UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
February 23, 2017
Date of Report (Date of earliest event reported)
Flex Pharma, Inc.
(Exact name of registrant as specified in its charter)
Delaware | 001-36812 | 46-5087339 | ||
(State or other jurisdiction | (Commission File Number) | (IRS Employer Identification No.) | ||
of incorporation) | ||||
800 Boylston Street, 24th Floor Boston, MA | 02199 | |
(Address of principal executive offices) | (Zip Code) | |
Registrant’s telephone number, including area code: (617) 874-1821
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligations of the registrant under any of the following provisions:
o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Item 7.01 Regulation FD Disclosure.
On February 23, 2017, Flex Pharma, Inc. (the "Company") will present a poster entitled "Flex-201: A Multicenter, Randomized, Blinded Study to Evaluate the Efficacy and Tolerability of FLX-787 in MS" at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017 Forum. The poster is furnished herewith as Exhibit 99.1.
The information contained in this Item 7.01 and Exhibit 99.1 attached hereto shall not be deemed "filed" for purposes of Section 18 of the Securities and Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, except as expressly set forth by specific reference in such filing.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
Exhibit No. | Description | ||
99.1 | Flex Pharma, Inc. poster. | ||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Flex Pharma, Inc. | ||
Dated: February 23, 2017 | ||
By: | /s/ Robert Hadfield | |
Robert Hadfield | ||
General Counsel and Secretary | ||
INDEX TO EXHIBITS
Exhibit No. | Description | ||
99.1 | Flex Pharma, Inc. poster. | ||
Novel Treatments
for Neuromuscular Conditions
Flex-201: A Multicenter, Randomized, Blinded Study to Evaluate the Efficacy
and Tolerability of FLX-787 in MS.
Jennifer Szegda, Brooke Hegarty MSHS, Laura Rosen MD PhD, Glenn F. Short III PhD, Jennifer Cermak PhD,
Christoph Westphal MD PhD and Tom Wessel MD PhD
Flex Pharma, Inc. Boston, MA 02199
Poster Number: P034
Background: FLX-787 is a TRPA1/TRPV1 ion channel activator that is efficacious in decreasing
muscle cramp intensity in an electrically-induced cramp (EIC) model in healthy volunteers and
cramp frequency in otherwise healthy subjects with nocturnal leg cramps (NLC). To
understand the potential safety and efficacy of FLX-787 in indications where spasticity is
prevalent, the Flex-201 study was initiated in patients with Multiple Sclerosis (MS).
Objectives: Flex-201 has been designed to assess the efficacy and tolerability of FLX-787 as
measured by: 1.) cramp/spasm frequency; 2.) Modified Ashworth Scale; 3.) Tardieu Scale; 4.)
Numerical Rating Scale; 5.) Barthel Activities of Daily Living; 6.) Timed 25-Foot Walk; 7.) Clinical
Global Impression; 8.) Quality of Life questionnaires (SF-36 and MSSS-88); and 9.) the Insomnia
Severity Index Sleep Survey.
Methods: Flex-201 is a multicenter, randomized, blinded, cross-over study to investigate the
effects of FLX-787 in subjects with MS and symptoms of spasticity, spasms and cramps (n=50
subjects). After a 2-week Run-in period to establish baseline spasticity and cramp/spasm
frequency, subjects were dosed with either FLX-787 or placebo for 14-days followed by a 7-day
intervening wash-out period and then crossed-over for an additional 14-days of dosing with
the other treatment.
Results: In this exploratory phase 2 study, FLX-787 will be assessed on both the initial parallel
portion of the study and the crossover period.
Conclusion: Results in human studies suggest that repeat dosing of FLX-787 may cause a
general increase in the inhibitory tone of spinal circuits, and limit cramps, spasms and
potentially spasticity in those living with MS. The beneficial characteristic of very low systemic
exposure to unconjugated FLX-787 may also reduce the risk of drug-drug interactions and
systemic effects seen with other MS agents.
Summary
1. Minetto MA, Holobar A, Botter A, and Farina D. Exerc. Sport Sci. Rev. 41(1): 3-10, 2013.
2. Milanov, I. Electromyogr Clin Neurophysiol. 32 (2): 73-9, 1994.
3. Okun, M. & Lampl, I. Nature Neurosci. 11: 535–537, 2008.
4. Beilefeldt et al., Am J Physiol Gastrointest Liver Physiol 294: G130–G138, 2008.
5. Yu et al., Am J Physiol Gastrointest Liver Physiol 297: G34–G42, 2009.
6. El-Tawil S. et al.. Cochrane Database of Systematic Reviews Issue 12, Art. No.: CD005044,2010.
7. National Institute of Neurological Disorders and Stroke
References
Topical Chemical Neuro Stimulation
Figure 1. Overview of suspected mechanism of muscle cramps and methods of cramp
inhibition by activation of TRP ion channels. Muscle cramping is caused by the uncontrolled
and repetitive firing of α-motor neurons in the spinal cord (1), resulting in maintained
contraction of the muscle. FLX-787 is thought to exploit a general principle of neural circuits
whereby strong excitatory sensory input from one source enhances overall inhibitory tone by
increased recruitment of inhibitory neurons, thereby reducing excitability in other parts of the
circuit (3). FLX-787 stimulates primary sensory neurons in the mouth, esophagus and stomach
by activating TRPV1 and TRPA1 ion channels (4,5). When activated, these sensory neurons,
which project both directly and indirectly to the spinal cord, enhance the inhibitory tone in
spinal cord circuits to reduce repetitive firing of α-motor neurons which prevents or reduces
the frequency and intensity of muscle cramps and spasms.
EIC Efficacy of FLX-787
Ion channel in cell
surface membrane
FLX-787, taken orally, topically stimulates primary
sensory neurons in the oropharynx and esophagus
by activating TRPV1 and TRPA1 ion channels.
Stimulated sensory neurons cause a reflex-
mediated increase in monoamine release at
the spinal cord terminals of the locus coeruleus
and dorsal raphe nucleus.
Modulation at the spinal level occurs either by
enhancing presynaptic inhibitory interneuron
signaling or by postsynaptic inhibition directly on
a-motor neurons.
OUR HYPOTHESIS
Inhibitory modulation of the a-motor neuron
circuit reduces excessive firing.
Reduction in a-motor neuron hyperexcitability
inhibits muscle cramp or spasm
1
5
2
4
a-motor
neuron circuit
3
0 1 0 2 0 3 0
0
5 0
1 0 0
1 5 0
M e a n ( + / - S D ) P l a s m a c o n c e n t r a t i o n s ( n g / m L )
o f F L X - 7 8 7 i n d o g p l a s m a
T i m e ( h )
C
o
n
c
e
n
tr
a
ti
o
n
(
n
g
/m
L
)
P a r e n t F L X - 7 8 7 ( d o g , 6 0 m g / k g / d a y )
T o t a l F L X - 7 8 7 ( d o g , 6 0 m g / k g / d a y )
1 0 2 0 3 0
- 5
0
5
1 0
1 5
2 0
2 5
M e a n ( + / - S D ) P l a s m a c o n c e n t r a t i o n s ( n g / m L )
o f F L X - 7 8 7 i n h u m a n p l a s m a
T i m e ( h )
C
o
n
c
e
n
tr
a
ti
o
n
(
n
g
/m
L
)
P a r e n t F L X - 7 8 7 ( h u m a n , 6 0 m g O D T )
T o t a l F L X - 7 8 7 ( h u m a n , 6 0 m g O D T )
• Bioanalytical methods for FLX-787 were validated with LLOQ of 0.100 ng/mL; Total FLX-787
methods are semi-quantitative with LLOQ of <0.200 ng/mL
• The variability noted in the metabolic conversion of FLX-787 to conjugates suggests rapid
and extensive phase 2 metabolism (first pass likely at the enterocyte level)
• Chemical Neuro Stimulation of TRPA1/TRPV1 by FLX-787 is a local, topical
phenomenon that does not require systemic bioavailability and may result
in indirect inhibition of a-motor neuron hyperexcitability.
• FLX-787 reduces muscle cramp intensity in an EIC-model of the foot.
• FLX-787 has shown the potential to reduce cramp frequency and pain in an
exploratory human NLC study.
• FLX-787 is well tolerated, and no treatment-related SAEs have been
reported in clinical studies to date.
• In the study population, cramps/spasms are strongly associated with pain.
• 40% of subjects who experience high prevalence of cramps/spasms also
experience more pain, which may effect overall quality of life.
• Given the observed correlations, if FLX-787 limits cramps/spasms in
patients with MS it could potentially reduce pain and stiffness as well.
• An exploratory Phase 2 study in MS, Flex-201, is currently underway with
planned data readout expected by year end.
0 1 0 2 0 3 0
0
2 0 0 0
4 0 0 0
6 0 0 0
M e a n ( + / - S D ) P l a s m a c o n c e n t r a t i o n s ( n g / m L )
o f F L X - 7 8 7 i n r a t p l a s m a
T i m e ( h )
C
o
n
c
e
n
tr
a
ti
o
n
(
n
g
/m
L
)
P a r e n t F L X - 7 8 7 ( r a t 5 0 0 m g / k g / d a y )
T o t a l F L X - 7 8 7 ( r a t , 5 0 0 m g / k g / d a y )
NLC Efficacy of FLX-787
Objectives and Endpoints
Objective: To assess the safety, tolerability, and exploratory efficacy of FLX-787 vs. inactive control
over a 2-week period in MS subjects with spasticity and muscle cramps/spasms as assessed by the
following endpoints:
Efficacy:
1) Cramp/spasm frequency (collected by daily IVRS);
2) Modified Ashworth Scale (MAS);
3) Tardieu Scale (TS);
4) Numerical Rating Scale (NRS which includes: spasticity severity (IVRS),
spasm severity (IVRS), pain intensity (IVRS), fatigue, tremors, bladder symptoms, sleep);
5) Barthel Activities of Daily Living (ADL);
6) Timed 25-Foot Walk (T25-FW);
7) Clinical Global Impression - Global Improvement (CGI-I) Scale;
8) Quality of Life (QoL) questionnaires – 36-Item Short Form Survey (SF-36)
and Multiple Sclerosis Spasticity Scale (MSSS-88);
9) Insomnia Severity Index (ISI) Sleep Survey.
Safety:
1) Percentage of subjects with treatment-emergent AEs
2) Change in vital signs or physical exam findings from Screening
3) Change in laboratory or ECG findings from screening
Low Systemic Exposure of FLX-787
Cramp/Spasm & Pain Prevalence
Conclusions
A cross-over, randomized, blinded, placebo-controlled study (n=72) was performed to study the effect
of FLX-787 orally disintegrating tablet (ODT) in night leg cramps.
An exploratory ANOVA sub-analysis was performed limited to subjects likely to have night leg cramps
based upon a post hoc questionnaire administered after study completion.
• 27 of 63 questionnaire respondents were independently adjudicated as having likely NLC.
• To avoid potential influence of carry-over effects observed during cross-over analysis,
ANOVA was restricted to the first treatment exposure.
• The analysis is based on the overall active (17 + 25 mg FLX-787) vs placebo (aspartame + 0.5 mg
FLX-787) comparison.
Effect size based on analysis: Cramp Frequency: 0.53 and Pain: 0.83
Average effect size of cramp frequency derived from quinine literature is 0.12 (95%CI[-3.5,-1.36]). (6)
Flex-201 Methods
Exemplary dataset demonstrating
that FLX-787 (29 mg), a single
molecule that co-activates TRPA1 and
TRPV1, affords a decrease in
electrically-induced muscle cramp
intensity. The treatment effect was
calculated based upon the area under
the curve (AUC) of a surface EMG
measurement of cramping relative to
a pre-treatment baseline cramp
(n=9). FLX-787 treatment led to a 5-
fold reduction in delta-AUC compared
to a study specific vehicle control.
FLX-787 treatment demonstrated a
significant difference from vehicle
control (ANOVA, p < 0.001).
Figure 2.
Figure 3.
Figure 4.
Run-In Analysis
Subject-reported muscle Cramp/Spasm frequency and overall pain is being recorded
by daily IVRS Collection.
Mid-point analysis (n=25) was performed on Run-in IVRS data to understand the overall
prevalence of muscle cramps and spasms, as well as associated pain, in the study
population.
Pearson Correlation Coefficient analysis performed to understand any correlations
which may exist between IVRS endpoints.
Correlation Analysis
Spasticity and Muscle Cramps/Spasms in MS
• 250-350k people with MS in the US. (7)
• Current anti-spasmodic therapies provide incomplete resolution of spasticity
and cramps/spasms.
• Aberrant a-motor neuron hyperexcitability is likely responsible for spasticity
and muscle cramps/spasms in MS patients.
• While common symptoms in MS, little data exists on the prevalence of muscle
cramps and spasms in the literature.
Figure 5. Multi-Center Trial in MS: A randomized, double-blind, placebo-
controlled, cross-over study to evaluate the effects of a FLX-787 on the frequency
of spasticity and muscle cramps/spasms when self-administered twice daily as a
oral solution containing 19 mg.
Period 1
FLX-787
14 days
Period 2
FLX-787
14 days
Period 1
Inactive Control
14 days
Period 2
Inactive Control
14 days
★
★
★
★
★ Study
Visit Completers
(N=50)
★
Recruitment and
Screening
(Spasticity ≥3 mo.
duration without
significant relief when
treated with anti-
spasmodics)
Target
N=60
enrolled
Include if:
1. Last 6 daily NRS
spasticity level
scores during
Run-in sum to
at least 24
2. 3-7 on the CGI
spasticity scale
Run-in
Placebo
capsule
14 days
Baseline assessment at end of 2-week Run-in period
Washout
7 days
• 92% (23/25) of subjects experienced at least one episode of cramps/spasms during the two week
Run-in Period.
• 84% (21/25) of subjects experienced pain associated cramps/spasms.
• Of the 40% of subjects (10/25) who experienced ≥ 25 cramps/spasms over the 2-week period:
• The mean cramp/spasm frequency was 82 cramps/spasms.
• The mean pain score (0-10 scale) was 4.2.
Figure 6.
Figure 7.
• Pearson Correlation analysis reveals
a strong correlation between cramp/
spasm occurrence and pain (p = 0.0002).
• Strong correlation between stiffness
and spasticity self-reported
scores (p = 0.0001).
• Correlation between pain and stiffness
(p = 0.0252).
Pearson Correlation Coefficients, N=25
Prob > |r| under H0; Rho=0