MELISSA: Greetings and welcome to the Trevena Corporate
Update.
At this time, all participants are in a listen only mode.
A question and answer session will
follow the formal presentation.
If anyone should require operator assistance
during the conference, please press
star-zero on your telephone keypad.
As a reminder, this conference is being recorded.
I would now like to turn the conference over
to your host Mr. Barry Shin, chief financial officer
for Trevena.
Thank you.
You may begin.
BARRY SHIN: Great.
Thanks, Melissa.
Good morning and thank you for joining
us to discuss our proof of concept data for TRV045.
With me today are Carrie Bourdow, our president and CEO,
and our chief medical officer, Mark Demitrack.
We'll also touch on other business updates.
And as a reminder, Olinvyk was approved by the FDA
in August 2020 and contains all the Saridon
an opioid, which is a Schedule II controlled substance
with a high potential for abuse similar to other opioids.
It's indicated in adults for the management
of acute pain severe enough to require an IV opioid analgesic
and for whom alternative treatments are inadequate.
As with all opioids, serious life-threatening or fatal
respiratory depression may occur in patients
treated with Olinvyk as indicated in the boxed warning.
The safety information, including the boxed warning
and full prescribing information are all
available on olinvyk.com.
We'll also be making forward looking statements
under federal securities law, which
are subject to risks and uncertainties related
to our business, including those covered in our filings
with the SEC.
We undertake no obligation to update these statements
beyond today.
I'll now turn the call over to Carrie.
CARRIE BOURDOW: Thank you, Barry.
Good morning, everyone.
Thanks for joining us today.
Trevena is a company with a novel
platform focused on innovative new medicines for CNS
disorders.
All of our assets are new mechanisms wholly owned
by us discovered in our own labs.
Alembic was our first new chemical entity
that we took from discovery to approval.
Today we're focusing on the middle box
on this slide, our novel S1P modulator program.
And it's an exciting day because we're here
to review preliminary results from two proof of concept
studies for TRV045, our novel S1P receptor modulator.
You may be familiar with other blockbuster S1Ps
like fingolimod.
And while TRV045 is part of this family,
it has a unique mechanism of action
that we believe will allow us to target
a range of CNS disorders.
Trevena has been doing work for the last few years
with TRV045 as a non-opioid for chronic pain conditions.
The NIH has been studying 045 in their epilepsy therapy
screening program known as ETSP and has generated interesting
non-clinical epilepsy data.
After we announced positive first in human phase I studies
late last year, we initiated two proof of concept studies
to gain further insight into the unique mechanism
and to evaluate CNS target engagement.
I'm very pleased with these results
because what we've demonstrated in both studies
is evidence of CNS activity.
And despite the small sample size,
we showed a statistically significant analgesic effect
in a validated model for neuropathic pain.
The TMS study showed interesting changes in EEG results
and early reduction in cortical excitability,
as well as additional evidence of CNS activity
that complements the target engagement pain card study.
We now have further insight into the novel mechanism of action
of TRV045 and we believe these results
support future development either on our own
or with a partner.
Let me now turn the call over to Mark
to walk through the results after which I'll
provide some additional business updates.
Mark?
MARK DEMITRACK: Thank you, Carrie.
As Carrie indicated, this has been
an exciting quarter for our clinical development team.
And today I'm pleased to report the preliminary findings
from our two proof of concept studies for TRV045,
our novel S1P receptor modulator.
Before discussing the data I'd like to provide some context
for why we are so excited about the opportunities we see in 045
And what sets it apart from other drugs in this class.
This slide highlights one of the main features of TRV045.
We believe that because of how rapidly the bound drug receptor
complex is internalized and recycled reflected
in the steps shown in the green box at the bottom,
TRV045 should be devoid of any effect on circulating
peripheral lymphocytes.
In our prior phase I study results
we saw no reduction in lymphocyte levels, which
we believe will lead to no long term immunosuppression.
This next slide shows another important property of 045,
namely its targeted specificity for the type I S1P receptor.
We believe this is important since the type I receptor is
highly expressed on cell targets of interest
in the brain, astrocytes and microglia,
both implicated in brain inflammation.
This was a critical aspect of 045 properties,
which led us to investigate its potential application
for disease targets like neuropathic pain and epilepsy
since these cells are believed to play an important role
in the regulation of brain signaling events key
to the development of chronic pain,
and to play key roles in the physiology of how seizures
develop and how they persist in causing epilepsy.
With that as background, we embarked on our clinical proof
of concept study program with two key goals
in mind outlined on this slide.
First, we wanted to provide evidence
that TRV045 penetrates the CNS and engages its target
as demonstrated by appropriately chosen pharmacodynamic outcome
measures in humans.
Second, we plan to measure plasma concentrations
during these studies to help guide future development
of our next generation drug formulation
and to help frame our dose selection
considerations for subsequent phase II development.
Finally, we wanted to provide additional safety
and tolerability data to support what we already
saw in our prior phase I study.
To accomplish these goals, we chose
to pursue two different, but complementary proof of concept
studies, each with different design
features, pharmacodynamic measures,
and clinical targets in mind to help guide our path forward.
The first study, which we've referred
to previously as the target engagement study employed
a variety of human experimental pain models to help
probe the peripheral and central actions
of TRV045 shown on this slide.
This study conducted in 25 male and female subjects
used a placebo-controlled single dose,
dose ranging crossover design.
The dose is chosen based on the PK parameters
we saw in our prior phase I study.
The pharmacodynamic endpoints examined in the target
engagement study are shown on the lower portion
of this slide, an assay at a broad range of pain modalities,
such as pressure, heat, electrical, and cold pain
and also used capsaicin as a skin irritant, which serves
as a model of neuropathic pain.
Second, proof of concept study used transcranial magnetic
stimulation, or TMS, to probe the potential effect of 045
on cortical excitability in the brain and was conducted in 25
male subjects.
This study used a placebo-controlled multiple
dose crossover design with 045 given over 4 days and measured
outcomes using electroencephalography, or EEG,
and electromyography, or EMG, to track changes in brain
electrical activity after dosing with TRV045.
We announced the preliminary results
from both of these studies today.
And I'm very pleased to report that the results provide us
with a wealth of encouraging information and offer insights
into the potential path forward for our future development
efforts with 045.
I'll summarize the most salient findings now.
While we expect to receive the final safety
and tolerability data by early fourth quarter of this year,
I'll note that there were no SAEs or discontinuations
due to study drug-related adverse events in either study.
In the target engagement study, despite the small sample size,
we saw a statistically significant
dose-dependent treatment effect on the principal model
for neuropathic pain, namely mechanical allodynia
by Von Frey testing measured on skin
exposed to topical capsaicin.
I'd like to note that the results seen with this model
are important since capsaicin irritation of the skin
is recognized as a valid experimental model
of neuropathic pain in humans and therefore, supports
the hypothesis for the potential use of TRV045
for neuropathic pain indications.
The analgesic effect of 045 in this model is shown in two ways
on this slide.
On the left side, you can see that this analgesic effect was
evident when measured in the area surrounding
the region of skin where the capsaicin was directly
applied, the so-called secondary allergenic area.
On the right, we also saw the analgesic effect
when we measured the total surface area affected,
which includes the area of capsaicin application
or the total allergenic area.
For each of these graphs, the surface area of pain is shown.
So as the bars go down, this means
that the area of painful sensation is shrinking.
In both analysis the results show
statistically significant reductions in pain sensation
or mechanical allodynia with both the 150 milligram and 300
milligram doses.
Note also that the effect is evident beginning
2 hours after dosing and nicely followed
the trajectory of the plasma concentrations of the drug,
which generally show maximal concentrations around 4
to 6 hours after dosing.
The PK exposure we achieved in this study
was consistent with the levels seen
at these doses in our earlier phase one work
and the half-life was comparable to the prior phase I
study, which would support anticipated once daily dosing.
To summarize, these data on the mechanical allodynia model
were statistically significant, dose-dependent and provide
support for the hypothesis that TRV045
has the potential for use in neuropathic pain in patients.
Also, the outcomes at the 150 milligram and 300 milligram
doses will help to guide future decisions about dose selection
as we advance towards future clinical studies in patients.
In addition to the mechanical allodynia findings,
additional trends were seen in several other pain models,
including on the cold pain test, on measures of heat pain,
and on one of two different measures of electrically
stimulated pain though these results did not achieve
statistical significance.
Some of the pain modalities studied, including pressure
pain and conditioned pain modulation
showed no statistically significant effects or trends.
It's important to note that this pattern of outcome
with a statistically significant effect on the most
relevant model for our intended neuropathic disease target
along with evidence of analgesic effect on select other pain
measures is encouraging as it suggests specificity
in the mechanism of pain relief.
Finally, results of the mechanical allodynia endpoint
indicate that TRV045 is entering the brain
since the pain signals in this model
depend upon central pain signaling processes sometimes
referred to as central sensitization.
We've had the opportunity to discuss these top line results
with several of our external advisors, all of whom
agree that the results are very exciting.
Results from the second proof of concept study using
TMS to probe brain electrical activity using both EEG and EMG
methods were also encouraging.
While many of the outcomes did not
achieve statistical significance,
the results did provide additional statistically
significant evidence indicating CNS penetrance of TRV045
as shown through measurable changes in select measures
of brain electrical activity on the resting state EEG power
spectral analysis.
Among the EEG-related endpoints measured in the study resting
state EEG obtained before and after administration of 045.
On the first and the last or fourth day of dosing
demonstrated statistically significant increases
in the power spectral density in several
of the middle to higher frequency bands including
alpha, beta, and gamma waves.
These changes were evident on day 1
and became more prominent on day 4 of dosing.
The changes on day 4 are shown on this slide for 045 compared
to placebo.
With 045, an increase in alpha waves was the most notable
observation with increased power evident in the frontal region
and in the parietal regions in the back of the brain in both
the left and right hemispheres.
The increase in beta and gamma wave power spectra
were noted over the frontal regions only.
Alpha waves are generally considered
to be associated with conscious arousal and alertness
while beta waves are thought to be associated
with GABA-mediated inhibitory corticospinal neurotransmission
and gamma waves are generally associated
with cognitive processing, learning, and memory.
In addition to these changes, we also
studied the slower brain wave spectrum in the delta and theta
wavelengths.
These EEG wavelengths are generally
associated with sedation and sleep.
And activity in these power spectra
are increased with some antiepileptic drugs
and are thought to correlate with their reported
adverse effects on cognitive function in patients.
Therefore, we noted with interest
that unlike the changes in the mid to higher frequency
brainwave bands, there was a statistically significant
decrease in the slow delta brain waves,
again, in the frontal region and no difference in slow theta
brain waves.
Among the EMG-related endpoints measured in the study
TRV045 demonstrated evidence of reduction
in cortical excitability on day 1 of drug dosing in response
to single pulse TMS.
The difference in mean peak motor
evoked potential or amplitude was minus 304 microvolts
though this result did not achieve
statistical significance.
This outcome for 045 is shown on the left of this slide.
For context, on the right side are the results
of the study guide in the same laboratory
also using TMS-EMG to monitor amplitude change
in a different population of subjects.
The map decrease, we observed in our study
it's of a magnitude similar to that
seen with other known antiepileptic drugs
in the other study shown here.
Although we can't directly compare these outcomes
as there have not been head-to-head comparative
studies, they do provide some context
for interpreting what we are seeing in our results.
There was no difference in mean peak map amplitude on day 4
and no differences in resting motor threshold on day 1,
or day 4, or on other EMG-related endpoints.
In our study, we examined only one dose of 045 and measured
amplitude and resting motor threshold only at one post-dose
timepoint due to the complexity of the testing demands of this
study.
Overall we believe these early results are encouraging.
We are very pleased with the results of these two studies.
And as I mentioned above, we've received
positive initial feedback from discussions with our advisors
on both of them.
Taken together we believe these data
show that TRV045 gains access to the CNS
and engages the brain in a manner
consistent with the results we observed in our animal models
in both neuropathic pain and epilepsy.
In addition, we demonstrated a statistically significant
treatment effect in the mechanical allodynia model,
which is particularly noteworthy since it is considered
to be a valid experimental model of neuropathic pain
and central sensitization processes in the brain.
We also showed interesting statistically significant
effects on brainwave activity that may
be relevant across indications.
And finally, we showed promising evidence of early reductions
in cortical excitability.
We'll study these preliminary results
in more detail in the coming months
and also expect additional data from the ETSP, which
is studying TRV045 as a potential disease modifying
therapeutic for epilepsy prevention.
We plan to continue to advance toward future clinical studies
in patients either on our own or with a strategic partner
and look forward to updating you soon.
I'd now like to open the call for questions.
Operator?
MELISSA: Thank you.
If you'd like to ask a question, please
press star-one on your telephone keypad.
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Our first question comes from the line of Jason Butler
with JMP Securities.
Please proceed with your question.
JASON BUTLER: Hi, thanks for taking the question
and congrats on the results.
Maybe just at a high level, can you just give us some thoughts
here on next steps.
How are you going to prioritize the two different settings
chronic pain versus epilepsy?
How you're thinking about the different epilepsy populations
you could study.
And then on the funding side of things, just how you're
thinking about prioritizing partnerships
versus go alone and different indications.
And I have a follow-up.
Thanks.
CARRIE BOURDOW: Great.
Thank you, Jason.
I appreciate the questions.
Yeah, so we are very excited about this data.
And as you heard, we're thinking about how we're
going to approach next steps.
First, I think we need to see the full safety
and tolerability data on the epilepsy side,
we're waiting for the NIH data on seizure prevention.
We're a little bit further ahead as a company
on neuropathic pain and I think this data then
could lead to a more definitive studies in patients
a little bit more quickly.
But the NIH has been really interested in this compound
and has been accelerating some of their work in epilepsy.
So I'd like to see what the seizure prevention data looks
like before we would declare, I think, on what models we might
be wanting to do in epilepsy.
But Mark, certainly has been thinking about it.
As you heard, he's meeting with KOLs both in neuropathic pain
and in epilepsy to prioritize and think about next steps.
As it relates to partnerships or doing on our own,
I think that was your question, there are certainly phase II
type studies that we could do on our own,
very targeted studies that could bring forward 045 and advance
it.
So those are some of the things that we're thinking about
and we'll be back out with our plans here relatively soon.
Mark, anything you want to comment around
the patient populations you're thinking about?
MARK DEMITRACK: Well, we've talked
in the past about the epilepsy targets of interest
and the data that we've assembled
to date we think certainly points us
in the direction of refractory epilepsy,
a lot of the basic models that ETSP has studied
modeled in that direction.
And more importantly, the changes that we've seen that
045 appears to exert on immune mediators in the brain is one
aspect of that's particularly excited our advisors as it may
play a potential role in actually modifying the course
of the disease and also for some orphan types of epilepsies
where inflammatory process or immune-mediated events play
a role in the propagation of those illnesses.
So there are a couple of different avenues
in front of us.
And I would say for neuropathic pain it's similar.
We've learned and we are learning a tremendous amount
from the data that we've generated here that point us
to particular understandings about the mechanism of 045.
The efficacy and the mechanical allodynia model,
for example, does suggest that receptors like TRPA1
may be an important target for us to think about.
That narrows down a bit the way we
might shape inclusion criteria or even
delete disease selection targets in the neuropathic pain space.
Small fiber neuropathy, for example,
comes up as an area that is, I think, a pretty fruitful for us
to dig into.
Even in some of the larger targets like OA,
for example, or other neuropathy targets, even though large
based on the mechanism we may be able to narrow down our focus
so that we can have an efficient understanding of proof
of concept in that work moving forward.
CARRIE BOURDOW: I think because Mark and his team
studied so many different aspects of pain it really
helped us think about and derisk frankly other
studies that we might want to take on.
So I there are some orphan pain indications you're also
thinking about in addition.
MARK DEMITRACK: That's right.
CARRIE BOURDOW: Yeah.
MARK DEMITRACK: That's right.
There are some orphan pain indications
where the literature suggests that central sensitization may
play an important role in things like sickle cell disease
even some subsets of patients with Ehlers-Danlos syndrome,
for example, are areas that we've been interested
in our discussions.
JASON BUTLER: Great.
And then just on the Capsaicin data, just data model data,
could you just put the magnitude of change
into context used for neuropathic pain
like gabapentin?
And then I know it's still early,
but can you maybe frame the size and scope of a phase II
study in patients that would be informative
or could be a next step?
MARK DEMITRACK: Sure.
Well, I can comment on the size of the effect
in a couple of ways.
One is just the shear strength of the statistical signal.
When you look at it as a stand alone piece of data
it is of a magnitude that in statistical terms,
we would consider large.
You have effect sizes that are approaching on the order of 0.9
or 1 here, that's a very meaningful change
in statistical terms.
The capsaicin model has been used in a variety of ways
and including with gabapentin.
And when we look at data from comparable models of capsaicin
irritation with drugs like that with opioids,
these are the kinds of changes that we see in those models.
I'd also point to some of the more recent data
even with some of the compounds like the nave inhibitors that
use similar types of neuropathic pain model targets.
So we're pretty pleased with the results we've seen here.
In terms of the phase II, like I was saying earlier,
our approach in the near term is going
to be to build on the understanding we have
as to where this data points us mechanistically
and then to think efficiently about clinical targets.
So again, think more selected populations
where we can get a homogeneous patient sample
and get a very robust signal in a quick manner.
So those are the kinds of things we're beginning
to think about at this stage.
CARRIE BOURDOW: Yeah, our plan is
or our thinking is to have a very targeted study
to get this drug into patients, that would be the next steps.
And so that's why Mark's been spending time with KOLs.
Obviously, we just got the data, so he's
been thinking about models by presenting the data now
to the KOLs and think through next steps
to get it a targeted phase II study in patients.
And as I mentioned, we're further ahead
with neuropathic pain, but I'm really
anxious to see the NIH's data on seizure prevention as well.
JASON BUTLER: OK, great.
Thanks for taking the questions.
And congrats, again, on the results.
CARRIE BOURDOW: Thank you, Jason.
Appreciate it.
MELISSA: Thank you.
Our next question comes from the line of Douglas Xu
with H.C. Wainwright.
Please proceed with your question.
DOUGLAS XU: Hi, good morning.
Can you hear me?
CARRIE BOURDOW: Yes.
DOUGLAS XU: So congrats on the data.
I'm just curious starting on the pain side,
is your inclination to start in broader indications
and then potentially narrow down or take
the opposite because that could potentially be a faster course?
And I guess a similar question in terms of epilepsy, what
are the immediate next steps?
I mean, is there anything that you can do or are you
really waiting to see what NIH comes up with?
Thank you.
CARRIE BOURDOW: Yeah.
Doug, so good questions.
And as I said earlier, let me take on the pain side.
So there are subsets in the broader markets,
as Mark talked about.
So if you think about OA or back pain,
some of these large markets, there are subsets of patients
within those markets that we think based on the mechanism
of action and the area where we're headed towards
neuropathic pain would be very interesting for 045.
And then as Mark described, there's
even potentially some orphan area like Ehlers-Danlos.
On the pain, I'm sorry, on the epilepsy front
I think it's going to be important for us
to see the seizure prevention.
We certainly could move forward without seeing the ETSP data,
without seeing the NIH data.
And so we're talking with our advisors
on next steps on epilepsy as well.
Mark, I don't know if there's some specifics
you want to give on that.
MARK DEMITRACK: Well, I can echo what I had mentioned earlier.
I think for us right now we've learned a tremendous amount,
we believe, about the mechanism here particularly from the pain
data.
So it points us in a more targeted way
when we think about selection of subjects in our first step
into patient-based studies.
So our goal here is to get a clear, unambiguous, convincing
signal in those next step studies.
So linking the mechanism in that way to selection of patients
is critical and it's an analogous type of approach
when we think about epilepsy.
I think the remaining ETSP data has been informative.
But don't forget that we've already
discussed with you in the past that we
have tremendous amount of data that ETSP has already
generated that we believe is quite informative.
Carrie?
CARRIE BOURDOW: Yeah the only other comment I want to make
is what Mark commented on and I did
as well is that we were talking about this on our own
or with potential partners.
And so some of those larger indications, both in pain
and in epilepsy, we think based on the discussions that we're
having with partners that would be
really interesting for a partner to take this forward.
And now that we've shown CNS target engagement activity,
those are going to make those conversations even more
fruitful.
So think about partners potentially
taking on some of those larger indications
and Trevena thinking about more of a targeted advancement
into a phase IIA type study.
Does that help, Doug?
DOUGLAS XU: Yeah, that's helpful.
Then I guess, Carrie, just maybe it'd
be helpful for everybody just to outline the timelines
that you're thinking about for next steps and milestones.
CARRIE BOURDOW: Yeah, great.
So the NIH data, the epilepsy data,
we're expecting that in the second half of this year.
The full safety, tolerability data
we're expecting that early next quarter
or early fourth quarter.
So those are the two data sets.
We actually have also a non-clinical study running
in infantile spasm, we're expecting
that in the second half of this year.
Those are the, I guess, three big data sets.
And then we announced preliminary data today.
We're not expecting too much more from this study,
but that's part of it.
Mark is already speaking with advisors, showing them the data
and talking about what we've seen
and looking at the CNS target engagement
and moving forward on that.
And so that gives you a sense that we're not
talking about a long time frame here
before we would get back to and let them know next steps.
DOUGLAS XU: OK, great.
Thank you.
CARRIE BOURDOW: Thank you.
MELISSA: Thank you.
Ladies and gentlemen, that concludes our question
and answer session.
I'll turn the floor back to Ms. Bourdow for any final comments.
CARRIE BOURDOW: Great.
Well, thank you, again, for joining us this morning.
And as you can hear, we've generated
evidence that supports TRV045 innovative mechanism of action
in CNS target engagement.
As we've talked about in part in the Q&A
the market opportunity for once daily novel solutions
in both chronic pain and epilepsy is large.
And so our next steps, as we've described,
first, we'll provide updates on the full safety
and tolerability results, which we're
expecting early fourth quarter.
We have promising evidence of the therapeutic potential
of TRV045 in neuropathic pain, statistically significant EEG
data now, we have that now in hand.
And as I mentioned, we're waiting for the NIH-ETSP data.
We're already working with our KOLs and potential partners
to plan the additional clinical studies in patients.
Before closing, let me also call your attention
to the business update we issued this morning where we announced
that our partner in China, Nhwa, achieved
the milestone of first commercial sale of Olinvyk.
As a result, we are now in receipt of the $15 million
tranche that was part of our ex-US royalty-based financing
with our bridge.
That funding is in addition to the 28.1 million
in cash we previously reported at the end
of the second quarter.
We also expect new Olinvyk data from the volition study
in the coming weeks and we announced new abstracts
that will be presented at the American
Society of Anesthesiologists next month.
Thank you, again, for calling in today.
MELISSA: Thank you.
This concludes today's conference call.
You may disconnect your lines at this time.
Thank you for your participation.