The ‘Tides are Turning

After more than 20 years of experience in chemistry, Director of New Modalities at CatSci Nigel Richardson has led numerous projects, including chemical route selection, clinical supply and control strategy development, regulatory submission generation, and technology transfer. He is also the founder of McLean Pharma Consulting, where his mission is to help companies accelerate the development and delivery of new therapies to waiting patient populations.

His interest in oligonucleotides began when he realized their potential to help treat Duchenne Muscular Dystrophy. Looking back to one project, Richardson says, “The mechanism of action was unlike any small molecule medicine I had worked on before, and the elegance of RNA interference to enable the production of a dystrophin-like protein as a potential cure for Duchenne is a fascinating area of scientific innovation with huge impact on the waiting patients.”

Richardson has since gone on to develop the necessary chemistry and analytical controls to ensure high-quality oligonucleotide medicines can be manufactured at a commercial scale in support of product registration. With the manufacture and characterization of oligonucleotide therapies being so extremely complex, we asked Richardson why they are so important – and what is likely to come next in their ongoing development.

Why is it so important for the pharma industry to invest in oligonucleotide research?
 

Oligonucleotides can be considered the third modality of therapeutics, building on traditional small molecule drugs and biopharmaceuticals. The most common oligonucleotide therapeutic agents include antisense oligonucleotides (ASOs), small interfering RNA (siRNAs), micro-RNA (mRNA), and aptamers. Oligonucleotide therapeutics are all based on short sequences of chemically modified or unmodified nucleic acids. The mechanism of action varies depending on the type of oligonucleotide, but the common factor for all types (except aptamers) relies on Watson-Crick base pairing to the target messenger RNA. The importance of oligonucleotide therapies is based on the unique ability of RNA interference to silence or, in some cases, enable protein production. This mechanism of action has the potential to develop medicines for formally undruggable diseases.

With the increased understanding of the human genome and the genetic link to many diseases, the drug discovery process for oligonucleotides (the design of a short oligonucleotide sequence to interfere with a specific messenger RNA) is accessible to many small biotechnology organizations and academic groups. This activity is accelerating innovation in the field, as well as increasing the number of clinical trials.

In what therapeutic areas are oligonucleotides making their mark? 
 

Depending on the definition used, around 14 oligonucleotide medicines have been approved across all marketing authorisation. A number of the approved medicines are ASOs for the treatment of Duchenne Muscular Dystrophy – and employ slicing modulation (exon skipping) mechanism for each specific mutation. Many of the other approved medicines target liver diseases. Perhaps the most significant of these is Inclisiran, marketed as Leqvio – an siRNA that silences the transcription of the protein PCSK9 to help reduce cholesterol in the blood. The drug represents a new treatment for people with high cholesterol that cannot be reduced by more conventional treatments and is the first oligonucleotide therapy for large patient populations. 

The application of oligonucleotides therapeutics in oncology is a large and developing field with a significant number of ongoing clinical trials. There is also a focus on ASOs for neurodegenerative diseases. Delivery to the brain was demonstrated with the approval of Nusinersen, marketed in the US as Spinraza, for the treatment of spinal muscular atrophy (SMA) in 2016. 

What other approvals in the field can be considered milestones?
 

The oligonucleotide therapies that have been approved over the last five years have demonstrated significant advances in the general technology platform. In 2016, patisiran, marketed as Onpattro, was the first siRNA to be approved. Onpattro, for the treatment of TTR amyloidosis, uses lipid nanoparticle technology to deliver the siRNA to the liver. This milestone achievement signaled the beginning of further siRNA therapeutics. In 2019, givosiran, marketed as Givlaari, was approved for acute hepatic porphyrias. Givosiran incorporates a GalNAc conjugate, a carbohydrate that binds to the highly liver expressed asialoglyco-protein receptor 1 (ASPGR) with high affinity, to target the liver. This approval marked the beginning of a further wave of oligonucleotide medicines that incorporate GalNAc. The approval of Inclisiran – an siRNA containing the GalNAc moiety – is the first oligonucleotide treatment for a large patient population.

What are the manufacturing challenges?
 

With the progression of oligonucleotide therapies into the large population diseases, the challenge of supplying the required quantities of drug substance is now significant. Therapeutic oligonucleotides are generally manufactured for clinical and commercial applications using phosphoramidite chemistry on a solid support. This solid-phase chemistry is well understood and has been used for decades. It can deliver high-quality oligonucleotide drug substances, but the solid-phase process is neither readily scalable nor environmentally friendly. In 2016, the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable identified the development of a greener process for oligonucleotides APIs as a critical unmet need. Many groups, including CatSci, are researching novel alternatives to solid-phase synthesis that can deliver an improved process with reduced waste, lower demand for acetonitrile, and improved atom efficiency.

You’re clearly excited about oligonucleotides, but do any other innovative areas spark your interest? 
 

I am excited about CRISPR, which has been used to knock out harmful mutant genes and to fix errors in coding sequences. In November 2021, the first base-editing therapy moved towards the clinic when Beam Therapeutics received FDA approval for an Investigational New Drug application to treat sickle cell disease (SCD). The BEAM-101 therapy uses base editing to reactivate the expression of fetal hemoglobin in autologous hematopoietic stem cells and is envisioned as a one-time treatment for SCD. 

Other companies are developing CRISPR technology for cardiovascular diseases, transthyretin (ATTR) amyloidosis, leber congenital amaurosis 10, SCD, Beta-thalassemia, cancer, and diabetes. I await all future developments with great anticipation!