2/24/2017 1 Antisense Oligonucleotide Purification Platform: How does it measure up? March 2, 2017 Kris Ruanjaikaen, Hien Nguyen, Ratnesh Joshi, Yannick Fillon, Robert Gronke 2 Biogen | Confidential and Proprietary • Biogen’s entry into ASO’s with a strategic alliance with Ionis Pharmaceuticals (Carlsbad, CA) • Pipeline: 8+ drug candidates with a neurology focus including SMA, ALS, Parkinson’s, and Alzheimer's diseases • Our lead ASO drug Spinraza: FDA approval granted in December 2016 for Spinal Muscular Atrophy (SMA) Antisense Oligonucleotides at Biogen
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2/24/2017
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Antisense Oligonucleotide Purification Platform: How does it measure up?
March 2, 2017
Kris Ruanjaikaen, Hien Nguyen, Ratnesh Joshi, Yannick Fillon, Robert Gronke
2Biogen | Confidential and Proprietary
• Biogen’s entry into ASO’s with a strategic alliance with Ionis
Pharmaceuticals (Carlsbad, CA)
• Pipeline: 8+ drug candidates with a neurology focus including SMA,
ALS, Parkinson’s, and Alzheimer's diseases
• Our lead ASO drug Spinraza: FDA approval granted in December 2016 for Spinal Muscular Atrophy (SMA)
Antisense Oligonucleotides at Biogen
2/24/2017
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3Biogen | Confidential and Proprietary
Introduction: Antisense oligonucleotides (ASOs)
o What are they?
o How are they made?
o Current process vs. Biogen’s platform
Structure and key impurities
Purification platform development
o Purification Strategies
o Evaluation of Biogen’s pipeline against platform
o Process development
Conclusions
Outline
4Biogen | Confidential and Proprietary
What are ASOs?
Rigo F, et al. The Journal of Cell Biology. 2012. 199(1):21-25.
• ASO are short, synthetic nucleic acid chain 8-50 units in length
• Designed to bind to complementary mRNA
• Has a broad range of effects on protein expression
Intrathecal Delivery
• Biogen has a strong interest in diseases of the brain
• Most of our ASO’s require intrathecal (IT) delivery (lumbar puncture) into cerebrospinal fluid
• Low concentration DP (< 10 g/L)
2/24/2017
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5Biogen | Confidential and Proprietary
ASOs : Structure
1 235
Chain length varies: 16 – 20 unit
5’ DMT blocking group • Used for synthesis
reaction sequences• Hydrophobic handle• Will be cleaved off
from product
Phosphorothioate linkage • S provides resistance to
nuclease degradation• Negative charge
Bases
• Can be modified for stability
2’ modifications• Added stability and potency
6Biogen | Confidential and Proprietary
ASO Manufacturing Overview: Existing Process
Automated Solid-Phase Synthesis
grow chemically (3’ to 5’) on a resin bead
G G U C …
…one unit at a time…
Purification
1) Reverse- Phase Chromatography
2) Detritylation3) Precipitation4) Lyophilization
Biogen’s assessment• High yielding process• Good purity• Downstream = bottleneck• Solvent intensive• Not fit into our MFG facility