Thank-you to Adam Feuerstein for publishing this article on the Serada bear thesis. For those of you who are interested in a bit more depth, the unedited version is featured here.
I don’t disagree with recent reports suggesting Serada,
Depomed’s proprietary extended release formulation of gabapentin represents
significant upside potential to the stock. Although, I think the probability of
a positive panel vote (and subsequent approval) is slim, this does however, provide
interesting trading opportunities into the run up to the panel on March 4, 2012
and the release of the FDA briefing documents expected no later than 2/28/2012.
1)
What’s the rationale for using gabapentin to
treat menopausal hot flashes?
Vasomotor
symptoms (VMS) of menopause or hot
flashes are experienced by the majority of women during the menopausal
transition, with prevalence rates varying by racial/ethnic group and being influenced
by risk factors such as age, BMI and smoking status . Although the
pathophysiology is not fully understood, a reduction in endogenous reproductive
hormones and thermoregulatory changes are both thought to contribute to the
etiology. Temperature information is
processed within the anterior hypothalamus in the preoptic area (POA), where it
is hypothesized that heat-sensitive neurons control the release of heat. Serotonergic neurons and noradrenergic
pathways have both been identified as projecting into the POA and hence, given data
linking estrogen fluctuations to a reduction of serotonin and norepinephrine,
it has been proposed that pharmacologic agents such as serotonin reuptake
inhibitors and serotonin–norepinephrine reuptake inhibitors may help to
reestablish levels of these neurochemicals within the thermoregulatory centers,
reducing the occurrence of VMS. The role
(if any) of GABA transmission in temperature regulation is undefined.
2)
Why
use gabapentin to treat hot flashes if there is no sound physiologic basis?
Good question, maybe the role of gabapentin in this setting
is tenuous at best. The results of the
Serada phase 3 program would tend to support this. BREEZE-1 and BREEZE-2 were two randomized,
double-blind, placebo-controlled studies of approximately 540 patients per
study, receiving treatment at either 1200mg or 1800mg daily or placebo. Total treatment duration in BREEZE-1 was six
months, with primary efficacy endpoints assessed after 4 and 12 weeks of stable
therapy. Persistence of efficacy was to be assessed at 6 months as a secondary
endpoint. Treatment duration in BREEZE-2 was three months, also with assessment
of efficacy at 4 and 12 weeks. In both studies, the coprimary end points were
to assess the mean change in frequency and severity of symptoms from baseline
to week 4 and 12. The results were
reported in 2009 and both studies failed to meet all of the primary end points
for statistical significance. There are
many issues with the data which only serve to raise questions as to the true
clinical benefit for this drug in a VMS setting. In BREEZE-1, 36% of patients receiving
treatment at 1200mg, and 30% of those receiving 1800mg failed to complete the
study. These are very high drop-out
rates for any trial and raise concerns as to why patients were leaving the
study. Some women can experience VMS for years, so any treatment needs to be
well tolerated, safe, and to demonstrate persistent benefit. Serada did not
consistently exhibit persistency of effect for even 12 weeks let alone 24. The 24 week data
were never reported fully reported but will hopefully surface in March. At
best, the results of BREEZE-1 and BREEZE-2 seem to indicate that treatment is
associated with ~1 less hot flash per day compared with placebo treatment for a
short period of time. Historically, the placebo effect in VMS studies has
always been ~50% response without explanation, so how “real” is the Serada treatment
effect and how meaningful is it to women who would be taking this especially in
light of the overall gabapentin adverse event profile? The FDA’s responder analyses will surely shed
light on some of this. Of course, there is a bull argument in favor of statistically
manipulating these data in order to get a positive outcome which has been
summarized here
by @JNapodano. I have previously quoted
a statistical adage that “if you torture the data long enough, it will confess
to anything”. Depomed certainly should be commended on their statistical
prowess in explaining why both BREEZE-1 and BREEZE-2 failed, but I am certainly
not convinced that removing 2 outliers from a study enrolling >500 patients
is enough to make it statistically meaningful.
However, statistics aside, it’s the absolute efficacy
benefit that will be a review issue and it will be interesting to see the
placebo adjusted frequency and severity scores debated at the Reproductive
Health Drugs Advisory Committee. It will also be interesting to see how the lack
of any meaningful persistency of effect at 24 weeks will be perceived, this is
after all a regulatory benchmark for approval.
Aspiring to seize victory from the jaws of defeat, Depomed went back to FDA and reached agreement
on a Special Protocol Assessment (SPA) for BREEZE-3, a double-blind,
placebo-controlled study of approximately 600 patients, randomized to receive either
placebo or a total dose of 1800mg of Serada. The co-primary efficacy endpoints were
reductions in the mean frequency of moderate-to-severe hot flashes, and the
average severity of hot flashes, measured after 4 and 12 weeks of stable treatment.
As in the prior BREEZE-1 trial, the treatment duration of the study was 24
weeks, to establish the regulatory requirement for persistence of efficacy. The
results were reported in October 2012: Using the pre-specified non-parametric
statistical analysis, the trial results for the co-primary endpoints were
statistically significant for the reduction in average frequency of hot flashes
at 4 weeks (p=0.0003), the reduction in the average severity of hot flashes at
4 weeks (p<0.0001) and 12 weeks (p=0.0102), but were not statistically
significant for the reduction in average frequency of hot flashes at 12 weeks
(p=0.10). The results were not statistically significant at 24 weeks for the
reduction of hot flash frequency (p=0.2351) or severity (p=0.1510). Oh dear.
At the end of the day, the conditions of the SPA were not fully
met in this study, the drug still doesn’t show a significant reduction in
frequency of hot flashes beyond 4 weeks, and given that the two supporting
trials failed to hit a single end point, it casts major doubts as to why Serada
would provide any meaningful clinical benefit in VMS, especially when women
experience symptoms for months to years.
3)
Bulls argue that we need safer alternatives to hormone
replacement therapy(HRT)
Firstly we know a lot more today about HRT and the long term
risk profile in women treated for early menopausal symptoms and late menopausal
symptoms. The 2012 Hormone Therapy Position
Statement of The North American Menopause Society clarifies the benefit-risk
ratio of estrogen therapy versus estrogen-progestogen therapy for both treatment
of menopause-related symptoms and disease prevention at various time intervals
since menopause. In many cases, estrogen
therapy with or without progesterone therapy (the most effective treatment for
VMS) and can be used safely for prolonged periods of treatment (e.g. 3-7 years)
without any increased risk of malignancy. Obviously there will be women whose
risk profile is not appropriate for HRT and there are effective alternatives in
the pipeline, which brings me to a major reason I feel Depomed will not get a
positive Committee Panel vote.
On March 4, 2013, during
the afternoon session, the Committee will discuss the NDA submitted by Noven
Therapeutics, LLC, for Low-dose Mesylate Salt of Paroxetine (LDMP) for the treatment
of VMS associated with menopause. Paroxetine is a potent and highly selective serotonin-reuptake
inhibitor and the putative mechanism for efficacy in VMS would relate to
regulation of serotoninergic transmission in the POA/thermoregulatory center.
Noven has completed 2
studies as part of the clinical development program. The first trial was a 24-week, multicenter,
double-blind, randomized, placebo-controlled, Phase 3 study of LDMP in
postmenopausal women with moderate to severe VMS. Eligible subjects entered a
12-day, single-blind run-in period, and were randomized 1:1 to receive LDMP 7.5
mg or placebo for 24 weeks. Unlike Serada which is dosed twice a day, LDMP is
taken as a single nightly dose. Primary efficacy end points were mean changes
in frequency and severity of moderate to severe VMS from baseline to Week 4 and
Week 12. Persistence of effect at week
24 was evaluated with a responder analysis, where a responder was defined as a subject
with ≥50% reduction in VMS frequency from baseline to Week 24. Mean weekly reductions
in VMS frequency were significantly greater for LDMP than placebo at Week 4
(–28.9 and –19.0, respectively; P<0.0001) and at Week 12 (–37.2 and –27.6,
respectively; P=0.0001). Of course, this
also needs to be translated into absolute placebo-adjusted efficacy benefit for
patients, but overall the study met all end points.
Importantly, unlike Serada, significantly more subjects
treated with LDMP than placebo were responders at Week 24 (47.5% vs. 36.3%,
respectively; P=0.0066), demonstrating persistence of treatment benefit. Most commonly reported treatment emergent
adverse events were nasopharyngitis (5.1% vs 4.9%), headache (4.3% vs 3.7%),
nausea (3.8% vs 1.4%),fatigue (3.4% vs 1.5%), diarrhea (2.9% vs 2.5%), and
dizziness (2.0% vs 0.8%).
Noven also reached SPA agreement with the FDA for the
second study in the clinical development program. This was a 12-week,
multicenter, double-blind, randomized, placebo-controlled, phase 3 study of
LDMP in postmenopausal women with moderate to severe VMS (>7-8 moderate to
severe hot flashes daily). This study
was identical in design to the first, with the same 12-day run in period prior
to randomization. Overall, 614 subjects were randomized, and importantly, 549
subjects(271/306 [88.6%] LDMP; 278/308 [90.3%] placebo) completed the study (a
stark contrast to the completion rates observed in BREEZE-1). Mean weekly
reductions in VMS frequency from baseline were significantly greater for LDMP
than placebo at week 4 (–33.0 and –23.5, respectively; P < 0.0001)
and at week 12 (–43.5 and –37.3, respectively; P = 0.0090). Mean weekly
reductions in the frequency of moderate to severe hot flashes were significantly
greater for the LDMP group than for placebo beginning at week 1 and continuing
until the end of treatment (P ≤ 0.0259 for all comparisons). Mean weekly
reductions in VMS severity from baseline were significantly greater for LDMP
than placebo at Week 4 (–0.09 and –0.05, respectively; P = 0.0048) but
not at week 12 (–0.10 and –0.09, respectively; P = 0.2893). Mean weekly
reduction in VMS hot flash composite scores (moderate and severe) from baseline
were significantly greater for LDMP than placebo at week 4 (–85.51 and –60.83
respectively; P < 0.0001) and at Week 12 (–111.9 and –96.85
respectively; P = 0.0063). There
were no new safety signals and the drug was well tolerated.
Now given that the Advisory committee will be
reviewing both NDA’s for the exact same indication on the same day, it is very
likely that the same panel members (or at least a large overlap) who review
Depomed Serada in the morning will be reviewing LDMP in the afternoon, and
hence will be reviewing both sets of briefing documents ahead of time.
Let’s don our committee member hats and consider the
two packages for a moment:
AM Session Serada : Minimal
mechanistic plausibility as to why it should work in VMS, dosed twice a day, high
patient dropout rates in clinical studies, failed to meet majority of
prospectively defined end points in two large randomized controlled studies,
failed to demonstrate significant reduction in frequency of hot flashes beyond
4 weeks in third confirmatory study, failed to demonstrate persistency of
benefit at 24 weeks in every study, overall side effect profile and
tolerability issues with gabapentin
PM Session LDMP: Mechanistic
rationale for efficacy in treating VMS, dosed once nightly, met 8/9
prospectively defined end points in two large, randomized controlled studies,
significantly reduced the frequency of moderate to severe hot flashes at 12
weeks, and maintained persistence of effect at 24 weeks, excellent overall
safety and tolerability profile
Hmmm….I know which way I would vote.
On a final note, in the extremely unlikely event that
FDA were ever to approve Serada for the treatment of moderate to severe VMS,
realistically, what could the drug potentially do in terms of peak sales? Here
is my liberal sales estimate with assumptions. (The conservative version is a
lot lower).
10 MM per year seeking treatment for hot flashes
75% agreeing to try pharmacotherapy following consultation
(high estimate)
30% requiring alternative to HRT
5% peak market share for Serada
90% patients given a prescription choosing to fill it
50% likelihood that prescription filled with Serada
first as opposed to generic substitution with gabapentin. (Note: this drug is
“extended release” yet needs to be dosed twice daily, there is no evidence that
this confers any benefit over generic gabapentin from a managed care
perspective so it is likely (if ever
approved) Serada will have a low tier formulary status and will frequently be
subject to generic substitution)
Average course of treatment 3 months (Note: 30% of
patients failed to complete the studies so there is no reason to believe real
world experience would be different, in fact I would predict a high drop off
rate after the first script. The drug does not demonstrate persistent effects
beyond 4 weeks under clinical trial conditions, so it is extremely unlikely the
average course of therapy will be as high as 9 months).
Average cost per script $225
Peak Sales Estimate: 10MM x 75% x 30% x5% x 90% x50%
x3 x 225 = $34 MM
Disclosure: I
am long in March puts
This article is not intended as, nor should it be
taken as investment advice. Do you own due diligence before trading securities.
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