusion, 0.2 to 0.6 mg/kg (dose to be determined)

1st Launch/Indication Diffuse Large B Cell Lymphoma (DLBCL)

2nd Launch/Indication mCRC

Patent No./Expiration US 7332582B2, EP 1575484A

Sales Force Size None

Cost Not available

Comments As of January 2013, Teva dropped their development agreement with Curetech on this product. At this point Teva is without a development partner and continues ahead with phase II trials.

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Nivolumab Lambrolizumab BMS936558, ONO4538 Synonyms MK3475, SCH900475

PD-‐1 checkpoint inhibitor, fully human mAb anti-‐PD-‐1 IgG4 receptor blocker. Blocks binding of PD-‐1

to PD-‐L1 and PD-‐L2

MOA Humanized mAb anti-‐PD-‐1, IgG4, receptor blocker. Blocks binding of PD-‐1 to PD-‐L1 and PD-‐L2

Ono Pharmaceuticals, Ltd./Medarex Originating Company Schering

BMS Licensing Company Merck

IV infusion, 3 mg/kg solution, Q2W, [phase I, 12 cycles (48 doses), 4-‐doses per cycle]

Formulation/Dose IV infusion over 30 minutes, 10 mg/.kg Q2W or 10mg/kg Q3W or 2mg/kg Q2W, [Phase I, 11-‐cycles (34 doses), 3-‐doses per cycle]

Not yet approved/NSCLC 1st Approval/Indication Not yet approved/NSCLC

Not yet approved/Melanoma 2nd Approval/Indication Not yet approved/Melanoma

COM 2027 (US) Patent No./Expiration

Sales Force Size

phase I, 12 cycles (48 doses) Duration of Therapy Phase I, 11-‐cycles (34 doses)

Not available Pricing Not available

Not available Cost of Treatment Not available

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Nivolumab Lambrolizumab •  ORR: 31% (n=107) •  ORR: 41% @ 3 mg/kg Q2W (n=17) •  mPFS: 3.7 months •  Yervoy treated ORR: 20%

Efficacy: Melanoma •  ORR: 38% (n=117) •  ORR: 52% @ 10 mg/kg Q2W (n=52), CR=10% •  mPFS: >7 months •  Yervoy treated ORR: 62% @ 10 mg/kg Q2W (n=13) •  Yervoy naïve ORR: 49% @ 10 mg/kg Q2W (n=39)

•  ORR: 17% RECIST [17.6% NSCC, 16.7% SCC] 1-‐yr survival=42%, 2-‐yr survival=24%, mOS=9.9 mths (n=129)

Efficacy: NSCLC •  ORR: 21% RECIST(n=38)

All Grade 3/4 = 14% •  Fatigue 2% •  Diarrhea 1% •  Pruritus 0.3% •  Nausea 0.3% •  Hb decrease 0.3%

ADEs All Grades 3/4 = 12.6% •  Fatigue 1.5% •  Rash 2.2% •  Pruritus 0.7%

Pneumonitis: 4% (any grade), 1% (grade 3/4) Notable Toxicities Pneumonitis: 4.4% (grade 1/2)

Warnings

Not available NCCN Guideline Not available

Manufacturer

Not available Sales Not available

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Nivolumab Efficacy in Phase I Trial (NCT00730639) Tumor

(dose, mg/kg) No. Patients

(n) ORR Duration of Response

(mths) Median PFS

(mths) Median OS

(mths) OS (1-‐yr)

OS (2-‐yr)

NSCLC (1-‐10) 127 16% 17.0 2.3 9.6 43% 32%

MEL (0.1-‐10) 107 31% 24.0 3.7 16.8 61% 44%

RCC (1 or 10) 34 29% 12.9 7.3 >22 70% 52%

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Nivolumab NSCLC Efficacy in Phase I Trial (NCT00730639)

Histology Dose (mg/kg)

ORR %

Stable Disease Rate (≥24 weeks )

Median OS (months)

SCC All doses 16.7% 14.8% 9.2

1 0% 26.7% 8.0

3 22.2% 5.6% 9.5

10 23.8% 14.3% 10.5

NSCC All doses 17.6% 6.8% 10.1

1 5.6% 5.6 9.9

3 26.3% 10.5% 18.2

10 18.9 5.4% 7.4 22

Combined Regimen (Nivoilumab + Yervoy) Nivolumab (mg/kg)

Yervoy (mg/kg)

Evaluable patients

CR (n) PR (n) ORR ≥80% Tumor

reduction at 8 wks 0.3 3 14 1 2 21% 4 (28%) 1 3 17 3 6 53% 7 (41%) 3 1 15 1 5 40% 5 (33%) 3 3 6 0 3 60% 0

All doses 52 5 16 40% 16 (31%)

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Nivolumab Clinical Trials

NSCLC RCC Melanoma

Phase II Trials 1.  Nivolumab in advanced or

metastatic squamous cell NSCLC, NCT01721759, n=100, i=11/2012, f=2/2014

Phase II Trials 1.  Nivolumab in clear cell

advanced RCC, NCT01354431, n=150, i=5/2011, f=5/2013

Phase II Trials 1.  Nivlumab w/ipilimumab in

advanced or metastatic melanoma, NCT01783938, n=80, i=4/2013, f=8/2014

Phase III Trials 1.  Nivolumab + ipilimumab – 1L

Advanced Melanoma, NCT01844505, n=915, i=6/2013, f=1/2017

2.  Nivolumab vs. dacarbazine or carbo/paclitaxel in advanced melanoma following anti CTLA-4, NCT01721746, n=390, i=12/2012, f=5/2015

3.  Nivolumab vs. dacarbazine, 1L metastatic melanoma, NCT01721772, n=410, i=1/2013, f=6/2020

Phase III Trials 1.  Nivolumab vs. docetaxel 2L

advanced or metastatic squamous cell NSCLC, NCT01642004, n=264, i=10/2012, f=8/2015

2.  Nivolumab vs. docetaxel 2L advanced or metastatic non-squamous NSCLC, NCT01673867,n=574, i=11/2012, f=11/2014

Phase III Trials 1.  Nivolumab vs. everolimus 2L

advanced or metastatic clear cell RCC, NCT01668784, n=822, i=10/2012, f=2/2016

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Tumor N Trial ID Scope Status T0 Tf Segment Treatment Endpoint Melanoma 915 NCT01844505 Global recruiting 6/2013 1/2017 1st line, untreated

advanced unresectable or metastatic

Nivolumab vs. 10: OS/PFS, ORR

Melanoma 390 NCT01721746 Global recruiting 12/2012 5/2015 Post CTLA-‐4, unresectable or metastatic

Nivolumab vs. dacarbazine or carbo tax

10: OS,ORR 20: PFS, HRQoL

Melanoma 410 NCT01721772 Ex-‐US recruiting 1/2013 6/2020 1st line, unresectable or metastatic

Nivolumab vs. dacarbazine

10: OS 20: PFS, ORR

NSCLC (NSCC)

264 NCT01642004 Global recruiting 10/2012 8/2015 2nd line, post platinum failure, advanced metastatic

Nivolumab vs. docetaxel

10: OS,ORR 20:PFS

NSCLC (SCC)

574 NCT01673867 Global recruiting 11/2012 11/2014 2nd line, post platinum failure, advanced metastatic

Nivolumab vs. docetaxel

10: OS 20:ORR, PFS

RCC 822 NCT01668784 Global recruiting 10/2012 2/2016 4th line, pre-‐treated advanced or metastatic clear cell RCC

Nivolumab vs. affinitor (everlimus)

10:OS

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2014 2015 2016 2017

NSCLC (2nd Line

advanced metastatic)

RCC 2nd Line

(advanced metastatic)

clear cell NCT01668784

Estimated approval 10/2015 (PDUFA V, 6-mth priority review)

Melanoma (1st Line


2013

Non-Squamous Cell NCT0167387

Complete 11/2014

Squamous Cell NCT0167387

Complete 8/2015

File 4/2015

File 1/2016 Estimated approval 7/2016 (PDUFA V, 6-mth priority review)

Complete 2/2016 File 7/2016



Vs. dacarbazine,or c/p NCT01721746

Complete 11/2014

+ ipilimumab NCT01844505

Complete 8/2015

File 5/2015


Vs. dacarbazine NCT01721772


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2014 2015 2016 2017

NSCLC (2nd Line


RCC 2nd Line

(advanced metastatic)

clear cell NCT01668784


Melanoma (1st Line


2013

Non-Squamous Cell NCT0167387

Complete 11/2014

Squamous Cell NCT0167387

Complete 8/2015

File 4/2015


Complete 2/2016 File 7/2016



Vs. dacarbazine,or c/p NCT01721746

Complete 11/2014

+ ipilimumab NCT01844505

Complete 8/2015

File 5/2015


Vs. dacarbazine NCT01721772


Phase II Study Complete 2/2014



Fast Track

Fast Track

Fast Track

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Will Roettger Principal Consultant

20/20 Market Insights, LLC 908-‐391-‐4362 [email protected]

PD1 & PD L1 Targeted Agents - Nivolumab Clinical & Commercial Development (110113)

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