A review of Migraine..A Disability...and the monoclonal antibody so designed showing positive outcomes...

1. ERENUMAB…
A new HOPE for MIGRAINE DISABILITY
University College of Technology,O.U
Submitted By
SANA YASMEEN
H.No.1008-17-884-015

2. CONTENTS
1. INTRODUCTION
2. CLASSIFICATION
3. SIGNS AND
SYMPTOMS
4. CAUSES
5. PATHOPHYSIOLOGY
6. MEDICATIONS
7. ERENUMAB PROFILE
8. CLINICAL TRIALS
AND DATA
9.STAGES OF ERENUMAB
DEVELOPMENT ANDFDA
APPROVAL.
10.PHARMACOKINETICS
11.CONCLUSION
12.REFERENCES

3. INTRODUCTION
 The word MIGRAINE is derived from Greek
word…..HEMIKRANIA i.e..pain on oneside of the head.
 A Migraine is a primary headache characterised by
recurrent headaches, that are moderate to
severe.Typically,the headaches affect one half of the head,
and are pulsating in nature lasting from 2 to 72 hrs.
 The International Headache Society,placed Migraines as
Headache along with tension-type headacheand cluster
headache.
 Globally,15%of the people are affected by Migraines.It is
more commom in women than men,which is associated
with the hormones,the risk is high during puberty,lowers
with pregnancy and even lowered at menopause.

4. CLASSIFICATION
Based on the Intensity and the Risk factors and
location.Migraines are of following types
Migraine without aura
Migraine with Aura
Hemiplegic and Spordic Hemiplegic Migraine
Basilar-type Migraine
Abdominal Migraine
Migraine associated with seizures
Acute and Chronic Migraine
Retinal Migraine
Menstrual Migraine….......

5. SIGNS AND SYMPTOMS
The signs and symptoms of Migraine can be easily
understood with its four phases….namely…
1. Aura phase
2.Prodrome phase
3.Pain phase
4.Postdrome phase

6. PRODROME PHASE
 Prodromal or premonitory symptoms occur in about
60% of those with migraines,with an onset that can
range from two hours to two days before the start of
pain or the aura.
 These symptoms may include a wide variety of
phenomena, including altered mood, irritability,
depression or euphoria, fatigue, craving for certain
food(s), stiff muscles (especially in the neck),
constipation or diarrohea, and sensitivity to smells or
noise.
 This may occur in those with either migraine with
aura or migraine without aura.

7. AURA PHASE
An aura is a transient focal neurological phenomenon that occurs before
or during the headache Auras appear gradually over a number of minutes
and generally last less than 60minutes.
Symptoms can be visual, sensory or motor in nature and many people
experience more than one.
 Vision disturbances often consist of a scintillating scotoma (an area of
partial alteration in the field of vision which flickers and may interfere
with a person's ability to read or drive).These typically start near the
center of vision and then spread out to the sides with zigzagging lines
which have been described as looking like fortifications or walls of a
castle. Usually the lines are in black and white but some people also see
colored lines. Some people lose part of their field of vision known ash
emianopsia while others experience blurring.
 Other symptoms of the aura phase can include speech or language
disturbances, world spinning, and less commonly motor problems.
Motor symptoms indicate that this is a hemiplegic migraine, and
weakness often lasts longer than one hour unlike other auras,Auditory
hallucinations or delusions are also witnessed.

8. PAIN PHASE
 Classically the headache is unilateral, throbbing, and moderate to
severe in intensity. It usually comes on gradually and is aggravated
by physical activity. In more than 40% of cases, however, the pain
may be bilateral and neck pain is commonly associated with it.
 The pain is frequently accompanied by nausea, vomiting,
sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue
and irritability. In a basilar migraine, a migraine with neurological
symptoms related to the brain stem or with neurological symptoms
on both sides of the body, common effects include a sense of the
world spinning, light-headedness, and confusion. Nausea occurs in
almost 90% of people, and vomiting occurs in about one-third. Many
thus seek a dark and quiet room.
 Other symptoms may include blurred vision, nasal stuffiness,
diarrhoea, frequent urination, pallor, or sweating.
 Swelling or tenderness of the scalp may occur along with neck
stiffness. Associated symptoms are less common in the elderly.
 Rarely, an aura occurs without a subsequent headache. This is
known as an acephalgic migraine or silent migraine.

9. POSTDROME PHASE
The migraine postdrome could be defined as that
constellation of symptoms occurring once the acute
headache has settled.
◘ Many report a sore feeling in the area where the
migraine was, and some report impaired thinking for
a few days after the headache has passed. The
person may feel tired or "hung over" and have head
pain, cognitive difficulties, gastrointestinal
symptoms, mood changes, and weakness.
◘ According to one summary, "Some people feel
unusually refreshed or euphoric after an attack,
whereas others note depression and malaise. For
some individuals this can vary each time.

10. CAUSES
The causes of Migraine can be studied as
GENETIC:
Familial hemiplegic migraine, a type of migraine with aura,
which is inherited in an autosomal dominant fashion. Four genes
have been shown to be involved in familial hemiplegic migraine.
Three of these genes are involved in ion transport.The fourth is an
axonal protein associated with the exocytosis complex. Another
genetic disorder associated with migraine is CADASIL syndrome
or cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy. One meta analysis found a
protective effect from an angiotensin converting enzyme
polymorphisms on migraine. The TRPM8 gene, which encodes for
a cation channel, has been linked to migraines.
 Studies of twins indicate a 34% to 51% genetic influence of
likelihood to develop migraine headaches.

11. TRIGGERS:
a.DIETARY ASPECTS:
Between 12 and 60% of people report foods as triggers.A clear explanation for why
food might trigger migraines is lacking.
b.PHYSIOLOGICALASPECTS:
Common triggers quoted are stress, hunger, and fatigue (these equally contribute to
tension headaches).Psychological stress has been reported as a factor by 50 to 80%
of people. Migraines have also been associated with post-traumatic stress disorder
andabuse.Migraines are more likely to occur around menstruation. Other hormonal
influences, such as menarche, oralcontraceptive use, pregnancy, perimenopause,
and menopause, also play a role.
ENVIRONMENTAL:
A review on potential triggers in the indoor and outdoor environment concluded
that there is insufficient evidence to confirm environmental factors as causing
migraines.However, people with migraines take some preventive measures related
to indoor air quality and lighting.

12. PATHOPHYSIOLOGY
Migraines are believed to be a neurovascular disorder with evidence supporting its
mechanisms starting within the brain and then spreading to the blood vessels.
researchers believe neuronal mechanisms play a greater role, while others believe
blood vessels play the key role. Others believe both are likely important. One theory
is related to increased excitability of the cerebral cortex and abnormal control of
pain neurons in the trigeminal nucleus of the brainstem. Low levels of the
neurotransmitter serotonin, also known as 5-hydroxytryptamine,are believed to be
involved.
AURA:
Cortical spreading depression, or spreading depression according to Leão, is
a burst of neuronal activity followed by a period of inactivity, which is seen
in those with migraines with an aura. There are a number of explanations for
its occurrence including activation of NMDA receptors leading to calcium
entering the cell After the burst of activity the blood flow to the cerebral
cortex in the area affected is decreased for two to six hours. It is believed
that when depolarization travels down the underside of the brain, nerves that
sense pain in the head and neck are triggered.

13. PAIN:
The exact mechanism of the head pain which occurs during a migraine is unknown.
Some evidence supports a primary role for central nervous system structures (such
as the brainstem and diencephalon), while other data support the role of peripheral
activation (such as via the sensory nerves that surround blood vessels of the head
and neck). The potential candidate vessels include dural arteries, pial arteries and
extracranial arteries such as those of these scalp.The role of vasodilatation of the
extracranial arteries, in particular, is believed to be significant.

14. MEDICATIONS
FIRST LINE THERAPY includes…
Opiramates,SodiumValproate,Propranolol,Metoprol.Others
include
Gabapentin,Pregabalin,Timolol,ACEinhibitors,Amitryptyline,Vanalofexi
n,Angiotensin receptor antagonist.Magnesium supplements are also found
to be effective.
ANALGESICS:
Recommended for initial treatment for those with mild to
moderate symptoms are simple analgesics such as nonsteroidal anti-
inflammatory drugs (NSAIDs) or the combination of paracetamol (also
known as acetaminophen), aspirin, and caffeine. Several NSAIDs, including
diclofenac and ibuprofen have evidence to support their use.Aspirin can
relieve moderate to severe migraine pain, with an effectiveness similar to
Sumatriptan.Ketorolac is available in an intravenous formulation
Paracetamol, either alone or in combination with metoclopramide, is another
effective treatment with a low risk of adverse effects. Intravenous
Metoclopramide is also effective by itself. In pregnancy, Paracetamol and
Metoclopramide are deemed safe as are NSAIDs until the third trimester.

15. TRYPTANS:
 Tryptans such as sumatriptan are effective for both pain and nausea in up to 75% of
people. When sumatriptan is taken with naproxen it works better. They are the
initially recommended treatments for those with moderate to severe pain or those
with milder symptoms who do not respond to simple analgesics. The different forms
available include oral, injectable, nasal spray, and oral dissolving tablets.
 In general, all the tryptans appear equally effective, with similar side effects.
However, individuals may respond better to specific ones. Most side effects are mild,
such as flushing; however, rare cases of myocardial ischemia have occurred.
 They are thus not recommended for people with cardiovascular disease, who have
had a stroke, or have migraines that are accompanied by neurological problems.
ERGOTAMINES:
 Ergotamine and dihydroergotamine are older medications still prescribed for
migraines, the latter in nasal spray and injectable
 forms. They appear equally effective to the tryptans and experience adverse effects
that typically are benign, In the most severe cases, such as those with status
migrainosus, they appear to be the most effective treatment option.
 They can cause vasospasm including coronary vasospasm and are contraindicated
in people with coronary artery disease.

16. ERENUMAB PROFILE
Erenumab is a fully human monoclonal antibody of calcitonin
gene-related peptide receptor (CGRPR) for the prevention of
migraine. It was the first of the group of CGRPR antagonists to
be approved in 2018.Other antimigranil Monoclonal Antibodies
includeEptinezumab
Fremanzeumab
Galcanzeumab
FDA approved: Yes (First approved May 17th, 2018)
Brand name: Aimovig
Generic name: erenumab-aooe
Dosage form: Injection
Company: Amgen Inc.
Treatment for: Migraine Prevention.

18. CLINICAL TRIALS AND DATA
 In the phase III STRIVE clinical trial 955 patients were
divided into three groups in a 1:1:1 ratio. Each group was
injected subcutaneously monthly with 0, 70 or 140 mg
erenumab over a period of 6 months.
 The results were measured as mean monthly migraine
days in months 4, 5, and 6. At baseline the patients
experienced between 4 and 14 migraine days per month
with an average of 8.3.
 The medication significantly reduced the number of
migraine days per month by 3.2 in the 70-mg group and
3.7 in the 140-mg group, versus 1.8 in the placebo (0-mg)
group.

19. STAGES OF ERENUMAB DEVELOPMENT
AND FDAAPPROVAL
May 15,2015: Amgen Presents First Phase 2 Data For AMG 334
In The Prevention Of Episodic Migraine.
Jun 8,2016: Amgen Announces Ereneumab (AMG 334)
Significantly Reduces Patients' Monthly Migraine Days In Phase 2
Study For The Prevention Of Chronic Migraine.
Sep 15,2016: Amgen Presents Positive Data At EHMTIC 2016
Demonstrating Ereneumab Significantly Reduces Monthly
Migraine Days In Patients With Chronic Migraine.
Sep 28,2016:Amgen Announces Ereneumab Significantly Reduces
Monthly Migraine Days In Patients With Episodic Migraine In
First Phase 3 Study.
Nov 16,2016:Amgen Announces Ereneumab Significantly
Reduces Monthly Migraine Days In Patients With Episodic
Migraine In Second Phase 3 Study.
May 18,2017 :Amgen Submits Biologics License Application to
the FDA for Ereneumab.

20. Jul 20, 2017: FDA Accepts Biologics License Application for Aimovig
(erenumab).
Sep 7, 2017: New Data Demonstrate Aimovig (Ereneumab) Reduced
Monthly Migraine Days In Patients who Failed Previous Preventive
Therapies.
Nov 29, 2017: Novartis Announces Phase III STRIVE Data Published
in NEJM Demonstrating Significant and Sustained Efficacy of
Ereneumab (AMG334) in Migraine Prevention.
Nov 29, 2017: Aimovig (Ereneumab) Phase 3 STRIVE Data Published
In The New England Journal Of Medicine Demonstrate Significant,
Sustained Efficacy In Migraine Prevention.
Jan 22, 2018: Novartis Reports Ereneumab Met All Primary and
Secondary Endpoints in Unique Phase IIIb Study in Episodic Migraine
Patients Who Have Failed Multiple Prior Preventive Treatments.
Apr 17, 2018: Amgen Presents First-Of-Its-Kind Data At AAN Annual
Meeting Reinforcing Robust And Consistent Efficacy Of Aimovig
(ereneumab) For Migraine Patients With Multiple Treatment Failures.
May 17, 2018:Approval FDA Approves Aimovig (ereneumab-aooe) as
a Preventive Treatment for Migraine.

21. PHARMACOKINETICS
MECHANISM OFACTION
Human monoclonal antibody; binds to the calcitonin gene-related peptide (CGRP)
receptor, which is thought to be causally involved in migraine pathophysiology,
ABSORPTION
Absolute bioavailability: 82%
Peak plasma time: 6 days
Peak plasma concentration: 6.1 mcg/mL (70 mg); 15.8 mcg/mL (140 mg)
AUC: 159 day·mcg/mL (70 mg); 505 day·mcg/mL (140 mg)
DISTRIBUTION
Vd: 3.86 L
ELIMINATION
Half-life: 28 days
2 elimination phases observed
Low concentrations: Predominantly through saturable binding to target (CGRP
receptor)
Higher concentrations: Largely through a nonspecific, nonsaturable proteolytic
pathway.

22. DOSAGE FORMS & STRENGTHS
Injectable solution
70mg/mL, single-dose prefilled syringe or SureClick autoinjector
Migraine Prophylaxis
Indicated for the preventive treatment of migraines70 mg SC once monthly
Some patients may need 140 mg SC once monthly (administered as 2 consecutive 70-mg
SC doses).
ADMINISTRATION
1. SC Administration
2. For subcutaneous use only
3. The needle shield within the white cap of the prefilled autoinjector and gray needle cap of the
prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic
reactions in individuals sensitive to latex
4. Intended for patient self-administration; provide proper training to patients and/or caregivers
on preparation and administration, including aseptic technique
5. Instructions
6. Prior to SC administration, allow syringe to sit at room temperature for at least 30 minutes
protected from direct sunlight
7. Do not warm by using a heat source (eg, hot water, microwave)
8. Do not shake the product

23. 9.Visually inspect for particulate matter and discoloration; do not use if the solution
is cloudy or discoloured or contains flakes or particles. Administer SC in the
abdomen, thigh, or upper arm; do not inject into areas where the skin is tender,
bruised, red, or hard. Both prefilled autoinjector and prefilled syringe are single-dose
and deliver the entire contents.
MISSED DOSE
• If a dose is missed, administer as soon as possible
• Thereafter, reschedule monthly dose from the date of the last dose
STORAGE
1. Refrigerate at 2-8°C (36-46°F) in original carton to protect from light
2. If removed from refrigerator, keep at room temperature (up to 25°C [77°F]) in
the original carton; must be used within 7 days; discard if left at room
temperature for >7 days
3. Do not freeze
4. Do not shake
5. Adding plans allows you to compare formulary status to other drugs in the same
class.
6. There is no formulary information available at this time.

24. ADVERSE EFFECTS:
1-10%
Injection site pain (5-6%)
Constipation (1-3%)
Cramps, muscle spasms (<1 to 3%)
CONTRAINDICATIONS:
A:Generally acceptable. Controlled studies in pregnant women
show no evidence of foetal risk.However,if taken repeatedly Risks
involved outweigh potential benefits. Go with Safer alternatives .
B:May be acceptable,if followed the regular dosing frequency
Either animal studies show no risk but human studies not available
or animal studies showed minor risks and human studies done and
showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show
risk and human studies not available or neither animal nor human
studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug
available. Positive evidence of human fetal risk.

25. CONCLUSION
*ERENEUMAB,is an effective and promising
anti-migranil(momoclonal antibody) with regular dosing
frequency.Unlike,the regular medication which weren’t
specific with the target and provided temporary
relief…causing excessive dose to be adminstered..
*The Use of Ereneumab hopefully lets, the
“Migraine………No More A Disability”.

26. REFERENCES
1. www.wikipedia.org
2. www.drugs.com
3. www.medscape.com