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Therapeutic Oligonucleotides on the Rise
Oligonucleotides are synthesized, polymeric sequences of nucleotides (RNA, DNA, and
their analogs) that are utilized extensively as PCR and microarray-based reagents in life
science research, as primer and probe reagents in DNA-based diagnostic test kits, and
increasingly they are being developed as direct therapeutic agents against a wide range
of disease conditions. The research on its application as a drug candidate began about 30
years ago, beginning with antisense oligonucleotides (ASOs) and aptamers and followed
about 15 years ago by siRNAs. During that lengthy period of time, numerous clinical
trials have been performed and thousands of trial participants accrued onto studies. Until
now, a total of eleven FDA-approved oligonucleotide therapeutic drugs are on the
market, but well over 100 are in the clinical pipeline and many more are in pre-clinical
development.

Oligonucleotides as therapeutic drugs come in a variety of forms from antisense
oligonucleotides (ASOs), small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs),
and anti-micro RNAs (anti-miRs)—which all affect "gene silencing" to aptamers, which are
short nucleic acid sequences that fold into unique, three-dimensional shapes and bind to
proteins/disease targets like small molecule drugs; to messenger RNAs (mRNAs), which
are long gene transcript sequences that can augment gene expression; to CRISPR/Cas9
constructs that enable gene editing and hold tremendous promise.

FDA Approved Oligonucleotide Therapies
In 1998, Novartis Pharmaceutical's Vitravene (fomiversen), an antisense oligonucleotide,
became the first oligonucleotide to be approved by the FDA. Vitravene was developed for
the local treatment of cytomegalovirus (CMV) retinitis afflicting HIV patients. Ultimately,
Vitravene was discontinued in 2004 because HIV treatment led to a reduction in the

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number of cases of CMV in HIV patients. Macugen (peaptanib sodium), an aptamer, was
approved in 2004 for the treatment of wet age-related macular degeneration (AMD).

Over a decade after the approval of Vitravene, FDA approval came for Kynamro
(mipomersen sodium) in 2013. This approval was followed by a flurry of activity that
resulted in FDA approvals for eight more oligonucleotides.
FDA Approval

Drug name

1998 (Withdrawn)

Vitravene (fomiversen)

Isis Pharmaecuticals/Novartis Cytomegalovirus (CMV)
Ophthalmics
Retinitis

Antisense
Oligonucleotide

2004 (Marketed)

Macugen (Pegaptanib)

OSI Pharmaceuticals

Age-related Macular
Degeneration (AMD) of
the Retina

Oligonucleotide

2013 (Withdrawn)

Kynamro (mipomersen
sodium)

Kastle Therapeutics LLC

Homozygous Familial
Hypercholesterolemia

Antisense
Oligonucleotide

2016 (Marketed)

Defitelio (defibrotide
sodium)

Jazz Pharmaceuticals Plc

Hepatic Veno-Occlusive
Disease

Oligonucleotide,
natural product

2016 (Marketed)

Exondys 51 (eteplirsen)

Sarepta Therapeutics

Duchenne Muscular
Dystrophy

Antisense
Oligonucleotide

2016 (Marketed)

Spinraza (nusinersen)

Biogen

Spinal Muscular Atrophy

Antisense
Oligonucleotide

Dynavax Technologies

Hepatitis B

Cytidine
phospho-guanosine
(CpG) oligonucleotide
as adjuvant

Akcea Therapeutics

Familial Amyloid
Neuropathies

Antisense
Oligonucleotide

2017 (Marketed)

Heplisav-B (hepatitis B
vaccine, adjuvanted)

Company

2018 (Marketed) Tegsedi (inotersen sodium)

Indication

Type

2018 (Marketed)

Onpattro (patisiran)

Alnylam Pharmaceuticals

Familial Amyloid
Neuropathies

siRNA

2019 (Marketed)

Givlaari (givosiran)

Alnylam Pharmaceuticals

Acute Hepatic Porphyria

siRNA

2019 (Marketed)

Vyondys 53 (golodirsen)

Sarepta Therapeutics

Duchenne Muscular
Dystrophy

Antisense
Oligonucleotide

FDA-approved oligonucleotide therapies

Drugs in Development

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The clinical pipeline of oligonucleotide drugs is rich with 157 drugs in Phase I to
pre-registration. The therapeutic areas for the drug candidates are diverse spanning
oncology, infectious disease, metabolic disorders, genetic disorders, and other areas.
Two oligonucleotide drug candidates to watch are in the pre-registration phase including
Atlantic Healthcare's alicaforsen and NS Pharma's viltolarsen.

Oligonucleotide Clinical Drug Pipeline Phase I to Pre-Registration

Therapeutic Importance of Oligonucleotides
Oligonucleotides have been utilized for the last two decades for their therapeutic
properties. Majorly these are used either for inhibition of genes or protein expression.
Following are a few areas in which these can be used:

• Neurodegenerative disorders: Oligonucleotides can be used as an effective therapy for
the treatment of Huntington's disease (HD) because it is an autosomal disease caused by
a mutation on a single allele. Oligonucleotides target the altered messenger RNA (mRNA)
and decrease the synthesis of the causative protein-Huntingtin. ASO can also be used as
a therapy for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral
sclerosis (ALS) and spinocerebellar ataxias.

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• Respiratory disorders: Oligonucleotides can be administered as an inhalation for the
treatment of asthma and COPD. They have fewer side effects as these molecules are
directly targeted to the lungs. In addition, their uptake is usually enhanced at the target
site which leads to their prolonged duration of action.
• Cancer: Antisense oligonucleotides have emerged as a new therapeutical approach for
the treatment of various types of cancers whereby, they attach with mRNA and inhibit
gene translation. However, non-specific protein binding and efficient delivery appear to be
the major hurdles for their use in cancer treatment.
• Diabetic retinopathy: Antisense oligonucleotides (e.g., iCo-007) are currently under trials
for the treatment of diabetic retinopathy. These act by downregulating the signaling
pathway of multiple growth factors that are involved in the ocular angiogenesis and
vascular leakage. They provide several advantages namely, increased half-life, lesser
degradation and improved safety profile. It is interesting to note that the only
oligonucleotide currently approved is Vitravene® (Novartis, New York, NY, USA), which is
used for cytomegalovirus retinitis, where the drug is directly administered to the site of
disease (intravitreal).

Challenges of Oligonucleotide Therapies
Oligonucleotide-based drugs have attracted considerable attention as promising
therapeutic agents for the treatment of various human diseases; however, several issues
must be overcome in the development of oligonucleotide-based drugs. These issues
include the instability of oligonucleotides against enzymatic degradation and rapid
renal clearance. In an attempt to stabilize oligonucleotides, many modifications on their
sugar motif and/or the phosphate backbone have been reported; however, these
modifications often cause unwanted bioactivities such as toxicity. Considering
toxicities, Polyethylene glycol (PEG) is very useful because it is categorized as
“Generally Regarded As Safe (GRAS)” by the FDA. PEGylation increases nuclease

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resistance and the circulating half-lives of oligonucleotides. Accordingly, stabilization
of oligonucleotides with PEG is a promising method for use in the development of
therapeutic oligonucleotides. In fact, one of the therapeutic
oligonucleotides, Macugen (Pegaptanib), consists of PEGylated oligonucleotides. In
this aptamer drug, the oligonucleotide is modified with branched PEG (40 kDa) at the 50
terminus. This modification increases the nuclease resistance of PEG-aptamer
conjugates. The extent of stabilization is dependent on the length of PEG.
High-molecular-weight PEG stabilizes molecules better than low-molecular-weight PEG.

Although the development of oligonucleotide therapies is still difficult, it is believed that
with the continuous development, improvement and progress of related technologies,
oligonucleotide therapies represented by antisense oligonucleotide and small interfering
RNA will surely set off a new wave in the pharmaceutical industry. And it will become an
indispensable backbone force in the third-generation pharmaceutical industry revolution
oriented by gene expression regulation.

As a global partner, Biochempeg can supply commercial quantities of high
quality functionalized PEGs, which are essential for your PEGylated therapeutic
Oligonucleotides. We will PEGylate your oligonucleotides and deliver your PEGylated
product with a certificate of analysis, as a regular end-product, for further testing at your
site.

References:
1. FDA-Approved Oligonucleotide Therapies in 2017.Mol Ther. 2017 May 3;25
(5):1069-1075. doi: 10.1016/j.ymthe.2017.03.023.
2. Pharmacology of Antisense Drugs. Annu Rev Pharmacol Toxicol 2017 Jan;57 81-105.
3. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic Acid Ther. 2017 April 1;
27 (2): 70–77.
4.Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nature
Neuroscience 20, 497–499 (2017) doi:10.1038/nn.4508


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