Oligo-conjugates: an answer to a delivery conundrum?
A pervasive issue
Oligonucleotide-based therapies have a significant presence within the pharmaceutical industry. According to Hanson Wade’s Beacon database, there have been 15 oligonucleotide-based drugs approved for the market, the first coming way back in 1998 with fomivirsen and the latest, vutrisiran, last year. Despite this apparent success, there remains a persistent issue within the space concerning the delivery of these molecules to target tissues. Oligonucleotide drugs accumulate in the liver, like many therapies that do not feature targeting ligands. Many currently approved therapies therefore target hepatocytes, or make use of direct injection into places such as the spinal cord or the eye to circumvent this problem. However, this severely limits the range of indications for which this modality can be utilised.
Peptides guiding the way
Many solutions have been presented to combat this issue, one of the most notable being the use of lipid nanoparticles (LNPs) which are most prominently used in several approved COVID-19 vaccines (including Comirnaty & Spikevax). However, another emerging technology in this area is that of peptide conjugation. Peptides provide an excellent source of tissue-specific targeting ligands, making them ideal for providing oligonucleotides with a route towards extrahepatic delivery. Owing to the diversity of potential peptide ligands available to choose from, companies are taking various different routes into the clinic in this emerging area.
Conjugates in the clinic
A number of companies are exploring approaches that they believe will speed up the effective clinical translation of oligo-conjugates. Dyne Therapeutics have harnessed the exceptional binding qualities of antibodies in order to power their oligo-conjugate. Their FORCE™ platform utilises a singular antibody Fab fragment conjugated to an oligonucleotide to generate therapeutic effect through correcting genetic mutations leading to defective translation. They have two Phase IIa-stage compounds, DYNE-101 and DYNE-251, looking to correct erroneous protein expression in Myotonic Dystrophy Type 1 (DM1) and Duchenne’s Muscular Dystrophy (DMD). Their platform has evidently allowed them to overcome issues with delivery to muscle cells and achieve clinically significant results, with DYNE-251 being rewarded with the FDA’s fabled Fast Track designation.
Likewise, PepGen have a clinical-stage oligo-conjugate asset targeting DMD, PGN-EDO51. This company have been able to develop the Enhanced Delivery Oligonucleotide (EDO) platform, featuring proprietary targeting ligands separate to existing immunological molecules. These peptides are engineered specifically to bind to and penetrate target cells in the muscles and has seen success at Phase I, allowing the company to anticipate initiating a Phase IIa patient trial.
While this modality is clearly still in its infancy, when considering the big problem of delivering life-changing oligonucleotide drugs outside of the liver, it is evident that plenty of potential lies in this emerging modality as we look to combat the effects of countless genetic defects.
Dyne Therapeutics receives FDA Fast Track Designation for DYNE-251 for the treatment of duchenne muscular dystrophy (https://investors.dyne-tx.com/node/8126/pdf)
PepGen anticipates initiating a Phase 2a multiple ascending dose trial of PGN-EDO51 in the first half of 2023 for the treatment of DMD (https://investors.pepgen.com/node/7036/html)
For further reading, download our recent report ‘Biopharma Deals in RNA Space: A post-Covid Landscape Review‘ where you’ll gain valuable insights on the main industry movement in the RNA space and development of RNA therapies.