10 BioPharm International eBook March 2021 www.biopharminternational.com
macological properties, Panagoulias
says. She explains that PRISM is also
a learning and improving platform,
which allows users to discover and
leverage many different design prin-
ciples, the intent being to fine-tune
each oligonucleotide for the disease
target. "For example," she notes, "we
recently announced new chemistry
modifications, called 'PN backbone
chemistry modifications,' which
were discovered through PRISM
and have been shown preclinically
to improve potency, exposure, and
durability across our silencing, splic-
ing, and editing modalities."
ADVANCING
COMMERCIAL POTENTIAL
The progress of ASOs from the
research bench to viable therapeu-
tic candidates has more to do with
industry transforming its view of
ASOs from one of the potential lim-
itations to a view that realizes their
opportunities, says Templin. "For
ASOs, the recent wave of regulatory
approvals and commercial launches
has resulted in greater attention by
researchers, the drug development
community, and investors," he states.
Moreover, the ASO field has had
its share of spotlight moments over
the last several years, but, neverthe-
less, it can be easy to review a man-
uscript or even a single approval
and conclude it is an isolated event.
"A major difference now, versus
when the first ASOs were approved,
is the depth of knowledge that has
accumulated over the last three to
four decades, even more so in the
last 10 years," Templin remarks.
" W h i le que st ion s r e m a i n for
the field, there are pathways for-
ward. For example, there has been
extensive investment in chemis-
try to provide greater stability and
increase activity. Specialized routes
of administration, such as intrathe-
cal for central nervous system-based
diseases, have been shown to be
well tolerated and provide thera-
peutic benefit," he adds.
Templin also explains that there
has been a careful and well-thought
selection of indications for which
ASOs provide a unique approach to
a previously unmet medical need.
"Thus, maturity of the ASO field is
not a 'just now' situation; it is more
consistent with success providing a
basis for an in-depth investigation
into the drug class. Once a deeper
dive is taken, the scope and potential
of an ASO can be recognized and the
future for all oligonucleotide-based
therapeutics better understood and
appreciated," he states.
Recent reg ulator y approvals,
with eight novel ASO compounds
having been approved since 2016,
have likely influenced perceptions
around the emergence of oligonu-
cleotide therapies as a promising
new class of drugs, Panagoulias adds.
She points out that, in fact, the first
oligonucleotide approval in the
United States occurred over 20 years
ago when FDA approved fomivirsen for
treating cytomegalovirus retinitis in
immunocompromised patients (6).
"That experience has only contin-
ued to grow. Therefore, ASOs have
been around for some time but the
recent successes in developing these
therapies in the US gives one the
impression that the viability of the
class was only recently established,"
Panagoulias states.
BENEFIT OF GUIDANCE
Although FDA's new ASO draft guid-
ance is directed to sponsor-investi-
gators who are considering how to
develop an ASO for a specific indi-
vidual patient, the benefit may yet
extend to research foundations and/
or family/patient sponsored pro-
grams, Templin observes. Realistic
approaches for individualized treat-
ments are recent, he notes, and the
play book for these approaches is
still being formulated. As described
in the draft guidance, a primary
objective is to outline the impor-
tance of early communications
between FDA and the sponsor-in-
vestigator, and the guidance sug-
gests ways to expedite and formalize
these communications, he says.
"The draft guidance also outlines
the expectations for the program,
most notable are nonclinical stud-
ies, appropriate CMC for product
quality, and clinical reporting. It
will be the initial talks on the estab-
lishment of a communication plan,
and the agreement on expectations,
that will determine how a program
can progress from basic research to
treatment in a rapid and efficient
manner while assuring patient
safety," Templin says.
Panagoulias notes that the guid-
ance might be of use to commercial
sponsors and manufacturers, beyond
those developing "N=1" medicines, if
it included more insights on the spe-
cific content requirements for these
submissions. In particular, it would
benefit sponsors and manufacturers
to have specific requirements out-
lined for regulatory expectations on
preclinical studies to assess safety
(species and duration) and informa-
tion on CMC (e.g., stability) as these
data could be extrapolated for use
in supporting INDs for ultra-rare
populations or very small subsets of
genetic diseases, she concludes.
REFERENCES
1. FDA, IND Submissions for Individualized
Antisense Oligonucleotide Drug
Products: Administrative and Procedural
Recommendations Guidance for Sponsor-
Investigators (CDER, January 2021).
2. ICH, "ICH Guidelines," ich.org, accessed
Feb. 23, 2021.
3. ICH M3(R2) Guidance on Nonclinical Safety
Studies for the Conduct of Human Clinical
Trials and Marketing Authorization for
Pharmaceuticals, Step 4 version (2009).
4. Berman, et al., Nucleic Acid Therapeutics
26 (2) 73–85 (2016).
5. FDA, "FDA Approves First Drug for Spinal
Muscular Atrophy," Press Release, Dec.
23, 2016.
6. FDA, Approval Letter to Isis
Pharmaceuticals, Aug. 26, 1998. BP
Regulatory Sourcebook Quality
