The nasal mucosa - Fitonasal 2Act Page 1 of 2 How does the nose work?

Underneath the epithelium is a dense network of capillary blood vessels.

The nasal mucosa is essential to correct operation of the entire respiratory system.

The nose works as it does thanks to various defensive mechanisms: its epithelium and dense network of capillaries, its mucus, the vibrating cilia which move the mucus, the cells of the immune system and many substances capable of combating bacteria and viruses and harmful substances.

The nasal mucosa - Fitonasal 2Act Page 2 of 2 The mucus traps harmful substances (viruses, bacteria, dust, pollens, etc.) on the surface of the mucosa and the vibratory cilia move the mucus toward the pharynx to eliminate it.

In 2001, I founded Hananja ehf, an Icelandic entity accredited by the European Union and a specialty biopharmaceutical company focused on discovery and development of innovative treatments for life-threatening diseases, specifically nasal spray drug products.

The physiological constraints of active ingredient uptake due to the nasal anatomy, as well as the very low solubility of benzodiazepines requires a higher skill set and knowledge than a POSA with a bachelor’s degree “with several years of experience.”

While benzodiazepine formulations had been developed for intravenous administration by 2008, the need for medical professionals to administer these therapeutic products greatly limited their use for epileptic patients requiring an immediate cessation of the seizure symptoms outside of a hospital or clinic setting.

Lau attempted to overcome these challenges by first solubilizing the benzodiazepines in an organic non-aqueous vehicle, including triacetin, dimethyl sulfoxide, polyethylene glycol 400, Cremophor EL (polyoxyethylated castor oil), Lipal-9-LA (laureth-9(polyoxyethylene-9 lauryl ether), isopropyl adipate and azone 1- dodecylazacycloheptane-2-one.

1986 Chemical Warfare – analysis & emergency Ministry of defense, Denmark Employment 1991-: Assistant (1991), Associated (1993) and Full Time Professor (1996) at the Faculty of Pharmaceutical Sciences, University of Iceland CEO of Lyfjaþróun biopharmaceuticals.

VALTOCO, Neurelis’ lead product candidate, is a proprietary formulation of diazepam ® incorporating the unique combination of a vitamin E-based solution and Intravail absorption enhancement.

“VALTOCO was developed to provide an eective combination of reliability, safety, and tolerability in a simple, ready-to-use nasal spray.” The NDA for VALTOCO is supported by an extensive clinical and pre-clinical package including studies in healthy volunteers and patients with epilepsy.

This NDA submission also represents a highly meaningful milestone for the Neurelis team, many of which have been intimately engaged in advancing epilepsy rescue treatment options over the last two decades.

This lack of novel and innovative therapies is a signicant unmet need in the epilepsy community that needs to be addressed.” More About VALTOCO VALTOCO nasal spray is a proprietary formulation of diazepam, delivered via a nasal spray formulation, developed for the management of pediatric, adolescent, and adult patients who require intermittent use of diazepam to control bouts of increased seizure activity, also known as cluster or acute repetitive seizures.

Neurelis is leveraging its expertise in the development and commercialization of CNS compounds and strong relationships with leading researchers and clinicians in these markets to advance unique product candidates, such as VALTOCO, to address signicant unmet medical needs.

"We are pleased to have received Orphan Drug Designation from the FDA based on the potential clinical benet of NRL-1 to patients who experience acute repetitive seizures" stated Craig C. Chambliss, President and Chief Executive Ocer of Neurelis.

"Pediatric, adolescent, adult patients and their caregivers desire an eective, reliable, and well-tolerated treatment alternative to either rectal diazepam or an emergency room visit.

There are over 2.7 million people with epilepsy in the United States with approximately 200,000 new patients diagnosed each year.

Studies have shown that prolonged or repetitive seizures can cause neurological damage and dramatically increase the risk of changes in neuropsychological function or even death.

Neurelis leverages expertise in the development and commercialization of CNS compounds and strong relationships with leading researchers and clinicians in these markets to advance unique product candidates to address signicant unmet medical needs.

Diagnosis Hyperventilation Migraine Panic attack Psychogenic seizures Syncope Transient global amnesia Transient ischemic attack Important Clinical Features Anxiety and overbreathing evident; often perioral cyanosis, hand paresthesias, and carpo pedal spasm are present; environmental trigger may be evident Slow progression of neurologic symptoms; visual symptoms prominent; basilar migraine has unusual features, including confusion, stupor, bilateral blindness; headache may be minimal or absent Abrupt onset with intense feeling of dread or fear; often sense of impending death or inability to breathe; prominent autonomic features (e.g., tachycardia, sweating, nausea); lasts longer (5–30 min) than typical seizure; no loss of consciousness Psychiatric history; patient usually motionless with eyes closed at onset; fluttering eye movements and forceful eye closure common; out-of-phase, thrashing limb move- ments and pelvic thrusting common; urinary incontinence unusual; refractory to treatment Precipitating circumstances usually identifiable; prodrome of wooziness but no aura or unilateral symptoms; loss of consciousness brief (<20 sec), with rapid return to nor- mal; a few muscle jerks (“convulsive syncope”) can occur at end because of hypoxia Isolated amnesic syndrome; prolonged duration (several hours); no alteration of con- sciousness; no confusion, weakness, or aphasia; persistent memory gap during period of attack; recurrence unusual Sudden onset without progression of symptoms; variable symptoms related to brain and vascular anatomy; negative features (e.g., weakness, loss of sensation, aphasia) predominate Evaluation The neurologic examination is normal in most pa- tients with epilepsy.

Patients should be discouraged from participating in ac- tivities for which a history of seizures increases the risk of injury or death; these activities include driving, operating high-risk power equipment, n engl j med 359;2 www.nejm.org july 10, 2008 The New England Journal of Medicine Copyright © 2008 Massachusetts Medical Society.

T h e ne w e ngl a nd jou r na l o f m e dicine tively inexpensive phadenopathy; rela- acial features, lym- sutism, coarsened gival hyperplasia, hir- increased risk of gin- Reduces bone density; f netics‡ lead to nonlinear ki- ed; more likely to Not always well tolerat-

How- ever, clinical trials in newly diagnosed epilepsy have not shown any advantage associated with phenytoin,27 and it is generally preferable to initi- ate whichever antiepileptic drug is considered to n engl j med 359;2 www.nejm.org july 10, 2008 The New England Journal of Medicine Copyright © 2008 Massachusetts Medical Society.

* Type of Medication Cardiac Psychiatric Antineoplastic Antiinfective Other Increased Clearance (and Need for Higher Doses) with Phenytoin, Phenobarbital, Carbamazepine Decreased Clearance (and Need for Lower Doses) with Valproic Acid Mexiletine, quinidine, amiodarone, propranolol, meto- prolol, nifedipine, felodipine, nimodipine, digoxin, lovastatin, simvastatin, dicoumarol, warfarin Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, citalopram, paroxetine, buproprion, haloperidol, chlorpromazine, clozapine, olanzapine, risperidone, quetiapine Cyclophosphamide, busulfan, etoposide, methotrexate, teniposide, some vinca alkaloids Praziquantel, albendazole, doxycycline, nevirapine, efavirenz, delavirdine, indinavir, ritonavir, saquinavir Cyclosporine, tacrolimus, diazepam, alprazolam, prednisone, oral contraceptive pills, theophylline, methadone Nimodipine Amitriptyline, nortriptyline, clomip- ramine, paroxetine Zidovudine, possibly others Lorazepam, diazepam * Data are from Patsalos and Perucca.46 This list is not comprehensive.