Semprana (dihydroergotamine oral inhalation) / AbbVie - LARVOL DELTA

Pharmacokinetic Comparison of STS101 (A Novel Investigational DHE Nasal Powder) with Liquid Nasal, Injectable and Oral Inhaled DHE Formulations (AAN 2022) - "Cmax and early exposure levels may be important for efficacy at 2 hrs. STS101 demonstrated greater PK values and less PK variability compared to the approved DHE LNSs. As compared with MAP0004, STS101 achieved similar Cmax, higher AUC at all time points after ~30 minutes and similar PK variability."

PK/PD data • CNS Disorders • Migraine

[VIRTUAL] The Efficacy of Dihydroergotamine versus Emerging Acute Migraine Medications (AHS 2020) - " Efficacy data from Phase 3 studies with orally inhaled dihydroergotamine (DHE, MAP0004), lasmiditan 200 mg, rimegepant 75 mg, rimegepant ODT 75 mg and ubrogepant 100 mg were compared. Orally inhaled DHE demonstrated superior anti-migraine efficacy compared to emerging treatments. However, DHE use has been limited by route of administration and/or performance of approved dosage forms. Newer investigational products, such as STS101 (intranasal DHE powder), that demonstrate Cmax and drug exposure comparable to or greater than MAP0004, may overcome these limitations and provide more consistent and reliable clinical performance."

Clinical • CNS Disorders • Migraine • Pain

Inhaled Drug Therapy Development for the Treatment of Migraine. (PubMed) - Expert Opin Pharmacother - "Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at anti-migraine serotonergic receptors 5-HT1B and 5-HT1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. Inhaled therapy clearly offers rapid systemic absorption but this route of delivery may not be appropriate for every drug. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes."

Journal • Biosimilar • Migraine • Pain

Reduced efficacy of sumatriptan in migraine with aura vs without aura. (PubMed) - "This post hoc analysis of pooled data from multiple randomized trials indicates that sumatriptan is less effective as acute therapy for migraine attacks with aura compared with attacks without aura. In the single study of inhaled DHE, the treatment had similar efficacy for migraine attacks with and without aura. Different responses of migraine with vs without aura to acute therapies may provide insight into underlying migraine mechanisms and influence the choice of acute therapies for different types of migraine attacks."

Journal • Biosimilar • Migraine • Pain

Pharmacokinetic Comparison of STS101, an Intranasal Dry Powder Formulation of Dihydroergotamine, with Other Intranasal, Injectable and Oral Inhaled DHE Formulations (AAN 2020) - "Design/ A literature search was performed to compare PK results of several formulations of DHE including the approved products Migranal and D.H.E.45 and the development-stage products INP104 (liquid nasal spray), MAP0004 (orally inhaled), and STS101 (nasal powder). The STS101 PK profile predicts that the acute migraine treatment goals should be achieved. Lower PK variability may lead to more consistent and reliable clinical performance. A large Phase 3 efficacy study with STS101 is ongoing to evaluate the product as an acute treatment for migraine (NCT 03901482)."

PK/PD data • CNS Disorders • Migraine

Allergan's Semprana and CoLucid's lasmiditan, two novel acute migraine therapies, will drive market growth through 2023 (PRNewswire) - "Decision Resources Group finds that the overall migraine market will grow from approximately $3 billion in 2013 to over $5 billion in 2023 in the United States, France, Germany, Italy, Spain, United Kingdom and Japan, with an average annual growth rate of 5.8 percent. This growth will occur mainly in the second half of the 2013-2023 forecast period and will be driven largely by the launch of two nontriptan acute therapies: Allergan's orally inhaled dihydroergotamine product Semprana (launching in the United States in 2016), and CoLucid's 5HT1F receptor agonist lasmiditan (launching in the major markets beginning in 2018)."

Anticipated launch • Anticipated sales • Migraine

Allergan: Annual Report 2014 (Allergan) - Anticipated expiry of patent in US between 2024 and 2031

Anticipated patent expiry • Migraine

Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: A randomized, double-blind, active- and placebo-controlled crossover study in healthy volunteers (Clin Ther) - P1, N=54; NCT01191723; The largest observed mean difference in QTcI between MAP0004 and PBO was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing; In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to PBO, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects

P1 data • Migraine

Allergan: Q4 2015 Results (Allergan) - Anticipated NDA submission in US for acute migraine in H2 2016

Anticipated NDA • Migraine

MAP Pharma: J.P. Morgan Healthcare Conference (MAP Pharmaceuticals) - "FREEDOM-301: Met All Four Co-Primary Endpoints"; AE's reported by at least 2% of LEVADEX patients and greater than placebo"

P3 data • Migraine

MAP Pharmaceuticals resubmits New Drug Application to FDA for LEVADEX orally inhaled migraine drug (MAP Pharmaceuticals) - “MAP Pharma has resubmitted...NDA...for Levadex...migraine in adults...Complete Response letter received in Mar 2012”

NDA • Migraine

Efficacy of MAP0004 in treating severe migraine (PAINWeek 2012) - P3, N=794; FREEDOM301; Severe baseline pain was reported in 366 of the 794 subjects; Subjects with severe migraine pain treated with MAP0004 experienced pain relief (p<0.05) as early as 10 minutes and at all subsequent prescheduled evaluation time points compared to PBO; These subjects were pain free (p<0.05) by 60 minutes and at all subsequent time points following treatment compared to PBO

P3 data • Migraine

Allergan receives Complete Response Letter from the US Food and Drug Administration for Levadex (dihydroergotamine) New Drug Application (Allergan) - "Allergan...announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to its New Drug Application (NDA) for Levadex (dihydroergotamine) inhalation aerosol for the acute treatment of migraine in adults...In addition to the response, the company has already received draft labeling from the FDA. Allergan anticipates minimal revisions to this labeling...Company estimates that the next FDA action will occur by the end of Q4 2013."

Anticipated FDA event • FDA event • Migraine

Allergan: Q3 FY 2016 Results (Allergan) - Anticipated regulatory submission in US for migraine in H2 2017

Anticipated NDA • Migraine

A CGRP receptor antagonist and dihydroergotamine (DHE) reduce migraine-like behaviors in a rat multisymptom model of migraine (Neuroscience 2012) - Presentation time: Saturday, Oct 13, 2012, 2:00 PM - 3:00 PM; The CGRP receptor antagonist MK-8825 was given ip 30mg/kg 60 min prior to IS application; DHE was given iv 100 microg/kg 30-60 min prior to IS on days 1-4 and 1mg/kg sc on day 5; Neither drug altered activity, reduced light or sound avoidance, but both drugs had effects in the allodynia task, reducing the latency to the first grooming event

Preclinical-animal • Migraine

A drug interaction study assessing the effects of CYP3A4 inhibition on the pharmacokinetics of MAP0004, an orally inhaled formulation of dihydroergotamine in healthy volunteers (AAN 2012) - Presentation time: Tuesday, April 24, 2012 2:00 PM; P1, N=24; CYP3A4 inhibition had no apparent effect on MAP0004 Cmax or elimination; The potential for CYP3A4 inhibition to enhance or prolong the pharmacologic effects of MAP0004 or its primary metabolite appeared minimal

P1 pharmacokinetic data • Migraine

MAP confident in Levadex, plans swift response to FDA (The Wall Street Journal) - The FDA in its letter, said it hadn't had sufficient time to review additional usability data it requested, and MAP provided, late in the review process; Executives said they believed MAP has already provided the information the regulator was looking for and didn't foresee any need to change the inhaler

Company Statement • FDA statement • Migraine

MAP Pharma: Preparing to ease regulatory pain of migraine drug (RTTNews) - MAP is ready to play its part of making resubmission for the inhalation aerosol; Based on its meeting with the FDA, the NDA will be resubmitted in the late Q3 Q4 2012; The FDA will determine the type of resubmission (Class 1 or Class 2) and the resulting review timeline after the resubmission has been accepted for filing; $60M up-front payment and up to $97M in additional payments upon meeting certain regulatory milestones

Anticipated financing • Anticipated NDA • Migraine

MAP Pharmaceuticals announces FDA acceptance for filing of NDA resubmission for Levadex (MAP Pharmaceuticals) - "MAP Pharmaceutical's NDA resubmission for Levadex, orally inhaled migraine drug for potential acute treatment of migraine in adults...accepted for filing by FDA...FDA has set Apr 15, 2013...as PDUFA data."

NDA • PDUFA date • Migraine

Allergan’s Botox, MAP’s Levadex for migraines a near match made in heaven, some caveats exist – Experts (Ft) - MAP has said it plans to refile its NDA in 2012, FDA has also requested existing inhaler usability data; Levadex label will likely indicate it for abortive treatments with migraines with or without auras

Anticipated NDA • Clinical protocol • Migraine

MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: Efficacy of early and late treatments (Mayo Clin Proc) - P3, N=1,195; MAP0004 CL P301; Treatment with MAP0004 was more effective than PBO in relieving pain at all treatment points (≤1 hr after start of migraine: 66% for MAP0004 vs 41% for PBO, p1 to ≤4 hrs: 60% vs 35%, p4 to ≤8 hrs: 53% vs 30% , p=0.008; & >8 hrs: 48% vs 24%, p=0.007); Pain-free rates were also higher with MAP0004 than PBO for treatment within 8 hours after migraine onset (≤1 hr: 38% for MAP0004 vs 13% for PBO, p1 to ≤4 hrs: 28% vs 10% p4 to ≤8 hrs: 22% vs 7%, p8 hrs (19% vs 9%, p=0.106)

P3 post hoc analysis • Migraine

Complete response for MAP’s Levadex could add year to approval: Analyst (WCG’s FDAnews) - The FDA’s complete response letter for MAP Pharmaceuticals’ migraine drug Levadex could tack on another year before approval, but the company says the letter should be fairly easy to deal with; The letter asks the company to address some chemistry, manufacturing and controls issues related to processes and process controls

Anticipated market approval • Migraine

Allergan Announces R&D Pipeline Update and U.S. FDA Approval; Company to Host Conference Call Today, Monday, June 30th at 10:30 AM ET (Allergan Press Release) - "Allergan has received a Complete Response Letter (CRL) from the FDA to its New Drug Application (NDA) for SEMPRANA™ (dihydroergotamine), formerly referred to as LEVADEX...FDA acknowledged that Allergan has made improvements in the canister filling process...estimates that the next FDA action will occur by the end of the second quarter of 2015."

FDA event • Migraine

MAP pharmaceuticals issued additional U.S. patent for methods of achieving rapid treatment of migraine based upon pharmacokinetic profile (Reuters) - MAP Pharmaceuticals announced that United States Patent and Trademark Office (USPTO) issued to the company U.S. Patent No. 8,119,639, titled "Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile"

Patent issuance • Migraine

MAP Pharmaceuticals reports second quarter of 2011 financial results (PRNewswire) - MAP Pharmaceuticals R&D expenses for three & six months ended June 30, 2011 were $7.3M & $18.8M respectively, compared to $8.2M & $18.0 M respectively, for the same periods in 2010; The decrease was primarily due to a decrease in clinical & other project expenses to support the Levadex P3 clinical program

H1 financial results • Q2 '11 financial results • Migraine