Article Pack

Drug Review
ProfilesNovember 2023

Introduction

The Pink Sheet’s unique Drug Review Profiles provide a deep dive into the dynamics behindinteresting – and sometimes precedent-setting – new drug approvals, with lessons learned for othersponsors.
Mining hundreds of pages of agency documents and following up with key interviews, our Pink
Sheet expert journalists illuminate how the regulatory process works in practice. Issues might
include how agency reviewers applied regulatory terminology to specific new drug and biologics
marketing applications. Other aspects that often come into play include trial design, whether
the product met criteria for expedited review mechanisms, questions of emerging science, howreviewers weigh evidence of efficacy, risk management, and manufacturing challenges. Our
analyses explore how sponsors worked with regulators to resolve areas of uncertainty and where
there might be regulatory flexibility – or not.
The resulting takeaways often are helpful for navigating regulatory review far beyond the specificproduct area in a Profile. Sponsors can anticipate challenging questions regulators might ask about
their own applications and work more productively with regulators. It all adds up to increasing thechance for product approval, with indications and labeling optimized for competitiveness in themarket.
Find all of this coverage on our Drug Review Profiles webpage.

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November 2023 

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Contents

CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy Overcame The Odds
On Nontraditional Path To Approval

04

Elevidys’ Age-Restricted Indication Not Negotiable, CBER’s Peter Marks Told Sarepta

10Expanding Cells, Expanding Access: Gamida Cell’s Omisirge Debuts New Donor Source
For Stem Cell Transplant

17

Leqembi Phase II Missed Clinical Endpoint But Still Provided Support For Amyloid Surrogate

23

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November 2023 

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CellTrans’ Lantidra:
Type 1 Diabetes Cell Therapy
Overcame The Odds On
Nontraditional Path To Approval
Sue Sutter
12 Sep 2023

Executive Summary

Despite a host of challenges with donislecel’s development
and BLA, the US FDA approved based on clinical datafrom only 30 patients, using a clinically meaningful insulin
independence endpoint and in a more carefully tailored
population. Pink Sheet’s Drug Review Profile takes a deep
dive into the FDA review of the first approved allogenic
pancreas islet cell product.

On its face, the odds for US approval of
CellTrans, Inc.’s type 1 diabetes cellular therapy
Lantidra (donislecel-jujn) would seem to havebeen stacked against the sponsor.
The product was a first-in-class, complex
biological treatment. The academia-based
sponsor was inexperienced in getting
therapeutics through the Food and Drug
Administration, and the quality of the biologics
license application was poor, with missing,inconsistent and uninterpretable data.

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November 2023 

In addition, a host of product quality
deficiencies had to be addressed after a firstcycle complete response letter.
On the clinical side, FDA reviewers concluded
the sponsor’s proposed indication for brittle
type 1 diabetes was not well defined, and theprimary efficacy analyses across two studies
based on severe hypoglycemic events andhemoglobin A1c levels was not interpretable due
to missing data and the characteristics of theenrolled population.

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CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy
Overcame The Odds On Nontraditional Path To Approval
Despite these challenges, the FDA identified apath to approval for Lantidra based on clinicaldata from only 30 patients, using an endpoint –insulin independence – that the agency deemedclinically meaningful, and in a more carefully
tailored patient population.

Key Takeaways

The FDA approved Lantidra on 28 June fortreatment of adults with type 1 diabetes (T1D)
who are unable to approach target HbA1c
because of current repeated episodes of severe
hypoglycemia despite intensive diabetes
management and education. (Also see “US
FDA Novel Approvals Total 35 In First Half 2023,
Riding Resurgent Biologics Wave” - Pink Sheet, 8Jul, 2023.)
Although the term “regulatory flexibility” does
not appear in either the FDA’s summary basis
for regulatory action or the clinical review – incontrast to some recent high-profile productapprovals in the neuroscience space – internal
memos make clear the agency took pains to get
Lantidra across the finish line for a rare disease
population with unmet need.
This included leveraging some of the agency’s
own patient preference work and relying uponan “implied” external control when assessing theinsulin independence data from the two singlearm trials.
CellTrans CFO Jenny Cook said the company’s
interactions with the agency during Lantidra’s
development and review amounted to an
education for both parties.
“We’re learning about what they need to see,and then we’re also kind of educating them on
our experience with our patients,” she said in aninterview with the Pink Sheet.
The agency “really did try to work with us,” Cooksaid. “They knew we were a very small group… and working in an academic medical centerand there’s limitations around that. At the sametime, they needed to meet their regulations, but
5November 2023 •	FDA reviewers said CellTrans’ proposed
indication for brittle type 1 diabetes
was not well defined, and the primary
efficacy analyses across two studies
based on severe hypoglycemic eventsand hemoglobin A1c levels was notinterpretable.
•	However, the agency concluded that
insulin independence experienced
by some Lantidra-treated subjects
was a clinically meaningful endpointand compared favorably to the wellestablished natural history of thedisease.
•	FDA leveraged its flexibility in getting
Lantidra through the approval processwith an indication that better defined
the target population.

they could see we were also doing as much as
possible, too.”“I think they really tried to be a bit flexible
knowing who we were and we want to keep thisproduct affordable for patients,” Cook said.
The Lantidra story is one of an unusual productdevelopment program, a nontraditional sponsor,
and an FDA that was willing to look outside thebox. With the burgeoning growth in gene andcell therapy development, and the continuingchallenges faced by academic sponsors withlimited regulatory expertise, the Lantidra
experience could be instructive for futureapplicants.
First Allogenic Pancreas Islet Cell Product
Under Review
Although insulin remains the primary treatment
for patients with T1D, allogenic transplant of
cadaveric donor pancreata has been used torestore the production of endogenous insulin for

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CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy
Overcame The Odds On Nontraditional Path To Approvalsome patients.

Independence From Insulin Becomes Efficacy
Focus
Lantidra’s development was unique in that theclinical trials supporting the BLA were single-site
studies conducted by Oberholzer.

The use of pancreatic islet cells isolated fromdonor pancreata and implanted in a patient’s
liver by infusion into the portal vein provides aless invasive approach and allows for the use ofdonor pancreata that are not suitable for wholeorgan transplantation.
Lantidra is a cellular therapy product containing
purified allogeneic deceased donor pancreas
derived islets of Langerhans. It was the firstallogenic pancreas islet cell product submitted
for FDA review under a marketing application.
CellTrans’ proposed indication was for thetreatment of brittle T1D (labile diabetes) in
adults whose symptoms are not well controlled
despite intensive insulin therapy.
The novel nature of the product createdcomplexities from a regulatory perspective,
Cook said.
“Some of the regulations they didn’t really fit our
product, and so I think actually the agency was
also struggling a bit with how to comply with
their own regulations [and] at the same time fit
the needs of a cell product,” Cook said. “Someof the regulations actually didn’t apply, but we
had to address them to kind of check the box.”
The investigational new drug application
was opened in 2004 by Jose Oberholzer at
the University of Illinois Hospital and Health
Sciences System (UI Health). Oberholzer
subsequently founded CellTrans, which
acquired the rights to the IND and the Lantidra
development program in 2017 with the purposeof supporting a BLA.
CellTrans initially submitted a BLA in 2017 but
withdrew it after the agency identified filingissues. The current BLA was submitted in May
2020.

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November 2023 

Efficacy and safety were evaluated in two
non-randomized, single-arm trials (UIH-001
and UIH-002) conducted at UI Health andenrolling a total of 30 participants with T1D andhypoglycemic unawareness.
The clinical development and regulatory review
were complicated by changes in the standardof care for T1D since the 001 and 002 studies
were initiated in 2004 and 2007, respectively,
Cook said. Continuous glucose monitors were
not the norm during the early part of the clinicalprogram, and incidents of hypoglycemia had tobe documented on paper, she said.
CellTrans’ primary efficacy analysis for the twostudies used a composite endpoint of HbA1c≤6.5% and absence of severe hypoglycemic
events (SHE) through one year after the
subject’s last transplant.
However, the FDA said this analysis was notinterpretable due to missing data and inclusionof a significant proportion of subjects who, atbaseline, had already met or nearly met the
primary efficacy endpoint. (Also see “CellTrans’Donislecel: Insulin Independence Data May
Offer Path To Market In Type 1 Diabetes” - Pink
Sheet, 13 Apr, 2021.)“There were significant issues with missing
baseline data and inclusion of 25/30 (83.3%)
subjects without recent baseline SHE and with
6/30 (20%) with a HbA1c at the target HbA1c;
this limits the interpretability of the applicant’s
primary analysis,” clinical reviewer Patricia
Beaston said in a memo.

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CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy
Overcame The Odds On Nontraditional Path To Approval“Restoration of endogenous insulin
production and insulin independence does
not occur spontaneously in T1D; the large
treatment effect is attributed to Lantidra.”– FDA Summary Basis For Regulatory
Actionfree period across the two studies. It also
leveraged some of its own patient preference
information work in this area.
The FDA Science of Patient Input, Office ofBiostatistics and Epidemiology (OBE) groupcollaborated with the University of CaliforniaSan Francisco on a project for patient
preferences in islet cell therapy. The grouppresented a poster at the FDA Science Forum in
2021.

Nevertheless, the studies showed 21 of
30 treated subjects (70%) did not require
exogenous insulin for at least one year after
treatment, and 10 subjects (33%) achieved
insulin independence for more than five years,
with a maximum reported insulin independenceof 12.8 years.
Insulin independence was the primary endpointin UIH-001 and a prespecified secondary
endpoint in UIH-002, the clinical review states.
“Restoration of endogenous insulin production
and insulin independence does not occur
spontaneously in T1D; the large treatment effectis attributed to Lantidra,” the summary basis forregulatory action states.
At an April 2021 meeting of the Cellular, Tissue
and Gene Therapies Advisory Committee,
the majority of panelists said the benefits of
independence from insulin outweighed the risks
from long-term immunosuppression necessary
with Lantidra. However, they said the therapy
should be limited only to a very small groupof patients, such as those who are eligible forpancreas transplant but cannot tolerate a big
operation, and those for whom closed-loop
insulin pump systems and continuous glucose
monitors were not well tolerated or effective.
(Also see “CellTrans’ Donislecel Gets US FDA
Panel Nod For Small Group Of Type 1 Diabetics”- Pink Sheet, 15 Apr, 2021.)
Patient Experience Data
The FDA performed extensive analyses of theability of study subjects to achieve insulin
independence and the durability of that insulin-

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November 2023 “The authors’ conclusion was that their study‘suggests that hard-to-control T1DM patients
may be willing to accept a certain level ofrisk (e.g., 5% risk of serious complications)to achieve a certain extent of benefit (thepossibility of having five years of insulin
independence),’” the clinical review states.
The main safety issues associated with Lantidra
treatment are risks of the cell product, thetransplantation procedure, and concomitant
immunosuppression.
The clinical review also notes that while CellTrans
did not provide a patient experience reportfor the subjects enrolled in UIH-001 or UIH002, it did include testimonials offered at theadvisory committee meeting by patients who
participated in the studies.
‘Implied’ External Control
The agency ultimately concluded that CellTransprovided substantial evidence of effectivenessand safety based on the two single-arm studies
and supportive evidence.
“Specifically, we consider the integrated datafrom UIH-001 and UIH-002 compared to
the well-established natural history of T1D tocompose a single adequate and well-controlled
investigation,” the summary basis for approvalstates. “Based on the objective endpoint, insulin
independence, and large treatment effect,
an external control is adequate to provide
substantial evidence of effectiveness.”

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CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy
Overcame The Odds On Nontraditional Path To Approval
The agency’s use of the term external
control is notable in that no specificdataset or nonconcurrent patient cohort
was formally offered as an external
control for comparison purposes with thetwo single-arm studies. Rather, the FDA
considered the well-understood natural
history of T1D as an external control in andof itself.
The agency’s use of the term external control
is notable in that no specific dataset or
nonconcurrent patient cohort was formallyoffered as an external control for comparison
purposes with the two single-arm studies.
Rather, the FDA considered the well-understoodnatural history of T1D as an external control
in and of itself, with Beaston’s clinical review
referencing a “performance goal thresholdbased on natural history (the implied control).”“To our knowledge, reversal to insulin
independence without therapeutic intervention
in patients with established T1DM (i.e., after
the so called ‘honeymoon period’) has notbeen reported outside of errors in diagnosing
monogenetic diabetes, or onset of insulinoma,”
Beaston said in her clinical review. “Therefore,
the occurrence of insulin independence can

8November 2023 

The agency also cited as supportive evidence
data from four subjects transplanted withdonislecel in a Phase III protocol conducted by
the Clinical Islet Transplantation consortium. The
results from these four subjects are “consistent
with those observed for the 30 subjects in UIH
studies. Thus, this clinical data and biologic
plausibility of beta cell replacement serves asconfirmatory evidence,” the summary basis forregulatory action states.
The clinical review reiterates a point made in the
FDA’s advisory committee briefing document
about the agency’s willingness in this case to
rely upon a post hoc efficacy analysis.

The clinical review cites the FDA’s 2009 guidanceon considerations for pancreatic allogeneic
pancreatic islet cell products. The document
states that a single-arm, open-label trial withhistorical controls may be able to provide
substantial evidence of efficacy and safety insubjects with metabolically unstable T1D.
“In part, this is because the major observed
benefits (insulin independence, spontaneous
loss of hypoglycemia with attainment of good
metabolic control) do not appear in the natural
course of the disease,” the guidance states.

provide an objective measure of the efficacy ofdonislecel transplant.”“It is very important to note that FDA does
not endorse a change in primary efficacy
endpoint for an integrated analysis of efficacy
after trials are conducted and analyzed, withrare exceptions in the past,” the review states.
“However, in this circumstance, the review teamunderstood that durable insulin independence
without evidence of hypoglycemia is a stronger
demonstration of clinical benefit comparedto adequate glycemic control without serious
hypoglycemia, is a more conservative endpoint
and, in addition, has been proposed in the 2009
FDA guidance as an alternative primary efficacy
endpoint.”
Revised Indication
The FDA took issue with CellTrans’ originalindication for the treatment of brittle T1D (labile
diabetes) in adults whose symptoms are notwell controlled despite intensive insulin therapy,
asserting it did not identify a specific patient
population.
Brittle T1D is a concept and not well defined,
the clinical review states, noting the term
“symptoms are not well controlled” also was notdefined.

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CellTrans’ Lantidra: Type 1 Diabetes Cell Therapy
Overcame The Odds On Nontraditional Path To Approval“In general, these patients would be unable
to achieve glycemic goals because of severe
metabolic events, severe hypoglycemic events(SHE) and/or diabetic ketoacidosis (DKA),
despite treatment/supervision by clinicians withexpertise in the treatment of type 1 diabetes
and access to the appropriate insulins anddevices based on the patient’s requirements,”
Beaston said. “It is important to recognize thatthe insulin products, available devices, andstandard of care have changed significantly
since the onset of the islet cell investigational
programs.”
The FDA revised the indication to focus on
adults with T1D who are unable to approachtarget HbA1c because of current repeatedepisodes of severe hypoglycemia despite
intensive diabetes management and education.
“While it may be tempting to specify a specifictarget of HbA1c in the indication, this approach
would not be reasonable as the target can bedifferent based on the patient’s age, durationof diabetes, and presence of complications(neuropathy, nephropathy, retinopathy),” theclinical review states.
“The use of ‘current repeated episodes’
identifies a patient population who is at risk for
SHE at the time islet cell transplantation would
be delivered, rather than those patients who
may have had one or more SHE episodes morethan one year prior to initial transplantation,”
Beaston said. “For a favorable benefit-risk
determination, patients should have an
ongoing risk of SHE to balance against thesignificant risks of the procedure and required
immunosuppression.”

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November 2023 

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Elevidys’ Age-Restricted
Indication Not Negotiable, CBER’s
Peter Marks Told Sarepta
Sue Sutter
07 Aug 2023

Executive Summary

FDA team held several internal meetings on the genetherapy after the 12 May advisory committee, culminating
in a teleconference with Sarepta in which the CBER director
outlined his accelerated approval decision and reiterated
recommendations to modify the ongoing EMBARK trial tobetter ensure confirmation of benefit. Pink Sheet’s Drug Review
Profile dives into the story behind the Elevidys review.

FDA Center for Biologics Evaluation andResearch Director Peter Marks’ conclusionthat Sarepta Therapeutics, Inc.’s gene therapy
Elevidys (delandistrogene moxeparvovec-rokl)
should receive accelerated approval for an
age-restricted indication amounted to a take-itor-leave-it offer for the sponsor, not subject tonegotiation.
In sharing his decision with Sarepta, Marks also
made clear agency concerns that the ongoing
EMBARK confirmatory trial was designed insuch a way that it may not be able to confirm
clinical benefit in the 4-5 year-old age group of
Duchenne muscular dystrophy patients covered

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November 2023 by the accelerated approval indication and,
consequently, adjustments should be made to
the statistical analysis plan.
FDA review documents reflect the extensive
internal deliberations on Elevidys that followed
a 12 May advisory committee meeting, in whicha slim majority of panelists favored accelerated
approval for the treatment of ambulatory DMD
patients.
Marks announced his plans to grant accelerated
approval limited to ambulatory patients ages
4-5 years old after meeting with review staff
and hearing their recommendations for a

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
complete response letter.
Marks’ own deputy, Celia Witten, also favored
a complete response in her role as acting
director of the Office of Therapeutic Products.
In a memo, she said she agreed with the review
team’s conclusion that available data do notsupport use of Elevidys micro-dystrophin
expression as a surrogate endpoint reasonably
likely to predict clinical benefit for accelerated
approval for the treatment of ambulatory
patients, or for a certain subpopulation of
ambulatory patients.
Elevidys, an AAV-directed gene therapy
formerly known as SRP-9001, received
accelerated approval on 22 June for treatmentof ambulatory pediatric patients ages 4-5
years with a confirmed mutation in the DMD
gene. Marks co-signed the approval letter with
Melissa Mendoza, director of CBER’s Office ofCompliance and Biologics Quality.
In granting accelerated approval, Marks
reasoned that despite the lack of benefit in the

Key Takeaways•	After the 12 May advisory committee
meeting, FDA’s clinical, clinicalpharmacology and biostatistics review
teams continued to recommend acomplete response letter for Elevidys.
•	CBER Director Peter Marks madethe decision to move forward withaccelerated approval for an agerestricted indication, telling Sarepta
the FDA’s position “is not up fornegotiation.”•	Marks urged Sarepta to considering
modifying the ongoing EMBARK trial tobe powered for demonstrating efficacy
in the 4-5 year-old age group.

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November 2023 

overall population of individuals ages 4-7 years
enrolled in Study 102, the data in the subgroupof individuals ages 4-5 years was compelling.
The results of Elevidys micro-dystrophin protein
expression and the results of the North Star
Ambulatory Assessment (NSAA) in this age
group support an association between the two,“such that Elevidys micro-dystrophin protein
expression is reasonably likely to predict clinicaloutcome in individuals ages 4 through 5 years
eligible for this treatment,” Marks said in his
decisional memo. (Also see “Sarepta’s DMD
Gene Therapy Helped Across Accelerated
Approval Finish Line By CBER’s Peter Marks” Pink Sheet, 22 Jun, 2023.)
However, this was not a conclusion easily
reached, review documents show.
FDA To Sarepta: We Have Concerns About The
Surrogate
In at least four meetings with Sarepta from
December 2018 to April 2022, agency staff
expressed concerns about the company’s
proposal to rely on SRP-9001 micro-dystrophin
as a surrogate endpoint to support accelerated
approval. Reviewers cited a lack of correlation
between expression of micro-dystrophin at week
12 and a clinically meaningful benefit. (Also see“Elevidys Clinical Development: Confidence In
Surrogate Endpoint A Longstanding Concern For
FDA Reviewers” - Pink Sheet, 9 Aug, 2023.)
In a meeting with Marks in November 2022, theapplication’s clinical reviewer recommended
the agency refuse to file the biologics license
application due to concerns about a lack ofdemonstrated efficacy and inadequacy of thesubmitted clinical studies. Marks overruled thisrecommendation, and the application was filed
and granted priority review, setting a user fee
goal date of 29 May 2023. (Also see “CBER
Director Marks’ Intervention On Sarepta Gene
Therapy Filing Decision Appears To Backfire” Pink Sheet, 15 Apr, 2023.)

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
The FDA told Sarepta in a 24 January mid-cycle
communication that no advisory committee
meeting was expected. However, by the 13
March late-cycle meeting, planning for anadvisory committee review was underway, andthe agency told Sarepta the meeting tentatively
was scheduled for late July based on panel
member availability.

the study population of DMD patients 4-7
years old. Positive results in the 4-5 year-old
age group were not prespecified and could
only be considered hypothesis-generating,reviewers said. (Also see “Let’s Go To The Video:
Recordings Of DMD Patients After Elevidys
Treatment ‘Compelling’ But Not Substantial
Evidence” - Pink Sheet, 10 Aug, 2023.)

This timeline subsequently was accelerated bymore than two months. The adcomm occurred
on 12 May, just more than two weeks before theuser fee goal date.

FDA staff also raised concerns about a lack ofanalytical comparability between the initial andto-be-commercialized manufacturing processes
for the gene therapy, and the potential impactof accelerated approval on the ongoing
EMBARK confirmatory trial (Study 301). In
addition, they noted that due to cross-reactivity
between different AAV serotypes, patients who
receive SRP-9001 but do not benefit would not
be able to receive another AAV-directed genetherapy in the future.

In a statement to the Pink Sheet, the agency
said that recognizing the tremendous interest
in SRP-9001, a determination was made late in
the review process that input from the Cellular,
Tissue and Gene Therapies Advisory Committee
would be critical to the agency’s evaluation.
“Therefore, the FDA worked expeditiously toschedule an advisory committee meeting tofacilitate an open and transparent discussion
related to the evaluation of the safety andeffectiveness of the product in a timely manner.”

The adcomm originally was scheduled forlate July, but that timeline was accelerated
by more than two months.
At the adcomm, Marks responded to a panelist
question about the agency’s reversal of courseon convening a meeting. “A management
decision was made that this would benefit frompublic discussion as an important gene therapy
for an indication under development,” he said.
FDA reviewers laid out their concerns about theability to rely upon SRP-9001 micro-dystrophin
as a surrogate endpoint reasonably likely to
predict clinical benefit. They noted the only
randomized data available to date – from Study
102, Part 1 – did not meet statistical significanceon the NSAA primary clinical endpoint in

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November 2023 

The committee voted 8-6 in favor of accelerated
approval, with those in the majority citing theadvanced state and imminent completion of
the fully enrolled EMBARK study, as well as theopinions of DMD researchers and clinicians who
supported approval. (Also see “Slim Adcomm
Majority Boosts Sarepta’s Gene Therapy In
Duchenne Muscular Dystrophy” - Pink Sheet, 12
May, 2023.)
Four Internal Meetings …
After the adcomm, FDA review staff held fourinternal meetings on the application, according
to the publicly available meeting summaries.
At a 15 May meeting, the clinical, clinicalpharmacology and biostatistics teams statedthat the adcomm discussion did not support
that Sarepta’s micro-dystrophin is reasonably
likely to predict clinical benefit to be used as asurrogate endpoint for accelerated approval.
These review teams continued to recommend acomplete response based on the available data.
Witten, the CBER deputy director who wasserving as acting director of OTP, said she

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
wanted to discuss the review team’s decision
with Marks before commenting on a pathforward.
Marks took part in a 16 May meeting with thereview team. The clinical, clinical pharmacology
and biostatistics review teams “all expressed thereasons that their position remained unchanged
and that they believe the application should
move forward as a complete response based on
the data provided,” a meeting summary states.
Marks said he wanted to consider the review
team’s position and justification before
commenting on a path forward. He requested
the review team examine the comments in the
public docket, including videos and a caregiverperspective study conducted Canary Advisors,
before making a final conclusion. (Also see“Sarepta’s External Controls Analysis Weakened
By Elevidys Placebo Data Comparison” - Pink
Sheet, 8 Aug, 2023.)
In an 18 May meeting with the review team,Marks “expressed that he has given thisapplication a fair amount of thought andthat there are some major issues on data theapplicant presented, issues on how the applicant
responded to the questions, issues with theexternal controls and issues on the explanationof the results of their 6-7 year-old population,”
the summary states.
“Dr. Marks concludes gene therapy may havean effect on the 4-5 years of age population
based on totality of information and that thebiomarker of micro-dystrophin expression may
be able to predict clinical benefit. Therefore, hewould like to move forward with an accelerated
approval (AA) for that age range based on
available data and exercising regulatory
flexibility. However, there is not any evidence
that the biomarker of micro-dystrophin
expression may be able to predict clinicalbenefit in the 6-7 year-old age range,” thesummary states.

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November 2023 

Limiting the indication in a narrow
patient population will minimize potential
disruption to the EMBARK trial, FDA’s Peter
Marks said.
Furthermore, limiting the indication in a narrow
patient population will minimize potential
disruption to the EMBARK trial, Marks said.
EMBARK, a randomized, placebo-controlled
study, is fully enrolled at 125 patients ages
4-7 years. The primary analysis requires 52week data from Part 1 of the study, and all US
patients are due to complete their 52-week visits
in September. All patients who were originallyrandomized to placebo can crossover to SRP9001 after one year.
At the adcomm, Sarepta said that accelerated
approval would not impact completion of
EMBARK because all 125 patients will have had
their 52-week, primary endpoint visit by theend of September 2023, and it likely will takeabout four months from the time of accelerated
approval for DMD patients in the US to getcommercial access. (Also see “Gene Therapy:
Four-Month Lag In Commercial Access Protects
EMBARK Study, Sarepta Says” - Pink Sheet, 13
May, 2023.)
The primary endpoint in EMBARK is change
from baseline in NSAA total score at week 52 in
the full study population.
“If the outcome from the ongoing confirmatory
trial is negative, FDA would have to withdraw
the AA. If it is positive, depending on the final
data analyses, the label may be expanded toinclude additional age group(s),” the meetingsummary states.
“Dr. Marks reiterated that the review teamshould write their memos as they feelappropriate. The review team will need to move
forward to revise the proposed label.”

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
Marks met with the review team again on 19
May to discuss an updated regulatory timeline,
and a new action due date of 22 June wasagreed upon.

that also may preclude treatment in the near
future with any one of a number of the several
other gene therapies in development.”… Followed By A Call With Sarepta
The CBER director, along with review teamrepresentatives, held a teleconference with
Sarepta on 22 May to discuss the plans for an
age-restricted accelerated approval and the
new target action date.
According to the teleconference summary,Marks conveyed the challenges in the BLA data,
including: remaining questions about how SRP9001 micro-dystrophin compares to full lengthand other truncated dystrophins; challenges withthe use of external controls; and the discrepancy
between the findings seen in Study 102 Part 1 in
the 4-5 year-old and 6-7 year-old groups.
The FDA needed to miss the PDUFA goal dateto engage in adequate labeling negotiations,Marks told Sarepta. “Moving forward, thelabeling negotiations will focus on considerationof the efficacy data from the 4- and 5-years old
subset of Study 102 and the overall safety data
set,” the summary states.
“FDA is already aware that you may not agreewith this parsing of the study data, but please
work with the agency on this, as the larger
population of ambulatory patients is not underconsideration for labeling at this time pending
the results of Study 301,” Marks told Sarepta.
“Although it is obvious that older patients
potentially have more urgent therapeutic need,
there are plausible explanations why microdystrophin expression might not predict clinicalbenefit in these individuals, particularly in thesetting of the negative results from Study 102
Part 1,” the summary states. “FDA must also
look at the potential issues with treating older
children with a therapy that has not clearly
demonstrated the likelihood of efficacy, and14

November 2023 Concerns About EMBARK’s Ability To Confirm
Benefit
The meeting summary states that in “thecontext of the lack of clinical evidence of benefit
in the 6 and 7 year-old children, as the team has
discussed with the applicant previously, FDA
again urged the applicant to consider modifying
the ongoing Study 301 trial to be powered fordemonstrating efficacy in the 4 to 5 year-old
subset, or to be prepared to have to conduct anadditional study if Study 301 fails its primary
endpoint yet indicates likely efficacy in 4 and 5
year-old subgroup.”“Though FDA hopes that this will not be thecase, FDA owes it to the patients to workthrough the potential contingency situations,”
the summary states.

“FDA again urged the applicant toconsider modifying the ongoing Study
301 trial to be powered for demonstrating
efficacy in the 4 to 5 year-old subset,
or to be prepared to have to conduct
an additional study if Study 301 fails its
primary endpoint yet indicates likely
efficacy in 4 and 5 year-old subgroup.” – 22
May meeting summaryMarks told Sarepta that the FDA has considered
all the issues, discussed them carefully
and has briefed senior agency leadership,including Principal Deputy Commissioner Janet
Woodcock.
As director of the Center for Drug Evaluation
and Research, Woodcock over-ruled review staff
and granted accelerated approval to Sarepta’s
Duchenne muscular dystrophy treatment

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
Exondys 51 (eteplirsen) in 2016, making it thefirst of four exon-skipping drugs approved on
the basis of increase in dystrophin as reasonably
likely to predict clinical benefit. Confirmatory
trials have not yet been completed for any of
the four drugs.
At the 22 May meeting, Sarepta representatives
shared their concern about limiting theindication to only 4-5 year-old patients,
including whether efficacy of SRP-9001 needs tobe demonstrated in all age groups.
“FDA reiterated that the agency does not knowwhether SRP-9001 is likely beneficial to the 6-7
years old subgroup based on available data.
FDA hopes Study 301 will provide [a] more clear
answer. Study 301 is only powered for the overall
population of 4 to 7 years old patients and theprimary endpoint will be tested solely on theoverall population.”“If the study fails in the overall population
but wins in the younger age subgroup of 4
to 5 years old, and if the applicant does not
specify an inferential subgroup analysis,
the applicant won’t be able to proceed withtesting the subgroup effect following a failed
test of the overall population,” the meetingsummary states. “FDA continues recommending
the applicant prespecify the inferential age
subgroup analysis based on findings of Study
102 Part 1. This means that the subgroup
analysis needs to be prespecified with adequate
power and proper alpha control.”with FDA’s position, please let FDA know within
the next day. The applicant agreed to follow up
with any concerns within the next day.”Sarepta Confident In EMBARK Design
When asked whether Sarepta had followed
the FDA’s statistical analysis design
recommendations for Study 301, the company
told the Pink Sheet: “EMBARK is powered toshow benefit across the population in the trial(ages 4-7) and the study was already fully
enrolled at the time of the suggestion. Assuming
EMBARK meets its objective, we intend to
pursue a non-age-restricted label for all
Duchenne patients.”“Duchenne is a heterogenous disease, andfunctional measures are better indicators of
disease status than age,” the company said.
“Elevidys works the same way in a 4 year-oldthat it does in a 6 year-old and what we haveseen in clinical trials to date is that patientstreated with Elevidys, regardless of age, aredoing better than natural history would predict.”
During an investor call on the day of Elevidys’
approval, Sarepta was asked what happens if
EMBARK is not a clear win or there are different
results in the two different age subgroups, andwhether the statistical plan was prespecified toallow for analysis of the data in a manner thatmaximizes the probability that the study will
fulfill its objectives in the eyes of the FDA.

“Ultimately, whether data from Study 301 would
support an indication broader than the 4-5
years old ambulatory patients with DMD will bea review issue,” the meeting summary states.
“It is premature to comment in the absence ofdata.”“We have managed our statistics in a way, I
think, that maximizes the potential for success,and that is by powering the study to see astatistically significant and clinically meaningful
effect across the entire patient population,” CEO
Douglas Ingram said. “If we started dividingthat up in smaller segments, you might lose
power.”The meeting summary concludes by stating: “Dr.
Marks made it clear that FDA’s position is not up
for negotiation. If the applicant does not agree

During Sarepta’s Q2 earnings call on 2 August,Chief Scientific Officer and R&D Head Louise
Rodino-Klapac said the company’s simulation

15

November 2023 

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Elevidys’ Age-Restricted Indication Not
Negotiable, CBER’s Peter Marks Told Sarepta
modeling suggests that statistical significancein EMBARK would be reached even if theobserved treatment effect in the overall intentto-treat population was as low as 1.3 points on
the NSAA total score.
Ingram said the company has not had
discussions with the FDA about the clinicalmeaningfulness of a particular number in termsof NSAA treatment effect in EMBARK. However,“this is a disease that is degenerative over time.
If we can see a statistically significant benefit ina mere 52 weeks, we have clearly changed the
trajectory of this disease in a very positive way.”16

November 2023 

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Expanding Cells, Expanding
Access: Gamida Cell’s Omisirge
Debuts New Donor Source For
Stem Cell Transplant
Bridget Silverman
18 May 2023

Executive Summary

Pink Sheet’s Drug Review Profile follows the FDA’s navigationof the first expanded umbilical cord blood graft with the firstindication grounded in neutrophil recovery and infection
incidence data.

Gamida Cell Ltd.’s Omisirge (omidubicelonlv) will be the first substantially modified
cord blood-based stem cell graft source forallogeneic hematopoietic progenitor celltransplantation following FDA approval, using
the Israeli company’s stem cell expansion andenhancement technology to improve clinicaloutcomes with umbilical cord blood grafts –and in doing so, address a significant healthinequity.
The FDA approved Omisirge on 17 April 2023
for adult and pediatric patients 12 years andolder with blood cancers who are planned forumbilical cord blood transplantation following

17

November 2023 

myeloablative conditioning. The cell therapy
is specifically indicated to “reduce the timeto neutrophil recovery and the incidence of
infection.”
Cord blood is “a relatively immunologicallynaïve source of cells,” chief medical officer Ronit
Simantov explained in an interview with the
Pink Sheet. Umbilical cord blood units therefore
require “much less stringent matching criteria
than the other donor sources that come fromadults.”The less stringent matching criteria make cord
blood the only option for patients who need

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Expanding Cells, Expanding Access: Gamida Cell’s Omisirge
Debuts New Donor Source For Stem Cell Transplant
hematopoietic stem cell transplant but cannot
find a match. However, “the main problem withcord blood is that there are too few cells,” sheobserved.
“It’s a very small volume of blood and very few
cells in there. That’s appropriate for perhaps thetiniest patients, for babies and children. But for
adults, it’s long been known to be associatedwith higher mortality after transplant and ahigher number of infections and a long, longtime to neutrophil engraftment.”
Omisirge has the promise to in essence increase
the cord blood supply.
“There are at least 1,200 patients each year in
the US who are eligible for transplant but cannot
find an appropriate donor,” chief operating
officer Michele Korfin told the Pink Sheet.
“Unfortunately, if you are non-Caucasian,it’s very difficult to find a match in the public
database. So, for example, if you are a whitepatient, there’s a 79% chance that you will finda match in the database. If you are a black or
African American patient, that’s 29%.”
Umbilical cord blood transplantation is feasiblefor 96% of Caucasians of European descent,
81% of Black patients, and 82-91% of otherminorities, Gamida Cell reported in its annual
SEC filing on 27 March 2023.
Thanks to the less stringent matching criteria,
Gamida Cell’s Phase III trial of Omisirge had“over 40% of patients who are racially andethnically diverse,” Korfin added. “Our data
indicates most hematology/oncology studies
are more like 5% to 7%.”
Simantov noted that the diverse enrollment“happened organically.”
Clinical trial diversity has been receiving
increasing scrutiny from the FDA. (Also see “US
FDA Calls For Clinical Trial Diversity Plan ‘As
Soon As Practicable’ In Product Development” Pink Sheet, 18 Apr, 2022.)

18

November 2023 

Indication Changed During Review
The FDA’s summary review of the Omisirge
BLA shows that Gamida Cell originally sought
an indication for “treatment of patientswith hematologic malignancies in need of ahematopoietic stem cell transplant,” a moregeneral claim than the approved indication
statement.
The typical FDA-approved HPC-cord blood
product indication is for “hematopoietic andimmunologic reconstitution in patients withdisorders affecting the hematopoietic system.”
The agency, however, focused on the specificoutcomes measured in the Phase III trial. “Theprespecified primary endpoint was a composite
of efficacy (time to neutrophil recovery)and safety (donor chimerism) assessed withdifferent windows of follow-up (42- and 100days following transplantation),” chair of the
CBER Omisirge review committee, Division of
Cell Therapy 1’s Elizabeth Lessey-Morillon, notedin the summary basis for regulatory action.
“This combination of parameters did not
clearly describe clinical benefit for the intended
population,” she stated.
The trial, which compared Omisirge withstandard cord blood in 125 hematologic cancer
patients, did show a statistically significant
effect on time to neutrophil engraftment: 87%of Omisirge patients and 83% of the UCB arm
achieved neutrophil recovery, but the Omisirge
patients had a median time to recovery of 12days compared with 22 days for UCBT.
“Although the trial was considered positive,the design of the trial did not support the
proposed indication since it was not designed todemonstrate an effect on an endpoint relevantto the treatment of hematologic malignancies(e.g., complete remission or overall survival),”Lessey-Morillon explained. “This presented
a challenge in determining an appropriate
indication statement supported by the data.”

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Expanding Cells, Expanding Access: Gamida Cell’s Omisirge
Debuts New Donor Source For Stem Cell Transplant
The agency looked at the therapeutic landscapeto determine appropriate outcomes andlanguage. “A significant disadvantage of UCBT
compared with transplantation from other donor
sources is delayed hematopoietic recovery,
including neutrophil recovery, and increased
serious and life-threatening infections,” LesseyMorillon observed.
“There are currently no marketed productsthat are designed to be used as HSCT graft
sources that are indicated to reduce the time toneutrophil recovery or reduce the incidence ofbacterial and fungal infections in patients withhematologic malignancies planned for UCBT
following myeloablative conditioning.”
Furthermore, “infection in the setting of severe
neutropenia is one of the most common causesof non-relapse mortality (NRM) in the earlypost-transplantation period,” she said. “FDA
considers a reduction in infection to be direct
evidence of clinical benefit for interventions
affecting myelopoiesis.”“The study, as designed, demonstrates aclinically meaningful benefit with Omisirge andaddresses an unmet need for a graft optionthat addresses the limitations of standard UCBT
by reducing the time to neutrophil recovery
and the incidence of infection in subjects withhematologic malignancies who are planned for
UCBT following myeloablative conditioning,”
the CBER reviewer summarized. “Therefore, theapplicant’s proposed indication statement wasrevised to reflect this assessment.”
November 2023 Creative Paths To Supportive Evidence
The FDA review also took a flexible approachto the supportive efficacy data. A single-arm
36-patient Phase I/II study did not include
incidence of infection through day 100 posttransplant as a protocol-specified analysis,but did collect infection data through day 180.
Gamida Cell provided a data file with gradingby the same criteria in the BLA, and a post hoc
analysis found a 19% incidence of grade 2/3
bacterial or grade 3 fungal infections throughday 100.
The post hoc 100-day infection data “wereconsidered supportive of the incidence of
infection seen in the omidubicel arm” of thePhase III trial, Lessey-Morillon said.

Secondary Endpoint Is ‘Evidence of Direct
Clinical Benefit’
The Phase III included a secondary endpoint ofGrade 2/3 bacterial or Grade 3 fungal infections
through day 100 following transplantation.
Infections occurred in 39% of Omisirge patientsand 60% of patients in the UCB arm. The
decreased incidence of infection provides“evidence of direct clinical benefit,” LesseyMorillon said.

19“We are pleased that this indication reflects
the patient population and key outcomes of
our Phase III clinical trial,” Jenkins told theteleconference. “These are critical advantages
that may improve the outcomes of patients
undergoing stem cell transplantation.”

Clinical pharmacology data was also crucial tothe intellectual structure of the FDA decision.
“Immune cell reconstitution (IR) after a HSCT isa dynamic process which includes the recoveryof the lymphoid cell subsets and maturation ofT-cells in the thymus including the induction andgeneration of a diverse, de-novo lymphocyte
repertoire,” she observed. IR analysis thus
“provides supportive clinical evidence for
Omisirge effectiveness.”“Transplantation with Omisirge resulted in rapid
and broad immune reconstitution of dendritic
cells, monocytes, Natural Killer (NK), CD4+ T
cells and CD8+ T cells as early as one-weekpost-transplantation, and B cells 28 days posttransplantation and all lineages throughout the
one-year follow-up period,” Omisirge labelingreports.
“Robust positive linear correlations between

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Expanding Cells, Expanding Access: Gamida Cell’s Omisirge
Debuts New Donor Source For Stem Cell Transplant
the CD34(+) cell content in the Omisirge CF,
and the reconstitution of T-cells and NK cells
were identified. Additionally, dose-response
analyses demonstrated a strong correlation
between the total CD34+ cell counts and dose/
kg for Omisirge with the kinetics of neutrophil
recovery.”

The Center for Biologics Evaluation andResearch staff “are definitely super busy, butthey were super engaged,” Simantov said.
Omidubicel has held a breakthrough therapy
designation since 2016, giving Gamida
Cell greater access to the agency during
development.

Lessey-Morillon called assessment of graftfunction “essential to ensure there was no
detriment introduced by manipulation of thegraft source.” Primary graft failure occurred
in 2% of Omisirge and 11% of UBCU patientsin Phase III, and the proportion of patientsachieving >90% donor chimerism was similar to
UCBU or higher at all timepoints. “No detrimentto graft function was observed with Omisirge incomparison to UCBT.”A New Kind Of Transplantation BLA
Gamida Cell’s process also brings the cells into
the realm of traditional biologics regulation,
instead of the lower data requirements
established by 2009 FDA guidance on minimallymanipulated allogeneic cord and peripheral
blood cells intended for hematopoietic
reconstitution.
A period of enforcement discretion for minimallymanipulated blood cells ended in October
2011, and since then eight umbilical cord bloodtransplant products have been approved under
BLAs, starting with the New York Blood Center’sHemacord (hematopoietic progenitor cells-cordblood) in November 2011.

Omisirge’s similarities to UCBT are notable inthe safety labeling approved by the FDA. “Therisks of Omisirge relate to its mechanism ofaction as an UCBT product,” Lessey-Morillon
observed. “These include infusion reaction,
GvHD, graft failure, and malignancies ofdonor origin and can be managed by routine
pharmacovigilance.”
The Manufacturing Challenge
The label reports that 8% of patientsrandomized to Omisirge could not receive thetherapy due to manufacturing failure. “EachOmisirge unit is specific to each patient,”labeling emphasizes. “In case of manufacturing
failure, a second manufacturing attempt may beconsidered.”
Gamida Cell’s commercial manufacturing
will take place at the company’s Kiryat Gat,
Israel facility, where the company has been
manufacturing clinical batches “for the lastyear,” Korfin said. “We had a very positive
inspection with FDA at the end of last year …
with no observations.”
The Gamida Cell execs also lauded the FDA’s“really deep knowledge and professionalism.”
20

November 2023 

Omisirge “is the first cell therapy to bothenhance and expand stem cells, one of thegreatest scientific challenges in cell therapy,”
Gamida Cell CEO Abigail Jenkins declared
during an 18 April teleconference. She called
Omisirge “the most significant innovation intransplantation in more than a decade.”
Process To Product“No other products or no other graft sources
go through this expansion and enhancement
technology,” Simantov emphasized to the Pink
Sheet.
One of the “key technical challenges” forcell therapy development is “the expansionof therapeutically functional cells,” Gamida
Cell’s 10K filing explained. While the numberof donor cells can be increased in cell culture,“the functionality of those cells often diverges
from the therapeutic functionality of the original

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Expanding Cells, Expanding Access: Gamida Cell’s Omisirge
Debuts New Donor Source For Stem Cell Transplant
donor cells.”

as T cells. “These mature cells cannot engraft
but can provide immunological support until T
cells derived from the stem cell graft recover,”the company said. Both the cultured and noncultured fractions are derived from the same
patient-specific cord blood unit.

Gamida Cell uses its nicotinamide (NAM)
technology to expand the number of progenitor
cells in cord blood while maintaining functional
therapeutic characteristics through a“proprietary combination of NAM, intended tomaintain silencing of cell differentiation andpreservation of gene expression, and particular
cytokines which promote cell growth.”“NAM technology overcomes the induction ofaccelerated proliferation, differentiation, cellularstress and signaling pathways that are typically
activated when [hematopoietic progenitor cells]
are removed from their natural environment,”
Omisirge labeling states. “Ex-vivo culturing ofcord blood derived HPCs in the presence of
NAM leads to preservation of their stemness,homing to the bone marrow (BM) and retained
engraftment capacity as demonstrated by
rapid neutrophil engraftment and multi lineage
immune reconstitution as observed in theclinical trials.”Once And Future Collaborations
Gamida Cell emphasized the outside actorsthat have contributed to omidubicel during
the conference call. Korfin pointed to a “verystrong partnership” with National Marrow
Donor Program/Be The Match “to support
transplant center access to Omisirge.” The
new cell therapy will be a donor source option
within MatchSource, Be The Match’s widely usedsearch platform, she said.
Be the Match registry offers “the most ethnicallydiverse listing of potential donors and umbilicalcord blood units in the world,” the company
said, including more than 22m potential donors
and 300,000 umbilical cord blood units.

Gamida Cell’s proprietary manufacturing
process runs “approximately 30 days from thetime we start manufacturing,” Korfin said. That
timeframe “actually has received very positive
feedback because an unrelated donor, which
the majority of patients are using, could take on
average two to three months to align a donor.”“As the Phase III study concluded, and we saw
the positive primary and secondary endpoints,
we worked with Be The Match to establish acommercial partnership upon potential FDA
approval,” Korfin said. “Our strong partnershipwith Be The Match allows us to have Omisirge
now listed as an option” on MatchSource “oncea transplant center’s onboarded.”“We’ve spent a couple of decades, honing ourskills at expanding and enhancing cells,” shecommented. “We were able to get the actual
harvest down to 21 or 22 days.”

Gamida Cell plans to onboard 10-15 transplant
centers this year. (Also see “Gamida Cell
Bounces Back With Omisirge US Approval” Scrip, 18 Apr, 2023.)

Omidubicel consists of two fractions of cord
blood separated based on expression of thecell surface marker CD133; the components areadministered in sequence with a process thattakes six pages of labeling to describe. CD133positive stem or progenitor cells are isolated
and cultured with NAM. The CD133-negative
cells represent other mature, differentiated cell
types, including immune system essentials such

A Slower Launch Than Planned
Gamida Cell also collaborated Be the Match
BioTherapies on the production of omidubicel,
including the ordering and supply of cord blood
units as starting material.

21

November 2023 

The approval for omidubicel came two weeks
before the BLA’s 1 May 2023 user fee goal date,but Gamida Cell is ready to launch – albeit in a
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Expanding Cells, Expanding Access: Gamida Cell’s Omisirge
Debuts New Donor Source For Stem Cell Transplant
conservative fashion reflecting the company’s
financial straits. On 27 March, just weeks before
the Omisirge approval, the company announced
the discontinuation of its preclinical pipeline andheadcount reductions.
“The company intends to allocate the vast
majority of its resources to executing a launchof omidubicel … although with a more limited
investment and slower ramp than previously
planned in order to manage its financial
resources,” Gamida Cell said.
The company is seeking a partner to provide
more marketing support for Omisirge. Gamida
Cell also recently retained Moelis & Company
LLC to “assist in the exploration of partnerships
or broader strategic alternatives that would
provide additional resources to support thelaunch of Omisirge and associated commercial
activities.”
The approval for omidubicel came two weeks
before the BLA’s 1 May 2023 user fee goal date,but Gamida Cell is ready to launch – albeit in aconservative fashion reflecting the company’s
financial straits. On 27 March, just weeks before

22

November 2023 

the Omisirge approval, the company announced
the discontinuation of its preclinical pipeline andheadcount reductions. “The company intends
to allocate the vast majority of its resources to
executing a launch of omidubicel … althoughwith a more limited investment and slower ramp
than previously planned in order to manage its
financial resources,” Gamida Cell said.
Gamida Cell does not appear to have directcompetition coming any time soon. Two otherexpanded umbilical cord stem cell therapies
have received FDA’s Regenerative Medicines
Advanced Therapy (RMAT) designation:• Magenta Therapeutics, Inc.’s MGTA456, which used a low molecular weightaryl hydrocarbon receptor antagonist to
expand the cells, and• ExCellThera Inc.’s ECT-001, which uses thesmall molecule UM171.
MGTA-456 was discontinued in 2020; ECT-001
completed enrollment in Phase II studies inhigh-risk leukemia and myelodysplasia patientsin November 2022 and is planning extensions.

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Leqembi Phase II Missed ClinicalEndpoint But Still Provided
Support For Amyloid Surrogate
Sue Sutter
06 Mar 2023

Executive Summary

Pink Sheet’s Drug Review Profile digs into the FDA memos on
Eisai/Biogen’s lecanemab; Phase II clinical efficacy results
were reviewed for whether they supported the likelihood ofamyloid plaque reduction to predict clinical benefit, rather
than whether they directly provided substantial evidence ofeffectiveness.

The failure of Eisai Co., Ltd. and Biogen, Inc.’s
Phase II Leqembi (lecanemab-irmb) trial on
its primary clinical endpoint did not undermine
the view that the drug’s ability to lower amyloid
plaque is reasonably likely to predict clinicalbenefit in Alzheimer’s disease, a US Food andDrug Administration clinical reviewer said.
In addition, although the imbalance in ApoE
ε4 carriers in the lecanemab 10 mg/kg
biweekly arm complicated interpretation of thePhase II study results, it did not render them
uninterpretable, said Kevin Krudys, the efficacy
reviewer on the lecanemab application.

23

November 2023 Rather, the clinical endpoint results suggest
lecanemab is “very likely to be effective andmore likely than not to be effective by at least
25%,” Krudys said. In addition, data fromthe recently completed Phase III trial should
provide a clearer picture of the drug’s effects inboth ApoE ε4 carriers and non-carriers, he said.
The FDA granted accelerated approval tolecanemab on 6 January. Krudys’ conclusions
about the Phase II data are detailed in the
drug’s clinical review.
Krudys also was a reviewer on Biogen andEisai’s application for Aduhelm (aducanumabavwa), the first amyloid-lowering antibody to

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Leqembi Phase II Missed Clinical Endpoint
But Still Provided Support For Amyloid Surrogate
reach market for treatment of Alzheimer’s.
Aduhelm received accelerated approval in June
2021.
Krudys supported regular approval of
aducanumab, concluding the one successful
Phase III trial was robust and exceptionallypersuasive, with a treatment effectdemonstrated on a clinically meaningful
endpoint. (Also see “Aduhelm’s ‘Complex’
Circumstances Drove Extensive In-House Advice
Process Before Accelerated Approval, Cavazzoni
Says” - Pink Sheet, 22 Jun, 2021.)
For lecanemab, he supported accelerated
approval based on the precedent set by theuse of a surrogate for aducanumab, as well as
the Phase II and published Phase III data on
clinical efficacy.
The lecanemab review documents highlightthe extent to which aducanumab’s accelerated
approval has proven to be a watershed momentin the therapeutic space.
In an October 2018 meeting, the review division
raised extensive concerns about the efficacy
data in the lecanemab Phase II trial, concludingthat the results could not support either regularor accelerated approval. However, almost
three years later – and three months after the
aducanumab nod – the agency met with Eisai
to discuss the contents of a BLA for accelerated
approval based on those same Phase II data.
(See sidebar for clinical development timeline.)
Unusual and Complex Trial Design
Lecanemab’s Phase II trial (Study 201) involved
an unusual and complex design and analysis.
In the placebo-controlled period, patients wererandomized to one of five lecanemab dosing
regimens, including the 10 mg/kg biweekly
regimen that ultimately was approved. The
study employed Bayesian response adaptive
randomization, which allows for interim analyses
during the study to update allocation based onclinical endpoint results.
During the study, the Data Safety Monitoring
Board recommended that the 10 mg/kg

24

November 2023 

biweekly dose no longer be administered tohomozygous ApoE ε4 carriers due to emerging
data indicating a higher risk of amyloid-related
imaging abnormalities (ARIA) in these patients.
This modification was implemented in Protocol
Amendment 4.
Following discussion with European healthauthorities, it was decided that all ApoE ε4carriers (homozygous and heterozygous) should
no longer be administered lecanemab 10 mg/kg
biweekly.
Under Protocol Amendment 5, all ApoE ε4carriers who had been receiving lecanemab
10 mg/kg biweekly for six months or less werediscontinued from study drug, and newly
enrolled ApoE ε4 carriers were randomized toplacebo or another lecanemab dose. Patients
who were randomized to the 10 mg/kg biweekly
dosing regimen and had been on treatment for
more than six months were allowed to continue
at that dose.
The primary clinical endpoint was change frombaseline in a cognitive composite measure,
the Alzheimer’s Disease Composite Score(ADCOMS) at week 53. The primary analysis was
based on Bayesian statistics.
Amyloid Plaque Reduction
Change from baseline in brain amyloid plaque,as measured by 18F-florbetapir PET and
quantified by a composite standard uptake
value ratio (SUVR), was assessed in a subset ofpatients at weeks 53 and 79. Although this wasa secondary endpoint, these data served as theendpoint supporting accelerated approval.
Compared with placebo, the lecanemab 10 mg/
kg biweekly arm demonstrated a statisticallysignificant reduction in brain amyloid plaque atweek 79 (mean difference of -0.31 SUVR or -73.5
Centiloids; p<0.001).
“Amyloid plaque is an underlying, fundamental,
and defining pathophysiological featureof Alzheimer’s disease. Although the roleof amyloid and its relationship to otherpathophysiological features of Alzheimer’s
disease, such as tau and neurodegeneration, is

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Leqembi Phase II Missed Clinical Endpoint
But Still Provided Support For Amyloid Surrogate
complicated, the presence of amyloid plaques
is a primary and essential finding in Alzheimer’s
disease, including early in the disease,” Krudys
said.

FDA Showed Flexibility On Clinical Endpoint
Results, Safety Database Size” - Pink Sheet, 11
Jan, 2023.)“It is reasonable to conclude that treatment thatis targeted at reducing amyloid plaque, and thatsuccessfully accomplishes that reduction, has
the potential to convey clinical benefit,” he said.
‘Very Likely To Be Effective’
Given the request for accelerated approval
based on amyloid plaque reduction, the clinicalefficacy endpoint results from Study 201 “arereviewed in the context of whether they support
the likelihood of the surrogate to predict clinicalbenefit, rather than whether they directly
provide substantial evidence of effectiveness ofclinical benefit for full approval,” Krudys said.

“The fact that the primary result was not
successful according to the prespecified
threshold should not be incorrectlyinterpreted as evidence of ineffectivenessof lecanemab. On face, this result suggeststhat lecanemab is very likely to beeffective and more likely than not to beeffective by at least 25%.” – FDA’s Kevin
Krudys25

November 2023 “The fact that the primary result was not
successful according to the prespecified
threshold should not be incorrectly interpreted
as evidence of ineffectiveness of lecanemab,”Krudys said. “On face, this result suggests thatlecanemab is very likely to be effective andmore likely than not to be effective by at least25%.”
Looking at secondary and exploratory clinicalefficacy endpoints, the 10 mg/kg biweekly
lecanemab dose demonstrated favorable
numerical results on the Clinical Dementia
Rating Sum of Boxes (CDR-SB) and nominal
statistical significance for ADCOMS and the
Alzheimer’s Disease Assessment Scale-Cognitive
Subscale (ADAS-Cog 14) at week 79.

Krudys noted that interpretation of the clinicalendpoints in the 10 mg/kg biweekly arm
was complicated by the “stark imbalance”
in the proportion of ApoE ε4 carriers in thisdosing group compared to the other arms,
the result of protocol amendments that led to
discontinuation of study drug in 25 patients on
this dose.

The primary Bayesian analysis of ADCOMS atweek 53 indicated that the lecanemab 10 mg/
kg biweekly had a 64% probability of being
superior to placebo by 25%, which did not meetthe prespecified criterion for success of 80%
probability. (Also see “Eisai’s Lecanemab: US

The probability of lecanemab 10 mg/kg
biweekly being superior to placebo by any
amount at week 53 was 98%.

‘Important Context’ For Clinical Endpoint
Results
The memo notes that in 2018, the review divisioncommunicated concerns about the clinicalefficacy data at an end-of-Phase II meeting.
These concerns included the proportion ofpatients with missing efficacy data, use of
ADCOMS as the primary endpoint, statisticalissues with multiplicity, and the imbalancein ApoE ε4 carriers between the 10 mg/kg
biweekly arm and placebo group.
“These concerns remain valid when considering
Study 201 in isolation,” Krudys said. “Thisapplication, however, is being considered foraccelerated approval based on whether thesurrogate endpoint of reduction in brain amyloid
plaque is reasonably likely to predict a clinicalbenefit to patients. Since 2018, accumulating
data on the association between amyloid
plaque reduction and treatment effects on

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Leqembi Phase II Missed Clinical Endpoint
But Still Provided Support For Amyloid Surrogate
clinical endpoints provide important context for
the favorable clinical endpoint observations inStudy 201.”
Krudys specifically addressed concerns about
the imbalance in ApoE ε4 carriers in the placebo
and 10 mg/kg biweekly lecanemab arms.
“One might reasonably hypothesize that theapparent treatment effect observed in thelecanemab 10 mg/kg biweekly arm is driven by
the preponderance of ApoE ε4 non-carriers, who
presumably have slower disease progression.
And, in fact, ApoE ε4 non-carriers were observed
to have slower progression than ApoE ε4carriers for ADCOMS in the placebo arm of
Study 201,” Krudys said.
However, other observations and results caution
against drawing such a conclusion, he said.
“First, it should be noted that slower progressionin ApoE ε4 non-carriers is not a universal finding
across clinical trials. Second, the progressionin ADAS-Cog 14 was greater in ApoE ε4 noncarriers than carriers in the placebo arm … yet
this endpoint demonstrated the largest overall
treatment effect with the smallest nominal
p-value,” he said. “Third, analyses using only
patients randomized before the change inrandomization scheme result in consistentfindings.”
Furthermore, the 10 mg/kg biweekly dose data
were combined with the 10 mg/kg monthly dose
data to create a group with comparable
proportions of ApoE ε4 non-carriers and carriers
to the placebo arm. “In this combined group,
the trends were consistent with the overall
results.”“Notwithstanding these lines of reasoning,the decision to cease randomization of ApoE
ε4 carriers to the 10 mg/kg biweekly regimen
introduced uncertainty which can only be fully
addressed with a larger dataset,” the review
states.
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November 2023 

The agency’s interpretation of the safety dataon amyloid-related imaging abnormalities
also was complicated by the ApoE ε4 carrier
imbalance.
Amyloid Reduction ‘Incompatible’ With Chance
Krudys concluded that lecanemab’s effect on
brain amyloid plaque in Study 201 meets thestatutory standard for substantial evidence ofeffectiveness to support accelerated approval,
and the magnitude of the reduction is consistent
with the observed reduction that supported
aducanumab’s accelerated approval.
“Although the reduction of brain amyloid plaque
was observed in only a subset of patients in asingle study, the results are highly persuasive.
As observed in the placebo arm of Study
201, amyloid plaque does not spontaneously
disappear in patients with Alzheimer’s disease.
The reduction observed in the lecanemab
10 mg/kg biweekly arm is thus incompatible
with variability or chance. Also, the results
demonstrated a clear dose- and concentrationresponse relationship over the dosing regimens
included in the study.”“The effects on amyloid are persuasive andconsistent across doses and subgroups,
supporting the ability of Study 201 to beconsidered a single adequate and wellcontrolled trial that is capable of providing
substantial evidence of effectiveness.”
The clinical endpoint results from Study 201
provide context for the amyloid reduction
observed in the study and inform the reasonable
likelihood that this effect on the surrogate will
predict clinical benefit.
“Despite limitations introduced by the underenrollment of ApoE ε4 carriers in the lecanemab
10 mg/kg biweekly arm and the adaptive designof the trial, the estimates of the treatment
effect at Week 79 across clinical endpoints are
consistent with a modest reduction of clinicaldecline,” Krudys said.

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Leqembi Phase II Missed Clinical Endpoint
But Still Provided Support For Amyloid Surrogate“Importantly, a similar degree of reduction(approximately 20% to 40%) in the decline ofclinical endpoints has been observed in otherstudies in which brain amyloid was reduced toa similar extent. This reduction corresponds to adelay in progression of several months over the
18 months of the study. Patients and caregivers
have clearly expressed that a delay of several
months at this stage of the disease is clinicallyimportant.”
Looking To Phase III Results For Additional
SupportFurthermore, the top-line results from thePhase III trial (Study 301) provide both
important context and additional support for
the reasonable likelihood that that reductionin brain amyloid plaque with lecanemab will
predict clinical benefit, Krudys said.
In the Phase III CLARITY-AD trial, resultsof which were published in the New England
Journal of Medicine in November, lecanemab
demonstrated a statistically significant benefit
on a clinical primary endpoint – a -0.45
difference versus placebo at 18 months on the
CDR-SB, representing a 27% slowing in the rateof decline versus placebo. (Also see “Eisai/
Biogen’s Lecanemab Effective Across Endpoints,
But Will Safety Limit Use?” - Scrip, 30 Nov,
2022.)
Eisai submitted the Phase III data in a
supplemental application seeking regularapproval on the same day that lecanemab
received accelerated approval. Consequently,
the agency had not yet reviewed these data indetail at the time of accelerated approval.
Nevertheless, Krudys said the positive top-line
results in Study 301 “appear to be consistent
with the results of Study 201 and what isalready known about the relationship between
brain amyloid plaque reduction and effect on
clinical endpoints. The top-line results for thegantenerumab studies, although negative, areentirely consistent with the known relationship
27

November 2023 

between amyloid plaque reduction and clinicalendpoints.”
Roche announced in November that its antiamyloid antibody gantenerumab was notstatistically significantly better than placebo at
slowing the rate of clinical decline in two Phase
III trials. Relative reduction in the rate of clinicaldecline compared to placebo was 8% and 6%
in the GRADUATE I and II trials, respectively,
based on CDR-SB scores at 116 weeks. Roche
also noted that amyloid was cleared from thebrains of gantenerumab-treated patients atlower levels than expected. (Also see “Roche’s
Alzheimer’s Drug Fails In Phase III Giving Eisai/
Biogen A Clear Run” - Scrip, 14 Nov, 2022.)
Statisticians Dissent
As was the case with aducanumab, the FDA’s
statistical team disagreed with the decision to
grant accelerated approval.
The statistical review cites many issues with
the Bayesian response adaptive randomization
design of Study 201, including: multiple interim
analyses performed to allow for possibly
stopping the trial earlier; failure to control for
Type 1 error at the level of 0.05 two-sided, or
0.025 one-sided, due to the Bayesian dose
selection; and interim analyses without any
multiplicity correction.

The apparent lack of clinical effects in
ApoE ε4 non-carriers “seems to not alignwith the biomarker treatment effect being
thought of as reasonably likely to predict a
corresponding clinical treatment effect for
all patients.” – FDA’s Tristan Massie“Due to the failure of the primary endpoint
and the large number of secondary endpoints,
all secondary endpoints should be considered
exploratory,” statistical reviewer Tristan
Massie said. In addition, the PET substudy
was voluntary, “so the balance of baseline
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Leqembi Phase II Missed Clinical Endpoint
But Still Provided Support For Amyloid Surrogate
demographics and disease characteristics
within the substudy may not be guaranteed andthe substudy sample may not be representativeof the randomized population.”
Massie said there do not appear to be clinicaleffects in ApoE ε4 non-carriers, even though
there were effects on amyloid SUVR in noncarriers comparable to those seen in ApoE ε4carriers.
“This seems to not align with the biomarker
treatment effect being thought of as reasonably
likely to predict a corresponding clinicaltreatment effect for all patients.”
Krudys’ review suggests Massie’s conclusion
about lack of clinical effects in ApoE ε4 noncarriers is premature.
Of the eight subgroups defined in the statisticalanalysis plan, “the statistical review presents
one (ApoE ε4 carrier status) to raise uncertainty
regarding the impact of amyloid reduction onclinical endpoints because there is no apparent
treatment effect on the clinical endpoint in ApoE
ε4 non-carriers,” Krudys said.
“Subgroup analyses on clinical endpoints are
better suited for the larger confirmatory Study301.
It is worth noting that in the top-line results
for that study, ApoE ε4 non-carriers appeared
to demonstrate a treatment effect on clinicalendpoints,” Krudys said, citing the NEJM
publication with the Phase III data.

28

November 2023 

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