CoLucid Pharmaceuticals, Inc., a biopharmaceutical company that is
developing lasmiditan oral tablets for the acute treatment of
migraine in adults, with or without aura, announced today that its
Phase 3 pivotal trial evaluating lasmiditan, the SAMURAI study, had
achieved secondary endpoints with statistical significance (p <
0.001 – p < 0.012). SAMURAI was a randomized, double-blind,
placebo-controlled parallel group study designed to evaluate the
efficacy and safety of lasmiditan (100 mg and 200 mg) in comparison
to placebo. Lasmiditan doses of 100 mg and 200 mg were efficacious
on headache pain freedom and the most bothersome symptom (MBS)
freedom at the two-hour time point (p < 0.001), the primary and
key secondary endpoints of the study. SAMURAI is the first of two
Phase 3 pivotal trials of lasmiditan, each being conducted under a
Special Protocol Assessment agreement (“SPA”) with the U.S. Food
and Drug Administration (“FDA”).
Secondary Endpoints
Efficacy
Secondary efficacy endpoints of lasmiditan (100 mg and 200 mg)
in SAMURAI included:
- the efficacy of lasmiditan in comparison to placebo based on
migraine headache pain relief two hours after dosing in the intent
to treat (ITT) population
- the efficacy of lasmiditan in comparison to placebo based on
freedom from migraine headache pain two hours after dosing when
used as a second dose for either rescue or recurrence in the ITT
population
- the efficacy of lasmiditan in comparison to placebo based on
the proportion of patients absent each associated symptom of
migraine (nausea, phonophobia or photophobia) two hours after
dosing in the ITT population
- the efficacy of lasmiditan in comparison to placebo based on
Patient Global Impression of Change (PGIC) two hours after dosing
in the ITT population
- the efficacy of lasmiditan in comparison to placebo based on
disability related to migraine two hours after dosing in the ITT
population
Data from the study were collected using electronic diaries
during the treated attack. Beginning pre-dose, patients indicated
their degree of headache pain on a 4-point scale: 0, no pain; 1,
mild pain; 2, moderate pain; or 3, severe pain. Patients also
indicated the presence or absence of nausea, phonophobia or
photophobia, and at the pre-dose time point identified the
associated symptom present that was “most bothersome.” At each time
point assessment, patients were asked to indicate the degree of
headache pain and the presence or absence of each associated
symptom. At the two-hour endpoint, patients indicated their Patient
Global Impression of Change (very much better, much better, a
little better, no change, a little worse, much worse, very much
worse). At the two-hour endpoint, patients also indicated their
disability related to migraine on a 4-point scale: 0, not at
all; 1, mild interference; 2, marked interference; 3, completely,
needs bed rest.
Migraine headache relief was defined as moderate or severe
headache pain at baseline reduced to mild or no headache pain at
the time point assessment. Lasmiditan was effective in relieving
migraine headache pain at two hours (p < 0.001) as compared to
placebo.
HEADACHE PAIN RELIEF (ITT) |
Lasmiditan 100mg |
Lasmiditan 200mg |
Placebo |
% of patients migraine headache pain relief at two hours |
|
59.4 |
% |
|
59.5 |
% |
|
42.2 |
% |
Odds Ratio (95% confidence interval) |
2.4 (1.8 - 3.1) |
2.5 (1.9 - 3.3) |
|
p-value |
p < 0.001 |
p < 0.001 |
|
Patients were randomized at 2:1 lasmiditan to placebo for a
second dose, unless the initial dose was placebo. Patients were
allowed to take a second dose of study drug after the two-hour time
point, but before the 24-hour time point, for rescue or recurrence.
Rescue was defined as a second dose taken for a migraine for which
headache pain freedom was not achieved at the two-hour time point
after initial dosing. Recurrence was defined as a second dose taken
for a migraine for which headache pain freedom was achieved at the
two-hour time point but reoccurred within 24 hours after initial
dosing. The utilization rate of a second dose was expressed as the
proportion of patients who took any second dose of study drug in a
treatment group to the safety population of the same treatment
group.
Patients dosed with lasmiditan were less likely to use a second
dose of study drug. Lasmiditan was effective on migraine headache
pain freedom at the two-hour time point assessment following a
second dose as a rescue medication as compared to placebo. The
number of patients who took a second dose of study drug for
recurrence was small (53 out of 1,671) with no significant
difference between five treatment groups.
SECOND DOSE UTILIZATION |
Lasmiditan
100mg(n=630) |
Lasmiditan
200mg(n=609) |
Placebo(n=617) |
Patients taking a second dose of study drug |
|
289 |
|
|
236 |
|
|
401 |
|
Utilization rate of a second dose of study drug |
|
46 |
% |
|
39 |
% |
|
65 |
% |
SECOND DOSE HEADACHE PAIN FREEDOM (ITT) |
100mg/100mg(n=139) |
100mg/Placebo(n=62) |
200mg/200mg(n=109) |
200mg/Placebo(n=52) |
Placebo/Placebo(n=319) |
% of Patients Pain Free at two hours after Rescue
Dose |
|
29.0 |
% |
|
12.9 |
% |
|
26.6 |
% |
|
23.1 |
% |
|
16.9 |
% |
Odds ratio (95% confidence interval) |
2.2 (1.4 - 3.6) |
|
2.0 (1.2 – 3.3) |
|
|
p value |
< 0.001 |
|
< 0.012 |
|
|
The MBS endpoint was patient-centric and measured treatment
effect of study drug on associated symptoms of nausea, phonophobia
and photophobia. Freedom from MBS at the two-hour time point
assessment was a key secondary endpoint of SAMURAI and conforms to
the FDA’s Draft Guidance for Industry, Migraine: Developing Drugs
for Acute Treatment, issued in October 2014. Patients treated with
lasmiditan 100 mg or 200 mg were more likely to be MBS free at the
two-hour time point assessment than patients treated with placebo
(p < 0.001).
The distribution of baseline associated symptoms present in each
dose group was relatively even.
BASELINE ASSOCIATED SYMPTOMS, n (%) |
Lasmiditan 100mg(n=503) |
Lasmiditan 200mg(n=518) |
Placebo(n=554) |
Nausea |
210 (41.7%) |
232 (44.8%) |
221 (42.2%) |
Phonophobia |
303 (60.2%) |
322 (62.2%) |
327 (62.4%) |
Photophobia |
386 (76.7%) |
391 (75.5%) |
416 (79.4%) |
None |
34 (6.8%) |
37 (7.1%) |
36 (6.9%) |
However, patients were more likely to select photophobia as MBS
if it were present at baseline than nausea or phonophobia.
This selection preference was expressed as a proportion of the
number of patients who selected that baseline associated symptom as
most bothersome versus the number of patients that had the baseline
symptom.
MBS SELECTED (mITT) |
Selection Preference of MBS |
Nausea |
|
52 |
% |
Phonophobia |
|
33 |
% |
Photophobia |
|
65 |
% |
The proportion of patients absent each associated symptom of
migraine (nausea, phonophobia or photophobia) two hours after
dosing was also measured as a secondary endpoint.
ASSOCIATED SYMPTOMS (ITT) |
Lasmiditan
100mg(n=562) |
Lasmiditan
200mg(n=555) |
Placebo(n=554) |
% of patients nausea free at two hours |
|
64.6 |
% |
|
64.1 |
% |
|
62.1 |
% |
% of patients phonophobia free at two hours |
|
60.7 |
% |
|
58.7 |
% |
|
52.5 |
% |
% of patients photophobia free at two hours |
|
53.9 |
% |
|
51.5 |
% |
|
38.1 |
% |
Patients dosed with lasmiditan had a positive Patient Global
Impression of Change (p < 0.001). The proportion of patients
with a Patient Global Impression of Change of much or very much
better at two hours was 37.2% for lasmiditan 100 mg treated
patients, 37.8% for lasmiditan 200 mg treated patients, and 21.8%
for placebo treated patients.
PATIENT GLOBAL IMPRESSION OF CHANGE [PGIC]
(ITT) |
Lasmiditan 100mg(n=562) |
Lasmiditan 200mg(n=555) |
Placebo(n=554) |
PGIC 2-hours post-dose, n (%) |
|
|
|
|
|
|
|
Very Much Better |
54 (9.6%) |
57 (10.3%) |
34 (6.1%) |
Much Better |
155 (27.6%) |
153 (27.6%) |
87 (15.7%) |
A Little Better |
153 (27.2%) |
143 (25.8%) |
159 (28.7%) |
No Change |
83 (14.8%) |
60 (10.8%) |
146 (26.4%) |
A Little Worse |
16 (2.8%) |
31 (5.6%) |
28 (5.1%) |
Much Worse |
8 (1.4%) |
13 (2.3%) |
14 (2.5%) |
Very Much Worse |
8 (1.4%) |
5 (0.9%) |
3 (0.5%) |
Missing |
85 (15.1%) |
93 (16.8%) |
83 (15.0%) |
|
|
|
|
p value |
< 0.001 |
< 0.001 |
|
Patients dosed with lasmiditan had a significant reduction in
disability related to migraine at the two-hour time point
assessment.
MIGRAINE DISABILITY AT TWO HOURS POST DOSE
(ITT) |
Lasmiditan 100mg(n=562) |
Lasmiditan 200mg(n=555) |
Placebo(n=554) |
Disability 2-hours post-dose, n (%) |
|
|
|
|
|
|
|
Not at All (0) |
181 (32.2%) |
180 (32.4%) |
119 (21.5%) |
Mild Interference (1) |
137 (24.4%) |
115 (20.7%) |
156 (28.2%) |
Marked Interference (2) |
95 (16.9%) |
92 (16.6%) |
122 (22.0%) |
Completely, Needs Bed Rest (3) |
64 (11.4%) |
75 (13.5%) |
74 (13.4%) |
|
|
|
|
p value |
< 0.001 |
< 0.001 |
|
Adverse Events
Lasmiditan was well tolerated as a second dose, with the
majority of treatment emergent adverse events (TEAE) being nervous
system related, and 99.8% of second dose TEAE in lasmiditan treated
patients being described as mild or moderate in nature.
Importantly, there was not a significant increase in cardiovascular
adverse events in patients who took a second dose of lasmiditan
versus placebo. The following table sets forth the percentage of
patients who experienced the specified treatment emergent adverse
event within the safety population following a second dose of study
drug.
TEAE FOLLOWING SECOND DOSE |
100mg/100mg(n=203) |
100mg/Placebo(n=86) |
200mg/200mg(n=159) |
200mg/Placebo(n=79) |
Placebo/Placebo(n=401) |
Dizziness |
5 (2.5%) |
7 (8.1%) |
12 (7.5%) |
9 (11.4%) |
6 (1.5%) |
Somnolence |
7 (3.4%) |
2 (2.3%) |
1 (0.6%) |
1 (1.3%) |
3 (0.7%) |
Paresthesia |
3 (1.5%) |
2 (2.3%) |
0 |
1 (1.3%) |
6 (1.5%) |
Fatigue |
5 (2.5%) |
1 (1.2%) |
2 (1.3%) |
1 (1.3%) |
2 (0.5%) |
Nausea |
3 (1.5%) |
1 (1.2%) |
1 (0.6%) |
2 (2.5%) |
3 (0.7%) |
Vomiting |
2 (1.0) |
0 |
1 (0.6%) |
1 (1.3%) |
3 (0.7%) |
Muscular Weakness |
3 (1.5%) |
0 |
0 |
0 |
0 |
Asthenia |
0 |
0 |
1 (0.6%) |
2 (2.5%) |
1 (0.2%) |
Tachycardia |
0 |
1 (1.2%) |
0 |
0 |
0 |
Palpitations |
1 (0.5%) |
0 |
0 |
0 |
0 |
Analysis
Analysis was conducted using a one-sided test from a logistic
regression model with treatment group and background use of
medication to reduce the frequency of migraines as covariates.
Symposium
Detailed results from SAMURAI were presented at a symposium
during the 5th European Headache and Migraine Trust International
Congress (EHMTIC 2016) that took place in Glasgow, Scotland on
September 17, 2016. A copy of the presentation that was
utilized at the symposium is available on CoLucid’s website at:
http://www.colucid.com/wp-content/uploads/2016/09/SAMURAI-Results-for-EHMTIC-2016-FINAL.pdf
“We have shown in SAMURAI across multiple secondary endpoints
that lasmiditan was effective in treating migraine headache pain
and reducing patients’ disability related to their migraine,” said
Bernice Kuca, Head – Clinical and Regulatory Operations at CoLucid.
“We are also very pleased that, based on the study results,
lasmiditan appears to be effective as a rescue medication and the
tolerability profile of lasmiditan after a second dose looks good,
with patients’ impressions of lasmiditan being favorable as
measured by the Patient Global Impression of Change. We look
forward to further analyses of SAMURAI data.”
About LasmiditanLasmiditan has been designed
for the acute treatment of migraine headaches in adults without the
vasoconstrictor activity associated with previous generations of
migraine therapies. It selectively targets 5-HT1F receptors
expressed in the trigeminal pathway. Lasmiditan has been
given the generic stem name “ditan,” which distinguishes it from
other drug classes, including triptans, the current standard of
care for migraine.
CoLucid is currently enrolling patients in a second pivotal
Phase 3 clinical trial of lasmiditan oral tablets, SPARTAN. The
objective of SPARTAN is to evaluate the safety and efficacy of
lasmiditan (50 mg, 100 mg and 200 mg) in comparison to placebo two
hours after dosing on freedom from migraine headache pain, which is
the primary endpoint, and on freedom from the most bothersome
associated symptom of migraine (nausea, phonophobia or
photophobia), which is the key secondary endpoint. SPARTAN is a
randomized, double-blind, placebo-controlled parallel group
study. The study is expected to treat a single migraine in up
to 2,226 migraine patients with lasmiditan at approximately 140
sites in the United States, United Kingdom and Germany.
CoLucid expects that migraine patients enrolled in SPARTAN will
include those who also have one or more cardiovascular risk
factors, stable cardiovascular disease or known coronary artery
disease (“CAD”). CoLucid has obtained an SPA agreement from the FDA
for SPARTAN. Top-line results from SPARTAN are expected in the
second half of 2017.
CoLucid is also currently enrolling patients in GLADIATOR, a
Phase 3 long-term, open-label trial of lasmiditan. GLADIATOR’s
objective is to evaluate the safety and efficacy of lasmiditan, as
well as resource utilization, functional outcomes and disability.
Migraine patients who have completed CoLucid’s first Phase 3
pivotal trial, SAMURAI, as well as CoLucid’s second Phase 3 pivotal
trial, SPARTAN, are eligible to enroll in GLADIATOR. GLADIATOR is
expected to enroll up to a total of 2,580 patients, who will be
randomized to receive 100 mg or 200 mg of lasmiditan, and treated
for up to eight migraine attacks per month for one year. Based on
the results of GLADIATOR, CoLucid intends to build an appropriate
safety database to support a New Drug Application (“NDA”) for
lasmiditan. At the time of the NDA submission, it is anticipated
that there will be more than 15,000 patient exposures to lasmiditan
in the entire clinical program.
About MigraineMigraine is the leading cause of
disability among neurological disorders in the United States
according to the American Migraine Foundation. An estimated
36 million Americans suffer from migraine. Migraine can be
extremely disabling and costly, accounting for more than an
estimated $20 billion in direct (e.g., doctor visits, medications)
and indirect (e.g., missed work, lost productivity) expenses each
year in the United States.
About CoLucid Pharmaceuticals, Inc.CoLucid
(Nasdaq:CLCD) was founded in 2005 and is developing lasmiditan oral
tablets for the acute treatment of migraine headaches in adults and
intravenous lasmiditan for the acute treatment of headache pain
associated with migraine in adults in emergency room and other
urgent care settings.
Forward-Looking Statements
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to CoLucid’s
expectations for lasmiditan’s efficacy, anticipated marked demand,
anticipated physician prescribing patterns, clinical trial
enrollment goals and the timing of future clinical trials. Actual
enrollment results, market demand, use of cash and other
developments may occur that differ materially from those projected
or implied in these forward-looking statements. Factors that may
cause such a difference include risks that enrollment goals will
not be met, trials may not be commenced or successful or may take
longer to complete than anticipated, regulatory approval may not be
obtained, physicians may not prescribe lasmiditan, and projected
cash needs and expected financial results may be different. More
information about the risks and uncertainties faced by CoLucid are
contained in its periodic reports filed with the Securities and
Exchange Commission. CoLucid disclaims any intention or obligation
to update or revise any forward-looking statements, whether as a
result of new information, future events or otherwise.
CONTACT
Thomas Mathers
Chief Executive Officer
CoLucid Pharmaceuticals, Inc.
(857) 285-6494
Hans Vitzthum
Managing Director
LifeSci Advisors, LLC.
(212) 915-2568
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