8 BioPharm International eBook March 2021 www.biopharminternational.com
a stark absence of treatment options
to correct the underlying cause. An
ASO provides a potential means to
treat these patients and has revealed
a development pathway for a long-
sought goal—individualized medi-
cine," he emphasizes.
Templin notes that, while not
specific to ASOs, in general prod-
uct quality, nonclinical assessment,
and clinical development of an ASO
are addressed by various guidance
documents from regulatory bod-
ies. What's more, the traditional
pathway—from IND to new drug
application (NDA) to commercial
product—has been successf ully
completed for several oligonucle-
otide-based therapies. Nevertheless,
programs were focused on diseases
common among a multitude of
patients and intended for broad use,
he adds; and the development path-
way to treat many patients does not
simply scale down to a single patient,
he points out.
" T h e n e w d r a f t g u i d a n c e ,
I N D S u b m i s s i o n s f o r I n d ivi d u a l ize d
A n t i s e n s e O l i g o n u c l e o t i d e D r u g
Products: Administrative and Procedural
Recommendations Guidance for Sponsor-
Investigators, is a major step in estab-
lishing the procedures and processes
for communication between FDA
and a sponsor-investigator with the
intent to treat a single patient with
a genetic-based disease for which
the genetic variant is unique to that
patient. In this situation, a research
IND is the means of establishing the
plan to initiate treatment," Templin
says. The treatment plan is highly
focused to the specific patient and
the disease state, he adds, and, as
the draft guidance points out, early
communication with FDA is para-
mount because it allows for more
focused efforts and progress—a
critical aspect because patients are
often in rapid decline. Furthermore,
early communication assures that
fundamental product quality and
clinical safety parameters are pre-
served, Templin says.
Jen n i fer Pa nagou l ias, sen ior
v i c e - p r e s i d e n t , R e g u l a t o r y,
Compliance & Policy, at Wave Life
Sciences, a biotechnolog y com-
pany specializing in nucleic acid
therapeutics, adds that, while FDA
has not issued an ASO -specific
guidance up until this point, the
industry has sought to have such
guidelines developed to help estab-
lish the regulatory considerations
relevant for these compounds.
"ASOs are large molecules with
molecular weights that fall between
a traditional small-molecule and bio-
logics, but, due to their complexity,
development and regulatory consid-
erations often straddle the fence, so
to speak, in terms of application of
concepts from the ICH [International
Cou nc il for Ha r moni zat ion of
Te c h n i c a l R e q u i r e m e n t s f o r
Registration of Pharmaceuticals for
Human Use] Quality and Safety guide-
lines (2)," Panagoulias says.
Although ASOs are reg ulated
as drugs, some ICH-Q guidelines
exclude them from their scope,
Panagoulias adds. She explains that
feedback from European regulators
suggests that the application of tradi-
tional nonclinical safety concepts, as
outlined under the ICH M3 (3) guideline,
are not always appropriate for ASOs
given their make-up and pharma-
cological characteristics. "For exam-
ple, while genotoxicity studies are
generally performed for oligonucle-
otides, they are unlikely to interact
with DNA as would small-molecule
chemicals. Few ASOs, if any, have
been demonstrated as genotoxic in
such studies (4), thus the consider-
ations for biologics where an evalu-
ation would be performed based on
a product-specific concern in lieu
of traditional studies may be more
appropriate," she says. Panagoulias
also states that regulatory guidance
specific to nonclinical, chemistry,
manufacturing, and controls (CMC),
and pharmacology considerations for
oligonucleotides would be of great
use to sponsors developing these
compounds.
CHALLENGES IN ASO DEVELOPMENT
One particular challenge in devel-
oping ASO therapeutics has been
the ability to improve their phar-
macologic properties, which would
enhance delivery and uptake, notes
Panagoulias. There have been chem-
ical modifications that have helped
improve distribution and tolerabil-
ity, and these improvements have
been critical in advancing this class
of drugs. Some companies have
spent years developing and enhanc-
ing their platform chemistry to opti-
mize the pharmacologic properties
of these types of drugs, Panagoulias
points out.
Cost of manufacture, demonstrat-
ing sufficient safety in nonclinical
and clinical studies, and validation
of clinical efficacy, to name a few,
have been and continue to be chal-
lenges in development of ASOs, says
Templin. However, he points out,
there has been extensive research
into the manufacture of oligonu-
cleotide-based therapeutics (oligos)
and improved chemical modifica-
tions for greater drug-like properties.
Furthermore, data from nonclini-
cal and clinical studies have signifi-
cantly expanded and increased the
underlying knowledge base for these
compounds. "All have been crucial
steps in the transition for oligos from
research to commercialization,"
Templin says.
Wave Life Sciences, for instance,
was founded on the principle of
applying novel optimization strate-
gies to oligonucleotide design, start-
ing with a unique ability to control
chirality in oligonucleotides, which
the company defines as "stereopure
oligonucleotide," says Panagoulias.
Through a focus on stereochemical
Regulatory Sourcebook Quality
