Three Pillars of Drug Development Case Study

W2 M1 PFIZER CASE STUDY:
MODELING AND SIMULATION TO OVERALL DRUG DEVELOPMENT PROCESS

Case study 2:
CCR5 antagonist for treatment of HIV infection Developing high confidence in three Pillars
of survival through preclinical and early clinical investigation C–C chemokine receptor type 5
(CCR5), which belongs to the G-protein-coupled receptor superfamily, is an attractive target for
HIV-1 therapy given that the genetic absence of surface-expressed CCR5D32 in the homozygous
population leads to this population being highly protected against HIV-1 infection; and the reduced
cell-surface-expression in the CCR5D32 heterozygote population is associated with a slower disease
progression. From an antiviral perspective, CCR5 is the co-receptor for the most commonly
transmitted HIV-1 strains that predominate during early stages of infection and remain the dominant
form in >50% of late-stage HIV-1-infected patients. Early evidence that a small-molecule CCR5
antagonist could be efficacious for the treatment of HIV-1 infection was provided by the exploratory
clinical development data for SCH351125, which was shown to be efficacious in vitro and in vivo.
PKPD understanding of maraviroc provides confidence in effective treatment of HIV

infection Maraviroc (UK427857) is a small-molecule CCR5 antagonist which is a product of a
medicinal chemistry program following identification of an imidazopyridine CCR5 ligand from a
high- throughput screen of the Pfizer compound file.
Maraviroc demonstrates potent antiviral activity against all CCR5-tropic HIV-1 viruses tested
with a geometric mean IC90 of 2 nM. In addition, maraviroc is active against 200 clinically derived
HIV-1 envelope-recombinant pseudoviruses, including those derived from viruses resistant to
existing HIV-1 inhibitor drug classes. PK profiling in preclinical species and subsequently in human
volunteers gave confidence that continuous systemic exposure (unbound Cmin >5 nM) could be
achieved above the geometric mean antiviral IC90 (2 nM) following oral dosing of >100 mg twice
daily. These data gave confidence that exposure at the target site of action (Pillar 1) could be
achieved in humans.
In addition, evidence that maraviroc could functionally bind to the target receptor at
pharmacologically relevant concentrations (Pillar 2) was established using cell-based assays. In
particular, maraviroc was shown to inhibit virus attachment to CCR5 in a CD4 cell preparation with
an IC50 of 11 nM. In addition, maraviroc blocked binding of viral envelope, gp120, to CCR5 with an
IC50 of 0.22 nM to prevent the membrane fusion events necessary for viral entry to CD4 cells.
Reference: Drug Discovery Today Volume 17, Numbers 9/10 May 2012;
www.drugdiscoverytoday.com
Building on the knowledge acquired through understanding of the pharmacology and PK in
preclinical species and human volunteers, a PKPD model was developed, in advance of clinical
trials in HIV patients, to understand better the link between CCR5 pharmacological activity, PK
exposure and clinical efficacy.
This model was developed consisting of three components:
a disease model,
a PD model and
a PK model, and
was based on a published viral dynamic model that was adapted for short-term treatment and for
the new mechanism of action owing to CCR5 antagonism. This modular structure allowed for the
integration of information from different sources such as the literature and in vitro and in vivo data.
In essence, this PKPD model can be considered to provide knowledge akin to that
described in Pillar 3 and, in the early stages of the maraviroc development program, the PKPD
model was used to optimize the design of a proof- of-principle study. As further clinical data
became available the model was updated and used to optimize the development plan toward the
choice of Phase III doses. The model accurately estimated that the maximum log10 viral load drop
would be observed with 300 mg bid administration with a log10 viral load decline of 1.6 and fraction
inhibition of viral load of 0.93. A 300 mg bid is the maximum effective dose, described in the US
product label, in the absence of cytochrome P450 (CYP) inhibitors or inducers.
Concluding remarks
This analysis demonstrates that there are three fundamental PK and PD principles that
collectively determine the likelihood of testing the mechanism of action and influencing the
likelihood of candidate survival in Phase II.
These fundamental principles, which we are termed the three Pillars of survival, are geared
toward understanding the drug exposure, target binding and pharmacological activity at the
target site of action in an integrated manner through application of PKPD and PBPK modeling.
The importance to R&D productivity of a thorough understanding of whether the NME

engages its target and has the desired pharmacological activity in humans is being acknowledged in
an increasing number of publications on drug survival.
Reference: Drug Discovery Today Volume 17, Numbers 9/10 May 2012;
www.drugdiscoverytoday.com

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W2 M1 PFIZER CASE STUDY:

MODELING AND SIMULATION TO OVERALL DRUG DEVELOPMENT PROCESS

PKPD understanding of maraviroc provides confidence in effective treatment of HIV

The importance to R&D productivity of a thorough understanding of whether the NME

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