Human Placenta-Derived Cells (PDA-001) For The Treatment of Adults With Multiple Sclerosis
Human Placenta-Derived Cells (PDA-001) For The Treatment of Adults With Multiple Sclerosis
Human Placenta-Derived Cells (PDA-001) For The Treatment of Adults With Multiple Sclerosis
CLINICAL TRIAL
a
Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, United States
b
Swedish Neuroscience Institute, 1600 East Jefferson, Suite 205, Seattle, WA 98122, United States
c
MultiCare Health System-Neuroscience Center of Washington, 915 6th Avenue, Suite 101 and 200,
Tacoma, WA 98405, United States
d
London Health Sciences Centre, University Hospital, Multiple Sclerosis Clinic, 7th Floor, 339 Windermere
Road, PO Box 5339, London, ON, Canada N6A 5A5
e
University of Minnesota, Clinical Neuroscience Research Unit, 717 Delaware Street SE, Suite 246,
Minneapolis, MN 55414, United States
f
University of Colorado Denver, 12631 E. 17th Avenue, Mail Stop B185, Room 5506, Aurora, CO 80045,
United States
g
The Ottawa Hospital Multiple Sclerosis Clinic, 501 Smyth Road, Box 607, Ottawa, Ontario,
Canada K1H 8L6
h
MS Comprehensive Care Center, MSC T12-020 SUNY, Stony Brook, NY 11794, United States
i
Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States
Received 11 June 2014; received in revised form 2 July 2014; accepted 14 August 2014
☆
Presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10–13, 2012, Lyon,
France.
n
Corresponding author. Tel.: +1 212 241 6854; fax: +1 212 241 0440.
E-mail addresses: [email protected] (F.D. Lublin), [email protected] (J.D. Bowen),
[email protected] (J. Huddlestone), [email protected] (M. Kremenchutzky),
[email protected] (A. Carpenter), [email protected] (J.R. Corboy), [email protected] (M.S. Freedman),
[email protected] (L. Krupp), [email protected] (C. Paulo), [email protected] (R.J. Hariri),
sfi[email protected] (S.A. Fischkoff).
http://dx.doi.org/10.1016/j.msard.2014.08.002
2211-0348/& 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).
Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis 697
KEYWORDS Abstract
Cell therapy; Background: Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-
Clinical trial; term human placenta, is a new approach in the treatment of patients with multiple sclerosis.
Immunomodulators; Objective: This safety study aimed to rule out the possibility of paradoxical exacerbation of
Multiple sclerosis; disease activity by PDA-001 in patients with multiple sclerosis.
Mesenchymal stromal
Methods: This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-
cells
dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary
progressive multiple sclerosis. The study was conducted at 6 sites in the United States and
2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001
(150 106 cells) or placebo, given 1 week apart. After completing this cohort, subsequent
patients received high-dose PDA-001 (600 106 cells) or placebo. Monthly brain magnetic
resonance imaging scans were performed. The primary end point was ruling out the possibility
of paradoxical worsening of MS disease activity. This was monitored using Cutter's rule ( Z5 new
gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly
basis for six months and also the frequency of multiple sclerosis relapse.
Results: Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary
progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001,
6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter's rule. One patient receiving
high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability
Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other
patient had an increase in Expanded Disability Status Scale score 40.5, and most had stable or
decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient
experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis.
Other adverse events were mild to moderate and included headache, fatigue, infusion site
reactions, and urinary tract infection.
Conclusion: PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple
sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of
lesion counts was noted with either dose.
& 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
efficacy considerations using weight scaling from doses used imaging on a monthly basis for six months and also the
in the murine EAE model. frequency of multiple sclerosis relapse. Secondary end
points included changes in MS-related disability and quality
of life.
2. Methods
Patients between 18 and 65 years of age with a pre-existing Patients were assigned to a dose level cohort (8 patients per
diagnosis of RRMS or SPMS per the 2005 McDonald Criteria cohort) based on the order of entry into the study. Using a
(Polman et al., 2005) and disease duration of at least 2 years randomization code generated by an independent statisti-
were eligible to participate in the study. Patients had cian, patients were randomly allocated 1:3 to receive low-
to have evidence of active disease as evidenced by clinical dose PDA-001, high-dose PDA-001, or placebo and stratified
progression, continued relapses, or worsening magnetic by type of MS (RRMS or SPMS). Treatment was double-
resonance imaging (MRI) scans after at least 1 year of blinded, with all patients receiving numbered drug infusion
attempted therapy. The MRI worsening is evidenced by an bags that were identical in appearance. All patients and
increase of at least 1 point in Expanded Disability Status investigators, excluding the pharmacist at each study site,
Scale (EDSS) score (if screening EDSS was r5.0) or 0.5 EDSS the independent statistician and the independent data
score (if baseline EDSS was Z5.5). Patients were excluded monitoring committee, were masked to treatment alloca-
if they were treated with systemic immunosuppressive tion during the study.
medications (eg, infliximab, cyclophosphamide, mitoxan- During the screening period, patients were evaluated for
trone, azathioprine, methotrexate, linomide, cyclosporine, study eligibility. Baseline cranial MRI scans were obtained
cladribine, deoxyspergualin) or natalizumab within 6 months within 14 days before all patients received their initial
before screening. Adequate cardiac, pulmonary, liver, and dose in the treatment phase. PDA-001 and placebo
renal function was required. All patients gave written units were supplied in a cryopreserved state. Immediately
informed consent before enrollment. before administration, units were thawed, reconstituted
with sufficient diluent (infusion grade dextran 40) for a total
2.2. Study design of 240 mL per infusion, and transferred to an infusion bag
through the port using sterile technique. Each PDA-001 unit
contained approximately 150 106 cells. Placebo contained
This phase 1b, randomized, double-blind, placebo-con-
all of the excipients and at the same concentrations as the
trolled, 2-dose escalation study was conducted from
PDA-001 product, but did not contain the PDA-001 cells.
November 2010 to August 2011 at 6 sites in the United
On study days 0 and 7 of the treatment phase, the first
States and 2 sites in Canada under an Investigational New
8 eligible patients (low-dose PDA-001 group) received infu-
Drug license from the US Food and Drug Administration and
sions of 150 106 cells or placebo, and then the next
a Clinical Trial Application from Health Canada. The study
8 eligible patients (high-dose PDA-001 group) received
protocol was approved by local institutional review boards.
2 infusions of 600 106 cells or placebo. Infusion occurred
The study was conducted in accordance with the ethical
over 2 h via a 20- to 22-gauge catheter connected to a
principles of Good Clinical Practice, as required by inde-
volumetric infusion pump and had to be completed within
pendent regulatory authorities and in accordance with the
4 h of thaw start time. Diphenhydramine 50 mg and hydro-
Declaration of Helsinki.
cortisone 50 mg were given as premedications 15 to 30 min
The study sequentially evaluated 2 dosage levels of PDA-
before each infusion. Patients' heart rate, respiration, blood
001 versus placebo, administered by intravenous infusion.
pressure, body temperature and blood oxygen saturation
The low-dose (1 unit; 150 106 cells) PDA-001 group was
were monitored every 15 min during the infusion and for at
enrolled and dosed first; after day 36 evaluation, the Data
least 2 h after the end of the infusion. After completing the
Monitoring Committee recommended enrollment of the
treatment period, patients entered the initial 6-month
high-dose (4 units; 600 106 cells) PDA-001 group. Each
follow-up period, during which safety and efficacy data
dose level cohort consisted of 8 patients, 6 randomized
were collected.
to receive PDA-001 and 2 randomized to receive placebo.
Patients received monthly MRI scans for 6 months. MRI
A pretreatment screening phase of up to 35 days was
data collected during the screening and initial follow-up
followed by an 8-day treatment phase (infusion of PDA-
period were analyzed at a central read facility; this analysis
001 or placebo on days 0 and 7), and an initial follow-up
occurred after all patients in the low-dose and high-dose
phase of 6 months plus an extended follow-up period of
groups completed the initial follow-up period. The
6 months. Patients were followed for the full 12 months
extended follow-up period (6 months) allowed for collection
regardless of clinical response.
of long-term safety data and additional efficacy observa-
tions and quality-of-life information. Concomitant MS med-
2.3. Assessments ications were maintained at a constant dose as long as
possible throughout the study.
The primary end point was ruling out the possibility of Data from MRI scans were utilized in the analysis of safety
paradoxical worsening of MS disease activity. This was and efficacy end points. MRI data were used to assess
monitored using Cutter's rule (Z 5 new gadolinium lesions the severity of clinical disease by evaluating change in the
on 2 consecutive scans) by brain magnetic resonance number of brain MS lesions at 6 months compared with
Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis 699
baseline. The safety evaluation included an on-going review dosing and month 1 MRI assessments for the low-dose group
of clinical laboratory tests, including blood and urine; to review safety information and cranial lesion counts
neurological and physical examinations, including vital before continuing enrollment into the high-dose group.
sign measurements; electrocardiograms; MRI or computed When a negative safety signal or paradoxical effect was
tomography scans of the chest, abdomen and pelvis; use identified, as defined by Cutter's rule (development of Z 5
of concomitant medications; and incidence and severity of new lesions present on 2 consecutive monthly scans)
infusion reactions and adverse events. (Riddell et al., 2011), or Z2 patients experienced a grade
The independent data monitoring committee reviewed all 2 or greater allergic reaction, an unexpected treatment-
safety information to ensure patient safety and determined related adverse event or dose-limiting toxicity within 28
study continuation and/or modifications. Lesion counts, as days of the initial treatment dose. Dose-limiting toxicity
determined by local assessment of MRI scans, were provided was defined as grade 2 toxicity not resolving within 14 days
to the data monitoring committee. These local readings or grade 3 or greater toxicity at least possibly related to
were superseded by the central readings for the final data treatment.
analysis. The committee was convened upon completion of The MRI effect was determined by evaluating the number
of gadolinium-enhancing lesions over 6 months versus
placebo. Changes in clinical function and quality of life
were evaluated using a standardized definition of relapse,
EDSS, Multiple Sclerosis Functional Composite, MS Fatigue
Impact Scale, and the MS Quality of Life scale, which were
administered at baseline, before each infusion, monthly
during the initial follow-up period, and every 3 months
during the extended follow-up period.
Age, median (range), y 52.5 (41–58) 47.5 (36–56) 47.5 (40–52) 48.0 (36–58)
Men, n (%) 2 (33) 1 (17) 2 (50) 5 (31)
White race, n (%) 6 (100) 6 (100) 4 (100) 16 (100)
Type of MS, n (%)
RRMS 5 (83) 2 (33) 3 (75) 10 (62.5)
SPMS 1 (17) 4 (67) 1 (25) 6 (37.5)
Time since diagnosis, median (range), y 6.2 (5.2–31.8) 10.8 (1.0–14.7) 11.35 8.5
(2.0–26.5) (1.0–31.8)
Gadolinium-enhancing lesions, median 0 (0–0) 0 (0–1) 0 (0–0) 0 (0–1)
(range)
EDSS score, median (range) 5.0 (4.0–5.5) 6.0 (1.5–6.5) 4.0 (4.0–4.0) 4.8 (1.5–6.5)
Abbreviations: EDSS, expanded disability status scale; MS, multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS,
secondary-progressive multiple sclerosis.
700
Table 2 Prior and concomitant multiple sclerosis medications.
Patient number MS Type Medication Prior (P) or Start date End date Reason
concomitant (C) [study day] [study day] for use
PDA-001 (1 unit)
003-1001 RRMS Glatiramer acetate P, C 2005 Ongoing MS
003-1002 RRMS Interferon-beta-1 A P, C 2007 Ongoing MS
Pregabalin P, C 2008 Ongoing Neuropathic pain
Amitriptyline P, C 2009 Ongoing Neuropathic pain
Baclofen P, C 2010 Ongoing Spasticity
003-1004 RRMS Interferon-beta-1 A P 2009 [ 604] 2010 [ 330] MS
Gabapentin C [72] Ongoing MS leg pain
Cyclobenzaprine C [134] [136] MS leg pain
Baclofen C [153] Ongoing MS leg pain
Natalizumab C [324] Ongoing MS
004-1005 RRMS Fingolimod P, C 2009 [ 495] Ongoing RRMS
Medical marijuana P, C 2010 [ 216] Ongoing Spasticity
004-1007 RRMS Glatiramer acetate P, C 1998 [173] RRMS
Baclofen P, C 2010 [ 453] Ongoing MS leg weakness
Tizanidine P, C 2010 [ 307] Ongoing MS leg spasticity
Fingolimod C [193] Ongoing RRMS
Naltrexone C [281] Ongoing RRMS
007-1008 SPMS Teriflunomide P 2007 [ 1343] 2010 [ 168] MS
Amantadine P, C 2007 [ 1385] Ongoing MS-related fatigue
PDA-001 (4 units)
007-2001 SPMS Natalizumab P 2009 [ 692] 2001 [ 184] MS
005-2003 SPMS Baclofen P, C 2004 [ 2586] Ongoing Muscle spasms
Gabapentin P, C 2004 [ 2460] 2012 [253] Neuropathic pain
Interferon-beta-1A P, C 2005 [ 2201] 2011 [11] MS
Prednisolone P 2011 [ 181] 2011 [ 179] MS relapse
002-2004 RRMS Interferon-beta-1A P 2006 2011 [ 110] MS
Interferon-beta-1A P, C 2011 [ 109] Ongoing MS
007-2006 SPMS Amitriptyline P, C 2011 Ongoing Muscle spasms
Gabapentin P, C 2011 Ongoing MS-related pain
001-2007 SPMS Interferon-beta-1A P, C 2001 [ 3,878] Ongoing MS
Glatiramer acetate P, C 2008 [ 987] Ongoing MS
Fampridine P 2010 [ 409] 2011 [ 89] Gait disturbance
MS-related fatigue
Neuropathic pain
MS-related pain
MS dysesthesia
MS relapse
MS relapse
Inc, Cary, NC, USA).
Mobility
RRMS
MS
MS
MS
MS
3. Results
2011 [ 193]
2011 [ 99]
Ongoing
Ongoing
P,
P,
C
C
P
P
groups.
The gadolinium-enhancing lesion counts (the primary end
point) are shown by month in Fig. 2. After 6 months of
follow-up, no patient met Cutter's rule, indicating a lack of
paradoxical effect of PDA-001 on MS lesions. Cutter's rule
required the development of Z5 new lesions present on
Glatiramer acetate
Interferon-beta-1A
10
Prednisolone
Natalizumab
Gabapentin
Gabapentin
Fampridine
ns
Fingolimod
Pregabalin
Enhancing Lesio
Modafinil
Baclofen
Vicodin
6
Number of Gd
4
RRMS
RRMS
RRMS
SPMS
2
its
Un
it el
Un ev
4
1 eL
0
s
6
Do
5
4
3
o
2
Pb
1
004-1003
004-1006
006-2002
008-2005
Time
Placebo
(mon B/L
ths )
2 consecutive monthly scans. One patient showed an disturbance, urinary tract infection, and nasopharyngitis
increase in gadolinium-enhancing lesions during an MS flare (25% each). Infusion-related adverse events (grade 1 or 2)
5 months after receiving high-dose PDA-001 but did not occurred in 2 patients in the low-dose PDA-001 group and in
meet Cutter's rule for 2 consecutive scans. This patient also 4 patients in the high-dose PDA-001 group (38%); these
showed an increase in EDSS score during this period (Fig. 3). included infusion site swelling (19%), hematoma (12%), site
No other patient had an increase in EDSS score greater than mass (13%), or pain (6%). Serious infusion-related events
0.5, and most patients had either stable or decreasing EDSS occurred in 2 patients in the high-dose group (grade
scores. No trends were seen over time in the Multiple 1 anaphylactoid reaction and grade 2 superficial throm-
Sclerosis Functional Composite, MS Fatigue Impact Scale, bophlebitis), both of which resolved without requiring a
or MS Quality of Life scale. change in study medication. Only 1 grade 3 adverse event
Adverse events were mild to moderate in intensity was reported (MS relapse on day 27; duration, 59 days), but
(Table 3). The most common adverse events (irrespective this event was not suspected as being related to study
of relatedness to study treatment) were headache (44%), therapy. No patient withdrew from the study due to an
upper respiratory infection (31%) and nausea, fatigue, gait adverse event, and no deaths were reported.
Fig. 3 Expanded disability status scores over a 12-month follow-up period for patients in (A) Low-dose and (B) high-dose Treatment
groups, nPatients received placebo. Abbreviations: RR, relapsed-remitting; SP, secondary progressive.