Currently, several monoclonal antibodies against the Calcitonin Gene-Related Peptide (CGRP) receptor pathway are in clinical trials and could provide a new and improved way to prevent chronic or episodic migraine. What to expect? I will exemplify the current development by demonstrating results from a phase II clinical trial of one of the drugs in development, AMG334.

1. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
What to expect from novel drugs for prevention of migraine?
Findings from a phase II study
1
Currently, several monoclonal antibodies against the
Calcitonin Gene-Related Peptide (CGRP) receptor pathway
are in clinical trials and could provide a new and improved way
to prevent chronic or episodic migraine.
What to expect?

2. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Why the CGRP Pathway ?
Study Setup
Results
Safety & Tolerability
Conclusions & Discussion
Findings from a phase II study
2
AMG 334 is a fully human monoclonal antibody specifically
designed for the prevention of migraine and targets and blocks
the Calcitonin Gene-Related Peptide (CGRP) receptor
1
What to expect from novel drugs for prevention of migraine?
I will exemplify the current development by demonstrating
results from a phase II clinical trial of one of the drugs in
development, AMG 334, published in Lancet Neurology.
Content

3. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Migraine – Research in Context
Why targeting the CGRP Pathway ?
3
Common neurological disorder, characterized by severe headache and physical impairment, frequently accompanied by nausea,
vomiting, photophobia and phonophobia. Seventh-highest specific cause of disability worldwide.
Treatment Options
Migraine
Acute Migraine Treatments Preventive Treatments
Triptans
Drowsiness, dry mouth, chest tightness,
contraindicated with cardiovascular disease
β-Adrenergic Blockers
Lethargy or depression, hypotension,
bradycardia, impotence, insomnia,
nightmares
Analgesics
Can lead to the development of chronic
daily headaches
Topiramate, Valproate,
Amitriptyline, Methysergide
Not designed specifically for migraine
Habitual overuse can lead to the
development of chronic daily headaches
Side-effects, poor adherence
So far, all available
treatment options are
associated with side
effects in almost all
patients, and many
people cannot tolerate
them for long periods
of time.
“
”

4. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Calcitonin Gene-Related Peptide (CGRP)
Why targeting the CGRP Pathway ?
4
Member of calcitonin family of
peptides (37-amino acids), which in
humans exists in α and β-form. α -
form in peripheral and central
neurons. Role in dilating arteries and
maintaining blood supply to brain2-4
Function of CGRP Research in Context
• CGRP spikes in migraine-attack
• Resulting inflammation in nerves
relayed as pain signal
• Powerful vasodilator of cranial
blood vessels
• Role in sensory transmission
• Acts as pain-signalling peptide5
• Potentiates substance P release
Activation of primary sensory
neurons in the trigeminal vascular
system can cause the release of CGRP
Antibody Target Route
ALD4037 CGRP IV
TEV-481258 CGRP SC
LY29517426 CGRP SC
AMG 3341 CGRP
receptor SC
All the anti-CGRP drugs in development
seem to show efficacy
CGRP-receptor
Complex
RAMP1
CALCLR
CGRP binds to a receptor composed
of a G protein-coupled receptor
called calcitonin receptor-like
receptor (CALCRL) and a receptor
activity-modifying protein (RAMP1)
Small-molecule CGRP-receptor
inhibitors
• Liver toxicity
• Small half-life

5. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Study Setup
Trial Method & Sites
5
Europe (46%)
Denmark, Finland, Germany,
Norway, Sweden & Portugal
North America (54%)
Canada, USA
Multicentre, Double-Blind,
Placebo-controlled, Phase II
59 Headache & Clinical Research Centres
Placebo (n=160)
7 mg (n=108)
21 mg (n=108)
70 mg (n=107)
AMG 334
randomly assigned
2:2:2:3 ratio
Electronic Diary
(eDiary, PHT Corp.)
Baseline
Screening Treatment
Safety Follow-up
wks

6. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Study Setup
Baseline Demographics
6
19% 81%
Primary Endpoint:
Change in monthly migraine days from
baseline to the last 4 weeks of the trial
Baseline Treatment
wks
“Women roughly
three times as
likely as men to
have an attack.”

7. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Results
Reduction in monthly migraine days
7
Data are least square means (SE). P-value equals placebo-group vs. 70mg dose-group.
Change from Baseline in mean monthly days
Changeinmigrainedays
7 mg
21 mg
• Treatment phase completed by 93% of patients, 89%
in placebo group.
70 mg
Significant reduction in monthly
migraine days from baseline at week 12
50% responder rate at week 12
was significantly greater
compared with placebo with no
difference in average severity
of migraine pain or
Symptoms.
“
”

8. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Safety & Tolerability
Safety Endpoints
8
Adverse events, clinical laboratory values, vital
signs, and anti-AMG 334 antibodies
Placebo
7 mg
21 mg
70 mg
AE‘s [%] 46 48 50 52 54 56 58
• AEs similar between treatment groups
• Most AEs were mild or moderate in severity
• Ruptured ovarian cyst (7mg group)
• Vertigo & Migraine (70mg group)
 Considered unrelated to treatment
• 98% of patients received at least one dose of investigational
product and were included in safety analysis

9. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Safety & Tolerability
Safety Endpoints
Clinical laboratory values:
Vital signs:
Anti-AMG 334 antibodies
• No significant findings
• No significant findings
7 mg
21 mg
70 mg
ABs [%] 08 09 10 11 12 13 14
nABs
Clinical significance of neutralizing antibodies
unknown; phase III trials are ongoing.
Potential but unknown cerebrovascular risks with
CGRP blockade9
• As vasodilator, CGRP may work as safeguard during
cerebral ischemia
• Transient ischemic events might be transformed into
full infarctions with CGRP blockade
Long Term Exposure
• Extremely low amount of adverse events
• High Tolerability
Safety Summary
• 3% (n=9) had neutralizing antibodies
• No apparent association with anti-AMG 334 and AEs
9

10. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
Conclusions & Discussion
10
• Monoclonal antibodies are too large to cross blood-brain
barrier, suggesting AMG 334 works by inhibiting CGRP
pathway from the periphery
• Site of action in migraine relief is the trigeminal ganglion,
the brain could still be having a migraine attack but the
pain-signal of that attack is blocked
• AMG 334 results consistent with phase 2 trials of CGRP
mABs LY2951742, TEV-48125 and ALD403
• For mABs in trials, data suggest the drugs work faster
(onset <= 3 days), for longer, and better than other
therapies
• Potential advantages in adherence & tolerability
• CGRP receptor provides a novel target in migraine
• Subcutaneous AMG 334 might be a potential therapy
for migraine prevention in patients with episodic
migraine
• 50% responder rates significantly higher with 70mg
AMG 334 than with placebo
AMG 334
Context
Mode of action
10
Source:
The Pharmaceutical
Journal

11. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 201711
1: As a multifactorial disease, migraine should be
managed through multimodal pharmacotherapy. At
70mg, AMG 334 has ~21 days half-life, supporting
monthly subcutaneous dosing.
Q: Compared to placebo, is this reduction of –1.1
days with AMG 334 for a patient having 8-9
migraine days at baseline meaningful?
2: In the AMG 334 trial only the highest dose was better
than placebo but theoretically, taking into account that
280 mg AMG 334 seemed to be well tolerated, higher
doses could increase efficacy.
3: Looking at all antibody trials, 15% of participants
noticed complete relief (super-responders), which could
mean that the antibodies could be very efficacious in a
subset of migraine patients.  Chronic Migraine is ideally
suited for a Precision Medicine approach !
“
”
In total that means 3.4 days of pain relief.
Efficacy results for the other antibodies
were very similar, with exception of TEV-
48125, which showed slightly better raw
data. However for the TEV-48125 trial, the
inclusion criteria were not entirely similar.
For example, patients were allowed to use
other preventive treatments during the
trial and the investigators only recruited
high-frequency episodic migraine cases.
Q: What is the take-away?

12. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 201712
ARISE trial, the first phase 3 study evaluating the
efficacy and safety of monthly subcutaneous AMG
334 (erenumab) 70mg in episodic migraine preven-
tion. A total of 577 patients enrolled in ARISE were
randomized to receive either placebo or AMG 334 at
70mg subcutaneously, once monthly. Those
receiving AMG 334 experienced a statistically
significant 2.9-day reduction from base-
line in monthly migraine days, as compared with a
1.8-day reduction in the placebo arm. The safety
profile of AMG 334 was similar to placebo.
 ARISE Trial
Patients enrolled in STRIVE study were
randomized to receive either placebo or one of two
AMG 334 doses, 70 or 140mg, subcutaneously, once
monthly, for 6 months. Over the last 3 months of the
double-blind treatment phase, patients in the 70 and
140mg AMG 334 treatment arms experienced a
statistically significant 3.2 and 3.7-day reduction from
baseline in mean monthly migraine days, respectively,
as compared with a 1.8-day reduction in the placebo
arm. The safety profile of AMG 334 was comparable
with Placebo across both treatment arms.
 STRIVE Study
All of the antibodies, ALD403, TEV-48125, LY2951742, and AMG 334 are either in phase-III trials, or those trials are
already finished. Preliminary phase-III results suggest that phase-II results could be confirmed. It is only a matter of
time till novel drugs against the Calcitonin Gene-Related Peptide (CGRP) receptor pathway will enter the market.

13. Opinion: Safety and efficacy of AMG 334 for prevention of episodic migraine – March 2017
THANK YOU !
13
KEEP IN TOUCH
REFERENCES
1: Sun et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. 2016;
15, No. 4:382–390
2: Russell FA, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94:1099-1142.
3: Bigal ME, et al. Calcitonin gene-related peptide and migraine current understanding and state of development. Headache. 2013;53:1230-1244.
4: Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552
5: Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61.
6: Oakes T. et al. Efficacy and safety of LY2951742 in a randomized, doubleblind, placebocontrolled, doseranging study in patients with migraine.
Headache. 2016;58. Abstract PS42.
7: Dodick et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine. Lancet
Neurol. 2014;13(11):1100-7.
8: Bigal ME et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine. Lancet Neurol. 2015;14:1091-1100.
9: Maassen van den Brink A, et al. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37:779-788
ClinicalTrials.gov # NCT01952574
+49-(0)176-80380763
dr.a.schumacher@gmail.com
@MethylogiX