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Specialty PharmaNeuroscience Focus

Invisio PharmaceuticalsPartnering Opportunities2018

Current Products

1. RasagiSOL™ - Rasagiline Oral Liquid (Strawberry Flavour)• 1mg/5ml• 150ml bottles• Amber Glass

2. ModaSOL™- Modafinil Oral Liquid (Raspberry Flavour)• 100mg/5ml• 150ml and 300ml bottles• Amber Glass

Dysphagia Negatively Impacts on QoL

1. ‘OD constitutes impaired or uncomfortable transit of food or liquids from the oral cavity to the esophagus, and…’

2. ‘It is included in the World Health Organization's classification of diseases.’

3. ‘It can cause severe complications such as malnutrition, dehydration, respiratory infections, aspiration pneumonia, increased readmissions, institutionalization, and morbi-mortality. ‘ (ref. 1)

4. ‘Aspiration pneumonia related to dysphagia is known to be the leading cause of death in patients with Parkinson's disease (PD).’ (ref. 2)

5. ‘This study suggests that there may be a strong relationship between depressive states and dysphagia in patients with PD.’ (ref 2.)

Ref 1: Baijens LW et al European Society for Swallowing Disorders - European Union Geriatric Medicine Society white paper: oropharyngeal dysphagia as a geriatricsyndrome.. Clin Interv Aging 2016 Oct 7;11:1403-1428.

Ref. 2 Han M et.al. Relationship between dysphagia and depressive states in patients with Parkinson's disease.. Parkinsonism Relat Disord. 2011 Jul;17(6):437-9.

Dangers of Crushing TabletsCrushing tablets or opening capsules: many uncertainties, some established dangers.

…The clinical consequences for the patient of crushing tablets or opening capsules can be serious:

• Alteration of the drug's absorption can result in sometimes fatal overdose, or conversely under-dosing, rendering the treatment ineffective.

• When a gastro-resistant layer is destroyed by crushing, under-dosing is likely.

• The active ingredient released may degrade on contact with light, moisture or the food with which it is mixed for administration.

• The person who crushes the tablets or opens the capsules is exposed to drug particles, which …are sometimes allergenic.

• In practice, there are many drugs that should never be crushed or opened. Before crushing a tablet or opening a capsule, it is better to consider and research the impact it will have on the drug's effects.

• It is sometimes preferable to use a different dosage form, or a different active ingredient.

Ref 1: No Authors Listed. Crushing tablets or opening capsules: many uncertainties, some established dangers. Prescrire Int 2014 Sep;23(152):209-11, 213-4.

(Ref 1)

ICH Q8 - Pharmaceutical Companies Begin to Recognize the Issue

1. Swallowing difficulties tend to involve difficulties initiating and subsequently continuing with the mechanical, muscular process of swallowing.

2. Solid material (such as tablets/capsules) seems to cause more problems than liquids.

3. The Pharmaceutical Industry has now established a process:

ICH Q8 - defines a Quality Target Product Profile (QTPP) for each product in each target patient population (eg. elderly, paediatric etc.) (ref. 1)

Ref. 1. An Industrial Perspective on the Design and Development of Medicines for Older Patients. Page S. et al. Int J Pharm 2016 Oct 30;512(2) 352-354

To Date - Oral Liquid Products are Lacking for PD treatment

Ref. 1. The Need for Oral Liquid Formulations of Pharmaceutical Agents. Pendleton R D; Poster Presentation PAUNS Oct 2018,

Current Products

RasagiSOL™ - Rasagiline Oral Liquid (Strawberry Flavour)• 1mg/5ml• 150ml bottles• Amber Glass

Rasagiline Tablet Mode Of Action

• Rasagiline is a Monoamine Oxidase B Inhibitor

It stops the breakdown of the Monoamines in the brain, in particular Dopamine, thus increasing the life of Dopamine and contributing to the normalization of Dopamine activity in the Parkinson’s brain.

It can be used alone or in combination with either L-DOPA therapy, or Dopamine Agonist

Benefits:

• Unlike the first generation MAO inhibitors, Rasagiline does not influence the metabolism of Tyrosine and so patients have no requirements for dietary limitations

• Selegiline is metabolised to amphetamines, Rasagiline is not• Rasagiline is up to 10x more potent than Selegiline at Inhibiting Monoamine Oxidase

Rasagiline Tablet Efficacy

Ref. 1. Efficacy of Rasagiline and Selegiline in Parkinson’s Disease: A Head to Head 3 year Retrospective Case Control Study. Cereda E. et al. J of Neurol. 2017, Jun, 264-6

• MAO-B inhibitor use was associated with ~2-fold lower change in daily dose of levodopa (p < 0.001) and lower dyskinesia scores (p = 0.028) than non-users.

• No intra-class differences were observed between selegiline and rasagiline.

• Long-term use of MAO-B inhibitors resulted in a significant reduction in levodopa requirements and a lower frequency of dyskinesias in patients with PD.

• Selegiline and Rasagiline had equal efficacy in controlling motor symptoms in PD patients on optimized therapy.

• Selegiline is metabolised to amphetamines, Rasagiline is not.• Rasagiline is up to 10x more potent than Selegiline at Inhibiting Monoamine Oxidase

Rasagiline Tablet Listed Side Effects

Dizziness Joint PainHeadache Depression HeartburnNauseaFeverMuscle PainDry MouthStomach Upset or Abdominal Pain Hair LossSkin Rash

Numbness or Tingly Feeling Loss of AppetiteConstipationDiahorreaVomitingWeight LossImpotenceLoss of Interest in Sex, AnorgasmiaStrange DreamsFlu Symptoms

Rasagiline Tablet Sales Prior to Patent Expiry

Worldwide Sales2013

0

50,000,000

100,000,000

150,000,000

200,000,000

250,000,000

300,000,000

350,000,000

400,000,000

450,000,000

500,000,000

Rasagiline Tablet PosologyDosage

• Initially – 1mg OD with or without food• Given with or without L-Dopa & Dopamine Agonists• Elderly – no requirement to alter dosing in elderly

Indications• Monotherapy treatment of motor and non-motor symptoms of Parkinson’s Disease• Adjunctive therapy treatment of Parkinson’s Disease with L-Dopa or L-Dopa/Carbidopa

combination• Adjunctive therapy treatment of Parkinson’s Disease with Dopamine Agonists therapy

RasagiSOL Price

Review

Special Medicine manufactured exclusively at PCCA in the UK following exacting standards

Formulated by Specialist Oral Liquid Formulation company

Fast World-wide Delivery

Pharmacist can order direct from PCCA or via Invisio

Price is standardised to be in the acceptable range for Special medicines

Price is fixed by Invisio and will not be inflated by distributor

RasagiSOL Current Status and Development

Made To OrderProduct

Batch Produced Product

Marketing Approval

• Batch Production Viability Testing• Stability Testing

• pK Study • Regulatory Dossier Preparations• Regulatory Processing

Planned for qtr2/2019

Planned for 2019/20

Current Products

ModaSOL™- Modafinil Oral Liquid (Raspberry Flavour)• 100mg/5ml• 150ml and 300ml bottles• Amber Glass

Modafinil Tablets can Alleviate Daytime Sleepiness & Fatigue

Excessive Daytime Sleepiness associated with narcolepsy with or without cataplexy

NICE recommends Modafinil tablets for Parkinson’s patients with Excessive Daytime Sleepiness or Sudden Onset of Sleep

Modafinil is a central stimulant chemically related to adrafinil. It is used in the treatment of excessive daytime sleepiness associated with the narcoleptic syndrome, obstructive sleep apnoea, and shift-work sleep disorder. It is very popular as a study drug (nootropic), as well as for the other off-label uses such as ADHD, depression, chronic fatigue syndrome, parkinsons disease, firomyalgia, multiple sclerosis, cerebral palsy, and even weight loss.

• Several studies show efficacy in Cognitive Decline associated with Unipolar/Bipolar Depression• Several studies show efficacy for adult ADHD particularly ADD• 2008 study shows evidence of efficacy for Fatigue from Chemotherapy for Lung cancer• 2008 review suggests good all-round Cognitive Enhancement in Neuropsychiatric conditions• 2010/2016 studies show normalization of sleep architecture during cocaine abstinence in addicts• Recent Phase II study suggests improved post-stroke rehabilitation

Modafinil Tablet Mode of Action

’…Modafinil affects a wide array of neurotransmitter systems including:

• Catecholamines (dopamine, norepinephrine), • Glutamate/GABA• histamine• orexin/hypocretin

Modafinil’s mechanism of action likely converges on the hypothalamus, which plays a well-characterized role in sleep regulation and circadian rhythm.’ (ref 1)

Modafinil: • Binds to the dopamine transporter (DAT), albeit with low affinity• Displaces the DA ligand raclopride and cocaine in the human brain.• Inhibits striatal and pallidal GABA release - increases GABA ratio • orexinergic signaling - Modafinil treatment has been reported to induce c-Fos expression in orexinergic neurons in the

perifornical regions of the hypothalamus and in the lateral hypothalamus

Ref 1: http://www.focuswish.com/modafinil-mechanism-of-action/

Poor Sleep leads to Poor Function

‘A number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones.’

‘…decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep.’

‘while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis.’

‘These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.’

(Ref. 1)

Ref. 1: Meerlo P et al. New Neurons in the adult brain: The role of sleep and consequences of sleep loss. Sleep Med Rev. 2009 Jun 13(3) 187-94

Modafinil Tablet Effectiveness

Better Nights means Better Memory

‘Sleep-specific brain activity when reaching a critical dose, beyond a mere reduction of interference, promotes synaptic plasticity in a hippocampal-neocortical network that underlies the consolidation of declarative memory’ (ref 1 )

Ref 1: The effect of sleep-specific brain activity versus reduced stimulus interference on declarative memory consolidation. Piosczyk H et.al. J Sleep Res. 2013 Aug;22(4):406-13.

Poststroke Fatigue and Apathy

Fatigue:

• ‘The prevalence of post-stroke fatigue ranges from 23% to 75%, depending on the definition of fatigue and the characteristics of the patients included.’ (ref 1)

• ‘Post-stroke fatigue is a persistent and debilitating symptom in some patients, and can have adverse affects on patient's neurological recovery, quality of life, and mortality’ (ref 1)

Apathy:

• ‘Post-stroke apathy affects 19-55% of patients’ (ref 2)

• ”It has a negative impact on functional recovery, general health, and quality of life, as well as being a source of significant burden for caregivers.” (ref 2)

Ref 1: Poststroke fatigue: an emerging, critical issue in stroke medicine. Choi-Kwon S et al. Intl J Stroke.. 2011 Aug;6(4):328-36. Ref 3: Circadian sleep/wake rhythm abnormalities as a risk factor of a poststroke apathy. Cosin C et al. Int J of Stroke. 2015 Jul;10(5):710-5.

Modafinil Tablet Side EffectsMore common:• Headache• Nausea• Dizziness • Nervousness• Trouble sleeping

Less common:• Back pain• Belching • Decrease in appetite• Diarrhea• Difficulty having a bowel movement• Dryness of the mouth• Dryness of the skin• Feeling of constant movement of self or surroundings• Flushing or redness of the skin• Heartburn• Indigestion• Muscle stiffness• Sores, ulcers, or white spots on the lips or in the mouth• Sour stomach• Stomach discomfort upset or pain• Stuffy or runny nose • Swelling• Tingling, burning, or prickling sensations in the skin• Vomiting Ref 1: https://www.drugs.com/sfx/modafinil-side-effects.html

Modafinil Tablet PosologyDosage

• Initially - 200mg BID in divided doses – morning and noon, or 200mg OD – morning only• Titrate - up to 400mg (oral liquid allows for refined titration• Elderly initially – 100mg OD (oral liquid allows for refined titration)

Indication• Excessive sleepiness associated with narcolepsy with or without cataplexy• NICE recommends Modafinil for Parkinson’s patients with excessive daytime sleepiness or

sudden onset of sleep ALSO it is widely used for fatigue with MS• Several studies show efficacy in Cognitive Decline associated with Unipolar/Bipolar Depression• Several studies show efficacy for adult ADHD particularly ADD• 2008 study shows evidence of efficacy for Fatigue from Chemotherapy for Lung cancer• 2008 review suggests good all-round Cognitive Enhancement in Neuropsychiatric conditions• 2010/2016 studies show normalization of sleep architecture during cocaine abstinence in addicts• One study suggests improved post-stroke rehabilitation with Modafinil

ModaSOL Price

Review

Special Medicine manufactured exclusively at PCCA in the UK following exacting standards

Formulated by Specialist Oral Liquid Formulation company

Fast World-wide Delivery

Pharmacist can order direct from PCCA or via Invisio

Price is standardised to be in the acceptable range for Special medicines

Price is fixed by Invisio and will not be inflated by distributor

ModaSOL Current Status and Development

Made To OrderProduct

Batch Produced Product

Marketing Approval

• Batch Production Viability Testing• Stability Testing

• pK Study • Regulatory Dossier Preparations• Regulatory Processing

Planned for qtr2/2019

Planned for 2019/20

Invisio – Other ProductsNuromate:

• Adherence and Monitoring App for Medications OR eg. Post-Stroke Exercise

• Reports back to the physicians to allow monitoring of medication between visits

• Can be an early warning system of something going wrong

• FREE for Patients and Physicians

Myogenes:

• Genetic Profiling of patients from mouthwash/saliva

• 12 pD and 6 pK tests

• Allows better guidance for pharmacotherapy choice and medication dosing

• Great value at £595 per battery of tests

• Genetics Company specialises in CNS testing