Impact and Burden of Episodic, Acute Migraine (I-BEAM): A Patient Experience Study

Poster presented at the International Headache Congress (IHC) 2019 in Dublin, Ireland.

Authors: Stephen B. Shrewsbury, Sutapa Ray

Objective:

The objectives of this patient survey were to better understand: 1) the experiences of episodic migraineurs and the effect of migraine on daily life; 2) the typical pathway and barriers to diagnosis and treatment; and 3) satisfaction levels with current treatments and to identify unmet needs.

Methods:

Participants were recruited via social media and referrals. A preliminary 15-minute online survey was conducted with current migraine sufferers to determine history, past and current treatments, and overall experience with migraine treatments. One hour individual-depth interviews (IDIs) were conducted with respondents in three major U.S. cities, and 1-hour web-enabled telephone-depth interviews (TDIs) were conducted with others throughout the United States.

Results:

Of study participants (n=50), 75% were female, 64% were aged 30-49 years, and 56% suffered from 3-5 migraines or 4-8 migraine-days a month. The two most common types of migraines reported were rapid-onset migraine (34%) and early morning migraines (30%). Although 96% took a prescription medication for migraines, only 30% were satisfied with their medication. Incomplete, unreliable and short lasting relief were cited as the biggest problems. Lack of speed to onset of effect was also a point of dissatisfaction with >50% reporting inability to resume normal activities within 4 hours after medicating. Up to 68% reported headache relief lasting less than 12 hours and pain returning or worsening afterwards. Further, 30% respondents had to seek emergency migraine care in the past year despite access to standard of care. Thus, the social, societal and economic burden of episodic migraine significantly impacts the daily lives and livelihoods of patients with migraine.

Conclusion:

This study further demonstrates the unmet needs of current episodic migraineurs. Patients described their ideal medication to be: (1) fast acting (15-30 mins) (2) long-lasting (12-24h) (3) providing complete or near complete relief (4) can be taken any time during the migraine and (5) with few or no side effects. Many are willing to accept minor side effects as a tradeoff for increased speed and efficacy. A product is being developed by Impel NeuroPharma to address all 5 of these requirements.

Citation:

Shrewsbury SB and Ray, Impact and Burden of Episodic, Acute Migraine (I-BEAM): A Patient Experience Study, IHC 2019 Abstracts. (2019). Cephalalgia, 39(1_suppl), 124-125. https://doi.org/10.1177/0333102419859835

Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration

Poster presented at the International Headache Congress (IHC) 2019 in Dublin, Ireland.

Authors: Kelsey H. Satterly, Stephen B. Shrewsbury, John Hoekman

Objective:

To compare plasma exposure in the first two hours following administration of INP104 (dihydroergotamine mesylate [DHE] by Precision Olfactory Delivery [POD®]), Migranal® Nasal Spray, D.H.E. 45® (IV) or MAP0004 (oral inhalation) using data obtained from the STOP 101 study and literature reports. IV DHE is a reliable and effective treatment for migraine approved in the US since 1946. DHE plasma exposure in the first 2 hours is critical to migraine pain relief, justifying an emphasis on AUC0–2hr when assessing novel DHE products. Although Cmax is also important for efficacy, research suggests that the high Cmax of IV administration may predict a higher rate of adverse events. INP104, a novel drug-device combination product in Phase 3 clinical development, targets delivery of a liquid DHE formulation to the upper nasal cavity using the POD device.

Methods:

PK results from STOP 101, a Phase 1, single dose, safety, tolerability, and bioavailability study in healthy subjects who received INP104 (1.45 mg), Migranal (2 mg), or D.H.E. 45 (IV) (1 mg) in a 3-way, 3-period crossover were compared. Trends of DHE PK, efficacy, and adverse events related to AUC0-2hr and Cmax reported in the literature were reviewed and are described.

Results:

AUC0-2hr following administration of INP104, Migranal, and D.H.E. 45 (IV) was 1,603, 387.5, and 3,022 hrpg/mL, respectively, in the STOP 101 trial. Cmax values were highest following IV DHE (14,190 pg/mL), then INP104 (1,301 pg/mL) and Migranal (299.6 pg/mL). A literature report of MAP0004 (1 mg), clinically developed but never marketed due to CMC challenges, states an AUC0-2hr value of 1,447 hrpg/mL. Another MAP0004 literature report describes onset of pain relief in migraineurs as early as 10 minutes and only 1 incidence of nausea. Lastly, a review of the literature suggests that the probability of nausea is <2% when plasma DHE Cmax is ≤5,000 pg/mL, whereas at 13,400 pg/mL, the probability of nausea is ≥50%.

Conclusion:

INP104 administration results in high plasma exposure to DHE in the first 2 hours, a goal for acute migraine products to enable rapid and sustained pain relief, as validated by the MAP0004 clinical program. Further, the significant reduction in Cmax of DHE following INP104 treatment, relative to IV, may lead to more favorable tolerability of INP104.

Citation:

Satterly KH, Shrewsbury SB, and Hoekman J.  Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration IHC 2019 Abstracts. (2019). Cephalalgia, 39(1_suppl), 33-34. https://doi.org/10.1177/0333102419859835

A History of Dihydroergotamine in Migraine

Poster presented at the International Headache Congress (IHC) 2019 in Dublin, Ireland.

Authors: Sutapa Ray, Stephen Shrewsbury

Objective:

Ergot use in obstetrics dates back to 1100 BC in China, 370 BC by Hippocrates and 1808 in the US. However, it was not until 1918 that ergotamine was isolated, subsequently modified to DHE and approved in 1946 for the treatment of migraine. For the next 40 years, DHE was available as the most specific, acute anti-migraine therapy until the advent of the Triptans. DHE is still used today, available in multiple formulations and remains a dependable choice for Neurologists and Headache specialists for acute migraine, status migrainosus and cluster headache. This work provides a history of dihydroergotamine (DHE) treatment from its synthesis in 1943 from ergotamine to modern day formulations and routes of administration.

Methods:

A primary literature review was conducted of the PubMed database for the study period (1946–2018) and seminal studies identified following methods similar to Tfelt-Hansen and Koehler, 2011. Market research data was also analyzed.

Results:

A timeline of major landmarks in the development and clinical use of DHE was identified and is presented. Despite sophisticated biologic treatments for migraines, DHE remains a leading treatment in migraine clinics for intractable migraines via the intravenous route of administration. The supportive body of clinical evidence for DHE is vast and impressive and suggests a risk profile that some consider as good as the triptans. Recent research and development efforts to provide improved bioavailability and consistency of DHE via the novel upper nasal cavity route may at last bring the benefits of IV DHE to patients and physicians via self-administered, in-home treatment.

Conclusion:

DHE has accumulated over 70 years of clinical practice data showing that it is a safe and reliable treatment when delivered consistently at adequate dose levels for acute migraines providing rapid and sustained relief, even when other options have failed.

Citation:

Ray S and Shrewsbury SB. A History of Dihydroergotamine in Migraine IHC 2019 Abstracts. (2019). Cephalalgia, 39(1_suppl), 141-142. https://doi.org/10.1177/0333102419859835

Impel NeuroPharma Announces Appointment of Diane Wilfong To Board of Directors

SEATTLE, October 17, 2019 Impel NeuroPharma, a late-stage biopharmaceutical company focused on the development and commercialization of transformative therapies for patients living with central nervous system (CNS) disorders with high unmet medical needs, today announced that Diane Wilfong has been appointed to the Company’s board of directors. Diane brings 30 years of financial and operations experience in large, multinational companies, including most currently serving as Senior Vice President, Controller and Chief Accounting Officer of Gilead Sciences Inc.

“Impel is rapidly advancing a late-stage pipeline of therapies for CNS disorders with high unmet medical needs, all of which are the result of over a decade of pioneering a unique approach to drug delivery,” said Jon Congleton, President and Chief Executive Officer of Impel. “We are pleased to welcome Diane to Impel’s board, and we look forward to leveraging her dynamic leadership experience and extensive background in finance as we continue to grow into a fully integrated R&D and commercial organization.”

Prior to joining Gilead in 2016, Diane was Vice President, Controller and Principal Accounting Officer at CSC (Computer Sciences Corporation), an IT consulting services company now known as DXC. From 2009 to 2014, she led the accounting and tax functions at Caesars Entertainment (formerly Harrah’s Entertainment) and spearheaded a major financial transformation initiative along with key elements of a public offering, and was responsible for Sarbanes-Oxley compliance in her role. Prior, Diane spent 10 years at Eastman Kodak Company in a series of executive, operational and financial roles, including serving as General Manager of the company’s Graphics and Printing Systems group, and later as the Corporate Controller and Chief Accounting Officer. Prior to Kodak, she held positions at Corning and at Price Waterhouse.

“I am quite impressed with Impel’s clinical progress and believe the current pipeline, enabled by Impel’s proprietary POD® technology, has the potential to redefine what rapid and consistent symptomatic relief means to patients living with serious conditions such as migraine, Parkinson’s disease and mental health disorders,” said Diane. “I look forward to collaborating closely with the Impel team and the board of directors as the Company continues to advance its late-stage clinical programs.”

Diane, a Certified Public Accountant, is a graduate of the University of North Carolina at Chapel Hill with a degree in business administration and accounting.

About Impel NeuroPharma

Impel NeuroPharma, Inc., is a privately-held, Seattle-based biopharmaceutical company devoted to creating life-changing, innovative therapies for central nervous system (CNS) diseases. Impel NeuroPharma is currently investigating INP104 (POD-DHE) for acute migraine headache, INP103 (POD-levodopa) and INP107 (POD-carbidopa/levodopa) for reversal of OFF episodes in Parkinson’s disease and INP105 (POD-olanzapine) for acute agitation in schizophrenia and bipolar I disorder.

Impel’s product candidates are delivered via its proprietary Precision Olfactory Delivery, or POD®, technology which targets the richly vascularized upper nasal cavity with the goal of achieving enhanced bioavailability of therapeutic molecules.

IMPEL, POD and the IMPEL Logo are trademarks of Impel NeuroPharma, Inc. To learn more about Impel NeuroPharma, please visit our website at https://impelnp.com.

About Precision Olfactory Delivery or POD® Devices

Impel NeuroPharma’s proprietary POD® nasal drug delivery device is designed to deliver drugs to the richly-vascularized upper nasal cavity to improve biodistribution and bioavailability of both small molecules and biologic drugs. By consistently and predictably delivering therapeutics to the upper nasal cavity, the POD device may improve overall bioavailability of drugs without IV injection. Impel has developed dry powder and liquid compatible POD devices to improve upon current treatment options for central nervous system (CNS) disorders.

Contact:

Melyssa Weible

Elixir Health Public Relations

Ph: (1) 201-723-5805

E: mweible@elixirhealthpr.com

STOP 301: Open-label Safety and Tolerability of Chronic Intermittent Usage for 24/52 Weeks of INP104 [Nasal DHE Administered by POD Device] in Migraine

Poster presented at International Headache Congress (IHC) 2019 in Dublin, Ireland

Authors: Stephen B. Shrewsbury, Maria Jeleva, Jasna Hocevar-Trnka, Meghan Swardstrom

Objective:

1) Establish safety and tolerability of repeated INP104 exposure 2) Explore efficacy of INP104 in migraineurs (compared to baseline) 3) Explore INP104 effects on Quality of Life and Healthcare Utilisation during the 24/52 weeks.

Methods:

~300 patients will enter the 24-week study, with ~80 enrolling into a further 28-week treatment period. Main inclusion criteria: 18 to 65 years; migraine with or without aura, ³2 attacks/month for previous 6 months; >80% e-dairy compliance; contracepting. Main exclusion criteria: trigeminal autonomic cephalalgias; migraine aura without headache, hemiplegic migraine or migraine with brainstem aura; chronic migraines, medication overuse headache or other chronic headache syndromes; status
migrainosus; coronary artery disease (CAD) or significant risk of CAD; abnormal, clinically significant laboratory tests at screening; recent acute illness or uncontrolled infection; recurrent sinusitis or epistaxis; significant pre-existing nasal disease or upper space mucosal abnormality; excessive triptan or ergot use; significant use of barbiturates or opiates in 2 months prior or during screening. All subjects will have extensive migraine history, healthcare utilization and quality of life assessments conducted during screening and treatment response recorded in an e-diary. Olfactory mucosal integrity and function will be collected by endoscopy of the upper
(and lower) nasal spaces and by University of Pennsylvania Smell Identification Test (UPSIT) at intervals.

Results:

As a result of the strategic considerations and to achieve the objectives of the study, the study design was formulated (see
image).

Conclusion:

STOP 301 is designed to assess safety, tolerability and explore efficacy of repeat administration of DHE drug to the
upper nasal space.

Citation:

Shrewsbury SB, Jeleva M, Hocevar-Trnka J and Swardstrom M. STOP 301: Open-label Safety and Tolerability of Chronic Intermittent Usage for 24/52 Weeks of INP104 [Nasal Dihydroergotamine Mesylate (DHE) Administered by Precision Olfactory Delivery (PODTM) Device] in Migraine Headache IHC 2019 Abstracts. (2019). Cephalalgia, 39(1_suppl), 208-209. https://doi.org/10.1177/0333102419859835

Impel NeuroPharma To Present Data From INP104 Clinical Program At The 19th Congress of the International Headache Society

The Safety & Tolerability of INP104 is Currently Being Evaluated in the Company’s Recently Fully-Enrolled Pivotal Phase 3 “STOP-301” Trial

New Data from a Patient Experience Survey Describe Dissatisfaction Levels with Current Available Treatments & Desire for New Options That Offer More Rapid & Complete Relief of Migraine Symptoms with a Lower Side Effect Profile

SEATTLE, September 5, 2019 Impel NeuroPharma, a late-stage biopharmaceutical company focused on the development and commercialization of transformative therapies for patients living with central nervous system (CNS) disorders with high unmet medical needs, today announced that it will present four scientific abstracts at the 19th Congress of the International Headache Society (IHC) being held September 5 – 8, 2019 in Dublin, Ireland.

“Our growing body of evidence supports the potential of INP104 to be a transformative new therapy for acute migraine. INP104 utilizes our sophisticated and proprietary new device technology to deliver optimal doses of dihydroergotamine (DHE) to the vascular-rich upper nasal cavity, resulting in peak drug concentration levels that may be more effective for patients,” said Stephen B. Shrewsbury, M.D., Chief Medical Officer of Impel NeuroPharma. “Importantly, because INP104 is designed to deliver a reduced dose of DHE compared to FDA-approved and investigational products in development, patients may be able to reap the established efficacy benefits of DHE, without the undesired side effects that are typically experienced with delivery to the lower nasal space.”

The meeting abstracts will be published in digital format within the official abstract book of the meeting which can be accessed on the IHC meeting website at http://www.ihc2019.com. Presented abstracts will also be published in Cephalalgia.

Four Impel-sponsored posters, including new findings from the I-BEAM patient experience and satisfaction survey, will be presented on Saturday, September 7 between 2:45-3:45 pm IST:

  • STOP 301: Open-label Safety and Tolerability of Chronic Intermittent Usage for 24/52 Weeks of INP104 [Nasal Dihydroergotamine Mesylate (DHE) Administered by Precision Olfactory Delivery (POD®) Device] in Migraine Headache [IHC-PO-377]
  • Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration [IHC-DP-036]
  • A History of Dihydroergotamine in Migraine [IHC-PO-323]
  • Impact and Burden of Episodic, Acute Migraine (I-BEAM): A Patient Experience Study [IHC-PO-299]

These data that will be presented at the meeting to support the ongoing “STOP-301 Trial” (Safety and Tolerability of POD-DHE), a Phase 3, open-label safety and tolerability trial evaluating long-term (24/52 week), intermittent use of INP104 for the treatment of acute migraine.

About INP104

INP104 is a drug-device combination product being studied for the treatment of acute migraine. It is comprised of a nasal formulation of dihydroergotamine (DHE) and Impel’s proprietary Precision Olfactory Delivery, or POD®, device. The family of POD devices are designed to deliver consistent and predictable doses of drug. INP104, an investigational new drug, delivers DHE to the richly vascularized upper nasal cavity, offering the potential for rapid and consistent biodistribution without injection. DHE is an established and highly effective treatment option for acute migraine treatment.

About Acute Migraine

Migraine is a common and debilitating neurological disease characterized by recurrent episodes of severe head pain and associated with nausea, vomiting, sensitivity to light and to sound. Migraine affects approximately 39 million people in the United States. Of the approximately 19 million diagnosed migraine patients, only four million are on prescription treatment. While triptans account for almost 70 percent of migraine therapies, approximately 30 to 40 percent of patients do not respond adequately to triptans and up to 79 percent of the treated patients report being dissatisfied with their current treatment and willing to try a new therapy. 

About Impel NeuroPharma

Impel NeuroPharma, Inc., is a privately-held, Seattle-based biopharmaceutical company devoted to creating life-changing, innovative therapies for central nervous system (CNS) diseases. Impel NeuroPharma is currently investigating INP104 (POD-DHE) for acute migraine headache, INP103 (POD-levodopa) and INP107 (POD-carbidopa/levodopa) for reversal of OFF episodes in Parkinson’s disease and INP105 (POD-olanzapine) for acute agitation in schizophrenia and bipolar I disorder.

Impel’s product candidates are delivered via its proprietary Precision Olfactory Delivery, or POD®, technology which targets the richly vascularized upper nasal cavity with the goal of achieving enhanced bioavailability of therapeutic molecules.

IMPEL, POD and the IMPEL Logo are trademarks of Impel NeuroPharma, Inc. To learn more about Impel NeuroPharma, please visit our website at https://impelnp.com.

About Precision Olfactory Delivery or POD® Devices

Impel NeuroPharma’s proprietary POD® nasal drug delivery device is designed to deliver drugs to the richly-vascularized upper nasal cavity to improve biodistribution and bioavailability of both small molecules and biologic drugs. By consistently and predictably delivering therapeutics to the upper nasal cavity, the POD device may improve overall bioavailability of drugs without IV injection. Impel has developed dry powder and liquid compatible POD devices to improve upon current treatment options for central nervous system (CNS) disorders.

Contact:

Melyssa Weible

Elixir Health Public Relations

Ph: (1) 201-723-5805

E: mweible@elixirhealthpr.com

Impel NeuroPharma Announces Last Patient Enrolled In Phase 3 Trial Evaluating INP104 For The Treatment Of Acute Migraine

Top-line Results of the STOP-301 Trial Evaluating the Safety and Tolerability of Long-term, Intermittent Use of INP104 Anticipated Early 2020

Pending Complete Review of the Data, Submission of a New Drug Application Anticipated in Second Half of 2020

SEATTLE, September 3, 2019 Impel NeuroPharma, a late-stage biopharmaceutical company focused on the development and commercialization of transformative therapies for patients living with central nervous system (CNS) disorders with high unmet medical needs, today announced the last patient has been enrolled in “STOP-301” (Safety and Tolerability of POD-DHE), the Company’s pivotal open-label Phase 3, multi-use, long-term safety and tolerability of INP104 for the treatment of acute migraine.

STOP-301 is evaluating the safety of long-term, intermittent use of INP104 for 24-week and 52-week data points and will also collect efficacy data of INP104 as assessed by change from baseline in migraine measures during the course of the study. Following a four-week screening period, a total of 360 patients have been enrolled in the study. A subset of 73 patients will continue into a 28-week treatment extension period and a two-week post-treatment follow-up period. There are currently 36 sites in the United States with patients enrolled in the study.

“INP104 has the potential to provide IV-like dihydroergotamine (DHE) effects in the home with rapid onset and long-lasting benefits because it reaches the vascular rich upper nasal cavity, an emerging new area of the body for drug administration,” said Stephen B. Shrewsbury, M.D., Chief Medical Officer of Impel NeuroPharma. “Although the use of DHE has been limited due to route of administration, it remains a trusted treatment for acute migraine in headache clinics. Importantly, because INP104 is designed to provide consistent delivery of DHE, it can be used anytime and anywhere by the patient. We look forward to sharing the top-line results of STOP-301 in early 2020.”

INP104 is a DHE product dosed via Impel’s proprietary Precision Olfactory Delivery, or POD®, nasal drug delivery device. DHE was first introduced in 1946, and over time, has demonstrated to be a safe and effective treatment for acute migraine, with a consistent response to intravenous administration. Based on discussions with the FDA, this pivotal Phase 3 safety study for INP104 and a previously completed comparative bioavailability trial between INP104, IV DHE and Migranal are the final clinical requirements to file a New Drug Application (NDA) for INP104. Pending complete review of the clinical study data, the Company expects to be in a position to file a NDA in the second half of 2020.

About INP104

INP104 is a drug-device combination product being studied for the treatment of acute migraine. It is comprised of a nasal formulation of dihydroergotamine (DHE) and Impel’s proprietary Precision Olfactory Delivery, or POD®, device. The family of POD devices are patient-friendly, simple-to-use and designed to deliver consistent and predictable doses of drug. INP104, an investigational new drug, delivers DHE to the richly vascularized upper nasal cavity, offering the potential for rapid and consistent biodistribution without injection. DHE is an established and highly effective treatment option for acute migraine treatment.

About Acute Migraine

Migraine is a common and debilitating neurological disease characterized by recurrent episodes of severe head pain and associated with nausea, vomiting, sensitivity to light and to sound. Migraine affects approximately 39 million people in the United States. Of those diagnosed, only four million are on prescription treatment. While triptans account for almost 70 percent of migraine therapies, approximately 30 to 40 percent of patients do not respond adequately to triptans and up to 79 percent of the treated patients report being dissatisfied with their current treatment and willing to try a new therapy. 

About Impel NeuroPharma

Impel NeuroPharma, Inc., is a privately-held, Seattle-based biopharmaceutical company devoted to creating life-changing, innovative therapies for central nervous system (CNS) diseases. Impel NeuroPharma is currently investigating INP104 (POD-DHE) for acute migraine headache, INP103 (POD-levodopa) and INP107 (POD-carbidopa/levodopa) for reversal of OFF episodes in Parkinson’s disease and INP105 (POD-olanzapine) for acute agitation in schizophrenia and bipolar I disorder.

Impel’s product candidates are delivered via its proprietary Precision Olfactory Delivery, or POD®, technology which targets the richly vascularized upper nasal cavity with the goal of achieving enhanced bioavailability of therapeutic molecules.

IMPEL, POD and the IMPEL Logo are trademarks of Impel NeuroPharma, Inc. To learn more about Impel NeuroPharma, please visit our website at https://impelnp.com.

About Precision Olfactory Delivery or POD® Devices

Impel NeuroPharma’s proprietary POD® nasal drug delivery device is designed to deliver drugs to the richly-vascularized upper nasal cavity to improve biodistribution and bioavailability of both small molecules and biologic drugs. By consistently and predictably delivering therapeutics to the upper nasal cavity, the POD device may improve overall bioavailability of drugs without IV injection. Impel has developed dry powder and liquid compatible POD devices to improve upon current treatment options for central nervous system (CNS) disorders.

Contact:

Melyssa Weible

Elixir Health Public Relations

Ph: (1) 201-723-5805

E: mweible@elixirhealthpr.com

Comparison of Early Plasma Exposure of DHE following Delivery by Nasal, Oral Inhalation, or Intravenous Administration

Poster presented at AHS 2019 Annual Meeting, poster #P134, selected for oral presentation.

Authors: Kelsey Satterly, Stephen Shrewsbury, John Hoekman

Background: 

The objective of this study is to compare plasma exposure in the first two hours following administration of dihydroergotamine mesylate (DHE) by INP104 (POD® nasal), Migranal® Nasal Spray, D.H.E. 45® (IV) or MAP0004 (oral inhalation) using data obtained from the STOP 101 study and literature reports. IV DHE is a reliable and effective treatment for migraine approved in the US in 1946 (Silberstein and Kori, 2013). DHE plasma exposure in the first 2 hours is critical to migraine pain relief (FDA guidance; Kellerman, 2013), justifying an emphasis on AUC0–2hr and Cmax when assessing novel DHE products. Further, while the Cmax is important for efficacy, research suggests that a high Cmax may predict a high rate of adverse events (Shrewsbury, 2008; Jividen, 2011; Silberstein, 2014). INP104, a novel drug-device combination product in Phase 3 clinical development, targets delivery of a liquid DHE formulation to the upper nasal cavity using the Precision Olfactory Delivery (POD®) device.  

Methods:  

(1) PK results from STOP 101, a Phase 1, single dose, safety, tolerability, and bioavailability study of healthy subjects who received INP104 (1.45 mg), Migranal Nasal Spray (2.0 mg), or D.H.E. 45 IV (1.0 mg) in a 3-way, 3-period crossover were compared.  

(2) Trends of DHE PK, efficacy, and adverse events related to Cmax reported in the literature were studied and are described. 

Results: 

AUC0-2hr following administration of INP104 (1.45 mg), Migranal (2 mg), and D.H.E 45 (1 mg IV) was 1603, 387.5, and 3022 hr*pg/mL, respectively, in the STOP 101 trial. Cmax values were highest following D.H.E. 45 (IV) at 14190 pg/mL followed by INP104 at 1301 pg/mL and Migranal at 299.6 pg/mL. A literature report describing the PK of orally inhaled DHE 1 mg (MAP0004: clinically developed but never marketed due to CMC challenges) states an AUC0-2hr value of 1447 hr*pg/mL (Kellerman, 2013). Further, research from a Phase 2 trial with MAP0004 reports onset of pain relief in migraineurs as early as 10 minutes and only 1 incidence of nausea (Aurora, 2009). Lastly, a review of the literature suggests that the probability of nausea is <2% when plasma DHE Cmax is ≤5,000 pg/mL, and at 13,400 pg/mL, the probability of nausea is ≥50% (Jividen, 2011; Silberstein, 2014).  

Conclusions: 

Delivery of INP104, DHE by the POD device, results in high plasma exposure to DHE in the first 2 hours, a goal for acute migraine products to enable potential pain relief. Further, an approximate 10-fold reduction in Cmax following DHE administration by INP104 may lead to more favorable tolerability compared to IV DHE. 

References 

Aurora SK, Rozen TD, Kori SH, Shrewsbury SB. Headache, 2009; 49:826-837. 

FDA Guidance for Industry: Migraine: Developing Drugs for Acute Treatment. February 2018. 

Kellerman DJ, Forst A, Combs DL, Borland S, Kori S. J Aer Med Pul Drug Del., 2013; 26(5): 297-306. 

Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. Headache, 2019; 0:1-16. 

Shrewsbury S, Cook RO, Taylor G, Edwards C, Ramadan NM. Headache, 2008; 48: 355-367. 

Silberstein S. Expert Opinion on Pharmacotherapy, 2012; 13:13, 1961-1968. 

Jividen H. Nausea associated with DHE is a function of maximum concentration and not route of administration. 53rd Annual Meeting of the American Headache Society, Washington, DC, June 2-5, 2011. 

Silberstein SD, Basile AS, Kellerman D, Davar G. Relationship between plasma dihydroergotamine concentrations and the occurrence of nausea after treatment with orally inhaled DHE. 56th Annual Meeting of the American Headache Society, Los Angeles, June 26-29, 2011.