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Vertex Pharmaceuticals Incorporated
Ve r t ex P h a r m a c e u t i c a l s I n c o r p o ra t e d -
Special Call - Vertex Pharmaceuticals
Incorporated
Thursday, December 19, 2024 8:00 AM
Event Participants
Executives
2
Susie Lisa, Reshma Kewalramani
Analysts
10
Jessica Fye, Salveen Richter, Geo!rey Meacham, Michael Yee, Evan Seigerman, William
Pickering, Philip Nadeau, Liisa Bayko, Eliana Merle, Mohit Bansal
Operator
Operator
Good morning, and welcome to the Vertex Pharmaceuticals suzetrigine Phase II results in
LSR conference call. \[Operator Instructions\] Please note this event is being recorded.
I would now like to turn the conference over to Ms. Susie Lisa, Senior Vice President, Investor
Relations. Please go ahead.
Susie Lisa
Executive
Thanks, Drew, and good morning all. I'm Susie Lisa, as the Senior Vice President of Investor
Relations. Thank you for joining us on this conference call to discuss results from Vertex's
Phase II study of ...

24/05/2025, 22:05
Page 1 of 13about:srcdoc
Vertex Pharmaceuticals Incorporated
Ve r t ex P h a r m a c e u t i c a l s I n c o r p o ra t e d -
Special Call - Vertex Pharmaceuticals
Incorporated
Thursday, December 19, 2024 8:00 AM
Event Participants
Executives
2
Susie Lisa, Reshma Kewalramani
Analysts
10
Jessica Fye, Salveen Richter, Geo!rey Meacham, Michael Yee, Evan Seigerman, William
Pickering, Philip Nadeau, Liisa Bayko, Eliana Merle, Mohit Bansal
Operator
Operator
Good morning, and welcome to the Vertex Pharmaceuticals suzetrigine Phase II results in
LSR conference call. \[Operator Instructions\] Please note this event is being recorded.
I would now like to turn the conference over to Ms. Susie Lisa, Senior Vice President, Investor
Relations. Please go ahead.
Susie Lisa
Executive
Thanks, Drew, and good morning all. I'm Susie Lisa, as the Senior Vice President of Investor
Relations. Thank you for joining us on this conference call to discuss results from Vertex's
Phase II study of suzetrigine in painful lumbosacral radiculopathy or LSR. Making prepared
remarks on today's call, we have Dr. Reshma Kewalramani, Vertex's CEO and President.
Joining her for the question-and-answer portion of the call is Charlie Wagner, Chief Financial
O"cer.
We recommend that you access the webcast slides as you listen to this call. The call is being
recorded, and a replay will be available on our website. We will make forward-looking
statements on this call that are subject to the risks and uncertainties discussed in detail in
today's press release and in our #lings with the Securities and Exchange Commission. These
statements, including, without limitation, those regarding Vertex's ongoing work with
suzetrigine in pivotal development in diabetic peripheral neuropathy and future studies in
lumbosacral radiculopathy including the anticipated timing of these studies. Our

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expectations for our suzetrigine programs in acute and peripheral neuropathic pain including
next steps and other programs in our pipeline are based on management's current
assumptions.
Actual outcomes and events could di!er materially. I'll now turn the call over to Reshma.
Reshma Kewalramani
Executive
Thanks, Susie. Good morning, all, and thank you for joining us on short notice. Vertex's
di!erentiated R&D strategy continues to progress in new disease areas, and we are pleased
to announce results this morning from our Phase II proof-of-concept study with the selective
NaV1.8 inhibitor, suzetrigine, in patients with painful lumbosacral radiculopathy or LSR. Let's
jump right into it with Slide 3. The study met its primary endpoint with suzetrigine achieving a
clinically meaningful and statistically signi#cant within group reduction from baseline of 2.02
points in the weekly average of daily leg pain intensity measured on the NPRS scale at week
12 of treatment.
The consistency of suzetrigine's within group treatment e!ect is remarkable, with a clinically
meaningful reduction in pain across all studies done to date.
However, the study also saw similar reductions in the NPRS in the placebo reference arm. The
placebo e!ect in this study was a 1.98 point reduction from baseline to week 12. In short, the
treatment response curve of suzetrigine did not separate from placebo as I'll detail shortly.
Importantly, suzetrigine's safety pro#le continues to be excellent, similar to the #ndings in our
Phase III study, the adverse event rate in the suzetrigine arm was lower than the adverse
event rate in the placebo group. Let me share two additional key points on this slide.
Our interpretation of the study. And our hypothesis emerging from this trial, informed by post
hoc analysis we conducted is that a high placebo response in this study led to a lack of
separation of the suzetrigine and placebo response curves. Importantly, we believe we can
innovate in pain clinical trial design to better control the placebo e!ect and in so doing,
succeed in pivotal development with suzetrigine. As such, our next steps are to: one, take all
the learnings from this Phase II trial and innovate on study design to better control the
placebo e!ect; two, prepare for regulatory interactions; and three, secure FDA's agreement
on an optimized Phase III clinical trial design and requirements for expanding the PNP or
peripheral neuropathic pain indication beyond diabetic peripheral neuropathy. Pending
regulatory agreement, we plan to advance suzetrigine into pivotal development.
To frame the challenge and the opportunity more fully, recall that peripheral neuropathic pain
is a collection of painful conditions uni#ed by the same underlying pathophysiology of nerve
impairment. There are approximately 10 million patients treated for PNP each year in the U.S.,
representing a multibillion-dollar market today despite the fact that essentially all
prescriptions are generic. Nearly 20% of these patients have DPN, where we are currently
enrolling a Phase III program and about 40% of these patients have LSR. These more than 4
million LSR patients have a signi#cant unmet medical need. The currently available treatment
options are associated with high rates of discontinuation, inconsistent dosing, polypharmacy
and o!-label use.
Unlike in DPN, where studies have been conducted for decades, study design, drug

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treatment e!ect, placebo treatment e!ects are well understood and multiple drugs have
secured regulatory approval. In LSR, no drug has been speci#cally approved for this
indication. There are very few Phase II randomized controlled studies and no Phase III trials
evaluating a systemic treatment. This leaves many gaps in understanding, including what
constitutes a meaningful between-group reduction in LSR. On the backdrop of these
challenges with LSR, we see opportunity.
To be clear, to be successful in LSR, we need to innovate in both discovering NaV1.8 and
NaV1.7 inhibitors, as we have been doing, and in clinical trial design to control the placebo
treatment as we see from this study. We look forward to doing so and bringing the promise of
suzetrigine and our portfolio of NaV1.7 and NaV1.8 inhibitors alone or in combination for this
di"cult-to-treat condition. Given the lack of studies and standards as LSR, we set out to learn
more and run a Phase II study in this condition with 3 goals in mind: one, gauge the magnitude
of the treatment e!ect of suzetrigine in LSR; two, understand the magnitude of the placebo
e!ect in LSR; and three, add to our knowledge of the 12-week safety pro#le of suzetrigine.
Our aim was to gather this information via the Phase II study, learn and then use those
learnings to inform our next steps for suzetrigine in LSR. I'll come back to this point.
But before we go there, let's go to Slide 6, which shows the Phase II study design. The
evaluated dose of suzetrigine was 69 milligrams once a day and included a placebo reference
arm. Patients were randomized to receive either suzetrigine or placebo following a 7-day run-
in period to establish their baseline pain score on the NPRS. The primary endpoint was the
within group change from baseline in the weekly average pain intensity on NPRS at week 12.
We also assess other e"cacy endpoints as well as the safety and tolerability of suzetrigine.
Patients, on background stable over-the-counter doses of ibuprofen and naproxen, were
allowed to continue taking these doses and acetaminophen was allowed as needed
throughout the study. Lastly, the placebo arm was included as a reference group, no direct
comparison between suzetrigine and placebos plan, and the study was not designed nor
powered for between group comparisons. Slide 7 details the baseline characteristics and
demographics which were generally balanced across parameters between the 2 groups. Just
over 40% of patients in each arm were on background end stage and continue taking it
throughout the trial. The weekly average of the NPRS was around 6.
The results are on Slide 8. For the primary endpoint of within group change from baseline in
the weekly average of the pain intensity on the NPRS at week 12, suzetrigine showed a
reduction of 2.02 points. This is both statistically signi#cant and clinically meaningful. The
placebo reference arm showed a similar within group reduction in the NPRS with a mean
change from baseline of minus 1.98 at 12 weeks. Slide 9 summarizes safety and tolerability,
which adds to the growing body of evidence supporting suzetrigine's favorable safety pro#le.
Suzetrigine was generally well tolerated with 12 weeks of treatment. The rate of suzetrigine-
related AEs was 22.9%. For context, the rate of placebo-related AEs was 32.4%. The majority
of AEs were mild to moderate. There were no serious AEs related to suzetrigine, and there
were no AEs that led to treatment discontinuation in the suzetrigine arm.
On Slide 10, we plot the time course of pain relief in the suzetrigine and placebo arms on 1
graph. Both the suzetrigine arm and the placebo arm showed similar reductions in the NPRS

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over time. The magnitude of the suzetrigine response from baseline to 12 weeks was
statistically signi#cant. It was clinically meaningful. It was consistent with clinical studies of
Vertex NaV1.8 inhibitors in other neuropathic pain clinical studies, and it was also consistent
with the magnitude of pain reduction with medicines approved for neuropathic pain.
Yet, despite these #ndings, the suzetrigine and placebo arms did not separate, which was
unexpected. To better understand these results, we further interrogated the data. The
placebo response in this study was high. Moreover, we found high site-to-site variability in the
placebo response with some sites having high and some sites having low placebo treatment
e!ects. Putting this all together, our hypothesis is that the high placebo treatment e!ect
observed in this study, driven by some sites led to a lack of separation of the suzetrigine and
placebo curves in the primary analysis.
Moving to Slide 11. To evaluate this hypothesis, we performed post hoc analysis. Let me
describe what we did, and then I'll describe the results shown on the slide. As mentioned,
when we looked at the NPRS data by site, we observed that there were sites with higher
placebo response curves de#ned as pain reduction of more than 2 points and lower placebo
response curves de#ned as pain reduction, less than 2 points.
We segregated the sites into these 2 groups. Of note, approximately 40% of sites were lower
placebo response sites. We then analyze the primary and other endpoints at these lower
placebo sites. What did we #nd when we did these analyses? In the lower placebo response
sites, as shown on this slide, we found that the suzetrigine treatment e!ect was similar to the
suzetrigine treatment e!ect in the primary or overall analysis.
And there was a separation of the suzetrigine arm and the placebo arm. This separation of
the NPRS score in the suzetrigine and placebo arms in this analysis is in line with
expectations. In other words, here, given the suzetrigine within group performance, of
approximately a 2-point reduction, the suzetrigine NPRS pain reduction curve did indeed
separate from the placebo NPRS curve. I want to emphasize that this is a post-hoc analysis.
And as such, comes with all of the caveats of such analyses and needs to be considered
hypothesis generating, not conclusive.
I put weight in this analysis because, one, we had su"cient number of sites to evaluate the
suz and placebo e!ect in the low placebo sites as 40% of the sites were such lower placebo
sites. Two, we performed additional analyses that support the robustness of this e!ect.
Three, the suzetrigine treatment e!ect is consistent in the lower placebo site analysis and the
overall or primary analysis. And the suzetrigine response in this study is consistent with the
treatment e!ect seen with other Vertex NaV1.8 neuropathic pain clinical trials. Four, it is also
consistent with the treatment e!ect of other approved medicines in neuropathic pain; and
#ve, high placebo e!ect and site-to-site variability are known challenges in this space.
Slide 12. In summary, the primary results from this Phase II study in LSR demonstrates
suzetrigine as a consistent and clinically meaningful 2 point within group treatment reduction
in pain and is well tolerated. The adverse event rate is 22.9% in the suzetrigine arm and 32.4%
in the placebo arm. Taken together, including the post-hoc analysis, we see the potential of
suzetrigine to o!er e!ective pain relief, strong safety and an attractive overall pro#le for
patients su!ering from LSR. This is our belief.

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We obviously have yet to demonstrate this potential. To do so, to demonstrate this potential,
we have to innovate in clinical trial design to better control the placebo e!ect. Gain
agreements with FDA on trial design and requirements to expand the suzetrigine indication
beyond DPN, and show that suzetrigine is superior to placebo in a large, well-designed and
controlled Phase III trial. This is exactly what we aim to do. Moving to Slide 13.
Vertex is all in on pain. This slide shows the breadth and depth of our programs. We've
discussed our plans in LSR at length. Let me close with some highlights in the pain portfolio
outside of LSR. We are excitedly awaiting potential approval for suzetrigine in moderate to
severe acute pain with the PDUFA date of January 30, 2025.
Acute pain impacts 80 million Americans and is a multibillion dollar market opportunity
despite being almost entirely generic. We are advancing additional molecules through clinical
development, including VX-993 in 2 Phase II studies, one in acute pain, one in DPN as well as
a Phase I study with the IV formulation. And we continue to make progress in preclinical
development with our NaV1.7 pain signal inhibitor program that may be used alone or in
combination with NaV1.8 inhibitors. With that, we'll be happy to take your questions. I'll turn it
over to you, Susie.
Susie Lisa
Executive
You ready, Drew?
Operator
Operator
\[Operator Instructions\] The #rst question comes from Jessica Fye with JPMorgan.
Jessica Fye
Analyst
My question is really about what's the right way to think about how you design and power a
Phase III trial and what kind of e!ect size you would want to size and power your trial or to the
extent that we can't really use the Phase II to tease that out per se? And then kind of related to
that, if there is the ability to identify sites that might have a lower placebo response, I imagine
you're going to need to go to a lot more sites in Phase III than in Phase II, i.e., not just be able
to kind of identify these Phase II sites where the placebo response is lower. You talked about
kind of innovative ways to manage that. Can you outline what some of those strategies are?
Reshma Kewalramani
Executive
Jess, this is Reshma. Really excellent questions. I'm going to give you a broad framework to
think about this because what we're in the process of doing is completing our interrogation of
the data set to understand every last bit of information that we can. And then, of course, we
have to go to the agency and con#rm that the innovative study design that we want to pursue
is acceptable to them for the indication we seek. But let me give you some broad strokes of
what we're doing.
So bottom line is sometimes when you do a Phase II study, it teaches you exactly what to do
in Phase III. And that's oftentimes the case. Sometimes what you do in Phase II and the results
you get teaches you that you need to do something di!erent. You need to innovate further in
Phase III. That's what we've learned from this trial.

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And so this trial has been exceptionally helpful because remember, the universe of studies in
this LSR condition are small. And even in the small universe, there are unfortunate
complexities like studies are of short duration. They are not necessarily done in the patient
population that we seek to work on, that is to say, pure radiculopathy amongst other
complexities. So #rst, let me tackle your question around sites. It's pretty clear to me that we
need to do some of the, let's call it, usual work that we do when you work on any kind of
subjective measure like pain, like a limited number of sites, really good training of these sites
and sites really training their patients for how to respond to the questionnaires around their
pain in a consistent way over time.
So we will not, in all likelihood, be going to more sites, but rather going to a circumscribed
number of sites. That might mean it takes a little bit longer to enroll, and that's an acceptable
trade-o!. With regard to study design, let me give you some examples. One thing that is done
in studies with subjective endpoints is a placebo run-in, and what that does is, it excludes
patients who have a pronounced placebo e!ect when you run everyone and you run the --
whoever you screen, you run both groups in on placebo. You then exclude patients with a
profound placebo response.
Another thing that's done is enrichment. That's to say, you run patients in on the study drug,
and you only include patients who have a response, i.e., if you're not going to ever feel pain
relief, you're not included in that design. Some people combine placebo run-in with
enrichment. You can do withdrawals as another technique. Withdrawal of the study drug,
withdrawal of placebo to test whether the pain that is a placebo response is equal when you
remove the study drug.
Those are a couple of examples of what can be done. There are others. And as I said in my
prepared remarks, if you want to have a leadership position in pain and you want to have
medicines across the pain spectrum, which is what we want to do in acute pain, oral, IV as
well as in neuropathic pain, we're going to have to innovate in bringing these medicines
forward from discovery research, but we're also going to have to innovate in managing the
placebo response, and I believe that we can do it. Now of course, we have to show that, and
we're looking forward to doing that in Phase III. I hope that helps.
Operator
Operator
The next question comes from Salveen Richter with Goldman Sachs.
Salveen Richter
Analyst
You touched on this a little bit, but could you just speak to what was di!erent about the sites
with the low placebo e!ect? And while clearly, there is a placebo e!ect, can you also expand
on your con#dence here that you enrolled LSR patients just given the heterogeneity with that
population?
Reshma Kewalramani
Executive
Yes. Yes. Salveen, I feel high con#dence from the data that we have interrogated that we did,
in fact, enroll patients with lumbosacral radiculopathy. You can see in the baseline
characteristics, everyone had a dermatomal pain distribution, which is what we would expect

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to see. That, I think, is correct.
With regard to sites and what's di!erent about these sites, these are all analyses that will
require us to think more deeply about. So I don't want you to think that this is certainly what
we're going to do. But I'll give you one example. The sites that had lower placebo response
rates had higher baseline and NSAID use. That is obviously important information that we're
going to take as we design this Phase III study.
Operator
Operator
The next question comes from David Risinger with Leerink Partners. We'll go to the next
question from Geo! Meacham with Citi.
Geo!rey Meacham
Analyst
Great. I wanted to ask you a few things. The #rst is in this Phase II, what strategies did you
guys use to try to mitigate the placebo response going into it? And the second thing is
beyond some of the innovations in Phase III, is there a way to take advantage of the novel
mechanism or something in a Phase III that could sort of convey to the FDA, look, this is an
opioid alternative, for example, maybe looking at sort of unmet need and sort of the opioid
segment of that population? I'm just trying to think of maybe even more creative ways to add
to the study beyond just pain scores and looking beyond the placebo washing kind of type of
thing.
Reshma Kewalramani
Executive
Yes. You bet about the details, Geo!. I'm happy to share. 100% on what you say about the fact
that this is a non-opioid and the magnitude of the treatment e!ect, and look, what I'm about
to say to you is cross-study comparisons and you have to take this with a grain of salt. But
when you look at opioid that are used in -- it's not exactly LSR, but an opioid, I think it's a
NUCYNTA was studied in a clinical trial of chronic low back pain with radiculopathy, so let's
call it similar.
The reduction in pain the -- within group reduction in pain in that opioid was a 2 on this NPRS
score. In that study, the placebo response was better controlled. So 100% that there is a lot
of innovation to be had and lots of ways in which by clinical trial design, by end points, by
statistical methods, we have to consider, work through and gain agreement with the agency
for how we can best conduct the Phase III study. You asked about what did we do? We -- let's
call it, conventional approaches.
We use all the conventional approaches to manage the placebo e!ect here, small number of
sites, training of the sites, sites trading the patients really being very attentive to the inclusion
criteria, all those traditional things were done here.
Operator
Operator
The next question comes from Michael Yee with Je!eries.
Michael Yee
Analyst
Great. Maybe just a two-part question. On the subgroup analysis of the 40% of patients that

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you showed on Slide 11, do you think that is a solid representation of what you think the
clinical magnitude of e"cacy is for this drug ultimately if you have to run the study, it looks
like about 0.75 bene#t. So maybe just talk about the overall e!ect of the drug that you think
this drug does have if you had run a correct study? And then secondly, just on the AE pro#le.
Can you just remind us if you saw anything on creatinine clearance or renal? I know that was a
question previously, and I just wanted to hear about that if there was anything here on AE
pro#les that you would want to point out.
Reshma Kewalramani
Executive
Yes. Mike, let me take the creatinine question #rst. Nothing on creatinine, nothing on creatine
clearance converted to GFR, use whichever formula you want, there was nothing there. And
as a reminder, this is also a 12-week study. On Slide 11, I think that's the slide that is the post
hoc analysis of the treatment e!ect in the suzetrigine arm plotted on the same plot as the
within group placebo e!ect.
Yes, I think that this is representative of the true treatment e!ect of suzetrigine. And I think
this is what we can expect if we are able to control the placebo e!ect in Phase III. Let me tell
you why. The suzetrigine treatment e!ect, the within-group treatment e!ect, is in this
analysis, it's minus 1.86. It's pretty darn close to what we saw in the overall study, which was a
minus 2.02.
Let's just call it approximately 2 both in the post hoc analysis and in the overall analysis. Let's
just call it a 2. That is what we see in Vertex NaV1.8 inhibitor studies, the small #ber
neuropathy study with VX-150 was about a 2. The DPN studies, as you know, was about a 2.2.
And if you look at all neuropathic pain, just because there's more studies in there, when you
have trials that are positive when the drugs are approved, the magnitude of the treatment
e!ect is about a 2.
So I feel like this is indeed the proper representation of suzetrigine, and you can get the
suzetrigine within group response here or in the overall study. The key, of course, is the
di!erence in the placebo response rate. Here, it's 0.86. In the overall study, it was, let's call it, a
2, it was 1.98 reduction, but let's just call it a 2.
And I do believe that you're not going to get to a placebo response of 0. No study has ever
gotten to that. But if you look at the totality of the evidence, you can get close to a 1, 1.3 in
that range. And that's the range that we would expect, innovate and plan to get down to in our
Phase III trial. And I just want to be clear, we haven't done yet.
We have to show that, and that's what we are intending to do.
Operator
Operator
The next question comes from Evan Seigerman with BMO Capital.
Evan Seigerman
Analyst
Thank you for all the details. Can you expand on whether there was any observed sleep
bene#t from the suzetrigine or placebo treatment? And if so, maybe quantify the magnitude

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of the bene#t. I know that was a key secondary endpoint.
Reshma Kewalramani
Executive
Yes. Evan, on the primary analysis, where there wasn't separation of the curve, there wasn't
separation of any of the secondary endpoints, including sleep bene#ts. In the post hoc
analysis, where there was separation of the curve where the suzetrigine treatment e!ect was
basically the same about a 2, but we had better placebo e!ect, let's call it, more in line with
the broader neuropathic pain condition. The DCIS, that's the sleep scale also showed
commensurate improvement. I don't have the numbers on me, but it was clearly separated in
the post hoc analysis.
It was clearly not separated in the primary analysis.
Operator
Operator
Next question comes from William Pickering with Bernstein.
William Pickering
Analyst
For the post hoc analysis, I was wondering if you could comment on the 2 arms. Were they
well-balanced in terms of baseline pain severity? And just any kind of broader comments on
the robustness of that post-hoc analysis.
Reshma Kewalramani
Executive
Yes. Yes, you bet. Yes, we looked at the balance between these 2 groups in the post hoc
analysis, One thing that we bene#t from is about 40% of the sites were the lower placebo
treatment e!ect sites, so we had enough sites to look at. And generally speaking, they were
balanced, these 2 groups. As I said, there were a couple of things that were di!erent.
For example, one thing that was di!erent is the use of NSAIDs. There was more NSAID use in
the lower placebo group. But generally speaking, they were balanced.
Operator
Operator
The next question comes from Phil Nadeau with TD Cowen.
Philip Nadeau
Analyst
Two from us. So I guess, #rst on the post hoc analysis. Mathematically, it seems like the only
way you can get the results on Slide 11, given what happened in Slide 10. Is it in the other
60% of sites, placebo beat suzetrigine by approximately 1 point. So can you describe the
data from the other 60% of the sites?
Was that di!erence because placebo had a minus 3 improvement in pain score? Or did
suzetrigine perform worse in those other sites than it did in the 40% of sites? That's question
one. And then question two, why is the next step of Phase III here? It seems like you're going
to test innovations, di!erent hypotheses on how to control the placebo e!ect.
Isn't there a faster and perhaps cheaper way to do that through a Phase II trial rather than
moving into a long and expensive pivotal?

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Reshma Kewalramani
Executive
Yes. So Phil, you have a very interesting and good question around the statistics. And
obviously, when you have an overall response where the 2 groups don't separate and you --
then you do a post hoc analysis where one group separates from the other, the overall e!ect
still has to be true. But no, it's not -- the e!ect in the other group, the higher placebo group is
basically a small di!erence, it's like, I don't know, 0.2 or something like that favoring placebo,
but it's not a 1-point di!erence. And what it basically tells you is that this is not a #nding by
chance, and of course, we did additional statistical analyses to understand any bias we may
have introduced by doing these analyses, and to understand whether this was a #nding by
chance.
And we're satis#ed that this is a good analysis, still it's post hoc and its hypothesis
generating, not conclusive. Regarding your question about Phase 2, this is an excellent
question. I think the reason the #eld is played by not having made progress in this condition is
because we haven't done large well-controlled studies and really examined with innovative
clinical designs, what we can do to manage the placebo e!ect. Whether you call it Phase II or
you call it Phase III, we need to do a study versus placebo that's large and well-controlled that
demonstrates statistically signi#cant di!erences between the 2 groups. When you do that,
you are doing a Phase III study.
I'm looking forward to doing it because I'd like to have that study then be represented in a
label and broaden the label in peripheral neuropathic game beyond DPN.
Operator
Operator
The next question comes from Liisa Bayko with Evercore ISI.
Liisa Bayko
Analyst
I hear everything you're saying. I wanted to understand sort of more about the regulatory
strategy in the event that you do go down this path. And for suzetrigine doesn't show
statistical separation from placebo and LSR, kind of what's the broader strategy for
expanding the label into neuropathic pain? I know you need more than one study, and I know
you have the other study going on. So just curious how you're thinking about that.
And I know also the guidelines are kind of on hold to some extent or have been withdrawn. So
curious about any FDA interactions you've had on that?
Reshma Kewalramani
Executive
Yes, you bet, Liisa. So our -- let me go back a few steps. In neuropathic pain, you know we
already have our program up and running for DPN. So this is all about how we expand beyond
DPN. You also know that there are many conditions in peripheral neuropathic pain in that
umbrella, DPN, LSR, herpetic neuralgia, small #ber neuropathy, et cetera, et cetera.
Our preferred path to expand the label is to go through DPN and LSR and have those 2
because in combination, that represents more than 50% of the PNP indication, have those 2
conditions and those studies then lead to a broad PNP label. There are, of course, other ways
to get there. Another way to get there would be, for example, 2 DPN studies and then studies

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in individual neuropathic pain conditions. In the old guidelines, the agency had particular
expectations about numbers of studies and how many indications and they would go one by
one. But I think the agency has also said that they are looking to evolve from that and perhaps
to a few indications, and that could lead to a broader indication.
So I think that my preferred path has not changed. I would still prefer to go via DPN and LSR
to PNP, but there are other ways.
Liisa Bayko
Analyst
Okay. And then just a #nal question from me. Can you comment at all on discontinuations and
how that was handled in the study and then any use of rescue meds?
Reshma Kewalramani
Executive
Yes, yes. The study had a high maintenance of their subjects that were enrolled. It was more
than 90% in both arms. For patients who were -- for patients with rescue therapy, over-the-
counter acetaminophen was allowed in both arms, and there was high use as is in all of these
studies in both arms of over-the-counter Tylenol and acetaminophen. It's like 80% or so in
both arms used PRN, that's to say, as needed acetaminophen.
No di!erences on that.
Susie Lisa
Executive
Drew, we'll take two more questions, please.
Operator
Operator
Yes. The next question comes from Ellie Merle with UBS.
Eliana Merle
Analyst
Could you just elaborate a little bit more on these other PNP indications of potential
strategies? So speci#cally, what other PNP indications do you think suzetrigine might be best
suited for and your latest thinking on development plans there? And I guess, do you have any
plans to start anything here in the near or medium term? And if so, what would that look like?
Reshma Kewalramani
Executive
Yes. My sentiment around PNP hasn't changed. This is underlying biology. Pain signaling, all
pain signaling goes through NaV1.7, which sets o! the action potential, initiates the action
potential and NaV1.8 which propagates the action potential. From everything we know and
just foundational basic biology that has been studied over the last many decades, that's the
case for all pain, not just neuropathic pain.
Therefore, my impression, my perspective on the best way to get to the full peripheral
neuropathic pain indication is by way of DPN and LSR, as I said, because when you put those
2 together, you're at more than 50% of the patients who have these PNP conditions. As I
mentioned, there are certainly other ways to do it. You could do individual studies in each of
these conditions. And we ourselves have done studies, for example, in small #ber neuropathy

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with the predecessor molecule VX-150, that one was also a positive study. The within group
treatment e!ect of VX-150 was about a 2, the placebo treatment e!ect in that study was
about 1.
So there are de#nitely other ways to do it, but my preferred path is still to go via DPN and PNP.
Those are the -- DPN and LSR to get to PNP. And those are -- that's part of the regulatory
conversations we need to have to gain their agreement on that.
Susie Lisa
Executive
Last question, Drew.
Operator
Operator
Yes. The last question will come from Mohit Bansal with Wells Fargo.
Mohit Bansal
Analyst
Just wanted to understand the clinical signi#cance of 1-point reduction, how meaningful that
is? And it seems like -- I mean, post hoc analyses on site selection and number of sites which
had placebo -- low placebo response kind of gets a lot of risk. So just wanted to understand,
isn't it a very risky path to take on with the Phase III trial given the variability in LSR indication?
Reshma Kewalramani
Executive
Yes. Thanks for the question, Mohit. The question you asked around what is reasonable to
expect for a between group di!erence is truly an excellent question and the #eld does not
have an answer. The way the #eld de#nes clinical meaningfulness is a within group change
from baseline. And while there's no speci#c measure of clinical meaningfulness in LSR,
broadly speaking, in the pain area, that is 2 points, within group 2 points.
That's exactly what suzetrigine achieved.
And as I said, it's just hard to do the analysis in LSR because there aren't many studies. But if
you broadly speaking, look at peripheral neuropathic pain, the average of all studies is around
2\. So I feel very good about the suzetrigine within group treatment e!ect. So what do you do
with the between group? What you do is you power it for statistical signi#cance because
there isn't an agreed-upon criteria for that.
And again, if you look at -- no one's ever taken a study to Phase III in LSR. So there's nothing
to look at there. There's no approved medicine speci#cally for LSR, so nothing to look there.
So if you look, broadly speaking, at peripheral neuropathic pain, which is kind of dominated by
DPN and chronic low back pain with radiculopathy, though that's kind of the study set that
you'll see, all of the positive studies have a treatment e!ect of above 2. Sometimes it's a 1.8,
sometimes it's a 2.2, but it's about a 2.
And the placebo response is something south of 1.3. There is one exception to the rule that I
laid out these numbers. It's one antidepressant study, where the treatment e!ect was closer
to a 3, but the placebo e!ect was closer to a 2. And so the di!erence between them is back
down and the achievement of statistical signi#cance was based on one. So there isn't an
agreed upon clinically meaningful bar from between groups.

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It's based on statistical signi#cance. I hope that helps.
Operator
Operator
The conference has now concluded. Thank you for attending today's presentation. A replay
of today's event will be available shortly after the call concludes until January 2, 2025, at
11:59 p.m. Eastern Time by dialing (1) 877 344-7529 or (1) 412 317-0088 using replay code
4965951\. Thank you.
You may disconnect your lines at this time.