Introduction
With the approvals of Luxturna® and Zolgensma® in Europe and the United
States, recombinant adeno-associated virus (rAAV)-based gene therapies
(GT) have shown promise for the treatment for diseases with genetic
disorders. Establishing dose response relationships in targeted patients
is foundational in the development of therapeutic drugs including GT.
The efficacy and safety of adeno-associated virus (AAV)-based GT are
largely dose-dependent in both preclinical species and
humans.1 However, it is still challenging to
extrapolate dose response of GT from animals to humans. For example,
dose response curves in preclinical species and humans are usually
nonlinear and does not follow a consistent pattern among
species.2 Traditional quantitative methods such as
PK-PD modeling used to predict human dose-response relationships of
small molecules and therapeutic proteins are difficult to apply to GT,
and model structures and parameter paradigms may not be directly
applicable to these complex GT products.3 A
mechanistic modeling approach incorporated with disposition of vector in
the body, transduction efficiency in target tissues, expression strength
in transduced cells, and duration of expression has been proposed to
establish human dose response relationships for GT.2However, our current understanding of GT pharmacology is still limited,
and experimental data are usually inadequate to validate a complex
mathematical model for GT products especially at early development
stage.
It was reported that the metabolic rate of cells (Bc) in
vivo in mammalian species decreased with increasing body weight
(Bc = B0 / W0.25,
where B0 is the cellular metabolic rate expressed as 3 ×
10−11 Watts per cell for organism with mass of 1.0
gram, and W is the mass of a mammalian species).4Since intracellular synthesis of transgene protein following GT is
dependent on metabolic rate of cells, Tang et. al. proposed a concept of
gene efficiency factor (GEF) to describe the efficiency of gene transfer
system and demonstrated a linear relationship between logGEF and logW
using preclinical and clinical data of three AAV vectors for hemophilia
B therapy, where W was the body weight of mammalian
species.5 Tang et. al. concluded that body
weight-based cross-species allometric scaling of GEF could be used to
predict first-in-human (FIH) dose of AAV-mediated hemophilia B GT.
However, Aksenov et. al. pointed out the limitation of Tang’s allometric
scaling approach that Tang et. al. assumed a linear dose response
relationship for serum factor IX (FIX) while the dose-response curves
observed in most preclinical species and hemophilia B patients were
nonlinear.2 Then, Aksenov et. al. used a powder
regression model (FIX concentration = a × Doseb) to
describe dose-FIX concentration relationships for AAV-FIX vectors, where
a was proportionality coefficient and b was the exponent for dose.
Aksenov et. al.’s analysis showed that the dose response curves of AAV
vectors did not follow a consistent pattern across species and no
obvious relationship for proportionality coefficient or exponent vs.
body weight was observed. Therefore, Aksenov et. al. concluded that
Tang’s allometric scaling was unable to accurately predict human dose
for AAV GT.
Enlightened by interspecies normalization of plasma drug
concentration-time curves using Dedrick plot,6 this
author hypothesized that interspecies normalization approach might be
applied to dose-response extrapolation from animals to humans. The
Detrick plot approach, also called species-invariant time method,
assumes that by normalizing the concentrations with body weight and
transforming chronological time to physiological time, the plasma drug
concentration–time curves should be superimposable in all
species.7 The transformed concentration–time curves
of various species are superimposed and then back-transformed to
estimate human plasma concentration–time profile. Since the expression
efficiency of a transgene product is reversely correlated with
W0.25, for a transgene product that functions in
systemic circulation, this author hypothesized that the total amount of
transgene product in blood circulation across species could be
normalized to a species-invariant scale using an exponent of 0.25. The
normalized transgene
product–dose curve can be back-transformed to predict human
dose-response curve.
Among different types of AAV programs, hemophilia GT has more
preclinical and clinical dose-response data available in literature. The
most common types of hemophilia are hemophilia A and hemophilia B,
caused by mutations in F8 or F9 , coding for factor VIII
(FVIII) and factor IX (FIX) proteins, respectively.8In this study, this author explored if the total serum amount of FVIII
or FIX following AAV-mediated GT could be normalized across species and
if the normalized dose response could be extrapolated to hemophilia
patients. Furthermore, the normalized serum FVIII or FIX-dose curves
were used to predict the FIH dose of AAV vectors. The predictive
performance of this interspecies normalization approach was compared to
that of two previously reported approaches, direct vg/kg conversion from
preclinical doses and allometric scaling.