Oligonucleotide therapy development around the world | Koken CO., Ltd.

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Oligonucleotide therapy development around the world

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Revival of oligonucleotide therapy development

At one point, many pharmaceutical companies were conducting research on oligonucleotide therapy, which employs chemically synthesized nucleotide-like small molecule drugs with potential specificity similar to that of therapeutic antibodies. However, the development of oligonucleotide therapy has since slowed, with some major pharmaceutical companies terminating the relevant research programs completely. One of the reasons is thought to be the immature state of the drug delivery system (DDS) that would be required for transporting nucleic acids to the target site. Nevertheless, the development of oligonucleotide therapy has again begun to draw attention along with research progress on oligonucleotide therapy without DDS, which has been achieved by increasing these drugs’ stability in the body by chemical modification of the nucleic acid-like molecules.

Types of oligonucleotide therapies

Although several types of oligonucleotide therapies exist, five of them are compared here, including the ones targeting nucleic acids (such as mRNA) or proteins, as well as others intended for stimulation of the immune system. DDS is generally used with oligonucleotide therapy, as it is difficult for these molecules to penetrate cell membrane when administered on their own.

Approved/late-stage development oligonucleotide therapies

As shown in the following list, seven products have been approved as of January 2018; most of these products are antisense oligonucleotides, and almost all have been chemically modified to enhance their stability in the body. Earlier approved products were limited to local injection into affected tissues, but subcutaneous and intravenous administration products are now on the market. It should be noted that Defitelio is not a synthetic oligonucleotide per se, but instead a polydispersed mixture of single-stranded oligonucleotides derived from porcine intestinal tissue, which is why this product is designated as “miscellaneous” here.

Approved oligonucleotide therapies
Company Trade name INN Type Indication Modification Administration
Novartis
[Co-developed with Ionis Pharmaceuticals (formaly Isis Pharmaceuticals)]
Vitravene
【withdrawn】
fomivirsen Antisense oligonucleotide
(ODN)
CMV retinitis in patients with AIDS S-oligo Intravitreal injection
Valeant Pharmaceuticals (formaly EyeTech Pharmaceutical)
[Co-developed with Pfizer]
Macugen pegaptanib Aptamer neovascular (wet) age-related macular degeneration 5′-pegylated
2′-F
2′-OMe
Intravitreal injection
Kastle Therapeutics
[Developed by Ionis Pharmaceuticals (formaly Isis Pharmaceuticals) and Sanofi Genzyme (formaly Genzyme)]
Kynamro mipomersen Antisense ODN Homozygous familial hypercholesterolemia S-oligo
2′-MOE
Subcutaneous injection
Sarepta Therapeutics Exondys 51 eteplirsen Antisense ODN Duchenne muscular dystrophy Phosphorodiamidate morpholino oligomer Intravenous injection
Biogen
[Co-developed with Ionis Pharmaceuticals (formaly Isis Pharmaceuticals)]
Spinraza nusinersen Antisense ODN Spinal muscular atrophy S-oligo
2′-MOE
Intrathecal injection
Dynavax Technologies Heplisav-B Hepatitis B
Vaccine (Recombinant) Adjuvanted
CpG ODN Hepatitis B S-oligo Intramuscular injection
Miscellaneous            
Jazz Pharmaceuticals (formaly Gentium) Defitelio Defibrotide ODN derived from porcine intestinal tissue Hepatic veno-occlusive disease Intravenous injection

Note: This list was produced on the basis of publicly available information; it may not reflect the most recent developments.

Given that only seven products have been approved, oligonucleotide therapies may appear to still be under development. However, there are another five products at the stage of approval review, 12 products in Phase III trials, and one cosmetic ingredient at the consumer test stage. According to data from the Japan patent office, 141 clinical trials with oligonucleotide therapies were being conducted as of October 2015. Given that nearly 20 products are approaching commercialisation and that the number of siRNA products is increasing, we can expect a variety of oligonucleotide therapies to be available in the near future.

Major late-stage development oligonucleotide therapies
Company Name Type Indication Stage
Alnylam Patisiran siRNA Hereditary amyloidosis Approval review
  Inclisiran siRNA Hypercholesterolemia P3
  Fitusiran siRNA Hemophilia and rare bleeding disorders P3
  Givosiran siRNA Acute hepatic porphyrias P3
Gene Signal Aganirsen Antisense ODN Neovascular-associated corneal graft rejection P3
  Aganirsen Antisense ODN Ischemic central retinal vein occulusion P3
Geron Imetelstat lipid-conjugated ODN Myelodysplastic syndromes P3
Ionis Pharmaceuticals Alicaforsen Antisense ODN Pouchitis Approval review
  Inotersen Antisense ODN TTR amyloidosis Approval review
  Volanesorsen Antisense ODN Familial chylomicronemia syndrome Approval review
  Volanesorsen Antisense ODN Familial partial lipodystrophy Approval review
Achive Life Sciences Custirsen Antisense ODN Non-small cell lung cancer P3
Quark Pharmaceuticals QPI-1002 siRNA Delayed graft function P3
  QPI-1007 siRNA Non-arteric anterior ischemic neuropathy P3
Sarepta Therapeutics SRP-4045 Antisense ODN Duchenne muscular dystrophy P3
  SRP-4053 Antisense ODN Duchenne muscular dystrophy P3
Sylentis Tivanisiran siRNA Dry eye syndrome P3
Miscellaneous        
RXi Pharmaceuticals RXI-23 siRNA Cosmetic ingredient Consumer test

Note: This list was produced on the basis of publicly available information; it may not reflect the most recent developments.

DDS research for oligonucleotide therapy

Neither of the currently approved oligonucleotide therapies uses DDS. Kynamro, which is administered subcutaneously, takes advantage of a characteristic property of oligonucleotide, namely the tendency to accumulate in the liver and kidney. Exondys 51, which is administrated intravenously, utilises the tendency toward increased uptake by muscle cells in patients with Duchenne muscular dystrophy. However, those advantages are not always available in other target tissues and/or diseases; a number of studies have investigated the effective delivery of nucleic acids using DDS. For example, PEGylated liposomes are well known for their longer blood circulation time, and vitamin A-modified liposomes have been used to target hepatic stellate cells. Last but not least, atelocollagen-based DDS has been developed. Unlike liposome-based DDS, atelocollagen has no toxicity and can facilitate permeation of blood vessels when complexed with nucleic acids.

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