Zarnestra NDA 21824

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ZarnestraZarnestra NDA NDA 2182421824

Qin Ryan MD, PhDQin Ryan MD, PhD

DODP/CDER/FDADODP/CDER/FDA

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OutlineOutline Regulatory BackgroundRegulatory Background Clinical Overview and Clinical Overview and

Proposed IndicationProposed Indication CTEP-20 DesignCTEP-20 Design CTEP-20 EfficacyCTEP-20 Efficacy CTEP-20 SafetyCTEP-20 Safety SummarySummary

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Regulatory Regulatory BackgroundBackground

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Regulatory BackgroundRegulatory Background In oncology, clinical benefit (CB) has been In oncology, clinical benefit (CB) has been

defined as a longer life, a better life or an defined as a longer life, a better life or an effect on an established surrogate for eithereffect on an established surrogate for either

In acute leukemias, durable complete In acute leukemias, durable complete remission (CR) has been considered remission (CR) has been considered evidence of benefitevidence of benefit

In some cases where leukemia CR’s were of In some cases where leukemia CR’s were of uncertain duration, CR was considered a uncertain duration, CR was considered a surrogate reasonably likely to predict CBsurrogate reasonably likely to predict CB

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Drug Approvals for AMLDrug Approvals for AMLDrug Indication Trial (s) Benefit

Idarubicin First-linecombination

4 randomizedtrials

CR 67-78% withAra-C versus 55-58% fordauno/Ara-CSurvival

Daunorubicin Remissioninduction

Single arm andrandomized

40-50% CR rate;53%-65% CRrate with Ara-C

Gemtuzumabozogamicin

Second-line, >60, CD33+,cannot toleratechemo

3 single armtrials

CR = 16%CR + CRp =30%

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Clinical Clinical OverviewOverview

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Induction Therapy for AML Induction Therapy for AML Untreated AML progresses rapidly to Untreated AML progresses rapidly to

deathdeath

Standard Rx in Adults < 60: Standard Rx in Adults < 60: 60-75% CR 60-75% CR < 20% treatment related death< 20% treatment related death DFS 20-50%DFS 20-50% 30-40% survive 30-40% survive >> 3 years 3 years

Factors affecting outcome: PS, organ Factors affecting outcome: PS, organ function, co-morbidity, age, function, co-morbidity, age, karyotype

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Induction Chemotherapy for Induction Chemotherapy for Elderly Patients with AMLElderly Patients with AML

Age 65-74 years (N=1,132)

75-84 years (N=1,082)

>85 years(N=433)

Total(N=2,657)

Received chemotherapy

44% 24% 6% 30%

Menzin et al., Arch Intern Med 2002, 162: 1597.

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Survival in Elderly Patients Survival in Elderly Patients with AMLwith AML

Menzin et al., Arch Intern Med 2002, 162: 1597.

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Elderly Patients with Poor-Elderly Patients with Poor-Risk AMLRisk AML

Higher mortality and morbidity seen Higher mortality and morbidity seen in elderly patients with poor-risk AML in elderly patients with poor-risk AML receiving standard chemotherapy receiving standard chemotherapy

Outcome Age < 65 Age >65 + Other factors

Treatment related death 10-20% > 25%

Complete remission rate 60-75% 30% - 50%

Survival rate 30-40% > 3 years < 6% at 2 years

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Clinical ProgramClinical Program

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ZarnestraZarnestra

Farnesyl transferase inhibitorFarnesyl transferase inhibitor

100 mg Tablets 100 mg Tablets

600 mg twice daily PO for 21 days, 600 mg twice daily PO for 21 days, followed by a rest period of 7 - 42 followed by a rest period of 7 - 42 daysdays

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Proposed IndicationProposed Indication

Treatment of elderly patients with Treatment of elderly patients with newly diagnosed poor-risk acute newly diagnosed poor-risk acute myeloid leukemia.myeloid leukemia.

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Zarnestra NDA: AML Zarnestra NDA: AML TrialsTrials

Clinical Study

Elderly poor-risk AML / AML

(Total Enrolled)

Study Description Endpoints

CTEP-20* 136 / 157(N=171)

Single arm, open label, previously untreated elderly poor-risk AML patients

Efficacy and safety

INT-17 99 / 252(N= 252)

Single arm, open label, refractory or relapsed AML patients

Efficacy, safety, and PK

CTEP-1* 14 / 25(N = 34)

Single arm, open label, dose escalation in hematologic malignancies

Phase 2 recommended dose, PK and tolerability

* Conducted by NCI, CTEP as part of a Cooperative Research and Development Agreement with J&J

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CTEP-20 DesignCTEP-20 Design

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CTEP-20 DesignCTEP-20 Design

Open-label, single-arm, multicenterOpen-label, single-arm, multicenter PopulationPopulation

Original: untreated poor-risk Original: untreated poor-risk hematological malignancieshematological malignancies

66thth amendment (after 110 amendment (after 110 enrollments): untreated elderly enrollments): untreated elderly poor-risk AMLpoor-risk AMLAge > 75Age > 75Age 65-74 AML with prior MDSAge 65-74 AML with prior MDS

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CTEP-20 DesignCTEP-20 Design Primary objective Primary objective

Original: RR (CR+PR)Original: RR (CR+PR) 66thth amendment: complete response (CR) rate amendment: complete response (CR) rate

in untreated elderly poor-risk AMLin untreated elderly poor-risk AML

Secondary objectives: Secondary objectives: Progression-free survival (PFS)Progression-free survival (PFS) Overall survival (OS)Overall survival (OS) Duration of responseDuration of response Safety Safety

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CTEP-20 Major EligibilityCTEP-20 Major Eligibility

After amendment #6After amendment #6 Inclusion:Inclusion:

Untreated newly diagnosed AML Untreated newly diagnosed AML >> 75 75 65-74 with prior MDS65-74 with prior MDS

Confirmation with Confirmation with >> 20% BM or PB blasts 20% BM or PB blasts PS 0 or 1, adequate renal and liver PS 0 or 1, adequate renal and liver

functionfunction..

Exclusion: circulating blasts Exclusion: circulating blasts >> 30,000/uL, 30,000/uL, APL (M3), CNS leukemia, DICAPL (M3), CNS leukemia, DIC

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CTEP-20 Efficacy CTEP-20 Efficacy AssessmentAssessment

Medical history and physical examination, Medical history and physical examination, BM aspirate and biopsy, hematological and BM aspirate and biopsy, hematological and chemistry labs at baseline and the end of chemistry labs at baseline and the end of each cycleeach cycle

CR determined by NCI sponsored AML CR determined by NCI sponsored AML criteria criteria (Cheson et al., J Clin Oncol 8: 813-819, 1990)(Cheson et al., J Clin Oncol 8: 813-819, 1990)

Subsequent treatment and follow upSubsequent treatment and follow up

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CTEP-20 EfficacyCTEP-20 Efficacy

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CTEP-20 Study CTEP-20 Study PopulationPopulation

*One elderly patient with AML did not receive treatment by the time of clinical cut off.

Patient PopulationNumber of Patients

Sponsor FDA

All Enrolled 171 171

All Treated AML 157 156

Elderly poor-risk AMLAge 75 yearsAge 65-74 years with prior MDS

1367561

1357461

Non AML 13 (8) 14 (8)

MDSb 8 (5) 9 (5)

CMML 5 (3) 5 (3)

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CTEP-20 Elderly Poor-Risk AML CTEP-20 Elderly Poor-Risk AML Population: Demographics Population: Demographics

Number of subjects (%) 65-74 y prior > 75 y Total

Baseline ECOG performance status

60 73 133

0 19 (32) 13 (18) 32 (24)

1 35 (58) 51 (70) 86 (65)

2 6 (10) 9 (12) 15 (11)

Ineligible for chemotherapya 61 75 136

Age 34 (56) 72 (96) 106 (78)

Risk factors 31 (51) 29 (39) 60 (44)

Other 15 (25) 10 (13) 25 (18)

a Some subjects had more than 1 reason for ineligibility for chemotherapy.

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CTEP-20 Elderly Poor-Risk AML Population: CTEP-20 Elderly Poor-Risk AML Population: Risk Factors Risk Factors

Risk factor 65-74 y prior MDS(N= 61) n (%)

> 75 y (N= 75) n (%)

Total (N= 136) n (%)

Prior MDS 61 (100) 50 (67) 111 (82)

Baseline organ dysfunction 31 (51) 52 (69) 83 (61)

Age > 75 years - 75 (100) 75 (55)

Unfavorable karyotype 37 (61) 29 (39) 66 (49)

Number of risk factors per subject

1 10 (16) 4 (5) 14 (10)

2 34 (56) 26 (35) 60 (44)

3 17 (28) 30 (40) 47 (35)

4 - 15 (20) 15 (11)

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CTEP-20CTEP-20 Primary Endpoint: Primary Endpoint: CR RateCR Rate

Total (N= 135)

CR (%) CRu Unavailable for Assessment

Investigators 17 (13) 2 1

Independent Review

15 (11) 3 2

FDA 15 (11) 3 2

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CTEP-20 CR Rate Analysis CTEP-20 CR Rate Analysis by FDAby FDA

Confirmed CR / No. of Patients

CR Rate (n/N)[95% CI]

15 / 135 11.1%6.6 – 18.0%

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CTEP-20 CR Rate CTEP-20 CR Rate Subgroup Analysis by Subgroup Analysis by

FDAFDACategory Group

Confirmed CR / No. of Patients

CR Rate (n/N)[95% CI]

Age

65 – 74 years 10 /6116.4%

8.6 – 28.5%

≥ 75 years 5 / 746.8%

3.1 – 18.8%

Prior MDS

Yes 14 / 11012.7%

7.4 – 20.8%

No 1 / 254%

0.2 – 22.3%

Karyotype

Unfavorable 5 / 657.7%

0.1 – 9.4

Favorable 9 / 6214.5%

0.1 – 19.8

Unkown 1 / 812.5%

0.7 – 53.3%

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CTEP-20 CR DurationCTEP-20 CR Duration

Analysis FDA Results

Number failed/Number assessed 7/15 (47%)

Median duration in days [95% CI]275

[127 – 376]

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CTEP-20 SafetyCTEP-20 Safety

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CTEP-20 Safety – CTEP-20 Safety – ExposureExposure

Category, n (%) Cycle 1 136 (100)

Cycle 2 64 (47)

Cycle 3 27 (20)

Cycle duration

1-28 days 39 (29) 13 (20) 7 (26)

29-35 days 21 (15) 12 (19) 5 (19)

36-42 days 29 (21) 19 (30) 8 (30)

43-49 days 26 (19) 10 (16) 5 (19)

50-56 days 7 (5) 4 (6) -

57- 63 days 6 (4) 3 (5) 1 (4)

> 64 days 8 (6) 3 (5) 1 (4)

Mean (SD) 36.8 (16.88) 37.6 (15.06) 36.4 (14.39)

Median 38 38 36

Range (3; 92) (5; 75) (10; 85)

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CTEP-20 Safety – Dose CTEP-20 Safety – Dose IntensityIntensity

Category Cycle 1 (N= 136)

Cycle 2 (N= 64)

Cycle 3 (N= 27)

Dose intensity, mg/day

Mean (SD) 749.4 (277.40) 597.3 (251.93) 631.2 (282.9)

% of planned 63 50 53

Median 663.2 566.4 586.1

Range (273.9; 1200.0) (168.0; 1200.0) (197.6; 1200.0)

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CTEP-20 Safety –CTEP-20 Safety – Common Common AEsAEs

Non-Hematologic

diarrhea, fatigue, nausea, skin rash, fever, anorexia, constipation, vomiting, dyspnea, dizziness, ataxia or abnormal gait, confusion, bacterial infection, fungal infection

Hematologic neutropenia with or without fever, purpura, thrombocytopenia, anemia

Metabolic increased creatinine, hypokalemia, hyponatremia

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CTEP-20 SafetyCTEP-20 Safety Frequent Frequent AEs Leading to AEs Leading to

Treatment ChangeTreatment ChangeTreatment

ChangeIncidence

(n=136, %)Most Frequent AEs

Termination 21 (15) increased creatinine, rash, increased pancreatic enzymes

Dose Reduction

47 (35) neutropenia, ataxia, increased creatinine or abnormal renal function, confusion, diarrhea, increased pancreatic enzymes, rash

Interruption 56 (41) neutropenia, increased creatinine, nausea/vomiting, rash, confusion, pancytopenia

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CTEP-20 Safety – Grade 3/4 CTEP-20 Safety – Grade 3/4 AEsAEs

WHO Preferred Term Total N= 136 (%)

Total no. subjects 113 (83)

Neutropenia febrile 40 (29)

Infection bacterial 25 (18)

Thrombocytopenia 23 (17)

Neutropenia without fever 16 (12)

Pneumonia 14 (10)

Creatinine increased 12 (9)

Rash 12 (9)

Anemia 11 (8)

Diarrhea 8 (6)

Hypokalemia 8 (6)

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CTEP-20 Safety - DeathCTEP-20 Safety - Death

Cause of Death TotalN= 136 (%)

Deaths during the study 31 (23)

Progressive disease 19 (14)

Adverse event 9 (7)

Drug related 1 (1)

Other 3 (2)

Early deaths 16 (12)

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CTEP-20 – Hospitalization on Study CTEP-20 – Hospitalization on Study

No. of patient treated 136

Total no. of hospitalizations 141

No. of subjects hospitalized during study, n (%) 81 (60)

1-2 hospitalizations 71 (52)

3-4 hospitalizations 8 (6)

> 5 hospitalizations 2 (1)

Total duration of hospitalization, days

N 81

Mean (SD) 17.9 (14.38)

Median 15.0

Range (2; 73)

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SummarySummaryZarnestra in Zarnestra in Elderly Poor-Elderly Poor-

Risk AMLRisk AML

Durable CR : an endpoint supportive of Durable CR : an endpoint supportive of clinical benefit in AMLclinical benefit in AML

Consider in the context of :Consider in the context of : 11.1% CRR with 275 days median duration11.1% CRR with 275 days median duration Poor risk patient populationPoor risk patient population 12% one-month death rate12% one-month death rate 60% hospitalization60% hospitalization

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QuestionQuestion

Does the risk benefit analysis Does the risk benefit analysis support regular approval of support regular approval of Zarnestra for the first-line Zarnestra for the first-line treatment of AML patients treatment of AML patients age 65 or older with prior age 65 or older with prior MDS or age 75 and older?MDS or age 75 and older?

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Additional SlidesAdditional Slides

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SummarySummary

Standard Treatment Risk & Benefit Standard Treatment Risk & Benefit in general and in elderly poor-risk in general and in elderly poor-risk AML patients:AML patients:

Outcome versus Age < 65 >65 + Poor-risk

Treatment related death 10-20% > 25%

Complete remission rate 60-75% 30% - 50%

2 year survival rate 30-40% > 3 years < 6% at 2 year

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SummarySummary Zarnestra Risk & Benefit in elderly Zarnestra Risk & Benefit in elderly

poor-risk AML patients compare to poor-risk AML patients compare to and Standard Treatment in elderly and Standard Treatment in elderly AML patients:AML patients:

Outcome versus Tx Zarnestra Standard

Complete remission rate 11.1% 30% - 50%

Treatment related death 7% > 25%

One month mortality 12% 30- 48%

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Approvals for APL, MDSApprovals for APL, MDSDrug Indication Trial (s) Benefit

Tretinoin Second-line APL One single arm trial and two cohorts

73%-80% CR’s ; cohorts 36%-68% CR rates

Arsenic Trioxide

Second-line APL

Single arm study

CR = 70%

5-Azacytidine MDS BSC vs BSC+vidaza 2 single arm trials

CR+PR=16% vs 0% transfusion independence: AML subgroup N=10 in vidaza arm 12.5% CR CR+PR=14% and 19%: AML subgroup N=17 and N=1, combined CR=18%

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Unfavorable KaryotypeUnfavorable Karyotype

Per the sponsor, the Per the sponsor, the karyotypes described as karyotypes described as unfavorable included: unfavorable included: del 5, del 5q, del 5, del 5q, del 7, del 7q, del 7, del 7q, trisomy 8, trisomy 8, 11q23, 11q23, complex (> 3 abnormalities). complex (> 3 abnormalities).

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Summary of Patients Summary of Patients with or without Prior MDS with or without Prior MDS

Population< 65 years

n (%)65-74 years

n (%)75 years

n (%)Totaln (%)

All Treated AML 7/9 (78%) 61/73 (84%) 49/74 (66%)117/156

(75%)

Elderly Poor-Risk AML

0/061/61 (100%)

49/74 (66%)110/135

(81%)

Per Protocol 0/048/48 (100%)

41/55 (75%)89/103

(86%)

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Sponsor’s RR by Risk FactorsSponsor’s RR by Risk FactorsTotal CR PR

Age 136 20 (15) 3 (2)

65-74 y 61 11 (18) 3 (5)

> 75 y 75 9 (12) -

Karyotype unfavorable 136 20 (15) 3 (2)

Yes 66 9 (14) 3 (5)

No 62 10 (16) -

Not done / not available 8 1 (13) -

Organ dysfunction 136 20 (15) 3 (2)

Yes 83 13 (16) 2 (2)

No 53 7 (13) 1 (2)

Prior MDS 136 20 (15) 3 (2)

Yes 111 18 (16) 3 (3)

No 25 2 (8) -

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CTEP-20: Complete Remission CTEP-20: Complete Remission CriteriaCriteria

Bone marrow < 5% myeloblasts with Bone marrow < 5% myeloblasts with normal maturation of all cell lines, an ANC normal maturation of all cell lines, an ANC >> 1000/uL, a platelet 1000/uL, a platelet >> 100, 000/uL, 100, 000/uL, absence of blasts in peripheral blood, absence of blasts in peripheral blood, absence of identifiable leukemic cells in absence of identifiable leukemic cells in the bone marrow, clearance of disease-the bone marrow, clearance of disease-associated cytogenetic abnormalities, and associated cytogenetic abnormalities, and clearance of any previously existing clearance of any previously existing extramedullary disease. extramedullary disease.

CR must be confirmed 4-6 weeks after CR must be confirmed 4-6 weeks after initial documentation. At least one bone initial documentation. At least one bone marrow biopsy should be performed to marrow biopsy should be performed to confirm CR.confirm CR.

NCI-Sponsored Workshop on Definitions of Diagnosis and Response in Acute Myeloid Leukemia, 1990.NCI-Sponsored Workshop on Definitions of Diagnosis and Response in Acute Myeloid Leukemia, 1990.

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CTEP-20 Safety – Overall AEsCTEP-20 Safety – Overall AEsNumber (%) of Subjects With: Elderly Poor- Risk AML All- Treated

AML

65-74 y prior MDSN = 61 (%)

> 75 yN = 75 (%)

TotalN= 136 (%)

Total(N= 157) (%)

AEs 60 (98) 74 (99) 134 (99) 155 (99)

Drug-related AEs 53 (87) 65 (87) 118 (87) 134 (85)

Grade 3 or 4 AEs 51 (84) 62 (83) 113 (83) 131 (83)

Drug- related grade 3 or 4 AEs 37 (61) 46 (61) 83 (61) 92 (59)

SAEs 38 (62) 50 (67) 88 (65) 103 (66)

Drug- related SAEs 23 (38) 35 (47) 58 (43) 64 (41)

AEs leading to treatment termination

11 (18) 10 (13) 21 (15) 26 (17)

Drug- related AEs leading to treatment terminationa

7 (11) 7 (9) 14 (10) 18 (11)

Deaths due to an AE 2 (3) 7 (9) 9 (7) 11 (7)

Drug- related AEs resulting in death

0 1 (1) 1 (1) 1 (1)

Early deaths due to an AE 2 (3) 3 (4) 5 (4) 6 (4)

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CTEP-20 Safety –CTEP-20 Safety – Common Non Common Non Hem. AEsHem. AEs


Diarrhea 64 (47)

Fatigue 60 (44)

Nausea 51 (38)

Rash 48 (35)

Fever 42 (31)

Anorexia 37 (27)

Constipation 33 (24)

Vomiting 32 (24)

Dyspnea 32 (24)

Dizziness 36 (26)

Ataxia + abnormal gait 27 (20)

Confusion 29 (21)

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CTEP-20 Safety – Common Hem & CTEP-20 Safety – Common Hem & Met AEsMet AEs



Purpura 29 (21)

Thrombocytopenia 26 (19)

Anemia 24 (18)

Neutropenia 17 (13)

Infection bacterial 27 (20)

Moniliasis and other fungal infection 22 (16)

Creatinine 62 (46)

Hypokalemia 59 (43)

Hyponatremia 57 (42)

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CTEP-20 SafetyCTEP-20 Safety AEs Leading to Treatment AEs Leading to Treatment

TerminationTerminationWHO Preferred Term Total N= 136 (%)

All Drug Related

Total no. subjects with AE 21 (15) 14 (10)

Creatinine blood increased 4 (3) 3 (2)

Rash 4 (3) 3 (2)

Pancreas enzymes increased 2 (1) 2 (1)

Dehydration 1 (1) 1 (1)

Diarrhea 1 (1) 1 (1)

Dizziness 1 (1) 1 (1)

Fatigue 1 (1) 1 (1)

Insomnia 1 (1) 1 (1)

Nausea 1 (1) 1 (1)

Neuropathy peripheral 1 (1) 1 (1)

Sweating increased 1 (1) 1 (1)

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CTEP-20 SafetyCTEP-20 Safety – – AEs Leading to Dose Reduction (AEs Leading to Dose Reduction (>>

2%)2%)WHO Preferred Term Total (N= 136) (%)

All Drug Related


Neutropenia febrile 9 (7) 6 (4)

Ataxia 5 (4) 5 (4)


Confusion 6 (4) 3 (2)


Neutropenia 4 (3) 3 (2)

Pancreas enzymes increased 3 (2) 3 (2)

Rash 5 (4) 3 (2)

Renal function abnormal 3 (2) 3 (2)

Amnesia 2 (1) 2 (1)

Bilirubinemia 3 (2) 2 (1)

Fatigue 2 (1) 2 (1)

Hypotension postural 2 (1) 2 (1)

Infection bacterial 3 (2) 2 (1)

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CTEP-20 SafetyCTEP-20 Safety – – AEs Causing Treatment Interuption (AEs Causing Treatment Interuption (>>

2%)2%)WHO Preferred Term Total N= 136 (%)

All Drug Related


Neutropenia 10 (7) 8 (6)


Nausea 6 (4) 6 (4)

Neutropenia febrile 8 (6) 6 (4)

Rash 5 (4) 5 (4)

Confusion 3 (2) 3 (2)

Pancytopenia 4 (3) 3 (2)

Vomiting 3 (2) 3 (2)

Ataxia 2 (1) 2 (1)

Bilirubinemia 3 (2) 2 (1)


Gait abnormal 2 (1) 2 (1)

Infection bacterial 3 (2) 2 (1)

Infection fungal 2 (1) 2 (1)

Neuropathy peripheral 2 (1) 2 (1)

Pneumonia 4 (3) 2 (1)

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CTEP-20 Safety – ACTEP-20 Safety – AEs Associated with Es Associated with DeathDeath


Total no. subjects who died 9 (7)

Cardiac failure 3 (2)

Sepsis 3 (2)

Infection fungal 2 (1)

Pneumonia 2 (1)

Arrhythmia atrial 1 (1)

Circulatory failure 1 (1)

Fibrillation atrial 1 (1)

Gastrointestinal hemorrhage 1 (1)

Hypoxia 1 (1)

Multiple organ failure 1 (1)


Pulmonary hemorrhage 1 (1)

Renal failure acute 1 (1)

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CTEP-20: Concomitant Therapy During CTEP-20: Concomitant Therapy During TreatmentTreatment

Total N= 136 (%)

Blood product transfusions 119 (88)

Human RBCsa 114 (84)

Platelets, human blood 89 (65)

White blood cells 3 (2)

Anti-infectives 116 (85)

Antibiotics 111 (82)

Antivirals 71 (52)

Antifungals 51 (38)

Hydroxyurea 3 (2)

Growth factors 12 (9)

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CTEP-20 – Reason for Hospitalization CTEP-20 – Reason for Hospitalization

Reason for hospitalization, N = 136 (%)

No. of subjects with recorded reason 81 (59)

AE related to study medication 51 (38)

AE related to disease 33 (24)

Other reason 18 (13)

Chemotherapy 2 (1)

Transfusion 2 (1)

AE related to medication (not tipifarnib) 2 (1)

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Sponsor’s Response Rate in Sponsor’s Response Rate in Relapsed AMLRelapsed AML

INT-17 and CTEP-1 INT-17 and CTEP-1

Response INT-17 (N= 99)

CTEP -1 (N= 22)

CR 2 (2%) 2 (9%)

PR 6 (6%) 6 (27%)

Zarnestra NDA 21824

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