Impel Pharmaceuticals upper-nasal delivery offers hope for migraine patients

Impel Pharmaceuticals has developed its Precision Olfactory Delivery (POD) system, which reportedly delivers drugs with absorption rates comparable to injection and intravenous delivery. Outsourcing-Pharma connected with Adrian Adams, chairman and CEO of Impel, to learn more about POD’s use for Trudhesa, and its potential for use with other types of treatments.

OSP: Could you please share an overview of how the migraine treatment landscape has evolved in recent years—what advances in new drugs or delivery have there been up until this point?​

AA: The migraine treatment landscape is as diverse and complex as the way the disease presents in people. The severity, frequency, and characteristics of migraine vary among patients, and often within individuals over time, and there is still no means of identifying symptom profiles or biomarkers that could help doctors predict efficacy and side effects at the individual level, so even with the emergence of new mechanisms of action such as 5-HT1F receptor agonists and calcitonin gene-related peptide antagonists, doctors still struggle to match their patients with the right medications for them.

That’s why we are pleased to be able to provide patients and physicians with a new treatment option, Trudhesa (dihydroergotamine mesylate [DHE]) nasal spray (0.725 mg per spray). Trudhesa was approved by the US Food and Drug Administration (FDA) in September 2021 and is the first and only therapeutic to use Impel's proprietary Precision Olfactory Delivery (POD) technology 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.

OSP: Looking at those developments, what challenges have these drugs/delivery methods presented, and how have they fallen short of patient and caregiver expectations?​

AA: Despite the breadth of available options for the acute treatment of migraine, current treatments do not work for everyone. In a 2017 U.S. survey of nearly 4,000 people using oral acute prescription medication for migraine, 96% said they were dissatisfied with at least one aspect of their treatment, from lack of sustained relief to inconsistent relief, to lack of relief from a rapid-onset attack. Common areas of unmet need included inadequate two‐hour pain freedom (49.0%) and headache recurrence within 24 hours (38%).

The high prevalence of related gastrointestinal conditions among people with migraine may require alternative routes of medication delivery. Evidence suggests 80% of people with migraine experience gastroparesis, delayed emptying of the stomach; 73% experience nausea; and 29% experience vomiting. The American Headache Society guidelines recommend a non-oral therapy for patients who have limited or no response to oral medicine.

OSP: Please tell us about Trudhesa—when it was developed/discovered, and the drug’s path to approval.​

AA: Trudhesa is the culmination of 13 years of research and advanced engineering to pair the proven efficacy of DHE, which was approved for the treatment of migraine in 1946 and boasts over 70 years of therapeutic use, with Impel’s proprietary POD technology. The U.S. FDA approved Trudhesa in September 2021 for the acute treatment of migraine with or without aura in adults in a first-cycle review.

The POD device delivers 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.

OSP: Then, please tell us about the POD technology—how it works, how the actuator works, and any drugs it has been used with prior to this point.​

AA: Impel NeuroPharma [now Impel Pharmaceuticals] was founded in 2008 with the mission to address unmet needs in treating central nervous system (CNS) diseases and it was believed that intranasal drug delivery to the brain could greatly improve the uptake and consistency of absorption of important therapeutic molecules. Despite this unmet need, it was recognized that no device existed that deposited drugs consistently to the vascular-rich upper nasal space. This resulted in the development of what is now the company’s proprietary POD technology.

Unlike traditional nasal delivery devices, the POD is specifically designed to reach this new area of the body for drug administration. 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- or caregiver-administration in a manner that improves patient comfort, and potentially, compliance. Additionally, the POD’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.

Trudhesa is the first and only therapeutic that uses the POD technology, and we are also using it in our investigational treatment for acute agitation and aggression associated with autism spectrum disorder (INP105).

OSP: Could you please tell us about how the Trudhesa and POD delivery combination came about?​

AA: Unlike other available treatments for migraine, DHE is known to bind to multiple receptors theorized to be implicated in migraine onset and duration. There are limitations to the delivery of DHE via intravenous administration, intramuscular injection, and the historic intranasal formulations.

Trudhesa combines the 70-plus years of experience that existed with DHE and uses the POD technology to deliver it to the upper nasal space in a consistent and predictable way.

OSP: Please share some detail about the studies your organization presented at the recent American Academy of Neurology gathering, including the highlights in the findings (including any surprises).​

AA: Impel presented multiple abstracts at the recent AAN annual meeting. The data were all subsets from the Phase III, open-label, pivotal safety trial, STOP 301, which is the longest trial ever conducted with DHE using nasal spray delivery. More than 5,650 migraine attacks were treated up to the study’s duration of 52 weeks. Conclusions can be summarized as follows:

• Repeated acute use of Trudhesa may have benefits on the patient’s quality of life, by reducing migraine-associated disability, prolonging headache-free period, and decreasing the number of migraine attacks over time. Abstract here.
• Trudhesa is an effective acute treatment for migraine patients who have previously used a variety of acute therapies. Abstract here.
• If Trudhesa relieves migraine pain for the first 2-3 migraine attacks, the study found that the patient likely will respond with long-term use. The finding can help inform prescribers.

OSP: What is next for Trudhesa?​

AA: We are currently focused on raising awareness among healthcare providers and increasing uptake of Trudhesa. The market is large and growing strongly. However, there is still a significant unmet need as evidenced by the considerable churnover with existing treatments. This represents a tremendous opportunity for Trudhesa given its efficacy and tolerability profile.

OSP: Do you have anything to add?​

AA: There is a great deal of competition in this space, but we do believe Trudhesa 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.

Impel continues to advance its combination product candidate, INP105, an intranasal olanzapine product (a widely used atypical, second-generation antipsychotic) being developed as an acute treatment for agitation in persons with autism spectrum disorder via Impel’s POD technology. Since filing the investigational new drug application in November of last year, the company has been working with the FDA to finalize the Phase IIa proof-of-concept clinical protocol and anticipates the study will start in H1 2022 with data readout anticipated at the end of 2022 or early 2023.