What do you think of oligotherapeutics? Have you ever heard of them?

For those not familiar with oligonucleotide therapeutics, here I share some of the fantastic initiatives taken by drivers in the field to develop medicines targeting populations as rare as n=1!

Working with a promising modality

Before we delve into the discussion, let me first share why I like to work with this promising modality so much!

Early in my career, I started working with antisense oligonucleotides in the laboratory hoping to find a suitable candidate to treat chronic inflammatory diseases. My professor at the time used to say: “This is the hottest topic, and it will revolutionize the field as a medicinal modality!” Turns out, he was right!

Following the first proof of concept of using small nucleic acids to modulate gene expression, a long period of maturation led to the first marketing authorization of an oligonucleotide-based therapy in the early ‘90s. Successive modifications have addressed the previous vulnerabilities of oligonucleotides.

I have since then worked on developing oligonucleotides to be used as therapeutic agents in various indications and in different programs. At Cytel, I support clients in tackling the challenges that can arise during pharmaceutical development — taking a promising oligo candidate from the lab bench to the clinic.

There are now more than a dozen approved oligonucleotide drugs on the market, and it is still fascinating to think of using a piece of DNA to successfully treat serious illnesses.

What Are Oligotherapeutics?

Oligonucleotide therapeutics are synthetically modified nucleic acids that can modulate gene expression via a range of processes, including RNA interference, target degradation by RNase H-mediated cleavage, splicing modulation, gene editing, and gene activation. They include Antisense Oligonucleotides (ASOs), small interfering RNA (siRNAs), microRNA (miRNAs), aptamers, and DNAzymes.

Why are oligonucleotides promising in pharmaceutical development?

1. They are specific. Oligonucleotides enable precision medicines, and the market for precision medicine is growing.
2. Rapid development is possible, compared to traditional small molecules or biologics due to their streamlined design and synthesis process.
3. Tend to have fewer side effects. As they act on specific targets, the side effects are likely to be less than for traditional medicines.
4. The potential for high efficiency through low doses.
5. Diverse applications. They can be used in a range of conditions, including genetic disorders, cancers, and viral infections, making them versatile therapeutic agents.
6. Possibility for genetic modulation.
7. Advancement in technology. Innovations in delivery methods and synthesis have improved the efficacy and stability of oligonucleotide drugs.

It is motivating to work to develop agents that generally tend to be well tolerated and have specific modes of action. The challenges include dealing with the regulatory expectations since different agencies worldwide may have varying experiences, which may lead to having to manage a wide variety of expectations and sometimes education is necessary. Nowadays, it is less often that oligos are confused for biologicals (see table below for a breakdown of these different therapeutics).

When might an oligo be an appropriate modality?

There are several instances in which oligonucleotides are appropriate, such as when:

• The causal gene acts principally on the disease through known cell type(s).
• Target is non-accessible or not modulable by other modalities.
• Reversibility of treatment is important.
• Long duration of action is desirable and safe.

CMC for oligo studies

When it comes to the early phases of pharmaceutical development, there are many aspects that need to be managed and completed on specific timelines. Disciplines like CMC (chemistry, manufacturing, and controls) can often be forgotten.

This is where I come in, and it is my job to remind the sponsor about the requirements. My work within CMC includes:

• Identifying and procuring services, such as the CDMO capable of manufacturing a suitable batch of oligonucleotides, taking modifications into account.
• Finding suitable drug product manufacturer/s.
• Selecting analytical laboratories and nonclinical CROs that are experienced with this type of modality.
• Acting as the main point of contact for the client with the above-mentioned vendors.
• Working to develop suitable drug formulations (i.e., for toxicology testing and clinical programs).
• Collaborating with experienced experts within toxicology and DMPK.
• Working cross-functionally with regulatory strategies, considering specific regulatory guidelines are vague or still missing for oligonucleotides.
• Writing quality documentation (e.g., IMPD and expiry date extensions).
• Interacting with regulatory bodies.
• Keeping track of emerging guidelines within this field.

Approved oligotherapeutics

The number of oligo program submissions to the FDA has increased since the first one filed in 1992 to about 30 in 2020. Initially targeting rare diseases and niche markets, oligonucleotides are now able to benefit large patient populations. Most known and widespread are the mRNA vaccines against Covid (the Pfizer mRNA vaccine Comirnaty was approved by the FDA in August 2021; the Moderna mRNA vaccine Spikevax was approved in January 2022).

To date, 13 ASO therapies have received approval from the FDA or the European Medicines Agency (EMA) for different rare diseases. The underlying molecular mechanism is similar for all of these indications: a single gene mutation is responsible for these diseases.

The approved oligonucleotide therapeutics act via a variety of different mechanisms correcting the affected gene, such as by blocking translation (fomivirsen, the first approved oligonucleotide drug but withdrawn due to safety issues), RNase H dependent degradation (mipomirsen, inotersen, and volanesorsen), splicing modulation (eteplirsen, nusinersen, golodirsen, milasen, and casimersen), siRNA dependent degradation (patisiran and givosiran), aptamer binding and blocking (pegaptanib), and aptamer binding and activating (defibrotide).

None of the approved oligotherapeutics to date target cancer, but there is a growing list of clinical trials using oligonucleotides in cancer treatment.

Personalized antisense oligonucleotides “for free, for life” to treat very rare diseases

The n-Lorem Foundation is a non-profit organization based in Carlsbad, California, established in 2020, to develop personalized medicines using antisense RNA to treat patients with very rare diseases. The mission of the n-Lorem foundation is to provide experimental oligonucleotide treatment for free for life, bringing hope to those with ultra rare genetic diseases. The mutation in these individuals should be unique to them (n=1) or having a gene mutation causing a disease in fewer than in 30 patients and are therefore not relevant for traditional drug development. The foundation’s CEO is the oligo-field pioneer Stanley T Crooke, founder and former CEO of Ionis Pharmaceuticals.

The FDA’s published recommendations, which were all predicated on characteristics of ASO technology and apply only to nonprofit efforts, focus on Severely Debilitating Life-Threatening (SDLT) disease with expected rapid progression.

The development of “free-for-life” is a collaborative activity between all charitable contributions from experts involved within antisense technology, genetics, regulatory, relevant disease, clinical care, clinical trial management, and bioethics. Step by step, the solution for the nano rare was created.

In the UK and Europe, several facilities have also been created to accelerate production of ASO therapies for rare disease patients, including for n = 1 cases, such as the Nucleic Acid Therapy Accelerator (NATA), the Rare Therapies Launch Pad, the Dutch Centre for RNA Therapeutics, the European Collaboration 1 Mutation 1 Medicine (1M1M) (=1 mutation,1 medicine), and the N = 1 collaborative.

Examples of free-for life nano rare diseases are CLN7 Batten disease, MCOPS12, and FUS mutation ALS (Amyotrophic Lateral Sclerosis).

What’s on the horizon for oligonucleotides?

It seems that the sky is the limit for what oligonucleotides can do and be used for.  IND submission patterns show that there is an increasing modification of the molecules and a broadening of what indications they are treating.

Oligonucleotides share a similar structure and are built by the same pool of building blocks, i.e., phosphoramidites. Due to this they share many chemical and physical characteristics.

The platform nature of oligonucleotides provides some opportunities, which could be beneficial to shorten the development time and enable regulatory benefits.

New regulatory guidelines have evolved from the FDA regarding nonclinical and clinical aspects, which are likely to facilitate the development of this exciting modality. Although slightly slower than expected, I am certain my professor was correct!

Are you working to develop oligotherapeutics?

At Cytel, we have broad experience of working with CMC and nonclinical toxicology plus DMPK aspects of pharmaceutical development for oligotherapeutics intended for various indications. For instance, in safety assessments, it is acknowledged to work case-by-case in these types of development programs. We have experience in clinical PK/PD: First-in-human dose predictions for oligotherapeutics.

Please reach out if you are interested in getting support within this area!

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