Recently, Impel Pharmaceuticals announced it had dosed the first subject in its PhaseIIa proof-of-concept study investigating acute treatment for agitation in patients with autism spectrum disorder (ASD). The treatment uses the company’s Precision Olfactory Delivery (POD) technology, designed to deliver drugs to the upper nasal space with injection-like absorption.
To learn more about the trial and the novel POD delivery system, Outsourcing-Pharma connected Stephen Shrewsbury, chief medical officer with Impel Pharmaceuticals
OSP: Could you please tell us a bit about Impel—who you are, what you do, key areas of specialty, and any recent accomplishments/developments you think are worth highlighting?
SS: Impel Pharmaceuticals is a commercial-stage pharmaceutical company focused on developing and providing transformative therapies that unlock the full potential of therapeutic molecules.
We are the first company to investigate targeting delivery to the upper nasal space, initially by optimizing the pharmacokinetics of long-established therapeutic molecules that have failed to meet their full potential due to inconsistency and unpredictability in effect. The engine behind Impel’s evolving clinical pipeline is our proprietary Precision Olfactory Delivery (POD) technology: an approach to drug delivery that administers drugs deep into the vascular-rich upper nasal space – a gateway for potential therapeutic administration of a wide range of molecules and formulations across multiple therapeutic areas.
The approval of Trudhesa (dihydroergotamine mesylate [DHE]) nasal spray (0.725 mg per spray) in September 2021 marked the first commercially available product to use the POD technology – we’re now close to one year into commercialization, and due to the momentum we’ve seen with prescriptions and the continued unmet need in the large and growing migraine market, we’ve expanded our sales force by 50% in August to 90 high-quality sales professionals.
With increasing awareness and usage of Trudhesa comes an ongoing need to share the supporting scientific data, including the emerging understanding about the opportunity presented by the upper nasal space and hence, we are also growing our Medical Science Liaison team.
We also announced in July 2022 that the first patient has been dosed in a Phase 2a proof-of-concept study (the CALM 201 Study) of INP105, a nasal olanzapine product using Impel’s POD technology that is being developed as an acute treatment for agitation in persons with autism spectrum disorder (ASD).
OSP: Please share a bit about how the POD technology works, its advantages, what types of conditions it is best suited for, and what you’ve applied it to so far.
SS: Impel Pharmaceuticals was founded in 2008 by John Hoekman, our Chief Technology and Development Officer, with the belief that nasal drug delivery to the systemic circulation could greatly improve the uptake and consistency of absorption of important therapeutic molecules. It was recognized that no device existed that deposited drug consistently to the vascular-rich upper nasal space where the olfactory mucosa is mainly located. This resulted in the development of the Company’s proprietary POD technology.
Unlike traditional nasal delivery devices, the POD technology is specifically designed to actively propel drug formulations through the nasal valve to this area of the nose where the central nervous system (CNS) comes into direct contact with the environment. Drug delivery via the POD device enables rapid absorption and provides enhanced bioavailability compared to intramuscular administration and reaches intravenous-like systemic levels quickly, which has the potential to transform treatment landscapes in multiple disease areas.
Importantly, the POD is unique because it ensures consistent and convenient dosing of therapeutics. It is enabled by a gas propellant delivery mechanism that eliminates the need for coordination of breathing, allowing for self-, caregiver, or healthcare practitioner-administration in a manner that improves patient comfort, and potentially, compliance.
Additionally, the POD device’s rapid and non-invasive profile means it may improve the overall patient-provider experience, particularly in cases when healthcare professionals are dealing with complications of mental illness and might otherwise have to consider an intramuscular injection, with or without the need for physical restraint. Currently, the POD technology is being used in Trudhesa to deliver DHE to the vascular-rich upper nasal space, bypassing the gut and potential absorption issues and offering rapid, sustained, and consistent symptom relief without injection or infusion, even when administered hours after the onset of a migraine attack.
In addition to Trudhesa for the acute treatment of migraine, Impel is advancing a pipeline of drug-device combinations, featuring different iterations of the POD device, including INP105 for the acute treatment of agitation and aggression in patients with ASD.
OSP: Could you please share some information about agitation and how it’s a challenge for ASD patients?
SS: Autism is the fastest-growing neurodevelopmental disorder in the US and there is an unmet need to help those living with autism and its related effects. Approximately one in 44 children in the U.S. and one in 160 children worldwide have been identified with ASD according to the Centers for Disease Control and Prevention and World Health Organization, respectively.
Agitation and aggression are frequent and difficult to manage symptoms and are associated with negative outcomes for patients with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Acute agitation often manifests in patients with other serious underlying mental health conditions as well, such as bipolar I disorder or schizophrenia. Between 1.7m and 7m episodes of acute agitation have been reported to lead to visits to US hospitals and emergency room settings each year.
Based on a study of emergency room usage in Canada, which found that 18% of individuals with ASD aged 12 and up had visited the emergency room within the past year and that approximately 34% of such visits were for mental health issues, we estimate that approximately 220,000 patients with ASD in the U.S. seek emergency room care annually.
There are no approved treatments for patients living with ASD once they become agitated and which may lead to aggression. Current chronic treatment strategies include functional behavioral assessment, reinforcement strategies, functional communication training, and the use of second-generation antipsychotics, which require daily dosing. These treatments tend to produce weight gain, increase the risk of diabetes, and require close monitoring from a physician. One option often used off-label in this situation is intramuscular (IM) olanzapine.
With an increasing rate of ASD diagnosis, we believe that the development of effective therapeutic and pharmacologic methods for preventing and treating agitation and aggression are essential to improving outcomes in this disorder. We believe that INP105 has the potential to be an on-demand therapy in this indication.
OSP: Specifically, what about the POD technology makes it especially suited for patients dealing with ASD of varying degrees? Is it more manageable for those dealing with attention or sensory issues, for example?
SS: Olanzapine is the most used treatment for acute agitation, but its use is limited to IM injection in a hospital setting, and there is nothing rapidly acting available for use in the community. With INP105, the POD delivers consistent and predictable doses of olanzapine to the richly vascularized upper nasal space to offer rapid, consistent, and optimized bioavailability that can be administered by the patient or a caregiver. We believe INP105 will be a preferred choice for the safe and rapid treatment of acute agitation, and because it is designed to be non-invasive, has the potential to expand the treatment setting beyond the emergency room, such as in-patient treatment or community care facilities and the patient’s home.
We compared INP105 with equivalent doses of IM-administered olanzapine in a two-part, single ascending dose Phase 1 clinical trial in 40 healthy adults. In part one, volunteers received IM olanzapine (or the oral disintegrating tablet). In part two, in three ascending dose cohorts, they received INP105 or placebo in a randomized, double-blind manner. The study demonstrated that INP105 enables rapid systemic absorption without an injection, was well tolerated, and led to similar exposure and faster plasma uptake than IM olanzapine injection.
Based on its pharmacokinetic profile and method of administration, we believe INP105, if approved, has the potential to treat acute agitation and aggression events in this under-served population and in patients’ homes, potentially reducing visits to the emergency department and limiting the need to call in reinforcements to help caregivers. INP105 also has the potential to be the first rapid-acting olanzapine product to treat agitation in multiple additional indications.
OSP: What are the next steps for use of the POD technology with ASD agitation symptoms—please share what you can.
SS: As previously mentioned, in July 2022, we announced the first patient has been dosed in a Phase 2a proof-of-concept study (the CALM 201 Study) to advance its combination product candidate, INP105, a nasal olanzapine product (a widely used atypical, second-generation antipsychotic) being developed as an acute treatment for agitation in persons with ASD using Impel’s POD technology. The trial is underway, and we expect to reach multiple study milestones over the next year: pilot phase completion (~Q4 2022), last patient, last visit (Q1 2023), and full study results (H1 2023).
We are also focused on raising awareness among healthcare providers around INP105’s potential to provide rapid and non-traumatic acute treatment for the treatment of ASD – there are over 100m agitation and/or aggression episodes a year in the approximately 600,000 children and adolescents with ASD. A vast majority of these episodes are not treated with acute (or PRN) medications, and so the only option healthcare professionals are left with to address this is by adjusting daily medications or using IM products off-label.
Acute dosing of INP105 may provide the efficacy of olanzapine while sparing patients many of the tolerability and safety issues seen with daily use of antipsychotics or avoiding the need for healthcare professional interaction and IM administration. The nature of the POD technology allows for non-invasive administration when medication is needed, and episodes may be aborted before escalation. INP105 would also offer more control for families by allowing caregivers to administer the drug in a home setting.
OSP: Do you have anything more to add?
SS: There is a great unmet need for medications to treat autism and ASD. We are proud of the success of the POD technology seen through the launch and commercialization of Trudhesa as we believe it has a unique value proposition that will help it emerge as a leader in the market: it is a proven drug with a new method of delivery that is less cumbersome on the physician and the patient.
We are clearly pleased to have initiated our Phase 2b proof-of-concept trial for INP105 and expect data readout in H1 2023. This is an exciting time for Impel as we continue to build and broaden our R&D pipeline by leveraging the unique POD technology through both internal and partnership-orientated product development.