1

Antonio Páez, MD

Senior Manager, Clinical Operations

Grifols

The AMBAR trial: an interim analysisASFA Annual Meeting

May 6, 2016. Palm Springs. CA

2

A multicenter, randomized, controlled study to evaluate the

efficacy and safety of short-term plasma exchange followed

by long-term plasmapheresis with infusion of human

albumin combined with intravenous immunoglobulin in

patients with mild-moderate Alzheimer’s disease

3

Study summary

3

Disease: mild-moderate Alzheimer’s disease

Design: Phase IIb/III, multicenter, randomized, controlled (sham), parallel-group, patient- and rater-blind

Patients: 364 patients randomized in 4 groups (1:1:1:1): 3 treatment groups + 1 control group (sham)

Treatments: Total Plasma Exchange with Albumin (Albutein®)

Low Volume Plasma Exchange with Albumin (Albutein®) or IGIV (Flebogamma DIF®)

Participation: maximum 14 months

Sites: 40 sites approx. (20 in Spain and 20 in US)

Endpoint: Changes from baseline in Cognitive Status + Activities of Daily Living (ADAS-Cog + ADCS-ADL)

Other endpoints: Changes in Aβ40 and Aβ42 in plasma and CSF + Brain volume (MRI) + Functional PET scan

Results of a previous Ph2 study with 42 patients presented in the ASFA Annual Meeting 2015

4

Main inclusion criteria

4

• 55 – 85 year-old

• A diagnosis of AD (NINCDS-ADRDA) and MMSE between

18 and 26

• Stable treatment with acetylcholine esterase inhibitors

(AChEIs) and/or memantine for the previous 3 months

• CAT or MRI obtained in the 12 months prior to recruitment

showing absence of cerebrovascular disease

• A stable care taker available that must attend patient study

visits

5

Main exclusion criteria

5

• Any contraindication for plasma exchange

• Hemoglobin < 10 g/dL

• Plasma creatinine > 2 mg/dL

• Uncontrolled high blood pressure (SBP ≥ 160 and/or DBP ≥ 100 mmHg)

• Myocardial infarction, severe or unstable angina, or heart failure (New

York Heart Association Class II, III or IV) in the past 12 months

• A history of frequent adverse reactions to blood products

6

Study treatments

Total Plasma Exchange (TPE)

• Processing of 1 plasma volume

• Replacement fluid: 5% Albumin (Albutein®)

• Central or peripheral access

• Once a week for 6 weeks: 6 procedures

• No IGIV is infused

Low Volume Plasma Exchange (LVPE)

• Removal of 690-880 mL of plasma (like a donation)

• Replacement with 20% Albutein® (different doses)

• Peripheral access

• Once a month for 12 months: 12 procedures

• IGIV is infused to replace endogenous IG

Sham Treatment

• Simulation of TPE and LVPE

• Central and peripheral accesses simulated

• Devices work in a closed-circuit manner

• Expired blood and colored fluid used to fill devices

• No fluid interchange between device and patient

7

364 patients

TPE: Total Plasma Exchange F: Flebogamma DIF 5% (IGIV) : AD Biomarkers : Lumbar Puncture : FDG-PET

LVPE: Low Volume Plasma Exchange A: Albutein 5% - 20% (Albumin) : Neuropsychological Tests : MRI

1 TPE/week - Alb5%

1 LVPE/month

FVA20%: 40g

F: 20g

A20%: 20g FV

A20%: 20g

F: 10gIVB FV

1 2-1 3 54 6 7 8 9 10 11 12 13 14

TPETPE TPE TPE TPE TPE

Control groupSham treatmentFVB IV

F AA A F A A A F A A A

Months

S S S S SS SS SS SS SS S S S S

F AA A F A A A F A A A

A AA A A A A A A A A A

8

Spain US Total

Participating

sites19 20 39

Active sites 18 19 37

Patients

recruited (Apr.)185 160 345

Current and interim status

Interim

End of interim

recruitmentJune 30th, 2015

Database lock September 9th, 2015

Patients recruited186 out of 364

(1/2 sample approx.)

9

Interim general considerations

9

• Description of the patients included as of June 30th, 2015.

• We describe patient characteristics, safety and tolerability,

and treatment feasibility.

• These are not interim results of the study outcomes. All

patients presented together (randomization codes not

broken).

10

Patient disposition

1

0

Recruited patients

(n= 186)

Enrolled patients

(n= 138)

Screening failures

(n= 48; 26%)

Treated patients

(n= 115)

Waiting initiation

(n= 14)

Waiting randomization

(n= 9)

Randomized patients

(n= 129)

Withdrawn patients

(n= 17; 14.8%)

Adverse events (n= 11)

Consent withdrawn (n= 1)

Other (n=5)

Completed

(n= 20)

Ongoing

(n= 78)

11

Enrolled patients: Baseline demographics

1

1

Total Enrolled

(N=138)

Age (yrs.)

N

Mean (SE)

SD

Median (min, max)

138

69.67 (0.689)

8.092

70.00 (53.0, 85.0)

Age group (n, %)

<65

65-75

>75

Missing

40 (29.0)

58 (42.0)

40 (29.0)

Sex (n, %)

Male

Female

68 (49.3)

70 (50.7)

Height (cm)

N

Mean (SE)

SD

Median (min, max)

137

162.45 (0.823)

9.634

163.00 (142.0, 182.9)

Weight (cm)

N

Mean (SE)

SD

Median (min, max)

138

68.18 (1.090)

12.805

67.15 (40.0, 117.1)

12

Treatment feasibility

1

2

• Number of procedures performed at present: about 2,500 (approx. 1,875

real procedures)

• Number of procedures for the interim analysis: 1,367 procedures on 115

patients (approx. 1,025 real procedures)

– 652 Total Plasma Exchange procedures performed on 115 patients.

• 102 patients out of 115 (85%) underwent the 6 TPE procedures

– 715 Low Volume Plasma Exchange procedures performed on 96

patients.

• 20 patients underwent 12 LVPE procedures. 78 patients ongoing

13

Safety: The most frequent AEs

1

3

SOC

Number of AEs during the

plasmapheresis periods

n (%)

Number of patients with AEs

n (%)

Number of AEs occurred

n (%)

Nervous system disorders

Dizziness

Presyncope

Syncope

62 (4.54)

15 (1.10)

13 (0.95)

12 (0.88)

43 (37.4)

13 (11.3)

12 (10.4)

10 (8.7)

68 (13.1)

16 (3.1)

15 (2.9)

12 (2.3)

General disorders and administration site

conditions

Catheter site related

Infusion site related

Thrombosis in device

76 (5.56)

22 (1.61)

24 (1.76)

1 (0.07)

42 (36.5)

24 (20.9)

5 (4.3)

1 (0.9)

83 (16.0)

28 (5.4)

10 (1.9)

1 (0.2)

Blood and lymphatic system disorders

Anaemia

Iron deficiency anaemia

41 (3.00)

32 (2.34)

5 (0.37)

33 (28.7)

26 (22.6)

5 (4.3)

42 (8.1)

32 (6.2)

5 (1.0)

Infections and infestations

Catheter related

38 (2.78)

7 (0.51)

32 (27.8)

7 (6.1)

39 (7.5)

7 (1.3)

Vascular disorders

Hypotension

47 (3.44)

34 (2.49)

32 (27.8)

17 (14.8)

58 (11.2)

34 (6.5)

Musculoskeletal and connective tissue disorders

Muscle spasms

36 (2.63)

26 (1.90)

25 (21.7)

14 (12.2)

43 (8.3)

28 (5.4)

Metabolism and nutrition disorders

Hypocalcaemia

Hypovolaemia

18 (1.32)

4 (0.29)

4 (0.29)

14 (12.2)

4 (3.5)

4 (3.5)

18 (3.5)

4 (0.8)

4 (0.8)

Cardiac disorders

Bradycardia

7 (0.51)

6 (0.44)

11 (9.6)

5 (4.3)

13 (2.5)

7 (1.3)

Total of procedures: 1,367 Total of patients: 115 Total of AEs: 520

14

Safety: SAEs

1

4

SOC

Number of SAEs during the

plasmapheresis periods

n (%)

Number of patients with SAEs

n (%)

Number of SAEs occurred

n (%)

Infections and infestations

Device related infection

Device related sepsis

Endocarditis staphylococcal

Lobar pneumonia

Sepsis

5 (0.37)

1 (0.07)

1 (0.07)

1 (0.07)

1 (0.07)

1 (0.07)

5 (4.3)

1 (0.9)

1 (0.9)

1 (0.9)

1 (0.9)

1 (0.9)

5 (29.4)

1 (5.9)

1 (5.9)

1 (5.9)

1 (5.9)

1 (5.9)

General disorders and administration site conditions

Intentional medical device removal by patient

Non-cardiac chest pain

Pyrexia

Thrombosis in device

3 (0.22)

0 (0.00)

1 (0.07)

1 (0.07)

1 (0.07)

4 (3.5)

1 (0.9)

1 (0.9)

1 (0.9)

1 (0.9)

4 (23.5)

1 (5.9)

1 (5.9)

1 (5.9)

1 (5.9)

Nervous system disorders

Lacunar infarction

Metabolic encephalopathy

Syncope

3 (0.22)

1 (0.07)

1 (0.07)

1 (0.07)

3 (2.6)

1 (0.9)

1 (0.9)

1 (0.9)

3 (17.6)

1 (5.9)

1 (5.9)

1 (5.9)

Gastrointestinal disorders

Large intestinal perforation

Pancreatitis acute

2 (0.15)

1 (0.07)

1 (0.07)

2 (1.7)

1 (0.9)

1 (0.9)

2 (11.8)

1 (5.9)

1 (5.9)

Eye disorders

Retinal detachment

1 (0.07)

1 (0.07)

1 (0.9)

1 (0.9)

1 (5.9)

1 (5.9)

Injury, poisoning and procedural complications

Hip fracture

1 (0.07)

1 (0.07)

1 (0.9)

1 (0.9)

1 (5.9)

1 (5.9)

Metabolism and nutrition disorders

Hypovolaemia

1 (0.07)

1 (0.07)

1 (0.9)

1 (0.9)

1 (5.9)

1 (5.9)

Total of procedures: 1,367

Percentage of SAEs: 1.2%Total of patients: 115 Total of SAEs: 17

15

Outcome measure: MMSE, change from baseline

1

5

Visits

Percentage of patients that improve/worsen(all patients, randomization code not broken)

Improvement Worsening

Month 2

(N=104)

Month 6

(N=70)

Month 9

(N=44)

Month 12

(N=35)

Month 14

(N=31)

TPE LVPE

Cut-off: 0 points

54.8%66.7%

72.7% 69.7% 74.2%

45.2% 33.3%

27.3%30.3%

25.8%

16

Outcome measure: MMSE, change from baseline

1

6

Visit

Percentage of patients that improve/worsen (-2 points)

Improvement Worsening

Month 2

(N=104)

Month 6

(N=70)

Month 9

(N=44)

Month 12

(N=35)

Month 14

(N=31)

TPE LVPE

28.8%

47.8%

54.5%48.5%

61.3%

71.2%

52.2%45.5%

51.5%38.7%

Cut-off: 2 points

17

Outcome measure: ADAS-Cog, changes from baseline

1

7

Visits

Percentage of patients that improve/worsen(all patients, randomization code not broken)

Improvement Worsening

Month 2

(N=104)

Month 6

(N=70)

Month 9

(N=44)

Month 12

(N=35)

Month 14

(N=31)

TPE LVPE

66.3%54.3% 61.4%

70.6%73.3%

33.7%45.7% 38.6%

29.4% 26.7%

Cut-off: 0 points

18

Outcome measures: ADAS-Cog, changes from baseline

1

8

Visits

Percentage of patients that improve/worsen (3 points)

Improvement Worsening

Month 2

(N=104)

Month 6

(N=70)

Month 9

(N=44)

Month 12

(N=35)

Month 14

(N=31)

TPE LVPE

36.5% 35.7%

52.3%

50.0%53.3%

63.5% 64.3%

47.7% 50.0% 46.7%

Cut-off: 3 points

19

Outcome measure: ADCS-ADL, changes from baseline

1

9

Visits

Percentage of patients that improve/worsen(all patients, randomization code not broken)

Improvement Worsening

Month 2

(N=104)

Month 6

(N=70)

Month 9

(N=44)

Month 12

(N=35)

Month 14

(N=31)

TPE LVPE

49.1%60.0%

68.2% 63.6% 58.6%

50.9%40.0%

31.8%36.4% 41.4%

Cut-off: 0 points

20

Summary

2

0

• The AMBAR trial has recruited 345 out of 364 patients (94%) in 39 sites

(Spain and US) as of April 2016.

• About 2,500 apheresis procedures (approx. 1,875 real)

• Interim data presented of the186 patients recruited as of June 2015 (1/2 sz)

• Close to 1,400 apheresis procedures performed (approx. 1,025 real)

• Randomization code not broken.

• Treatment is feasible with an acceptable adverse event profile.

• Main outcome measures show promising improvement/worsening rates

(global).

21

Thank you!