Targeting Complement to Reduce Disease Activity: Quantitative Systems Pharmacology (QSP) to Enhance Efficient Drug Development (Part One)

• April 15, 2024
• Blog

Keywords:alzheimer's disease, COMPLEMENTsym, drug development, non-alcoholic fatty liver disease, QSP (quantitative systems pharmacology), Systemic Lupus Erythematosus

Deficiency or dysfunction in regulatory factors that control the complement cascade critically contribute to several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and hereditary angioedema (HAE) among others. Complement activity has been implicated in several more common diseases as well.

The approval of drugs targeting complement proteins has provided evidence that this strategy can be effective, but many questions remain related to how to effectively impede complement activity in each disease given multiple routes for initiation, an amplification cycle, multiple targets, and target characteristics (e.g., high plasma concentrations, short half-lives). The mathematical and mechanistic representation of the complement cascade in quantitative systems pharmacology (QSP) models provides a rigorous platform to address many of these questions.

This is part one in a blog series on targeting the complement system to treat disease and the potential of QSP to inform and enhance drug development. As the initial offering, this blog addresses the following:

• What is the complement system and why would we consider targeting it?
• Are there existing QSP models of the complement cascade?
• What are different options for using QSP to inform my drug development program?
• What is the SLP QSP offering in complement?

What is the Complement System?

The complement cascade is part of the innate immune system, critically involved in eliminating pathogens through the generation of membrane attack complexes (MACs), pores in pathogen cell membranes. Complement activity can be initiated through the classical or lectin pathways (CP, LP), and the response is amplified by the alternative pathway (AP) which also drives inflammation, while the terminal pathway assembles MACs at the cell surface. The complement system comprises over 40 proteins, including primary proteins and regulatory proteins that are readily measured in circulation, intermediate products that are critically important but very transient and poorly characterized, and various split products that may have independent effector activity (e.g., C3a pro-inflammatory activity) and/or may be useful as biomarkers of complement activity (e.g., C3d). Notably, the relative importance of different complement pathways (e.g., CP vs LP) varies by disease, and the presence of a feed-forward amplification loop (AP) adds the potential for unexpected responses resulting from inhibition of downstream factors.

Why Target the Complement System?

Despite the positive effects in pathogen clearance, complement over-activity has the potential to contribute to disease pathology. More on these and other aspects of the complement system have been extensively described in the literature 1-3. Experimental studies and in silico modeling, including QSP, have aimed to continually improve understanding of key pathways and system responses.

For the last few decades, researchers have been developing drugs to target complement-mediated diseases. Eculizumab, a monoclonal antibody (mAb) specific for complement protein C5, was approved in 2007 for the treatment of PNH. Eculizumab data demonstrated that patients with PNH, a relatively rare disease characterized by dysfunction in some key complement regulatory proteins leading to pathologic complement-mediated hemolysis 4-6, could be effectively treated with a complement inhibitor 7-9. The opportunity to help patients by targeting complement is not limited to C5 protein or to PNH.

As of February 2024, there were five approved treatments that target complement proteins:

• Eculizumab: IgG2/4κ mAb, specific for complement protein C5, initially approved in 2007 for the treatment of PNH, and subsequently for the treatment of aHUS, generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD)
• Ravulizumab: IgG2/4κ mAb, specific for complement protein C5, initially approved in 2018 for the treatment of PNH, and subsequently for the treatment of aHUS and gMG
• Pegcetacoplan: two identical pentadecapeptides bound to a linear PEG molecule, specific for C3 (and binding C3 and C3b), initially approved in 2021 for the treatment of PNH
• Sutimlimab-jome: IgG4 isotype mAb, specific for complement protein C1s (a serine protease), initially approved in 2022 for the treatment of hemolysis in adults with cold agglutinin disease (CAD)
• Avacopan: a small molecule compound, specific for the complement C5a receptor (C5aR), initially approved in 2021 for the treatment of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis in combination with standard therapy

In some diseases where therapies targeting complement have already shown efficacy, there may yet be room for improvement. For example, anti-C5 treatments (eculizumab, ravulizumab) impede MAC formation improving erythrocyte survival for many PNH patients, but some patients fail to respond, respond incompletely, or lose their response with time. Mechanistic studies revealed that incomplete C5 blockade could account for some instances of residual hemolysis 10, but in other cases, breakthrough hemolysis was due to extravascular (vs. intravascular) hemolysis, supported in part by ongoing AP activity leading to extensive C3 labeling of erythrocytes 11-14.

While thus far, complement treatments have applied to relatively small patient populations, complement activity has been implicated in several more common diseases, including non-alcoholic fatty liver disease (NAFLD), systemic lupus erythematosus (SLE), and Alzheimer's Disease (AD) 15-19.

But with all these potential avenues for complement therapeutics comes a large set of drug development challenges, including considerations that apply to all drug development:

• Choosing a disease indication
• Selecting the right dose per indication
• Selecting the right target/compound per indication
• Selecting the right target/compound based on druggability
• Identifying plausible combination therapies that improve treatment outcomes

As well, there are challenges related to the complement cascade more specifically, such as…

• Identifying the levels of target inhibition required to reduce complement activity by a desired degree
• Assessing the additional effect of inhibiting more than one complement pathway on complement activity
• Understanding the relationship between complement activity and disease activity
• Identifying the effect of local complement production and consumption on effectiveness
• Estimating the margin between reduced disease activity and increased infection-risk based on complement inhibition

QSP models of complement are mathematical mechanistic representations of the complement cascade in the context of health or disease. They have the potential to address many of these questions and could prove useful by providing the ability to rapidly assess different scenarios that a program is considering.

QSP Approaches Inform Development of Drugs Targeting Complement

Mathematical approaches to illuminate the complement cascade have been in use for many years. Early efforts focused on describing the various complement components, their interactions, and key unknowns 20-22. Several models have placed the complement cascade in the context of pathogen exposure or clearance, including classical or lectin pathway initiation, amplification by the alternative pathway, complement regulation, and complement-mediated pathogen killing 23-27. As well, a number of models have focused on alternative pathway dysregulation 28-31.

Adding to the armamentarium of complement QSP resources is COMPLEMENTsym, a new QSP model of complement we've developed in collaboration with a pharmaceutical partner. The general version is based entirely on publicly available data. COMPLEMENTsym leveraged a published minimal model of the alternative pathway 29 as a starting point, extending this model to include additional regulators, the terminal pathway, classical pathway initiation, and three treatments (eculizumab, pegcetacoplan, and iptacopan). Other published models were leveraged to inform the representation and/or parameter values 30,31. The representation focuses on the fluid phase to leverage multiple published data sets on circulating complement proteins and regulators. Simulated populations reproduce the reported range across multiple complement analytes and reproduces the measured reduction in complement activity for the three therapies (Clemens 2024).

Application of these models to inform drug development can be illustrated by sensitivity analyses to identify molecular entities within the complement cascade capable of reducing overall complement activity or representation of treatments targeting complement, e.g., compstatin, eculizumab 26,28,30,31. Beyond comparing the potential benefit of overall complement target modulation on complement activity, QSP models have also been used to assess the ability of large vs. small molecules to effectively engage targets 31. Together, the published data provide clear evidence for the suitability of complement activity to QSP modeling, as well as the potential to inform drug development.

Learning More About COMPLEMENTsym

COMPLEMENTsym is (initially) a biomarker-focused representation of the alternative and terminal pathways in complement. Dysregulation in complement leading to disease is illustrated by representation of PNH, including over 2000 simulated patients reflecting the reported ranges of complement analytes. Biomarker and hemolytic responses to eculizumab, pegcetacoplan, and iptacopan have been simulated and compared with published clinical data. In its current state, COMPLEMENTsym can be applied to assess alternate complement targets in PNH and or in other diseases through the development of additional simulated patient populations. Beyond these applications, COMPLEMENTsym can be extended to the classical and lectin pathways, to the representation of target organs, and/or to the inclusion of additional clinical endpoints.

If you'd like to learn more about COMPLEMENTsym, watch our on-demand webinar or contact us.

Conclusion

Targeting the complement cascade has tremendous potential to help patients in many therapeutic areas, if we can efficiently engage the right targets for each disease. In this post, I hope you have gained a better understanding of the challenges in complement drug development and the suitability of QSP to address these challenges.

References

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