Trial 9403: Baseline Characteristics Demographic Parameter Placebo (N = 84) Memantine (N = 82) MMSE Mean  SD Mean  SD 6.1   2.6 Min, Max Min, Max 0, 9 HIS Mean  SD Mean  SD 5.7   2.9 Min, Max Min, Max 1, 12 BGP care dependency Mean  SD Mean  SD 21.8   7.6 BGP cognitive Mean  SD Mean  SD 5.4   2.6

Trial 9403: Baseline Characteristics by HIS Score Demographic Parameter HIS ≤ 4 (AD) HIS > 4 (VaD) Placebo (N = 38) Memantine (N = 41) Placebo (N = 46) Memantine (N = 41) MMSE Mean  SD Mean  SD 6.8     2.8 Min, Max Min, Max 1, 9 0, 9 HIS Mean  SD Mean  SD 2.7     2.1 Min, Max Min, Max 1, 4 5, 12 BGP care dependency Mean  SD Mean  SD 19.0     8.32 BGP cognitive Mean  SD Mean  SD 4.6     2.62

Trial 9403: FDA Defined AD Subpopulation (LOCF) Placebo N = 25 Memantine N = 38 M-P Mean SD MeanSDp-value BGP-Care Dependency BGP-Cog CGI-C < 0.001

HIS > 4) Trial 9403: Change from Baseline in BGP Care Dependency: VaD Subpopulation (HIS > 4) PlaceboMemantine p-value* NMeanSDNMeanSD Endpoint (LOCF) Week 12 (OC) *Wilcoxon rank sum test (stratified by center)

ADCS-ADL 19 Item Analyses ItemPoints ItemPoints Eating0-4Find personal belongings0-3 Walking0-3 Obtain a beverage 0-3 Toileting0-3 Dispose of garbage appropriately 0-3* Bathing0-3Travel beyond home 0-4 Grooming0-3Left on own 0-3 Dressing0-4 Run water for washing without help 0-1 Using a telephone0-5 Turn off water after using without help 0-1 Watching television0-3 Turn on a light when entering a dark area 0-1 Attend to conversation0-3 Turn off light when leaving or going to sleep 0-1* Clear dishes after meal/snack 0-3 *p<.10

Trial 9605: ADCS - ADL 19 : Cumulative Percentage of Patients Completing 28 Weeks of Treatment

Trial 9605: Severe Impairment Battery: Cumulative Percentage of Patients Completing 28 Weeks of Treatment

Trial 9605: RUD Residential Status Placebo N = 76 (%) Memantine N = 90 (%) p-value* Baseline Institution End point Institution *Chi-square test Based on the TTP subset at week 28. Community = patient’s own home or friend’s/relative’s home. Institution = intermediate care facility, home oriented towards dementia care, or other long-term care facility. Institutionalization

ADCS - ADL 19 Item Analyses ItemPointsItemPoints Eating0-4Find personal belongings0-3* Walking0-3 Obtain a beverage 0-3 Toileting0-3 Dispose of garbage appropriately 0-3 Bathing0-3Travel beyond home 0-4 Grooming0-3**Left on own 0-3 Dressing0-4 Run water for washing without help 0-1 Using a telephone0-5 Turn off water after using without help 0-1 Watching television0-3* Turn on a light when entering a dark area 0-1 Attend to conversation0-3* Turn off light when leaving or going to sleep 0-1 Clear dishes after meal/snack 0-3 *p <.10; **p < 0.01

Trial MD-02: NPI p = p < p = Improvement Worsening Treatment Week

Trial MD - 02: CIBIC+ Subgroup Analyses Subgroup PlaceboMemantine p-value NMeanMedianSDNMeanMedianSD MMSE ≤ MMSE > MMSE ≤ MMSE > Van Elteren test.

PCS Vital Sign Values – Criteria Vital Sign Parameter Observed Value Change Relative to Baseline Systolic Blood Pressure  180 mm Hg Increase of  20  90 mm Hg Decrease of  20 Diastolic Blood Pressure  105 mm Hg Increase of  15  50 mm Hg Decrease of  15 Pulse  120 bpm Increase of  15  50 bpm Decrease of  15 Weight Any Increase of  7% Any Decrease of  7%

Mean Change in Blood Pressure Placebo (N = 604) n (%) Memantine (N = 606) n (%) Diastolic Blood Pressure (mm Hg) Baseline, mean (SD) 78.0 (9.9) 78.1 (10.2) Change From Baseline, mean (SD) -0.7 (9.2) -0.4 (10.2) Systolic Blood Pressure (mm Hg) Baseline, mean (SD) (16.6) (16.5) Change From Baseline, mean (SD) -0.8 (17.0) -1.0 (16.6) Double-Blind, Placebo-Controlled Dementia Trials

NMDA Receptor Antagonist - Related Neuropathology  Membrane bound cytoplasmic vacuoles within the first day of dosing  Vacuoles are dilated endoplasmic reticulum and Golgi in neurons of cingulate, retrosplenial cortex  Visualization requires aldehyde perfusion  Not observed in frozen or immersion fixed brain tissue  Neuronal vacuolization progresses to necrosis in proportion of neurons, 2+ days after NMDA antagonist exposure  Membrane bound cytoplasmic vacuoles within the first day of dosing  Vacuoles are dilated endoplasmic reticulum and Golgi in neurons of cingulate, retrosplenial cortex  Visualization requires aldehyde perfusion  Not observed in frozen or immersion fixed brain tissue  Neuronal vacuolization progresses to necrosis in proportion of neurons, 2+ days after NMDA antagonist exposure

NMDA Antagonist Neuropathology  Rodent specific  Class effect of NMDA antagonists  Not observed in primates at doses inducing significant clinical signs  Clinical relevance unknown  Rodent specific  Class effect of NMDA antagonists  Not observed in primates at doses inducing significant clinical signs  Clinical relevance unknown

Memantine Neuropathology is Rodent Specific  Neuropathology only observed in rats and at doses 12 or more times the MRHD (on a mg/m 2 basis)  Neuropathology observed at doses 2 - 4x’s higher than ataxia  Neuropathology not observed in non - rodent species  In dogs at dose which causes seizure and death  In baboons at doses which cause significant clinical signs  Neuropathology only observed in rats and at doses 12 or more times the MRHD (on a mg/m 2 basis)  Neuropathology observed at doses 2 - 4x’s higher than ataxia  Neuropathology not observed in non - rodent species  In dogs at dose which causes seizure and death  In baboons at doses which cause significant clinical signs MRHD = maximum recommended human dose, 20 mg/day.

Efficacy in MMSE Subpopulation: < 10, and ≥ 10 – CIBIC+ p = p = p = p = p = p = 0.121

Functional Activities Staging (FAST) 1.No difficulties, either subjectively or objectively 2.Complains of forgetting locations of objects; subjective work difficulties 3.Decreased job functioning evident to coworkers; difficulty in traveling to new locations; decreased organizational capacity 4.Decreased ability to perform complex tasks 5.Requires assistance in choosing proper clothing 6.(a) Difficulty putting clothing on properly (b) Unable to bathe properly; may develop fear of bathing (c) Inability to handle mechanics of toileting (d) Urinary incontinence (e) Fecal incontinence 7.(a ) Ability to speak limited (1 to 5 words a day) (b) All intelligible vocabulary lost (c) Nonambulatory (d) Unable to sit up independently (e) Unable to smile (f) Unable to hold up head up 1.No difficulties, either subjectively or objectively 2.Complains of forgetting locations of objects; subjective work difficulties 3.Decreased job functioning evident to coworkers; difficulty in traveling to new locations; decreased organizational capacity 4.Decreased ability to perform complex tasks 5.Requires assistance in choosing proper clothing 6.(a) Difficulty putting clothing on properly (b) Unable to bathe properly; may develop fear of bathing (c) Inability to handle mechanics of toileting (d) Urinary incontinence (e) Fecal incontinence 7.(a ) Ability to speak limited (1 to 5 words a day) (b) All intelligible vocabulary lost (c) Nonambulatory (d) Unable to sit up independently (e) Unable to smile (f) Unable to hold up head up 9605

ADCS - ADL 19 Items Item ItemPoints ItemPoints Eating0-4 Find personal belongings 0-3 Walking0-3 Obtain a beverage 0-3 Toileting0-3 Dispose of garbage appropriately 0-3 Bathing0-3 Travel beyond home 0-4 Grooming0-3 Left on own 0-3 Dressing0-4 Run water for washing without help 0-1 Using a telephone 0-5 Turn off water after using without help 0-1 Watching television 0-3 Turn on a light when entering a dark area 0-1 Attend to conversation 0-3 Turn off light when leaving or going to sleep 0-1 Clear dishes after meal/snack 0-3

ADCS - ADL 19 Item Selection Criteria  Used ADCS subjects with MMSE 0-15  50% of sample was able to do item (score > 0)  Item Kappa ≥ 0.4 for test-retest reliability  Item showed sufficient stepwise scaling  Compared performance/nonperformance ratios across MMSE scores  Decline ≥ 0.2 points at 12-months  Cronbach’s alpha > 0.80 for total score  Used ADCS subjects with MMSE 0-15  50% of sample was able to do item (score > 0)  Item Kappa ≥ 0.4 for test-retest reliability  Item showed sufficient stepwise scaling  Compared performance/nonperformance ratios across MMSE scores  Decline ≥ 0.2 points at 12-months  Cronbach’s alpha > 0.80 for total score Galasko et al submitted

ADCS - ADL 19 Item Formats  Items 1-6  Regarding grooming, in the past 4 weeks, which best describes {S} optimal performance?  3 = cleaned and cut fingernails without physical help  2 = brushed and combed hair without physical help  1 = kept face and hands clean without physical help  0 = needed help for grooming of hair, face, hands, and fingernails  Items 7-15  In the past 4 weeks, did {S} dispose of garbage or litter in an appropriate place or container at home?  0 = No  0 = Don’t know  If Yes; which best describes how {S} usually performed:  3 = without supervision or help  2 = with supervision  1 = with physical help  Items  In the past 4 weeks, did {S} usually turn off the faucet after finishing running water without help?  1 = Yes  0 = No  Items 1-6  Regarding grooming, in the past 4 weeks, which best describes {S} optimal performance?  3 = cleaned and cut fingernails without physical help  2 = brushed and combed hair without physical help  1 = kept face and hands clean without physical help  0 = needed help for grooming of hair, face, hands, and fingernails  Items 7-15  In the past 4 weeks, did {S} dispose of garbage or litter in an appropriate place or container at home?  0 = No  0 = Don’t know  If Yes; which best describes how {S} usually performed:  3 = without supervision or help  2 = with supervision  1 = with physical help  Items  In the past 4 weeks, did {S} usually turn off the faucet after finishing running water without help?  1 = Yes  0 = No

ADCS - ADL 19 Reliability  Test-retest reliability  ADCS data, N = 145 MMSE 0-15, M = 7.3 ± 4.7 (Galasko et al submitted)  1-month: Kappa = 0.93  2-month: Kappa = 0.89  9605 (placebo group)  1-month: ICC = 0.92  MD-02 (placebo group)  1-month: ICC = 0.92  2-month: ICC = 0.92  Internal Consistency (Cronbach’s alpha)  9605 baseline placebo data = 0.92  MD-02 baseline placebo data = 0.92  Test-retest reliability  ADCS data, N = 145 MMSE 0-15, M = 7.3 ± 4.7 (Galasko et al submitted)  1-month: Kappa = 0.93  2-month: Kappa = 0.89  9605 (placebo group)  1-month: ICC = 0.92  MD-02 (placebo group)  1-month: ICC = 0.92  2-month: ICC = 0.92  Internal Consistency (Cronbach’s alpha)  9605 baseline placebo data = 0.92  MD-02 baseline placebo data = 0.92

SIB Concurrent Validity Correlations  100 pt version  Baseline correlations (ADCS; Schmitt et al 1997)  MMSE = 0.83  CDR = -0.65; Sum of boxes = -0.75; GDS = -0.68, FAST =  12-month change score correlations (ADCS; Schmitt et al 1997)  CDR = -0.25; Sum of boxes = -0.38; GDS = -0.19, FAST =  Baseline correlations (9605 placebo subjects)  ADCS-ADL 19 = 0.63; CIBIC (K-Tau) = -0.18; NPI = 0.10; FAST =  Baseline correlations (MD-02 placebo subjects)  ADCS-ADL 19 = 0.58; CIBIC (K-Tau) = -0.20; NPI = -0.29; FAST =  152 pt version; MMSE 0-13 (Saxton et al 1990)  MMSE = 0.74  133 pt version; MMSE 0-13 (Saxton et al 1993)  MMSE = 0.76; Mattis DRS = 0.88  100 pt version  Baseline correlations (ADCS; Schmitt et al 1997)  MMSE = 0.83  CDR = -0.65; Sum of boxes = -0.75; GDS = -0.68, FAST =  12-month change score correlations (ADCS; Schmitt et al 1997)  CDR = -0.25; Sum of boxes = -0.38; GDS = -0.19, FAST =  Baseline correlations (9605 placebo subjects)  ADCS-ADL 19 = 0.63; CIBIC (K-Tau) = -0.18; NPI = 0.10; FAST =  Baseline correlations (MD-02 placebo subjects)  ADCS-ADL 19 = 0.58; CIBIC (K-Tau) = -0.20; NPI = -0.29; FAST =  152 pt version; MMSE 0-13 (Saxton et al 1990)  MMSE = 0.74  133 pt version; MMSE 0-13 (Saxton et al 1993)  MMSE = 0.76; Mattis DRS = 0.88

BGP Scale  Description  Comprehensive geriatric symptomatology rating scale  Developed for nurses administration in geriatric settings  Beoordelingsschaal vor Oudere Patienten (BOP)  Beurteilungsskala fur geriatrische Patienten (BGP)  “Rating Scale for Geriatric Patients”  Based on Stockton Geriatric Rating Scale  (Meer and Baker, 1966)  Lower scores = greater function (35 items, 0-2 points)  Areas include  Aggressiveness, disability, disorientation, depression, inactivity, impaired communication, ADL impairment  Items primarily rated “never,” “sometimes,” or “often”  Description  Comprehensive geriatric symptomatology rating scale  Developed for nurses administration in geriatric settings  Beoordelingsschaal vor Oudere Patienten (BOP)  Beurteilungsskala fur geriatrische Patienten (BGP)  “Rating Scale for Geriatric Patients”  Based on Stockton Geriatric Rating Scale  (Meer and Baker, 1966)  Lower scores = greater function (35 items, 0-2 points)  Areas include  Aggressiveness, disability, disorientation, depression, inactivity, impaired communication, ADL impairment  Items primarily rated “never,” “sometimes,” or “often”

BGP Care Dependency 3.Requires assistance with eating 4.The patient is urinary or feces incontinent at daytime 10.The patient makes himself understood (by speaking, writing, or gestures) 11.The patient finds his way in the nursing home (e.g., to his room, to the toilet, to his/her place at the table) [around the house] 12.The patient understands in what home or clinic he is [where he/she lives] 13.The patient knows the names of the staff [of family members and close friends] 14.The patient understands what you communicate to him (by speaking, writing, or gestures) 17.The patient reacts when being called by his name 18.The patient keeps self occupied in useful activities out of therapeutic activities (e.g., working, reading, playing games, hobbies, talking to others) 20.The patient socializes to one or several other patients [friends] 3.Requires assistance with eating 4.The patient is urinary or feces incontinent at daytime 10.The patient makes himself understood (by speaking, writing, or gestures) 11.The patient finds his way in the nursing home (e.g., to his room, to the toilet, to his/her place at the table) [around the house] 12.The patient understands in what home or clinic he is [where he/she lives] 13.The patient knows the names of the staff [of family members and close friends] 14.The patient understands what you communicate to him (by speaking, writing, or gestures) 17.The patient reacts when being called by his name 18.The patient keeps self occupied in useful activities out of therapeutic activities (e.g., working, reading, playing games, hobbies, talking to others) 20.The patient socializes to one or several other patients [friends] 21.The patient urinates or defecates in inappropriate places 22.The patient helps other residents [family members/friends] on his own initiative (e.g., moving the wheelchair, passing items) 23.The patient is cooperative to do what is asked 25.The patient always repeats the same movements of no use (e.g., walking to and fro, toddling back and forth, wringing hands, and 26.The patient makes sounds which are directed to no one 27.The patient enters into a conversation on his own initiative 28.The patient is allowed to go out 30.The patient drowses during the daytime [takes naps during the day] 31.The patient requires assistance with dressing 32.The patient is urinary or feces incontinent at night 33.A special support is required to prevent the patient from falling out of bed 34.The patient disturbs other residents at night 35.The patient is restless at night Italic text= Cognitive subscale Bracketed text indicate changes for MD-02

Treatment Duration Double-Blind Open-LabelMemantine (N = 856) Total Memantine (N = 1357) Placebo (N = 922) Memantine (N = 940) Treatment Duration, n (%)  4 weeks (28 days)  4 weeks (28 days) 884 (95.9) 884 (95.9) 896 (95.4) 896 (95.4) 835 (97.5) 835 (97.5) 1306 (96.3) 1306 (96.3)  12 weeks (84 days)  12 weeks (84 days) 802 (87.0) 802 (87.0) 818 (87.1) 818 (87.1) 778 (90.9) 778 (90.9) 1202 (88.6) 1202 (88.6)  24 weeks (168 days)  24 weeks (168 days) 553 (60.0) 553 (60.0) 584 (62.2) 584 (62.2) 506 (59.1) 506 (59.1) 862 (63.6) 862 (63.6)  36 weeks (252 days)  36 weeks (252 days)00 42 (4.9) 42 (4.9) 429 (31.6) 429 (31.6)  48 weeks (336 days)  48 weeks (336 days)00 37 (4.3) 37 (4.3) 387 (28.5) 387 (28.5) Core Dementia Trials

Dosing Scheme – Double-Blind Phase Previous Treatment Memantine Titration Group Week 1 Week 2 Week 3 Placebo Group A AM0 5 mg/day PM 10 mg/day Group B AM000 PM 5 mg/day 10 mg/day 15 mg/day Group C AM 5 mg/day 10 mg/day PM 5 mg/day 10 mg/day Group D AM000 PM 10 mg/day 20 mg/day Memantine Group E AM 10 mg/day PM Group F AM000 PM 20 mg/day Ongoing Trials – MD-03

Patient Populations Trial Groups Treatment Groups Estimated Memantine First Time Exposure Estimated Placebo/ Active Control Total Enrolled per Trial Trials in Dementia Population MEM-MD MEM-MD MEM-MD MRZ † IE2101 † MEM-MD MEM-MD MRZ IE MRZ /3 OLEX 0‡0‡0‡0‡0105 Ongoing Trials

Agitation - MMSE <10 Agitation - MMSE >=10 Urinary Incontinence - MMSE <10 Urinary Incontinence - MMSE >=10 Fall - MMSE <10 Fall - MMSE >=10 Headache - MMSE <10 Headache - MMSE >= 10 Dizziness - MMSE <10 Dizziness - MMSE >= 10 Adverse Events (Reported by >5% Patients in the Memantine Group) Trials 9605 and MD-02 Combination (Moderate to Severe AD Patients) (1 of 2) AE Preferred TermRR (95% CI’s)RR (95% CI) DecreaseIncrease.515> (0.38, 1.16) 0.41 (0.21, 0.82) 1.20 (0.53, 2.74) 1.07 (0.45, 2.53) 0.93 (0.39, 2.21) 1.16 (0.51, 2.62) 2.55 (0.89, 7.33) 2.92 (0.76, 11.20) 1.66 (0.48, 5.79) 0.99 (0.46, 2.12)