The development of Potent and Selective RET inhibitors Rami Rahal, - - PowerPoint PPT Presentation

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The development of Potent and Selective RET inhibitors Rami Rahal, - - PowerPoint PPT Presentation

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The development of Potent and Selective RET inhibitors Rami Rahal, PhD Blueprint Medicines April 18, 2016 2016 AACR Annual Meeting Rami Rahal I have the following financial relationships to disclose: Employee of Blueprint Medicines -and- I

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The development of Potent and Selective RET inhibitors

Rami Rahal, PhD Blueprint Medicines April 18, 2016

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SLIDE 2

2016 AACR Annual Meeting Rami Rahal

I have the following financial relationships to disclose:

Employee of Blueprint Medicines

  • and-

I will not discuss off label use and/or investigational use in my presentation

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SLIDE 3

3

REarranged during Transfection (RET)

  • Receptor tyrosine kinase that transduces

signals from GDNF-family ligands

  • One of the first kinase fusions cloned

from an epithelial tumor

Mulligan, NRC, 2014

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4

RET Kinase Deregulation in Cancer

Thyroid NSCLC

  • 1-2% of lung adenocarcinomas

harbor RET kinase fusions

  • Non-overlapping with known driver

mutations (e.g. EGFR, ALK fusions)

Papillary Thyroid Cancer (PTC) PTC1 = RET RET = RTK 1985

1990

Lung Adeno

2012

CMML

2013

Colon, Breast, Salivary, Ovarian Tumors

2014

1987

1993-4

Medullary Thyroid Cancer (MTC)

2015

Inflammatory Myofibroblastic Tumors

Papillary

Medullary

Follicular Anaplastic ~10% RET

fusions RET activating mutations

Extracellular domain mutations Gatekeeper mutations: (V804L V804M) Kinase domain mutations

~50% of MTC patients harbor

  • ncogenic RET mutations

Kinase RET Dimerization domain Kinase

Fusion Partner RET Fusion

+

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Approved Multi-Kinase Inhibitors Targeting KDR Have Been Repurposed for RET-Driven Malignancies

Compound Target KDR Biochem. IC50 (nM) RET Biochem. IC50 (nM) KDR-associated Adverse Events? Cabozantinib KDR/MET 1 7 Yes Vandetanib KDR/EGFR 2 5 Yes Ponatinib ABL/pan-RTK 2 1 Yes Lenvatinib KDR 4 2 Yes Sorafenib RAF/VEGF 21 6 Yes

  • Broad-kinome activity
  • Dose limiting toxicities hamper ability to fully inhibit RET
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Ideal RET Inhibitor Profile

KIF5B-RET Ba/F3 proliferation

d

IC50 (nM) Ratio (WT)

WT V804 L V804 M V804 E

BLU6864 167 1.2x 1.3x 1.0x Ponatinib 12 10x 32x 122x Cabozantinib 603 4x 4x 18x Vandetanib 688 14x 13x 13x RET KDR KDR/RET ratio BLU6864 1.5 73 49x Ponatinib 2 1 2x Cabozantinib 7 1 0.14x Vandetanib 5 2 0.4x

Biochemical IC50 (nM)

  • Greater than 100-fold selective
  • ver 95% of the kinome
  • Similar activity on RET WT and resistance

mutants

1. Potently inhibit RET wild-type fusions (NSCLC & other cancers) 2. Potently inhibit oncogenic RET mutants (thyroid cancer) 3. Spare KDR in a kinome-selective manner 4. Prevent on-target resistance mutations

V804 and Y806 are resistance hotspots Screens for resistance mutations to multi-kinase inhibitors

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Ideal RET Inhibitor Profile

KIF5B-RET Ba/F3 proliferation

d

IC50 (nM) Ratio (WT)

WT V804 L V804 M V804 E

BLU6864 167 1.2x 1.3x 1.0x Ponatinib 12 10x 32x 122x Cabozantinib 603 4x 4x 18x Vandetanib 688 14x 13x 13x RET KDR KDR/RET ratio BLU6864 1.5 73 49x Ponatinib 2 1 2x Cabozantinib 7 1 0.14x Vandetanib 5 2 0.4x

Biochemical IC50 (nM)

  • Greater than 100-fold selective
  • ver 95% of the kinome
  • Similar activity on RET WT and resistance

mutants

1. Potently inhibit RET wild-type fusions (NSCLC & other cancers) 2. Potently inhibit oncogenic RET mutants (thyroid cancer) 3. Spare KDR in a kinome-selective manner 4. Prevent on-target resistance mutations

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BLU6864 Potently Inhibits pRET and Suppresses Proliferation of RET-Dependent Cancer Cells

Compound Ba/F3 KIF5B-RET LC2/ad (CCDC6-RET) TT (C634W RET) MZ-CRC1 (M918T RET) TPC-1 (CCDC6-RET) Fusion Fusion Mutant Mutant Fusion

BLU6864

167 517 285 138 76

Cabozantinib

603 365 315 97 150 Proliferation IC50 (nM)

pRET (Y1062) pSHC (Y239/240)

6864 (nM)

Mulligan, NRC, 2014

pY1062 SHC pY239/240 Proliferation, survival, migration

10,000 2,500 625 156 39 9.8 2.4 0.6 0.15

Ba/F3 KIF5B-RET Pharmacodynamic Markers Thyroid Lung

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WT KIF5B-RET Fusion (Ba/F3) V804L KIF5B-RET Fusion (Ba/F3)

Targeted RET Inhibitors Demonstrate Efficacy on RET Fusion WT and V804 Mutant Tumors

KIF5B-RET Fusion (V804L)

BLU6864

[ 4h ] [ 12h ] [ 24h ] [ 4h ] [ 12h ] [ 24h ] [ 4h ] 12h ] [ 24h ] [ 4h ] [ 12h ] [ 24h ]

Veh 10mpk BLU6864 20mpk Ponatinib 30mpk BLU6864 60mpk BLU6864

pRET pShc tRET GAPDH

Reference

Vehicle QD Ponatinib 20mpk QD BLU6864 10mpk QD BLU6864 30mpk QD BLU6864 60mpk QD Vehicle QD Ponatinib 20mpk QD BLU6864 10mpk QD BLU6864 30mpk QD BLU6864 60mpk QD

Reference BLU6864

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Lung Adenocarcinoma PDX KIF5B-RET Fusion

Targeted RET Inhibition Induces Regression in RET- Altered Lung and Thyroid Tumor In Vivo Models

Medullary Thyroid Cancer Xenograft Mutant (RET C634W)

Cabo 60mpk BLU6864 10mpk Vehicle 4 4 12 24 4 12 24 4 12 24 4 12 24 hr hr BLU6864 30mpk BLU6864 60mpk pShc tShc Stasis Stasis Regression

Vehicle QD Ponatinib 20mpk QD BLU6864 30mpk QD BLU6864 100mpk QD Vehicle QD Cabozantinib* 60mpk QD BLU6864 10mpk QD BLU6864 30mpk QD BLU6864 60mpk QD *MTD

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BLU-667: Targeted RET Inhibitor Optimized for Progression to Clinical Studies

d

IC50 (nM) Ratio (WT)

WT V804L V804E

BLU-667

16 0.9x 1.3x

BLU6864

167 1.2x 1.0x

Ponatinib

12 10x 122x

Cabozantinib

603 4x 18x

Vandetanib

688 14x 13x RET KDR KDR/RET ratio

BLU-667

0.5 35 70x BLU6864 1.5 73 49x Ponatinib 2 1 2x Cabozantinib 7 1 0.14x Vandetanib 5 2 0.4x

KIF5B-RET Ba/F3 Proliferation IC50 (nM) Biochemical IC50 (nM)

Greater than 100-fold selective

  • ver 95% of the kinome

KIF5B-RET Fusion (V804L)

Vehicle QD Cabozantinib 60mpk QD BLU-667 3mpk BID BLU-667 10mpk BID BLU-667 30mpk BID

BLU-667 currently progressing through IND-enabling studies

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Increasing Patient Benefit by Anticipating On-Target Resistance

Kinase Tyrosine Kinase Inhibitor Drug-Resistant Mutant BCR-ABL Imatinib, Dasatinib, Nilotinib T315I ALK Crizotinib L1152R, C1156Y, V1196M, G1202R, G1269A EGFR Gefitinib, Erlotinib, Osimertinib T790M, C797S KIT Imatinib V654A, T670I, N822K, D816V NTRK Entrectinib G595R, G667C,

  • On-target resistance remains an issue for targeted therapies

*Gatekeeper

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BLU-667 Prevents RET Resistance Mutants

BLU-667 allows more potent and selective RET inhibition and decreases the frequency of resistance

16x IC50 Cabozantinib

680 1800 2680 2360 2280 2120 1480 720 960 1640 1800 680 1760 4679160 11992160 9725240 9626840 10200080 8318560 1480 2200 8452360 5716120 1440 2080 7121520 2480 3320 10179720 3480 6182800 1800 9287960 2760 2952720 960 1280 4567960 2760 8036600 8070800 10838240 8459720 1360 840 1040 4059880 1240 640 1320 7138520 2802600 1800 4517240 7543360 800 400 1080 4987960 1120 1600 1160 7418120 8945640 1240 4070320 1200 720 880 960 5861160 1000 480 560 960 12560 6600 760 4335120 680 2552400 960 760 480 600 480 440 8520 680 480 680 520 840 480 600 280

ENU (mutagen) 8x - 64x IC50 2-3 weeks Ba/F3 KIF5B-RET (WT) Cell Number (ATP; Luminescence)

400 400 400 360 480 360 480 320 320 280 440 400 480 360 440 480 520 520 440 440 280 480 360 360 440 480 400 400 480 480 400 440 320 320 400 240 400 360 520 560 440 480 440 360 440 400 320 520 400 440 440 400 520 400 360 440 360 360 440 400 400 440 360 640 480 480 440 480 480 440 440 480 440 360 560 440 400 280 400 400 280 360 360 360 440 400 400 400 720 400 600 520 480 480 440 560

8x IC50 BLU-667

9000 50000 300000 1100000

10k- 100k 100k - 1000k >1000k <10k Luminescence

V804E V804M V804L Y806C

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Conclusions

  • BLU inhibitors

 Potently inhibit RET wild-type fusions (NSCLC & other cancers)  Potently inhibit oncogenic RET mutants (thyroid cancer)  Spare KDR in a kinome-selective manner  Prevent on-target resistance mutations

  • BLU compounds induce tumor regression and a similar dose-efficacy relationship in

multiple in vivo models, including

  • Lung adenocarcinoma PDX driven by KIF5B-RET fusion
  • Medullary thyroid cancer xenograft models driven by RET C634W mutant
  • KIF5B-RET Ba/F3 allograft

BLU-667 has the potential to be a transformative medicine for patients with RET-driven malignancies

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Acknowledgements

Terri Alvarez-Diez Natasja Brooijmans Jason Brubaker Fong Cao Ethan Cerami Lucian Dipietro Erica Evans Paul Fleming Alex Gardino Tim Guzi Wei Hu Vic Kadambi Joe Kim Advisors & Collaborators Brian Druker Marc Lang Nick Lydon Charles Sawyers Alice Shaw Tim Labranche Michelle Maynard Stephen Miller Mike Palmer Mike Sheets Nico Stransky Csani Varga Weifan Weng Steve Wenglowsky Doug Wilson Kevin Wilson Ben Wolf Yulian Zhang