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8:15 am Coffee & Registration

8:55 am Chair’s Opening Remarks

Novel Approaches to Understand Complement in Physiology and Disease

9:00 am Classical Pathway Activation in Alzheimer’s Disease (AD)

Synopsis

• Expression of the classical pathway is induced in glial cells in both amyloidosis and tauopathy mouse models
• Knockout of C1q or C3 rescues plaque-associated synapse loss in amyloidosis mice, and ameliorates brain atrophy in tauopathy mice
• C1q and C3 are elevated at synapses in AD patient brains
• Elevated levels and activation of C4 and C3 are detected in AD patient cerebrospinal fluid

9:30 am Characterizing C5 Inhibition with the SMART-Ig Anti-hC5 Antibody Crovalimab in PNH Patients Using Free Available Paratopes

  • Alexandre Sostelly Project Clinical Pharmacologist, Immunology, Inflammation & Infectious Diseases, Roche

Synopsis

  • Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017)7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL – 4mL) in C5 mediated diseases
  • The conventional PK metrics to determine optimal target inhibition is drug concentration, however this has some limitations when considering an abundant fluctuating soluble target such as C5. Therefore, we proposed to characterize C5 inhibition by quantifying the level of crovalimab free paratopes (i.e. the concentration of free crovalimab antigen-binding sites not bound to C5) and to illustrate how it can be used to estimate the available binding capacity reserve of crovalimab
  • Free paratope concentration enables characterization of available binding reserve of crovalimab. The capacity to adequately control C5 increase due to the SMART-Ig engineering is expected to result in a better control of breakthrough hemolysis in PNH patients compared with an antibody without this technology. For soluble targets, this approach provides more stringent criteria than antibody concentration as it defines the capacity of the drug to bind free target at any time. Therefore, this metric should prove helpful in guiding dose selection for monoclonal antibodies binding a soluble target.

10:00 am A Diverse Pipeline of Targets and Modalities: Novartis’ Approach to Modulating the Alternative Complement Pathway

  • Thomas Smith Senior Research Investigator, Lead Discovery, Novartis
  • Christopher Adams Senior Investigator, Global Discovery Chemistry, Novartis

Synopsis

Research vignettes covering efforts to target Factor B (LMW), Factor D (LMW), Factor P (Ab) and C5 (Ab and LMW)

11:00 am Morning Refreshments and Speed Networking

12:00 pm CB 2782-PEG: A Complement Factor C3-Inactivating Protease and Potential Long-Acting Treatment for Dry AMD

Synopsis

• CB 2782-PEG is a 68 kDa engineered protease to specifically cleave C3 into inactive fragments. It has a ~500 kDa MW on SEC due to the large hydrodynamic radius
• The increased size of CB 2782-PEG resulted in enhanced ocular half-life in rabbits (3.9 vs 1.9 days for the unmodified CB 2782) and in non-human primates (3.7 vs. 1.7 days)
• Single intravitreal injection of 125 μg CB 2782-PEG achieved complete, rapid and sustained PD inhibition (>99%) of vitreous C3 for at least 28 days in African green monkeys
• The long pharmacodynamic effect is the result of the catalytic mechanism and a distinct advantage over traditional stochiometric binding inhibitors
• CB 2782-PEG has potential for anti-C3 best-in-class efficacy and convenience in geographic atrophy dry AMD with anticipated intravitreal human dosing three or four times a year

12:30 pm Development of Oral Complement Factor D inhibitors

Synopsis

• Update Achillion Development Pipeline
• Report Interim Danicopan Phase 2 Data in PNH Patients
• Provide Topline Summary on 2nd Generation of Oral Complement Factor Inhibitor

1:00 pm Update On the Retrospective MAC Plus Study of 1,000 aHUS Genetic Results and Other Laboratory News

1:30 pm Lunch & Networking

2:30 pm The Importance of Target Specificity in the Terminal Complement Cascade

Synopsis

  • Mechanism of action of avacopan, a highly potent and selective inhibitor of the complement 5a receptor (C5aR)
  • Scientific rationale of C5aR inhibition in complement-mediated diseases such as ANCA Vasculitis and C3 Glomerulopathy
  • Avacopan differentiation and advantages of targeting the C5a receptor and why preserving other C5a pathways are beneficial

3:00 pm Developing the First in Class Anti-C5a Antibody IFX-1: Lessons Learned from Clinical Trials

Synopsis

  • Outlining the anti-inflammatory and tissue saving potential of IFX-1
  • Discussing the potential IFX-1 holds for various inflammatory disease indications
  • Hearing clinical trials results and examining lessons learned

3:30 pm Afternoon Refreshments & Poster Session

4:30 pm Speed Learning: Exploring Complement Therapeutics in Various Indications & Hearing Novel Solutions

Synopsis

Short yet focused sessions allowing for multiple indications and challenges to be addressed in detail. Each table will be hosted by a leader who will give a 5 minute presentation, you then get the opportunity to discuss the topic and question the host for 10 minutes before moving on to your next table.
• Discover complement’s involvement in new indications
• Explore novel methods to evaluate complement targeting therapeutics
• Dive into discussion on groundbreaking complement research

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6:00 pm Chair’s Closing Remarks

6:05 pm End of Day One