We give an overview of the antisense drug discovery and development programs that are in the pipeline for RNA targeted medicine. It is based on manual collection of data from company websites and clinicaltrials.gov. Main author is Stine Møllerud.
A data table is available here as a google spreadsheet. You are welcome improve the table if you find mistakes or have additional info. Below we do descriptive statistics on it. In later posts we will follow up on specific aspects and more analysis.
Antisense technology has been pursued for more than two decades but despite the heavy research in the field, only two RNA therapeutics have been approved. The first antisense oligonucleotide to reach the market was fomivirsen, which was approved by the Food and Drug Administration (FDA) in 1998 for the treatment of cytomegalovirus retinitis in patients with AIDS. It was discontinued by the marketing authorisation holder in 2002 for commercial concerns. Recently ISIS Pharmaceuticals and Sanofi have achieved approval from FDA for kynamro (generic name mipomersen), an antisense oligonucleotide targeting apolipoprotein B100, for the treatment of homozygous familial hypercholesterolemia.
More than a hundred oligonucleotides are in the pipelines of more than 30 companies. The table below lists the antisense drug candidates that, according to company homepages and clinicaltrials.gov currently, are under development.
Approximately half of the listed drug candidates have reached the state of clinical development, five of which are in phase III clinical trials, including the recently approved Kynamro.
When it comes to the mechanism of action, single stranded antisense and siRNA dominate the clinical pipelines, whereas a large number of antimiR programs appears in preclinical research.
The field has many players and the table contains 46 pharmaceutical or biotech companies which are either the developing company or a partner. Almost one third of these companies are involved in 4 or more projects. ISIS Pharmaceuticals is the dominating player, as they are involved in nearly one of four drug candidates in the pipeline (26 out of 109) or almost every third of those in clinical trials (18 out of 58).
|Phase I||Phase Ib||Phase II||Phase IIb||Phase III||pre-clinical|
Cancers are the prevailing indication for the drug candidates in the pipeline (31 out of 109) followed by cardiovascular and related diseases (14), ocular disorders (10), and muscle dystrophies (10). Antisense oligonucleotides to treat cancers are also the disease area with the most involved companies.
The drug candidates in phase III clinical trials have the indications: Hypercholesterolemia, transthyretin amyloidosis, prostate cancer, Duchenne’s muscular dystrophy, and corneal neovascularisation.
One of the challenges for oligonucleotide based therapy is to deliver the drugs to the relevant tissue and achieve a satisfactory PK-profile. A multitude of chemical modifications, conjugations and formulation techniques are being used.