Oligonucleotides: Opportunities, Pipeline and Challenges

At long last, nucleic acid therapeutics are coming of age

By Tracy Tredenick, Head of Regulatory and Quality Assurance, BioTechLogic

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Although meaningful progress toward the development of oligonucleotide therapeutics began in the 1970s, nearly a half century later, only three oligonucleotide drugs have been approved by the FDA. However, the field is gaining momentum and the clinical benefits of the more than 135 oligonucleotide therapeutics currently in various stages of clinical trials are extremely promising.

What is so attractive about oligonucleotide therapeutics? Although this class of therapeutics is quite diverse, the excitement and dedication to this work is rooted in the following factors:

● Oligonucleotides offer promising treatment for a wide range of medical conditions.
● They allow for the development of therapeutics that affect protein targets that cannot be effectively treated by small-molecule or protein therapeutics.
● Interfering with RNA function at the cellular level, specific malfunctioning genes can be targeted, manipulated, silenced and/or modulated.
● Immune system modification is possible, offering the possibility of treatment for a multitude of autoimmune disorders that are in many cases extremely challenging to treat with currently available drugs.
● Oligonucleotides are synthesized pieces of chemically modified RNA or DNA. Scaling up for commercial-scale GMP production is more feasible than it is for many cell therapies or other biologic therapies.
● Side effects for many oligonucleotides are more controllable and minimal than the side effects experienced with other classes of drugs.
● As reported by Ryszard Kole in 1993, oligonucleotides can be used to modulate pre-mRNA splicing. Much work has been done to develop therapies targeting Duchenne muscular dystrophy, including progress treating the splicing mutation that causes Duchenne muscular dystrophy. These learnings hold much promise for a number of other conditions as well.
● In concept, when compared to small-molecular drugs as well as to large-molecule biopharmaceuticals, oligonucleotide pharmaceuticals are much more straightforward to both design and develop.

Given the relatively new commercial viability of the oligonucleotide market, it is difficult to establish a precise value of the market. However, all indications point to a very promising future for viability and future growth. For instance, the oligonucleotide synthesis market is estimated to be $1.92 billion USD by 2020, up from $1.08 billion USD in 2015. Compounding Annual Growth Rate (CAGR) in the oligonucleotide synthesis market is approximately 10.1 percent.

Given the small number of approved oligonucleotide drugs currently on the market—currently three in the U.S.—it is helpful to take a closer look at arguably the leader in the space, Ionis Pharmaceuticals (name changed from Isis Pharmaceuticals in 2015). For its 25-year existence, Ionis Pharmaceuticals has dedicated its existence to oligonucleotide therapeutic development, particularly antisense oligonucleotide (ASO) therapeutics. While Ionis Pharmaceuticals is still operationally losing money most quarters, its future looks strong, and that is being reflected in its stock market performance. For much of the last four years, the Ionis Pharmaceuticals stock (IONS), has outperformed the NASDAQ Composite and NASDAQ Biotechnology indexes.

While the market performance of oligonucleotide therapies is still not as predictable as other segments, the future as reflected by both the leaders in the space and the amount of investment and R&D activity, looks very promising. This is not to say, however, that there are not significant challenges to contend with.

While there are numerous challenges the field is currently grappling with, this paper will focus on four: enabling technologies, diversity within this class of therapeutics, delivery challenges and regulatory complexity.

Enabling Technologies
Antisense oligonucleotide (ASO) therapeutics currently represent the most promise and have experienced the most success within the overall oligonucleotide class. As mentioned at the beginning of this paper, it is commonly accepted that the modern age of oligonucleotides and the birth of Antisense Oligonucleotide (ASO) work began in the early 1970s after Nobel laureate Gobind Khorana published his ground-breaking work.

Despite these early days and critical steps in the 1970s, Antisense Oligonucleotide (ASO) therapeutics as a promising set of entities for commercialization began in the early 1990s. However, during this period, there were ongoing supply chain delays, limited synthesis methods which sharply limited the amount of available drug substance, analytical methods were not well developed and analytical instrumentation technology was often not advanced enough to support the needs of the market.

Advancing analytical methods that better characterize and quantitate both the oligonucleotide of interest as well as any synthesis contaminants have been critically important enabling technologies. For example, new LC/MS methods have been introduced in the last few years that use both low levels of triethylamine (TEA) and hexafluoroisopropanol (HFIP) as a mobile-phase buffer. For reversed-phase (RP) separations, this approach has facilitated reasonable mass spectroscopy (MS) sensitivity. Given that HPLC methods alone are inadequate, this has been one of numerous important analytical advancements as the resolution and richness of characterization that mass spectroscopy (MS) offers is needed.

In addition to analytical method limitations, it was expensive and difficult to produce chemically modified oligonucleotides, therefore, only very small quantities were generally produced causing supply chain problems and shortage of product to work with. However, market leaders have dedicated significant resources toward improving manufacturing efficiency and capacity.

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