Conference Day Two

Thursday July, 11

8:00 am Coffee & Networking

8:25 am Chair’s Opening Remarks

DECODING BRAIN DISTRIBUTION PATTERNS: ASSESSING AND OPTIMIZING OLIGONUCLEOTIDES FOR EVEN BRAIN DISTRIBUTION

8:30 am Human Brain Biodistribution After Intrathecal Administration of Tominersen

Synopsis

  • Human data on brain exposure of tominersen and HTT mRNA after IT administration of tominersen will be discussed
  • The comparison of this data to preclinical model predicted biodistribution exemplifies the value of translational PK models
  • In addition, comparison to control brains provides critical direct insight into the relationship between tominersen IT dosing, brain biodistribution, and pharmacodynamic effect of the ASO in an individual treated with Tominersen

9:00 am Utilization of PK Model In Guiding Selection of Dose/Regimen in Clinical Studies

  • Meena Meena Senior Vice President, Translational DMPK & Clinical Pharmacology, Stoke Therapeutics Inc.

Synopsis

  • Building and verifying monkey PK models and scaling to human PK models
  • Predicting the human exposure with various dose regimens
  • Verification of the human model with clinical data

9:30 am Roundtable Discussions: Balancing Dose, Distribution, Toxicity and Stability: What is the Future of Oligonucleotide Development?

Synopsis

Splitting into diverse, cross-disciplinary groups, to crowdsource and troubleshoot queries to on oligonucleotide distribution and dosing regimens

Adding Chemical Modifications for More Even Oligonucleotide Distribution to Penetrate Deeper Layers of the Brain

  • Even distribution of drug is critical to treat deeper layers of the brain requiring treatment that are quite inaccessible with standard approaches
  • There are more brain structures that do not receive enough oligonucleotide to be effective – uniform delivery of oligonucleotides across the CNS is crucial for high efficacy of oligonucleotide treatment
  • Alternatively, there must be solutions to penetrating through the right brain regions to reach the right tissues

Improving Scalability of Oligonucleotides Dosing across Rodents, NHPs & Humans to Establish Safe & Effective Doses

  • Identifying maximum tolerated dose during dose-escalation studies and establishing a safety margin to identify ideal therapeutic window to inform starting dose in clinical trials
  • Identifying potential adverse effects through rigorous preclinical toxicology studies in relevant animal models to assess the safety of oligonucleotides and guide dose selection in human trials
  • Limiting dose volume and ensuring proper hydrophilic encapsulation to avoid aggregation by oligonucleotide interaction with serum proteins and thus reduce immunogenicity

Lowering Dose Frequency by Improving Potency & Reducing Degradation Without Compromising on Toxicity

  • Improving half-life of therapeutics administered by intrathecal injection while not compromising on safety, to reduce
    incidence of post-surgical infection and reduce patient burden
  • Improving PK/PD of oligonucleotides for a longer lasting effect of dose
  • Assessing which molecules need to be developed to reach the target and have a long lasting effect

10:00 am Morning Break & Networking

OVERCOMING INHERENT OLIGONUCLEOTIDE TOXICITY FOR SAFE AND EFFECTIVE ASOS

11:00 am SNCA-targeting siRNAs Prevent Disease Progression in a Synucleinopathy Mouse Model

Synopsis

  • Validating efficacy of siRNA in halting dopaminergic neurodegeneration in murine models, mitigating pathological effects associated with SNCA aggregation
  • Evaluating the potential of siRNAs in preventing disease progression in synucleinopathy to improve motor function, reduce neuroinflammation or preserve DA neurons
  • Preclinical validation of reduced siRNA toxicity to ensure safe treatment of neurodegeneration

11:30 am Non-Clinical Strategies for Toxicological Evaluation of siRNA for CNS Disorders

  • Eloise Hudry Director & Head of Investigative Translational Toxicology, Novartis AG

Synopsis

  • Exploring considerations beyond ICH landscape in meeting regulatory expectations of siRNAs
  • Nonclinical evaluation and cross reactivity of siRNAs: tailoring for species selection in siRNA programs
  • Key parameters for toxicology studies: exploring route of administration, dosing regimen and repeat dosing for the future of patient treatment

12:00 pm Lunch & Networking

1:00 pm Demonstrating Translatable Oligonucleotide Tolerability & PKPD Across In Vitro & NHP Models

  • David Eyerman VP, Translational Neurology, Apellis Pharmaceuticals

Synopsis

  • Accumulating tolerability data in vitro and in vivo to predict optimum sequence and formulation for larger species dosing
  • Integrating efficient in vitro and in rodent models to better predict candidate tolerability and efficacy in higher species
  • Improving in silico models to better predict human dose selection

1:30 pm Reducing the Burden of In Vitro and In Vivo Studies for IND Submission by Streamlining Oligonucleotide Development to the Clinic

Synopsis

  • Identifying mis-splicing targets with FlexASO technology to recover loss of TDP- 43 in ALS
  • Using in silico analysis, chemistry and scaffold of the oligonucleotide to forecast candidate toxicity of test material to avoid unexpected toxicity
  • Getting the most out of in vitro studies prior to in vivo studies to give as much credibility as possible for IND submissions to prove safety and efficacy to regulator standards in a more streamlined timeline

2:00 pm Degrading SPTLC1 RNA to Reduce Lipid Production in ALS with LTX-002 ASO

Synopsis

  • Translating ASO potency in mice to CNS target engagement with repeat IT dosing target engagement in rodents with repeat IT dosing in patients
  • Reviewing NfL reduction as a surrogate endpoint at 3 months for 12 months sustained reduction
  • Establishing SPTLC1 ASO LTX-002 for safety, target engagement and biodistribution to critical CNS regions in NHP brains

2:30 pm Afternoon Break & Networking

FORMULATING THE FUTURE: STRATEGIC OPTIMIZATION & QUALITY CONTROL FROM CLINICAL TO COMMERCIAL SCALE MANUFACTURING

3:00 pm Considerations for selection of a CDMO to reproducibly manufacture a low endotoxin antisense oligonucleotide for intrathecal injection

  • John Tukianen Lead Development Engineer, Amylyx Pharmaceuticals Corp.

Synopsis

  • Managing analytical/process development and manufacturing virtually
  • Sources of endotoxin introduction and facility/equipment/process designs to reproducibly control to low endotoxin thresholds
  • How your IT bolus and dosing strategy will define DS and DP endotoxin specifications at your CDMO

3:30 pm Chair’s Closing Remarks

3:35 pm End of Conference