Delivering Therapies To The Olfactory Region

By Rick Geoffrion, CEO, Cyrano Therapeutics

For decades, drug developers have struggled to deliver therapies directly to the olfactory region of the nasal cavity, one of the more anatomically and physiologically complex targets in the human body. This region, nestled high within the upper nasal cavity, is home to the olfactory epithelium, the tissue within which the olfactory receptors reside, which are in part responsible for our sense of smell. Reaching it precisely is critical for treating certain conditions, such as post-viral hyposmia, but doing so with a medication that is both effective and safe remains one of the most underexplored frontiers in drug delivery science.

Treating post-viral hyposmia, a chronic condition characterized by the mild to severe loss of the sense of smell following a viral infection, is challenging. The condition affects tens of millions of people worldwide and has long been overlooked despite its significant impact on quality of life, nutritional health, and personal safety. When the sense of smell is lost, the sense of taste is diminished by as much as 80%, which means that two of the basic five senses are severely affected. The COVID-19 pandemic brought “smell loss” into the public mind and as the virus has now become endemic, the rate at which people lose their sense of smell each year continues to be much higher than it was 10 years ago

Why Systemic Treatments Fall Short

From a therapeutic development standpoint, olfactory loss presents a unique set of challenges. While some systemic medications have been tried off-label, their efficacy has been inconsistent and their side effects often problematic. One of the primary limitations of systemic treatment is the difficulty in delivering a sufficient dose to the olfactory region without exposing the entire body to elevated levels of the drug. This has led to adverse events and has limited the ability to target the neurons responsible for olfactory function in a sustained and precise way.

While phosphodiesterase (PDE) inhibitors have shown potential in modulating olfactory signaling, the doses required to reach the upper nasal cavity through systemic circulation proved intolerable in practice. Patients were unable to tolerate the side effects associated with the high systemic drug levels needed for therapeutic effect in the olfactory region. This experience highlighted the limitations of systemic treatment and underscored the importance of delivering drug directly to the site of action while avoiding unnecessary exposure elsewhere in the body. The rationale for a localized delivery approach is reinforced by these past failures with systemic administration of similar compounds.

A New Approach To An Old Problem

What is needed is a new way of thinking about how and where we deliver therapeutics. In the case of post-viral hyposmia, that means designing a formulation and delivery approach that can deposit drug precisely to the olfactory cleft while avoiding unnecessary systemic exposure. That need was the genesis of our development program for an intranasal spray formulation containing a broad-spectrum PDE inhibitor designed to restore olfactory function by enabling olfactory receptor neurons to thrive in a less-nourishing post-viral environment and a proprietary delivery device that has been designed to effectively deliver the formulation to the olfactory region.

Developing an effective spray therapy requires solving three fundamental problems:

1. how to formulate the drug in a way that allows it to be absorbed by the olfactory epithelium
2. how to deliver that formulation to a small, hard-to-reach region high in the nasal cavity
3. how to ensure that this can be done repeatedly, consistently, and, in today’s world, cost-efficiently across diverse patient nasal anatomies, without risking toxicity in other parts of the body.

We designed CYR-064, the investigational compound we are advancing in clinical studies, with these delivery challenges in mind. To do that, we leveraged a proprietary spray technology that produces a soft mist with a specific droplet size and low velocity, allowing the drug to reach the upper nasal cavity with minimal runoff and waste. The droplet size, in particular, is critical. Too large and the spray will settle in the lower nasal cavity. Too small and it will be inhaled into the lungs. Achieving roughly 20 to 40 microns in droplet diameter is essential for ensuring the spray reaches and adheres to the olfactory cleft repeatedly and consistently. The targeted delivery to the nasal cavity means that up to 500x less drug may be needed per treatment, with the intention to lower the risk of toxicity and associated side effects.

Validating That Delivery Actually Works

But delivery mechanics are only part of the solution. Equally important is validating that the drug is actually reaching the intended site. To address that, we worked with imaging experts and engineers to develop and validate deposition models using nasal cavity replicas and advanced imaging techniques. These models incorporated the use of radiolabeled tracers and particle tracking to confirm that the mist was reaching the olfactory region at therapeutic concentrations. This rigorous validation process helped ensure that our delivery system was not just conceptually promising but practically effective.

Broader Implications For Nasal Drug Delivery

These insights have direct implications for developers across the broader field of nasal drug delivery. While much of the nasal drug development to date has focused on systemic delivery through the rich vascular bed in the lower nasal cavity, the olfactory region offers a potential gateway to both local and central nervous system targets, if the delivery challenge can be overcome. Our work suggests that with the right combination of formulation science, device engineering, and anatomical validation, this is achievable.

We believe that our work may have broader implications for other CNS and sensory conditions. Smell dysfunction is not only common in patients with neurodegenerative disease but it has been validated as an early symptom in many cases. By intervening early, we hope to better understand whether restoring olfaction can improve quality of life and potentially even offer insights into the broader neurological disease process. As the field continues to explore intranasal delivery as a non-invasive route for targeting the brain and sensory systems, our lessons learned may help inform strategies for other drugs, molecules, and indications that require precise targeting with minimal systemic exposure.

Unlocking A New Frontier In Drug Delivery

The broader takeaway is clear. Delivering therapies to the olfactory region requires a fundamentally different approach than delivering to the lungs or the lower nasal cavity. It requires an understanding of fluid dynamics at a micro scale, validating delivery pathways through careful modeling and designing devices that are intuitive for patients and cost-effective, while sophisticated in the way they operate.

Ultimately, advancing drug delivery to the olfactory region is not just a technical challenge but a clinical imperative. Millions of people suffer from the daily frustrations and hidden dangers of smell and taste loss. Many more are at risk of neurological decline with no outward early symptoms except for their diminishing sense of smell. If we can reach this difficult target safely and effectively, we may open the door to new therapies that improve lives in ways that have long been considered out of reach.

About The Author

Rick Geoffrion is the CEO and cofounder of Cyrano Therapeutics, a clinical-stage regenerative medicine company developing treatments for post-viral smell loss. With more than 35 years of leadership experience in the pharmaceutical and medical device sectors, Geoffrion has founded seven therapeutic companies and helped advance multiple products from concept to commercialization. His professional work is informed by personal experience; having lived with smell and flavor loss himself, he is deeply committed to developing effective therapies for this overlooked and often misunderstood condition.