PRODUCTS

PRODUCTS

NASAL LORAZEPAM

INTRODUCTION

In March 2007, Amarin acquired a global license to develop and market a novel, nasal formulation of the approved benzodiazepine lorazepam for the out-patient treatment of seizure emergencies in epilepsy patients.

A seizure emergency is a prolonged seizure or continuous state of frequently occurring seizures. One common type of seizure emergency is called status epilepticus (SE). SE may be defined as a prolonged seizure lasting anywhere between 10 and 30 minutes. SE is also defined by a series of repeated seizures without the return of consciousness in between seizures. SE has an annual incidence estimated at approximately 150,000 cases in the US alone with approximately 40,000 deaths per year.

Another type of seizure emergency is acute repetitive seizures (ARS), which is a bout or cluster of seizures over a short period of time in which the patient regains consciousness between seizures. It is estimated that up to 200,000 people in the United States suffer from ARS (more on epilepsy, status epilepticus and acute repetitive seizures).

Amarin’s formulation utilizes the patent protected NanoCrystal® technology from Elan Corporation, plc. One of the main challenges in the formulation of a benzodiazepine for nasal delivery is stability. For the most part, benzodiazepines are stable in a solid state but unstable in solution which is required for intranasal delivery. Elan’s NanoCrystal technology enables formulation of poorly water soluble drugs via creation of a NanoCrystal Colloidal Dispersion (i.e. the insoluble drug is split into numerous “solid” nanoparticles and dispersed throughout a solution). Lorazepam has a low water solubility profile which represents an ideal candidate for the technology.

Intellectual Property

As lorazepam itself is generic, there exists no patent protection relating to the compound itself. All IP protection currently stems from the IP licensed from Elan and which relates to its NanoCrystal technology platform which includes six issued patents that expire in 2019 and 2020, and two pending patents that expire in 2021 and 2026, respectively.

Amarin plans to seek Orphan drug designation for its nasal lorazepam candidate which means it would have seven years marketing exclusivity post its approval in the US, and up to 10 years in Europe.

Opportunity – Unmet Need

Benzodiazepines, primarily lorazepam and diazepam, are the first line of treatment for SE and ARS in the hospital / emergency room. The FDA approval of Diastat (rectal diazepam gel) in 1997 for ARS paved the way for out-patient treatment of seizure emergencies. Diastat’s orphan drug exclusivity has now expired. It remains the first and only acute treatment approved to date which can be administered in an out-patient setting for seizure emergencies. However, there are a number of drawbacks with its route of administration which limit the drug’s market potential. These may be described as follows:

  • Social implications from administration by family and non-family members
  • Embarrassment
  • Loss of administered anti-epileptic drug into the stool
  • Expulsion from cathartic effect on bowels
  • Commercial kit expensive

Consequently, Diastat is typically only used at home by parents with young children and there exists an opportunity for the development of a benzodiazepine with an alternative route of administration which would allow for broader out patient treatment of SE and ARS in children and adults.

A nasally delivered therapy would be an ideal out patient product for acute seizures for a number of reasons:

  • Nasal administration is second only to IV in terms of speed of onset whereby drugs may be rapidly absorbed via solution instilled in the nasal mucosa.
  • Nasal administration is a preferred route vs intramuscular (IM), buccal and sublingual. IM speed of onset is too slow for effective use with emergency seizures. Concerns with buccal and sublingual administration include provoking gagging, coughing, aspiration or oral loss of drug.
  • Nasal administration is a more convenient and socially acceptable route vs rectal administration.
  • Nasal administration allows for the drug to get to the brain directly and systemically.

Data from clinical trials conducted by other organizations suggest lorazepam may be superior to diazepam as a first line treatment for SE and ARS1-6. Lorazepam differs from diazepam in two important respects (i) it has a longer duration of clinical effect and (ii) it has a longer duration of action. However, the currently available forms of lorazepam (oral, intravenous and intramuscular) restrict its use for treatment of emergency seizures to a hospital setting.

DEVELOPMENT TO DATE

Preclinical Development

In January 2008, Amarin announced the successful completion of a preclinical proof of concept study using its novel nasal formulation of lorazepam. The preclinical study evaluated the extent of absorption of lorazepam after nasal administration and the pharmacokinetics of the novel formulation. The results support further development of the nasal formulation for the intended indication.

REFERENCES
  1. Cock et al – Q J Med 2002;95:225-231 – “A Comparison of Lorazepam and Diazepam as Initial Therapy in Convulsive Status Epilepticus”
  2. MC Walker - “How Should Serial Seizures and Status Epilepticus be Treated?” MC Walker - www.rcpe.ac.uk/publications/articles/epilepsy_supplement/I_Walker.pdf
  3. Alldredge et al – N Engl J Med 2001;345:631-637 – “A Comparison of Lorazepam, Diazepam and Placebo for the Treatment of Out-of-Hospital Status Epilepticus”
  4. Internet Article - “What are the Optimal Routes of Antiepileptic Drug Administration in Seizing Patients Without IV access?” – www.ferne.org/Lectures/AEDRoutes0502.htm
  5. Internet Article -“Status Epilepticus” - www.emedicine.com/emerg/topic554.htm
  6. Sirven et al – American Family Physician 2003;68:469-476 – “Management of Status Epilepticus”