ASP7316 ISN 7316-CL-0006 Stargardt’s Macular Dystrophy ...

ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

Name of Sponsor/Company: Astellas Institute for Regenerative Medicine

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Name of Finished Product: Not applicable

Name of Active Ingredient: Human embryonic stem cell-derived retinal pigment epithelial cells from the MA09 cell line (MA09 hRPE cells [ASP7316])

SYNOPSIS

Title of Study: Follow-Up to 5 Years of a Phase I/II, Open-Label, Multi-Center, Prospective Study to Determine the Safety and Tolerability of Sub-retinal Transplantation of Human Embryonic Stem Cell Derived Retinal Pigmented Epithelial (hESC-RPE) Cells in Patients with Stargardt's Macular Dystrophy (SMD) (ACT hESC-RPE SMD 01FU EU [7316-CL-0006])

Investigators/Coordinating Investigator:

PPD

Study Center(s): This multicenter study was conducted at 2 contracted sites in the UK.

Publication Based on the Study: Not applicable.

Study Period:

Study Initiation Date (Date of First Enrollment):

16 Jan 2013

Study Completion Date (Date of Last Evaluation):

02 Oct 2019

Phase of Development: Phase 1/2

Objectives: To evaluate the long-term safety and tolerability of human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE cells [ASP7316]) in subjects with advanced Stargardt's macular dystrophy (SMD) from 1 to 5 years following the surgical procedure to implant ASP7316.

Methodology:

The current study (ACT hESC-RPE SMD 01FU EU [7316-CL-0006]) was a long-term follow-up (LTFU) study to the ACT hESC-RPE SMD 01 EU phase 1/2 dose escalation study. The dose escalation study was an openlabel, nonrandomized, dose escalation, multicenter study in which a maximum of 12 subjects with SMD were transplanted with sequential doses of ASP7316, starting at a dose of 50000 (50K) cells and increasing to a maximum dose of 200000 (200K) cells. The dose escalation was recommended by the Data Safety Monitoring Board after a full safety assessment of all 3 subjects in each cohort when the third subject in each cohort had completed 4 weeks of follow-up and before the first subjects in the next cohort received a cell transplant.

Informed consent for this LTFU study was obtained at its first visit, which occurred at the 12-month visit of the dose escalation study.

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Subjects were evaluated at 18, 24, 36, 48 and 60 months posttransplant (or more frequently as clinically indicated). Follow-up included obtaining information about ophthalmological findings, serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) of special interest.

Number of Subjects (Planned, Enrolled and Analyzed):

No formal sample size calculation was performed. All 12 subjects who were treated in the dose escalation study enrolled in the LTFU study and were analyzed.

Diagnosis and Main Criteria for Inclusion:

Subjects had been treated with ASP7316 in the dose escalation study and were able to understand and willing to sign the informed consent to participate in the LTFU study.

Test Product, Dose and Mode of Administration, Batch Numbers:

Not applicable.

Duration of Treatment (or Duration of Study, if applicable):

The duration of this study was up to 48 months (months 12 up to 60 after the subretinal injection of ASP7316 in the dose escalation study).

Reference Product, Dose and Mode of Administration, Batch Numbers:

Not applicable.

Criteria for Evaluation:

The following exploratory efficacy endpoints were assessed:

Change from baseline to each visit in best corrected visual acuity (BCVA) (letters) Categorized change from baseline to each visit in BCVA (no change; hand motion [HM] or counting

fingers [CF] to 2 letters; HM to CF; > 0 to < 5 letters increase; 5 to < 10 increase; 10 to < 15 increase; 15 increase; > 0 to < 5 decrease; 5 to < 10 decrease; 10 to < 15 decrease; 15 decrease; 2 letters to CF or HM; CF to HM) Change from baseline to each visit in National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) subscales (socioemotional scale; visual functioning) Change from baseline to each visit in area of atrophy

The primary safety endpoints were incidence of treatment-emergent SAEs and TEAEs of special interest.

TEAEs of special interest were defined as follows:

SAEs that were neurologic, infectious, hematologic or fatal Any new diagnosis of an ocular or immune-mediated disorder Pregnancy in a female subject or in the partner of a male subject and pregnancy outcome Any adverse event (AE) that caused the subject to withdraw from the study Cancer (irrespective of prior history) Ectopic or proliferative cell growth (retinal pigment epithelial [RPE] or non-RPE) with adverse clinical

consequence

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Unexpected, clinically significant AEs possibly related to the cell transplant procedure or the investigational product (ASP7316)

The following secondary safety endpoints were assessed:

Incidence of graft failure or rejection Changes in ocular examinations or images:

o Change in appearance (area, intensity) of hyperpigmentation o Presence of pigmented cell clusters o Presence of epiretinal membrane (ERM) o Retinal thickness in central segment, inner circle and outer circle

Statistical Methods:

Baseline was defined as either the screening values (1 to 45 days prior to surgery) or the baseline visit (1 to 7 days prior to surgery) of the dose escalation study, whichever was later.

Analysis Sets

The safety analysis set (SAF) consisted of all subjects who signed the informed consent form of Study ACT hESC-RPE SMD 01FU EU and were enrolled in the dose escalation study and treated with the investigational product. The SAF was used for the summaries of all the variables (including the efficacy endpoints) using the as-treated principle from the dose escalation study.

Exploratory Efficacy

The exploratory efficacy endpoints were summarized for the SAF. No hypothesis testing was performed. Separate summaries were produced for all SAF subjects and for SAF subjects excluding those with cataract and large drop in BCVA and/or unreliable BCVA.

Safety

TEAEs were coded using MedDRA v18.0 and summarized by frequency, severity (i.e., mild, moderate, severe), seriousness and ASP7316-relatedness. Percentage of subjects with TEAEs, serious TEAEs, TEAEs leading to discontinuation, TEAEs of special interest (including Advanced Therapy Investigational Medicinal Product [ATIMP] events) and ATIMP events were summarized by SOC, preferred term and treatment group. Ocular AEs and nonocular AEs were presented separately. Summaries displaying ocular AEs were presented by treatment group, overall and by eye treatment status (treated/untreated/both). Any ocular event recorded as occurring in both eyes was reported once (in the both eyes group), and not included separately in the values for treated and untreated eyes. Nonocular AEs were presented by treatment group and overall.

Summary of Results/Conclusions:

Disposition, Demographics and Other Baseline Characteristics, Exposure:

All 12 subjects who were treated in the dose escalation study enrolled in the LTFU study and completed the LTFU study. All 12 subjects were included in the SAF [Table 1].

In the SAF, the proportion of male subjects was higher than that of female subjects (83.3% and 16.7%, respectively). All subjects were White. The median (range) age at time of entry into the LTFU study (i.e., informed consent date for the LTFU study) was 45.0 (35-54) years [Table 2].

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Overall, the mean (SD) duration of observation from the subretinal injection of ASP7316 was 60.68 (1.67) months.

Exploratory Efficacy Results:

From baseline to month 60 posttransplant, no dose trend in BCVA improvements was observed [Table 3].

In the overall group with a measurable letter score (6/12 subjects and 8/12 subjects for the treated and

untreated eyes, respectively), the treated and untreated eyes were similar in mean baseline BCVA values

(6.5 and 6.9 letters, respectively) and in mean changes in BCVA letter score from baseline to month 60

posttransplant (2.8 and 2.0 letters, respectively).

None of the subjects had a 15-letter gain from baseline in BCVA score in the treated or untreated eye at

any of the LTFU visits [Table 4].

Between months 12 and 36 posttransplant, the mean VFQ-25 visual functioning score was largely

unchanged in the overall group [Table 5].

Of the 6 subjects with color fundus photographs available at baseline, 2 subjects (both in the 200K group)

had area of atrophy that could be measured within the grid. In 1 of the 2 subjects, the area of atrophy in

the treated and untreated eyes (

PPD

respectively) increased from

baseline to month 60 by

PPD

, respectively. In the other subject, the area of atrophy in the

treated and untreated eyes (

PPD

, respectively) increased from baseline to

month 60 by

PPD

, respectively.

Safety Results:

Treatment of advanced SMD with ASP7316 in doses ranging from 50K to 200K cells was safe and well

P

tolerated. Safety outcomes were noted to be similar between dose groups.

No deaths or serious ocular TEAEs were reported and no TEAEs resulted in study discontinuation. Three

of 12 (25.0%) subjects reported at least one serious nonocular TEAE, all of which were assessed by the

investigator as unrelated to ASP7316. None of the ocular or nonocular TEAEs resulted in study

discontinuation.

Overall, ocular TEAEs with onset during the LTFU or dose escalation studies were reported for

3/12 (25.0%) subjects in the treated eye, 1/12 (8.3%) subject in the untreated eye and 4/12

(33.3%) subjects in both eyes [Table 6]. Two of 12 (16.7%) subjects had ocular TEAEs that were assessed

by the investigator as related to ASP7316 (vitreous floaters, injection site discoloration, vitreous disorder);

all were mild in severity. No severe ocular TEAE was observed.

Nonocular TEAEs were reported for 8/12 (66.7%) subjects [Table 7]. None of these events were assessed

by the investigator as treatment-related.

Overall, 3/12 (25.0%) subjects reported a total of 3 serious nonocular TEAEs (sialoadenitis and human

immunodeficiency virus [HIV] test positive, 50K group; anal abscess, 150000 [150K] group) [Table 8],

which were not related to ASP7316.

No subject had evidence of graft failure or rejection or of a possible immune response to ASP7316.

The appearance (area, intensity) of treatment-emergent subretinal hyperpigmentation was mostly stable in

appearance from months 18 through 60 posttransplant. In the treated eye of 2 subjects (1 subject each in

the 100000 [100K] and 150K groups), the area of treatment-emergent subretinal hyperpigmentation

disappeared in some areas after month 36 posttransplant. In the treated eye in the 200K group (n = 3), the

Reading Center observed an increase in the area of subretinal hyperpigmentation in 1 subject at month 36

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

and in a second subject at month 48 and observed an increase in both the area and in the intensity of subretinal hyperpigmentation in the third subject at month 60 posttransplant. The presence of pigmented epiretinal cell clusters with epiretinal membrane was observed more frequently in the treated eye than the untreated eye.

CONCLUSIONS:

Subretinal injection of ASP7316 in doses ranging from 50K to 200K cells in subjects with SMD is safe and well tolerated for up to 60 months after transplantation. Safety outcomes were noted to be similar between the dose groups and none of the subjects had evidence of a possible immune response to ASP7316. Additional prospective studies are warranted to further investigate the efficacy and safety of human embryonic stem cell-derived RPE cell therapy.

Date of Report: 22 Jun 2020

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Table 1

Subject Disposition and Analysis Set

Parameter

50K

Subjects treated in dose escalation study

3

Subjects treated in dose escalation study who 0

did not enroll in LTFU study

Subjects who enrolled in LTFU Study

3

Parameter Subjects enrolled at year 1 visit (12 months posttransplant) LTFU study discontinuation?

No Yes Reason for study discontinuation Completed study Adverse event Withdrawal by subject Protocol deviation Lost to follow-up Analysis Set Safety analysis set?

50K n = 3 n (%) 3 (100)

3 (100) 0

3 (100) 0 0 0 0

3 (100)

ASP7316 Dose Group

100K

150K

3

3

0

0

3

3

ASP7316 Dose Group

100K

150K

n = 3

n = 3

n (%)

n (%)

3 (100)

3 (100)

3 (100) 0

3 (100) 0 0 0 0

3 (100)

3 (100) 0

3 (100) 0 0 0 0

3 (100)

200K 3 0 3

Overall 12 0 12

200K n = 3 n (%)

3 (100)

Overall n = 12 n (%)

12 (100)

3 (100) 12 (100)

0

0

3 (100) 0 0 0 0

12 (100) 0 0 0 0

3 (100) 12 (100)

K: 1000; LTFU: long-term follow-up.

Dose escalation study is Study ACT hESC-RPE SMD 01 EU.

Subjects with informed consent for the LTFU study.

? LTFU study discontinuation means a subject did not complete the year 5/end of study visit.

? All subjects who signed the informed consent form of Study ACT hESC-RPE SMD 01FU EU and were enrolled in the dose escalation study and treated with the investigational product.

Source: End-of-Text Tables 12.1.1.1, 12.1.1.2 and 12.1.1.3

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Table 2

Summary of Demographic Characteristics (SAF)

Parameter

ASP7316 Dose Group

50K

100K

150K

n = 3

n = 3

n = 3

n (%)

n (%)

n (%)

Sex, n (%)

Male

3 (100)

2 (66.7)

2 (66.7)

Female

0

1 (33.3)

1 (33.3)

Ethnicity, n (%)

Missing

3 (100)

3 (100)

3 (100)

Race, n (%)

White

3 (100)

3 (100)

3 (100)

Black or African American

0

0

0

Asian

0

0

0

Other

0

0

0

Age at informed consent for LTFU study (years)

Mean (SD)

42.3 (6.4) 46.3 (5.1) 45.3 (7.5)

Median (Min, Max)

45.0 (35, 47) 45.0 (42, 52) 41.0 (41, 54)

Age Group, n (%)

< 65 years

3 (100)

3 (100)

3 (100)

65 to < 85 years

0

0

0

85 years

0

0

0

200K n = 3 n (%)

3 (100) 0

3 (100)

3 (100)

0 0 0

46.0 (5.0)

46.0 (41, 51)

3 (100)

0 0

Overall n = 12 n (%)

10 (83.3) 2 (16.7)

12 (100)

12 (100)

0 0 0

45.0 (5.5) 45.0 (35, 54)

12 (100)

0 0

All subjects who signed the informed consent form of Study ACT hESC-RPE SMD 01FU EU and were enrolled in the dose escalation study and treated with the investigational product (SAF).

K: 1000; LTFU: long-term follow-up; max; maximum; min: minimum; SAF: safety analysis set.

Source: End-of-Text Table 12.1.2.1

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ASP7316 Stargardt's Macular Dystrophy CONFIDENTIAL

ISN 7316-CL-0006 EudraCT number 2012-002827-14

Table 3

Summary of BCVA Letter Score (SAF)

Analysis Visit, n

Statistical Parameter

50K

n = 3

T

U

Baseline, n

2

2

Mean (SD)

4.5 (0.7)

5.0 (2.8)

Median (Min, Max)

4.5 (4, 5)

5.0 (3, 7)

Month 12, n

2

2

Mean (SD)

7.0 (5.7)

7.0 (2.8)

Median (Min, Max)

7.0 (3, 11) 7.0 (5, 9)

CFB to Month 12, n

2

2

Mean (SD)

2.5 (4.9)

2.0 (0)

Median (Min, Max)

2.5 (-1, 6) 2.0 (2, 2)

Month 18, n

2

2

Mean (SD)

8.5 (4.9)

7.5 (2.1)

Median (Min, Max)

8.5 (5, 12) 7.5 (6, 9)

CFB to Month 18, n

2

2

Mean (SD)

4.0 (4.2)

2.5 (0.7)

Median (Min, Max)

4.0 (1, 7)

2.5 (2, 3)

Month 24, n

2

2

Mean (SD)

10.0 (5.7)

9.0 (7.1)

Median (Min, Max) 10.0 (6, 14) 9.0 (4, 14)

CFB to Month 24, n

2

2

Mean (SD)

5.5 (4.9)

4.0 (4.2)

Median (Min, Max)

5.5 (2, 9)

4.0 (1, 7)

Month 36, n

2

2

Mean (SD)

7.0 (2.8)

7.0 (1.4)

Median (Min, Max)

7.0 (5, 9)

7.0 (6, 8)

CFB to Month 36, n

2

2

Mean (SD)

2.5 (2.1)

2.0 (1.4)

Median (Min, Max)

2.5 (1, 4)

2.0 (1, 3)

Table continued on next page

ASP7316 Dose Group

100K

150K

n = 3

n = 3

T

U

T

U

1

1

1

3

1.0

4.0

8.0

5.3 (3.2)

1.0 (1, 1) 4.0 (4, 4) 8.0 (8, 8) 4.0 (3, 9)

1

1

1

3

3.0

3.0

11.0

6.7 (4.6)

3.0 (3, 3) 3.0 (3, 3) 11.0 (11, 11) 4.0 (4, 12)

1

1

1

3

2.0

-1.0

3.0

1.3 (1.5)

2.0 (2, 2) -1.0 (-1, -1) 3.0 (3, 3) 1.0 (0, 3)

1

1

1

3

2.0

4.0

5.0

6.0 (1.0)

2.0 (2, 2) 4.0 (4, 4) 5.0 (5, 5) 6.0 (5, 7)

1

1

1

3

1.0

0

-3.0

0.7 (2.5)

1.0 (1, 1)

0 (0, 0) -3.0 (-3, -3) 1.0 (-2, 3)

1

1

1

3

1.0

4.0

4.0

4.7 (2.1)

1.0 (1, 1) 4.0 (4, 4) 4.0 (4, 4) 4.0 (3, 7)

1

1

1

3

0

0

-4.0

-0.7 (1.5)

0 (0, 0)

0 (0, 0) -4.0 (-4, -4) -1.0 (-2, 1)

1

1

1

3

1.0

5.0

11.0

8.7 (6.4)

1.0 (1, 1) 5.0 (5, 5) 11.0 (11, 11) 6.0 (4, 16)

1

1

1

3

0

1.0

3.0

3.3 (3.2)

0 (0, 0)

1.0 (1, 1) 3.0 (3, 3) 2.0 (1, 7)

200K

n = 3

T

U

2

2

10.5 (2.1) 12.5 (2.1)

10.5 (9, 12) 12.5 (11, 14)

2

2

15.5 (4.9) 20.5 (6.4)

15.5 (12, 19) 20.5 (16, 25)

2

2

5.0 (2.8)

8.0 (4.2)

5.0 (3, 7) 8.0 (5, 11)

2

2

16.5 (4.9) 16.5 (3.5)

16.5 (13, 20) 16.5 (14, 19)

2

2

6.0 (2.8)

4.0 (1.4)

6.0 (4, 8) 4.0 (3, 5)

2

2

16.5 (9.2) 20.0 (7.1)

16.5 (10, 23) 20.0 (15, 25)

2

2

6.0 (7.1)

7.5 (4.9)

6.0 (1, 11) 7.5 (4, 11)

2

2

14.0 (7.1) 18.5 (6.4)

14.0 (9, 19) 18.5 (14, 23)

2

2

3.5 (4.9)

6.0 (4.2)

3.5 (0, 7) 6.0 (3, 9)

Overall n = 12

T 6 6.5 (3.9) 6.5 (1, 12) 6 9.8 (6.1) 11.0 (3, 19) 6 3.3 (2.9) 3.0 (-1.0, 7) 6 9.5 (6.7) 8.5 (2, 20) 6 3.0 (4.1) 2.5 (-3, 8) 6 9.7 (8.0) 8.0 (1, 23) 6 3.2 (5.7) 1.5 (-4, 11) 6 9.0 (6.1) 9.0 (1, 19) 6 2.5 (2.7) 2.0 (0, 7)

U 8 6.9 (4.1) 5.5 (3, 14) 8 9.8 (7.7) 7.0 (3, 25) 8 2.9 (3.8) 2.0 (-1, 11) 8 8.8 (5.2) 6.5 (4, 19) 8 1.9 (2.2) 2.5 (-2, 5) 8 9.5 (7.8) 5.5 (3, 25) 8 2.6 (4.4) 1.0 (-2, 11) 8 10.3 (6.7) 7.0 (4, 23) 8 3.4 (3.0) 2.5 (1, 9)

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