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日本語訳版 アデュカヌマブ(ADUHELM)US添付文書(2021年6月承認時点)

目次

添付文書のハイライト(HIGHLIGHTS OF PRESCRIBING INFORMATION)

これらのハイライトには、 ADUHELMTMを安全かつ有効に使用するために必要なすべての情報が含まれているわけではない。ADUHELMの詳細な処方情報を参照のこと。These highlights do not include all the information needed to use ADUHELM™ safely and effectively. See full prescribing information for ADUHELM.

ADUHELM(aducanumab-avwa)静注用 ADUHELM™ (aducanumab-avwa) injection, for intravenous use

米国での初回承認:2021年 Initial U.S. Approval: 2021

効能・効果(INDICATIONS AND USAGE)

  • ADUHELMは、アルツハイマー型認知症の治療を適応とする抗アミロイドβ抗体である。本適応症は、 ADUHELM投与患者で認められたアミロイドβプラークの減少に基づき、迅速承認下で承認されている。検証的試験で臨床的ベネフィットが確認されれば、この適応に対する承認を継続することができる。
    ADUHELM is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). (1)

DOSAGE AND ADMINISTRATION

  • 投与開始には漸増が必要である。Titration is required for treatment initiation. (2.1)
  • 維持用量は10 mg/kgが推奨され、約一時間かけて点滴静注する。The recommended maintenance dosage is 10 mg/kg administered as an intravenous infusion over approximately one hour every four weeks. (2.1)
  • 投与開始前の直近(1年以内)の脳MRIを実施する。Obtain a recent (within one year) brain MRI prior to initiating treatment. (2.2, 5.1)
  • 7回目及び12回目の投与前にMRIを実施する。放射線学的に重度のARIA-Hが認められた場合は、臨床的評価及び追跡MRIにより放射線学的安定性が示された後にのみ、慎重に投与を継続してもよい(例:ARIA-Hの大きさや数の増加無し)。Obtain MRIs prior to the 7th and 12th infusions. If radiographic severe ARIA-H is observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H). (2.2, 5.1)
  • 投与前に、 100 mLの0.9%塩化ナトリウム注射液(USP)で希釈する必要がある。Dilution in 100 mL of 0.9% Sodium Chloride Injection, USP, is required prior to administration. (2.4)
  • 0.2又は0.22ミクロンのインラインフィルターを用いて約一時間かけて点滴静注する。Administer as an intravenous infusion over approximately one hour via a 0.2 or 0.22 micron in-line filter. (2.5)

剤形・含量(DOSAGE FORMS AND STRENGTHS)

注射(Injection):

  • 170 mg/1.7 mL(100 mg/mL)溶液、単回投与バイアル 170 mg/1.7 mL (100 mg/mL) solution in a single-dose vial (3)
  • 300 mg/3 mL(100 mg/mL)溶液、単回投与バイアル 300 mg/3 mL (100 mg/mL) solution in a single-dose vial (3)

禁忌(CONTRAINDICATIONS)

  • なし。None. (4)

警告及び使用上の注意(WARNINGS AND PRECAUTIONS)

  • アミロイド関連画像異常(ARIA):ADUHELMによる治療の最初の8回の投与中、特に用量調節中は、 ARIAに対する臨床的監視を強化することが推奨される。患者にARIAを示唆する可能性のある症状が認められた場合、必要に応じてMRI検査を含む臨床評価を実施する。Amyloid Related Imaging Abnormalities (ARIA): Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration. If a patient experiences symptoms which could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated. (2.2, 5.1)
  • 過敏症反応:血管浮腫及び蕁麻疹が発現している。過敏症反応が発現した場合は、本剤の投与を速やかに中止し、適切な治療を開始すること。Hypersensitivity Reactions: Angioedema and urticaria have occurred. If a hypersensitivity reaction occurs, promptly discontinue the infusion of ADUHELM and initiate appropriate therapy. (5.2)

副作用(ADVERSE REACTIONS)

  • 主な副作用(プラセボと比較して発現率が10%以上高い)は、 ARIA-浮腫、頭痛、 ARIA-H微小出血、 ARIA-H表在性鉄沈着症及び転倒であった。Most common adverse reactions (at least 10% and higher incidence compared to placebo): ARIA-Edema, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and fall. (6.1)
  • 副作用が疑われる場合は、 バイオジェン(1-833-425-9360)又はFDA(1-800-FDA-1088又はfda.gov/medwatch)に連絡すること。To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-833-425-9360 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
  • 患者への情報提供及び患者向け医薬品ガイドについては17項を参照。See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

詳細な処方情報(FULL PRESCRIBING INFORMATION)

1 効能・効果(INDICATIONS AND USAGE)

ADUHELMはアルツハイマー病の治療を適応とする。本適応症は、 ADUHELMの投与を受けた患者で認められたアミロイドベータプラークの減少に基づき、迅速承認下で承認されている[臨床試験(14)参照]。検証的試験で臨床的ベネフィットが確認されれば、この適応に対する承認を継続することができる。
ADUHELM is indicated for the treatment of Alzheimer’s disease. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Instructions

最初の漸増後、 ADUHELMの推奨用量は10 mg/kgである(表1参照)。After an initial titration, the recommended dosage of ADUHELM is 10 mg/kg (see Table 1).

ADUHELMは、約一時間かけて静脈内(IV)注入により、4週間毎に1度、少なくとも21日以上の間隔をあけて投与する。ADUHELM is administered as an intravenous (IV) infusion over approximately one hour every four weeks and at least 21 days apart.

Table 1: Dosing Schedule
静脈内投与(4週ごと)

IV Infusion (every 4 weeks)

ADUHELMの用量(約1時間かけて投与)

ADUHELM Dosage (administered over approximately one hour)

Infusion 1 and 2 1 mg/kg
Infusion 3 and 4 3 mg/kg
Infusion 5 and 6 6 mg/kg
Infusion 7 and beyond 10 mg/kg

2.2 アミロイド関連画像異常のモニタリング(Monitoring for Amyloid Related Imaging Abnormalities)

治療開始前の直近(1年以内)の脳磁気共鳴画像検査(MRI)を実施する。7回目投与(10 mg/kgの初回投与)及び12回目投与(10 mg/kgの6回目投与)の前にMRIを実施する。10件以上の新規微小出血又は2ヵ所を超える表在性鉄沈着症の局所領域(放射線学的重症ARIA-H)が認められた場合は、臨床評価及び追跡調査のMRIにより放射線学的安定性(すなわち、ARIA-Hの大きさや数が増加しない)が示された後にのみ、慎重に投与を継続することができる[警告及び使用上の注意(5.1)参照]。
Obtain recent (within one year) brain magnetic resonance imaging (MRI) prior to initiating treatment. Obtain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth dose of 10 mg/kg). If 10 or more new incident microhemorrhages or > 2 focal areas of superficial siderosis (radiographic severe ARIA-H) is observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H) [see Warnings and Precautions (5.1)].

2.3 投与し忘れた際のADUHELMの再開(Resuming ADUHELM After Missed Dose)

投与し忘れた場合は、できる限り速やかに同一用量で投与を再開すること[用法・用量(2.1)参照]。投与は4週間ごとに21日間以上の間隔をあけて行う。
If an infusion is missed, resume administration at the same dose as soon as possible [see Dosage and Administration (2.1)]. Infusions are to be administered every 4 weeks and at least 21 days apart.

2.4 希釈方法(Dilution Instructions)

  • 点滴静注用ADUHELM希釈液を調製する際は無菌操作を行うこと。各バイアルは単回投与用である。残液は廃棄すること。Use aseptic technique when preparing the ADUHELM diluted solution for intravenous infusion. Each vial is for single-dose only. Discard any unused portion.
  • 患者の実際の体重に基づいて、投与量、必要なADUHELM溶液の総容量、必要なバイアル数を計算し、。各バイアルのADUHELM濃度は100 mg/mLである。1回の投与で複数のバイアルが必要な場合がある。Calculate the dose, total volume of ADUHELM solution required, and the number of vials needed based on the patient’s actual body weight. Each vial contains an ADUHELM concentration of 100 mg per mL. More than one vial may be needed for a full dose.
  • 必要な容量の正しいバイアルを選択する[剤形及び含量(3)参照]。Select the correct vial(s) for the required volume [see Dosage Forms and Strengths (3)].
  • ADUHELM溶液が透明~乳白光を呈する無色~黄色の溶液であることを確認する。不透明な粒子、変色、その他の異物がある場合は使用しないこと。Check that the ADUHELM solution is clear to opalescent and colorless to yellow solution. Do not use if opaque particles, discoloration, or other foreign particles are present.
  • バイアルからフリップオフキャップを外す。シリンジの針をゴム栓の中央からバイアルに挿入する。Remove the flip-off cap from the vial. Insert the syringe needle into the vial through the center of the rubber stopper.
  • 必要量のADUHELMをバイアルから抜き取り、100 mLの0.9%塩化ナトリウム注射液(USP)の輸液バッグに加える。ADUHELM希釈液の調製に他の静脈内希釈剤を使用しないこと。Withdraw the required volume of ADUHELM from the vial(s) and add to an infusion bag of 100 mL of 0.9% Sodium Chloride Injection, USP. Do not use other intravenous diluents to prepare the ADUHELM diluted solution.
  • ADUHELM希釈液の入った点滴バッグを静かに逆さにして、完全に混合する。振盪しないこと。Gently invert the infusion bag containing the ADUHELM diluted solution to mix completely. Do not shake.
  • 希釈後は直ちに使用することが望ましい。直ちに投与しない場合は、希釈したADUHELMの0.9%塩化ナトリウム注射液(USP)溶液を2℃~8℃(36°F~46°F)で3日間まで冷蔵保存するか、室温で30℃(86°F)まで12時間まで冷蔵保存すること。After dilution, immediate use is recommended. If not administered immediately, store the diluted solution of ADUHELM in 0.9% Sodium Chloride Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 3 days, or at room temperature up to 30°C (86°F) for up to 12 hours.
  • 投与前にADUHELM希釈液を室温に戻しておく。Prior to infusion, allow the ADUHELM diluted solution to warm to room temperature.

2.5 投与方法(Administration Instructions)

  • 投与前にADUHELM希釈液に粒子や変色がないか目視検査すること。変色していたり、不透明なものや異物が認められた場合は使用しないこと。Visually inspect the ADUHELM diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, or opaque or foreign particles are seen.
  • ADUHELM希釈液を、0.2又は0.22ミクロンのインラインフィルターを備えた滅菌低タンパク結合静脈ラインから約一時間かけて静脈内に投与する。Infuse ADUHELM diluted solution intravenously over approximately one hour through an intravenous line containing a sterile, low-protein binding, 0.2 or 0.22 micron in-line filter.
  • 過敏症型反応と一致する徴候又は症状が最初に観察された場合は、直ちに投与を中止すること[警告及び使用上の注意(5.2)参照]。Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction [see Warnings and Precautions (5.2)].

3 剤型・含量(DOSAGE FORMS AND STRENGTHS)

ADUHELMは無色~黄色の澄明~乳白光を呈する溶液であり、剤型・含量は以下の通り。ADUHELM is a clear to opalescent and colorless to yellow solution, available as:

  • Injection: 170 mg/1.7 mL (100 mg/mL) in a single-dose vial
  • Injection: 300 mg/3 mL (100 mg/mL) in a single-dose vial

4 禁忌(CONTRAINDICATIONS)

なし。None.

5 警告及び使用上の注意(WARNINGS AND PRECAUTIONS)

5.1 アミロイド関連画像異常(Amyloid Related Imaging Abnormalities)

ADUHELMは、 MRIで脳浮腫又は脳溝滲出液として認められるアミロイド関連画像異常-浮腫(ARIA-E)、及び微小出血及び表在性鉄沈着症を含むアミロイド関連画像異常-ヘモシデリン沈着(ARIA-H)を引き起こす可能性がある。
ADUHELM can cause amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalitieshemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.

投与開始前の直近(1年以内)の脳磁気共鳴画像法(MRI)を実施する[用法・用量(2.2項)参照]。投与開始前に限局性の表在性鉄沈着症、10ヵ所以上の脳内微小出血及び/又は1 cmを超える脳出血が認められた患者における投与開始後1年以内のADUHELMの安全性は確立していない。
Obtain recent (within one year) brain magnetic resonance imaging (MRI) prior to initiating treatment [see Dosage and Administration (2.2)]. The safety of ADUHELM in patients with any pre-treatment localized superficial siderosis, 10 or more brain microhemorrhages, and/or with a brain hemorrhage greater than 1 cm within one year of treatment initiation has not been established.

ADUHELMの臨床試験では、 ARIAの重症度を表2に示す放射線学的基準により分類した。
In clinical studies of ADUHELM, the severity of ARIA was classified by radiographic criteria, as shown in Table 2.

Table 2: ARIA MRI Classification Criteria
ARIA Type Radiographic Severity
Mild Moderate Severe
ARIA-E FLAIR hyperintensity confined to sulcus and or cortex/subcortical white matter in one location < 5 cm FLAIR hyperintensity 5 to 10 cm, or more than 1 site of involvement, each measuring < 10 cm FLAIR hyperintensity measuring > 10 cm, often with significant subcortical white matter and/or sulcal involvement. One or more separate sites of involvement may be noted.
ARIA-H microhemorrhage ≤ 4 new incident microhemorrhages 5 to 9 new incident microhemorrhages 10 or more new incident microhemorrhages
ARIA-H superficial siderosis 1 focal area of superficial siderosis 2 focal areas of superficial siderosis > 2 focal areas of superficial siderosis

試験1及び2では、 ARIA(-E及び/又は-H)が計画用量10 mg/kgのADUHELM投与患者の41%(1105例中454例)に認められたのに対し、プラセボ投与患者では10%(1087例中111例)であった。
In Studies 1 and 2, ARIA (-E and/or -H) was observed in 41% of patients treated with ADUHELM with a planned dose of 10 mg/kg (454 out of 1105), compared to 10% of patients on placebo (111 out of 1087).

ARIA-EはADUHELM 10 mg/kg群の35%、プラセボ群の3%に認められた。ARIA‐Eの発生率はアポリポ蛋白質Eε4(ApoEε4)キャリアの方がApoEε4非キャリアよりも高かった(それぞれ42%及び20%)。ARIA-Eの放射線学的事象の大部分は投与早期(最初の8回の投与期間内)に発現したが、 ARIAはいつでも発現する可能性がある。計画用量のADUHELM 10 mg/kgを投与され、 ARIA-Eが認められた患者では、 X線画像上の最大重症度は、患者の30%が軽度、 58%が中等度、 13%が重度であった。ARIA-E患者の68%は検出後12週までに、 91%は20週までに、 98%は全体的に回復した。ADUHELM 10 mg/kgを投与した全患者の10%がARIA-Eを複数回発現した。
ARIA-E was observed in 35% of patients treated with ADUHELM 10 mg/kg, compared to 3% of patients on placebo. The incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4) carriers than in ApoE ε4 non-carriers (42% and 20%, respectively). The majority of ARIA-E radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of ADUHELM 10 mg/kg who had ARIA-E, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients. Resolution occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. 10% of all patients who received ADUHELM 10 mg/kg had more than one episode of ARIA-E.

ADUHELM 10 mg/kgの使用に伴うARIA-EにおいてARIA-HはADUHELM 10 mg/kg投与患者の21%に認められたのに対し、プラセボ投与患者では1%であった。ADUHELMとプラセボ間の孤立性ARIA‐H(すなわち、 ARIA-Eも経験していない患者におけるARIA-H)の不均衡はなかった。ADUHELMとプラセボ間で1 cm超の出血の不均衡はなかった。
ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg/kg was observed in 21% of patients treated with ADUHELM 10 mg/kg, compared to 1% of patients on placebo. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between ADUHELM and placebo. There was no imbalance in hemorrhage greater than 1 cm between ADUHELM and placebo.

ARIA(-E及び/又は-H)が認められたADUHELM 10 mg/kg投与患者の臨床症状は24%に認められたのに対し、プラセボ投与患者では5%であった。ADUHELM 10 mg/kgのARIA治療患者で最も一般的な症状は頭痛(13%)であった。その他の主な症状は、錯乱/せん妄/精神状態変化/失見当識(5%)、浮動性めまい/回転性めまい(4%)、視覚障害(2%)及び悪心(2%)であった。ADUHELM 10 mg/kgの投与を受けた患者の0.3%にARIAに関連する重篤な症状が報告された。
Clinical symptoms were present in 24% of patients treated with ADUHELM 10 mg/kg who had an observation of ARIA (-E and/or -H), compared to 5% of patients on placebo. The most common symptom in patients treated with ADUHELM 10 mg/kg with ARIA was headache (13%). Other frequent symptoms were confusion/delirium/altered mental status/disorientation (5%), dizziness/vertigo (4%), visual disturbance (2%), and nausea (2%). Serious symptoms associated with ARIA were reported in 0.3% of patients treated with ADUHELM 10 mg/kg.

臨床症状は大部分の患者(88%)で観察期間中に消失した。ADUHELMの最初の8回の投与中、特に用量調節中はARIAの大部分が試験1及び2で観察された時期であるため、 ARIAに対するより厳格な臨床的監視が推奨される。患者にARIAを示唆する可能性のある症状が認められた場合、必要に応じてMRI検査を含む臨床評価を実施する。臨床症状の存在下でMRI検査でARIAが認められた場合、投与を継続する前に慎重な臨床評価を実施すること。
Clinical symptoms resolved in the majority of patients (88%) during the period of observation. Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration, as this is the time the majority of ARIA was observed in Studies 1 and 2. If a patient experiences symptoms which could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated. If ARIA is observed on MRI in the presence of clinical symptoms, careful clinical evaluation should be performed prior to continuing treatment.

ADUHELMの7回目投与(10 mg/kgの初回投与)及び12回目投与(10 mg/kgの6回目投与)前に脳MRIを実施し、無症候性ARIAの有無を評価する。ARIAのX線所見を有する患者については、臨床的監視の強化が推奨される。臨床的に必要な場合、追加のMRIを検討してもよい。放射線学的に重度のARIA-Hが認められた場合は、臨床的評価及び追跡MRIにより放射線学的安定性が示された後にのみ、慎重に投与を継続してもよい(すなわち、ARIA-Hの大きさや数が増加しない)。ARIA-E又は軽度/中等度のARIA-Hの場合、投与は慎重に継続する。投与を一時的に中断した場合、同じ用量及び漸増スケジュールで投与を再開することができる。放射線学的に中等度又は重度のARIAが検出された後のADUHELMの継続投与に関する系統的なデータはない。試験1及び2では、放射線学的に中等度又は重度のARIA-E及び放射線学的に中等度のARIA-Hに対して休薬が必要であった。試験1及び2では、放射線学的に重症のARIA-Hに対して投与の永続的な中止が必要とされた。
Obtain brain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth dose of 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA. For patients with radiographic findings of ARIA, enhanced clinical vigilance is recommended. Additional MRIs may be considered if clinically indicated. If radiographically severe ARIA-H is observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H). For ARIA-E or mild/moderate ARIA-H, treatment may continue with caution. If dosing is temporarily suspended, dosing may resume at that same dose and titration schedule. There are no systematic data on continued dosing with ADUHELM following detection of radiographically moderate or severe ARIA. In Studies 1 and 2, temporary dose suspension was required for radiographically moderate or severe ARIA-E and radiographically moderate ARIA-H. In Studies 1 and 2, permanent discontinuation of dosing was required for radiographically severe ARIA-H.

休薬の可能性を評価する際には、 10 mg/kgの用量を維持することのベネフィットを考慮すること。
The benefits of reaching and maintaining the 10 mg/kg dose should be considered when evaluating a potential dose suspension.

5.2 過敏症反応(Hypersensitivity Reactions)

試験1及び2のプラセボ対照期間中に1例に血管浮腫及び蕁麻疹が発現し、 ADUHELMの投与中に発現した。過敏症反応に一致する徴候又は症状が最初に認められた時点で直ちに投与を中止し、適切な治療を開始すること。
Angioedema and urticaria were reported in one patient in the placebo-controlled period of Studies 1 and 2, and occurred during the ADUHELM infusion. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy.

6 ADVERSE REACTIONS

以下の副作用は添付文書の別の箇所に記載されている。The following adverse reactions are described elsewhere in the labeling:

  • アミロイド関連画像異常[警告及び使用上の注意(1)参照]Amyloid Related Imaging Abnormalities [see Warnings and Precautions (5.1)]
  • 過敏症反応[警告及び使用上の注意(5.2)参照]Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

6.1 臨床試験での使用経験(Clinical Trials Experience)

臨床試験は様々な条件下で実施されるため、ある薬剤の臨床試験で認められた副作用の発現率を他の薬剤の臨床試験での発現率と直接比較することはできず、臨床現場で認められた発現率を反映していない可能性がある。
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

ADUHELMの安全性は、 ADUHELMの投与を受けた3,078例で評価されている。アルツハイマー病患者を対象としたプラセボ対照試験2試験(試験1及び2)では、合計1105例にADUHELM 10 mg/kgを投与した[臨床試験(14)参照]。これら1105例のうち、約52%が女性、 76%が白人、 10%がアジア人、 3%がヒスパニック系又はラテン系民族であった。試験登録時の平均年齢は70歳(範囲50~85歳)であった。
The safety of ADUHELM has been evaluated in 3,078 patients who received at least one dose of ADUHELM. In two placebo-controlled studies (Studies 1 and 2) in patients with Alzheimer’s disease, a total of 1105 patients received ADUHELM 10 mg/kg [see Clinical Studies (14)]. Of these 1105 patients, approximately 52% were female, 76% were White, 10% were Asian, and 3% were of Hispanic or Latino ethnicity. The mean age at study entry was 70 years (range from 50 to 85).

試験1のプラセボ対照期間及び長期継続投与期間の併合データでは、 2,834例がADUHELM 10 mg/kgの月一回投与を6ヵ月以上、 551例が12ヵ月以上、 309例が18ヵ月以上受けた。プラセボ対照期間と長期継続投与期間を合わせた場合、 10 mg/kg群の5%(1386例中66例)が副作用のため試験を中止した。プラセボ対照期と長期継続投与期を合わせた治験中止に至った主な副作用はARIA-H表在性鉄沈着症であった。表3にADUHELMの投与を受けた患者の2%以上に報告され、プラセボ投与を受けた患者よりも2%以上高い頻度で報告された副作用を示す。
In the combined placebo-controlled and long-term extension periods of Studies 1 and 2, 834 patients received at least one dose of ADUHELM 10 mg/kg once monthly for at least 6 months, 551 patients for at least 12 months, and 309 patients for at least 18 months. In the combined placebo-controlled and long-term extension periods, 5% (66 out of 1386) of patients in the 10 mg/kg dose group withdrew from the study because of an adverse reaction. The most common adverse reaction resulting in study withdrawal in the combined placebo-controlled and long-term extension periods was ARIA-H superficial siderosis. Table 3 shows adverse reactions that were reported in at least 2% of patients treated with ADUHELM and at least 2% more frequently than in patients on placebo.

Table 3: Adverse Reactions Reported in at Least 2% of Patients Treated with ADUHELM 10 mg/kg and at Least 2% Higher Than Placebo in Studies 1 and 2
Adverse Reaction ADUHELM
10 mg/kg
N=1105
%
Placebo
N=1087
%
ARIA-E 35 3
Headachea 21 16
ARIA-H microhemorrhage 19 7
ARIA-H superficial siderosis 15 2
Fall 15 12
Diarrheab 9 7
Confusion/Delirium/Altered Mental Status/Disorientationc 8 4
  1. Headache includes the adverse reaction related terms headache, head discomfort, migraine, migraine with aura, and occipital neuralgia.
  2. Diarrhea includes the adverse reaction related terms diarrhea and infectious diarrhea.
  3. Confusion/Delirium/Altered Mental Status/Disorientation includes the adverse reaction related terms confusional state, delirium, altered state of consciousness, disorientation, depressed level of consciousness, disturbance in attention, mental impairment, mental status changes, postoperative confusion, and somnolence.

6.2 免疫原性(Immunogenicity)

すべての治療用タンパク質と同様に、免疫原性の可能性がある。抗体産生の検出はアッセイの感度と特異性に大きく依存する。さらに、アッセイで観察された抗体(中和抗体を含む)陽性の発生率は、アッセイ法、検体の取扱い、検体採取のタイミング、併用薬、基礎疾患などのいくつかの要因の影響を受ける可能性がある。これらの理由から、以下に記載する試験における抗体の発現率を他の試験における抗体の発現率又は他のアデュカヌマブ製品と比較することは、誤解を招く可能性がある。
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other aducanumab products may be misleading.

ADUHELMの免疫原性は、抗aducanumab-avwa抗体の検出のためのin vitroアッセイを用いて評価した。
The immunogenicity of ADUHELM has been evaluated using an in vitro assay for the detection of binding anti-aducanumab-avwa antibodies.

試験1及び2のプラセボ対照期間と長期継続投与期間を合わせた最長41ヵ月間の投与で、 ADUHELMを月1回投与された患者の最大0.6%(15/2689例)に抗aducanumab-avwa抗体が発現した。
In up to 41 months of treatment in the combined placebo-controlled and long-term extension periods of Studies 1 and 2, up to 0.6% (15/2689) of patients receiving ADUHELM once monthly developed anti-aducanumab-avwa antibodies.

抗aducanumab-avwa抗体陽性となった患者数は限られていたことから、抗aducanumab-avwa抗体の中和活性が曝露量又は有効性に影響を及ぼす可能性に関する所見は認められなかった。しかし、得られているデータは限られているため、 ADUHELMの薬物動態、安全性又は有効性に対する影響について最終的な結論を導くことはできない。中和抗aducanumab-avwa抗体の定量は実施していない。
Based on the limited number of patients who tested positive for anti-aducanumab-avwa antibodies, no observations were made concerning a potential effect of neutralizing activity of anti-aducanumab-avwa antibodies on exposure or efficacy; however, the available data are too limited to make definitive conclusions regarding an effect on pharmacokinetics, safety, or efficacy of ADUHELM. Quantification of neutralizing anti-aducanumab-avwa antibodies has not been assessed.

8 特別な集団への投与(USE IN SPECIFIC POPULATIONS)

8.1 妊娠(Pregnancy)

リスクの要約(Risk Summary)

妊婦におけるADUHELMの使用に関して、重大な先天異常、流産又はその他の母体及び胎児の有害な転帰の薬剤関連リスクを評価する十分なデータはない。
There are no adequate data on ADUHELM use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

米国の一般集団では、臨床的に確認された妊娠における重大な先天異常及び流産の推定背景リスクは、それぞれ2~4%及び15~20%である。適応集団における重大な先天異常及び流産の背景リスクは不明である。
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data
Animal Data

器官形成期の雌ラットにaducanumab-avwa(0、100、300又は1000 mg/kg/週)を静脈内投与したところ、胚・胎児発生に対する有害な作用は認められなかった。
Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to female rats through organogenesis had no adverse effect on embryofetal development.

妊娠及び授乳期間中の雌ラットにaducanumab-avwa(0、100、300又は1000 mg/kg/週)を静脈内投与したところ、出生前及び出生後の発生に有害な影響は認められなかった。
Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to female rats throughout pregnancy and lactation had no adverse effects on pre- or postnatal development.

Aducanumab-avwaの薬理学的標的である凝集アミロイドβはラットには存在しないため、これらのデータのヒトへの関連性は限定的である。
The relevance of these data to humans is limited because aggregated amyloid beta, the pharmacological target of aducanumab-avwa, is not present in rat.

8.2 授乳(Lactation)

リスクの要約(Risk Summary)

Aducanumab-avwaのヒト乳汁中への移行、母乳栄養乳児への影響又は乳汁産生への影響に関するデータはない。授乳による発育及び健康への利益は、母親のADUHELMに対する臨床的必要性及びADUHELM又は母体の基礎疾患による授乳児への潜在的な有害作用とともに考慮すべきである。
There are no data on the presence of aducanumab-avwa in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADUHELM and any potential adverse effects on the breastfed infant from ADUHELM or from the underlying maternal condition.

8.4 小児への投与(Pediatric Use)

小児患者における安全性及び有効性は確立されていない。
Safety and effectiveness in pediatric patients have not been established.

8.5 高齢者への投与(Geriatric Use)

試験1及び2では、患者の年齢は50歳~85歳、平均年齢は70歳であった。
In Studies 1 and 2, the age of patients ranged from 50 to 85 years, with a mean age of 70 years;

79%が65歳以上、 32%が75歳以上であった。これらの年齢群間で副作用の発現率に顕著な差は認められず、 65歳以上の患者ではそれより若い患者と比較して安全性上の新たな懸念は認められなかった。
79% were 65 and older, and 32% were 75 and older. There were no notable differences in the incidence of adverse reactions between these age groups, and no additional safety concerns in patients 65 years of age and older compared to younger patients.

11 組成・性状(DESCRIPTION)

Aducanumab-avwaは、凝集した可溶性及び不溶性アミロイドβに対する組換えヒト免疫グロブリンγ1(IgG 1)モノクローナル抗体であり、チャイニーズハムスター卵巣細胞株で発現している。Atucanumab-avwaの分子量は約146 kDaである。
Aducanumab-avwa is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta, and is expressed in a Chinese hamster ovary cell line. Aducanumab-avwa has an approximate molecular weight of 146 kDa.

ADUHELM(aducanumab-avwa)注射剤は、 170 mg/1.7 mL(100 mg/mL)又は300 mg/3 mL(100 mg/mL)の濃度のADUHELMが単回投与用バイアルで供給される希釈後の静脈内投与用の防腐剤無添加、無菌、透明~乳白光、無色~黄色溶液である。
ADUHELM (aducanumab-avwa) injection is a preservative-free, sterile, clear to opalescent, and colorless to yellow solution for intravenous infusion after dilution supplied in single-dose vials available in concentrations of 170 mg/1.7 mL (100 mg/mL) or 300 mg/3 mL (100 mg/mL) of ADUHELM.

溶液のmLは100 mgのaducanumab-avwaとL-アルギニン塩酸塩(31.60 mg)、 L-ヒスチジン(0.60 mg)、 L-ヒスチジン塩酸塩水和物(3.39 mg)、 L-メチオニン(1.49 mg)、ポリソルベート80(0.50 mg)及び注射用水を含み、 pHは約5.5である。
Each mL of solution contains 100 mg of aducanumab-avwa and L-arginine hydrochloride (31.60 mg), L-histidine (0.60 mg), L-histidine hydrochloride monohydrate (3.39 mg), L-methionine (1.49 mg), polysorbate 80 (0.50 mg), and Water for Injection at an approximate pH of 5.5.

12 臨床薬理(CLINICAL PHARMACOLOGY)

12.1 作用機序(Mechanism of Action)

Atucanumab-avwaは、凝集した可溶性及び不溶性のアミロイドβに対するヒト免疫グロブリンγ1(IgG 1)モノクローナル抗体である。脳におけるアミロイドベータプラークの蓄積は、アルツハイマー病の病態生理学的特徴を明確にしている。
Aducanumab-avwa is a human, immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease.

ADUHELMは、試験1, 2及び3で評価したアミロイドβ斑を減少させる[臨床試験(14)参照]。
ADUHELM reduces amyloid beta plaques, as evaluated in Studies 1, 2, and 3 [see Clinical Studies (14)].

12.2 薬力学(Pharmacodynamics)

アミロイドβ病理に対するADUHELMの効果(Effect of ADUHELM on Amyloid Beta Pathology)

試験1,試験2及び試験3において、 ADUHELMはプラセボと比較してアミロイドβプラークを用量及び時間依存的に減少させた[用法・用量(2.1)及び臨床試験(14)参照]。
ADUHELM reduced amyloid beta plaque in a dose- and time-dependent manner in Study 1, Study 2, and Study 3, compared with placebo [see Dosage and Administration (2.1) and Clinical Studies (14)].

脳のアミロイドβプラークレベルに対するADUHELMの効果を、 PETイメージング(18 F‐フロルベタピールトレーサー)を用いて評価した。標準取り込み値比(SUVR)法を用いてPETシグナルを定量化し、アルツハイマー病の病変により広範な影響を受けると予想される脳領域(前頭皮質、頭頂皮質、側頭外側皮質、感覚運動皮質、前帯状皮質、後帯状皮質)の複合体におけるアミロイドβプラークの脳内濃度を、そのような病変を受けないと予想される脳領域(小脳)と比較して推定した。SUVRはまた、 Centioidスケールでも発現した。
The effect of ADUHELM on amyloid beta plaque levels in the brain was evaluated using PET imaging (18F-florbetapir tracer). The PET signal was quantified using the Standard Uptake Value Ratio (SUVR) method to estimate brain levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer’s disease pathology (frontal, parietal, lateral temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region expected to be spared of such pathology (cerebellum). The SUVR was also expressed on the Centiloid scale.

試験1及び試験2のサブ試験では、 ADUHELMは脳内のアミロイドβプラークレベルを低下させ、 ADUHELMの低用量及び高用量、並びに26及び78週時の両時点でプラセボと比較して低下した(p<0.0001)。減少の程度は時間及び用量依存的であった。試験1及び試験2の長期継続投与期では、最初にADUHELMに無作為に割り付けられた患者において、 132週目に脳アミロイドβプラークレベルの持続的な低下が認められた。
In sub-studies of Study 1 and Study 2, ADUHELM reduced amyloid beta plaque levels in the brain, producing reductions at both ADUHELM low dose and high dose levels and at both Weeks 26 and 78 (p < 0.0001), compared to placebo. The magnitude of reduction was time- and dose-dependent. In the long-term extension of Study 1 and Study 2, a continued decrease in brain amyloid beta plaque levels was observed at Week 132 in patients initially randomized to ADUHELM.

試験3では、 ADUHELMは脳のアミロイドβプラークレベルを低下させ、 3 mg/kg, 6 mg/kg及び10 mg/kgのADUHELM投与群では26週に、全ADUHELM投与群では54週に、プラセボと比較して統計的に有意な用量及び時間依存的な低下をもたらした。試験3のプラセボ対照期間中にADUHELMを投与された被験者のうち、脳のアミロイドβプラークレベルは、 222週までの長期継続投与期間中、時間及び用量依存的に低下し続けた。
In Study 3, ADUHELM reduced amyloid beta plaque levels in the brain, producing statistically significant dose- and time-dependent reductions compared to placebo in the 3 mg/kg, 6 mg/kg, and 10 mg/kg ADUHELM treatment groups at Week 26, and in all ADUHELM treatment groups at Week 54. Among those dosed with ADUHELM during the placebo-controlled period in Study 3, amyloid beta plaque levels in the brain continued to decline in a time- and dose-dependent manner in the long-term extension period through Week 222.

タウ病態生理に対するADUHELMの効果(Effect of ADUHELM on Tau Pathophysiology)

ADUHELMは、試験1及び試験2においてタウの病態生理マーカー(CSFのp-Tau及びTau PET)及び神経変性マーカー(CSFのt-Tau)を減少させた[臨床試験(14)参照]。ADUHELMは、試験1及び試験2で実施したサブ試験においてCSF中p-Tau濃度を低下させた。プラセボ群と比較して、 CSF中p-Tau濃度のベースラインからの調整平均変化量は、試験1の78週時点でのADUHELM低用量群(p<0.01)及び高用量群(p<0.001)で良好であった。試験2の結果はADUHELMが数値的に良好であったが、統計的に有意ではなかった。
ADUHELM reduced markers of tau pathophysiology (CSF p-Tau and Tau PET) and neurodegeneration (CSF t-Tau) in Study 1 and Study 2 [see Clinical Studies (14)]. ADUHELM reduced CSF levels of p-Tau in sub-studies conducted in Study 1 and Study 2. The adjusted mean change from baseline in CSF p-Tau levels relative to placebo was in favor of the ADUHELM low (p<0.01) and high (p<0.001) dose groups at Week 78 in Study 1. Results in Study 2 numerically favored ADUHELM but were not statistically significant.

ADUHELMは、試験1及び試験2で実施したサブ試験においてCSF中t-Tau濃度を低下させた。試験1では、 CSF中t-Tau濃度のベースラインからの調整平均変化量は、プラセボ群と比較して78 ADUHELM低用量群(p<0.05)及び高用量群(p<0.01)で良好であった。試験2の結果はADUHELMが数値的に良好であったが、統計的に有意ではなかった。
ADUHELM reduced CSF levels of t-Tau in sub-studies conducted in Study 1 and Study 2. The adjusted mean change from baseline in CSF t-Tau levels relative to placebo was in favor of the ADUHELM low (p<0.05) and high (p<0.01) dose groups at Week 78 in Study 1. Results in Study 2 numerically favored ADUHELM but were not statistically significant.

PETイメージング(18 F‐MK 6240トレーサ)を用いてタウ蛋白質から成る神経原線維変化に対するADUHELMの効果を評価するために、研究1と研究2の両方でサブスタディを実施した。SUVR法を用いてPETシグナルを定量し、試験集団のアルツハイマー病の病理により影響を受けると予想される脳領域(内側側頭葉皮質、側頭葉皮質、前頭皮質、帯状皮質、頭頂皮質、後頭皮質)におけるタウの脳内濃度を、そのような病理の影響を受けないと予想される脳領域(小脳)と比較して推定した。サブスタディからのデータをプールし、 37人の患者を縦断的追跡調査した。追跡時のプラセボと比較したタウPET SUVRのベースラインからの調整平均変化は、内側側頭(p<0.001)、側頭(p<0.05)と前頭部(p<0.05)でADUHELM高用量の方が良好であった。帯状皮質、頭頂皮質、後頭皮質では統計的有意差は認められなかった。
Sub-studies were conducted in both Study 1 and Study 2 to evaluate the effect of ADUHELM on neurofibrillary tangles composed of tau protein using PET imaging (18F-MK6240 tracer). The PET signal was quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer’s disease pathology (medial temporal, temporal, frontal, cingulate, parietal, and occipital cortices) in the study population compared to a brain region expected to be spared of such pathology (cerebellum). Data from the substudies were pooled, comprising 37 patients with longitudinal follow-up. The adjusted mean change from baseline in tau PET SUVR relative to placebo at follow-up was in favor of ADUHELM high dose in the medial temporal (p<0.001), temporal (p<0.05), and frontal (p<0.05) brain regions. No statistically significant differences were observed for the cingulate, parietal, or occipital cortices.

用量-反応関係(Exposure-Response Relationships)

試験1及び2のモデルに基づく曝露量-反応解析から、 ADUHELMの曝露量が高いほど、 CDR-SB, ADASCog 13及びADCS-ADL-MCIの臨床的低下が大きく減少することが示された。また、試験1及び2では、 ADUHELMの曝露量が高いほどアミロイドベータプラークの減少が大きかった。アミロイドβプラークの減少とCDR‐SBでの臨床的低下の間の関連も認められた。
Model based exposure-response analyses for Studies 1 and 2 demonstrated that higher exposures to ADUHELM were associated with greater reduction in clinical decline on CDR-SB, ADASCog13, and ADCS-ADL-MCI. In addition, higher exposures to ADUHELM were associated with greater reduction in amyloid beta plaque in Studies 1 and 2. An association between reduction in amyloid beta plaque and clinical decline on CDR-SB was also observed.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of ADUHELM were characterized using a population PK analysis with concentration data collected from 2961 subjects with Alzheimer’s disease who received ADUHELM in single or multiple doses.

Steady-state concentrations of ADUHELM were reached by 16 weeks of repeated dosing with an every 4-week regimen, and the systemic accumulation was 1.7-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of ADUHELM increased dose proportionally in the dose range of 1 to 10 mg/kg every 4 weeks.

Distribution

The mean value (95% CI) for volume of distribution at steady state is 9.63 L (9.48, 9.79).

Elimination

ADUHELM is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. ADUHELM clearance (95% CI) is 0.0159 (0.0156, 0.0161) L/hr. The terminal half-life is 24.8 (14.8, 37.9) days.

Specific Populations

Body weight, age, sex, and race were found to impact exposure to ADUHELM. However, none of these covariates were found to be clinically significant.

Patients with Renal or Hepatic Impairment

No studies were conducted to evaluate the pharmacokinetics of ADHUELM in patients with renal or hepatic impairment. ADUHELM is not expected to undergo renal elimination or metabolism by hepatic enzymes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted.

Impairment of Fertility

Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to male and female rats prior to and during mating and continuing in females to gestation day 7 resulted in no adverse effects on fertility or reproductive performance.

The relevance of these data to humans is limited because aggregated amyloid beta, the pharmacological target of aducanumab-avwa, is not present in rat.

14 臨床試験(CLINICAL STUDIES)

ADUHELMの有効性は、アルツハイマー病患者を対象とした二重盲検、無作為化、プラセボ対照、並行群間比較試験(試験1, NCT 02484547及び試験2, NCT 02477800)で評価した(アミロイド病変の存在が確認されており、軽度認知障害又は軽度認知症の病期がステージ3及びステージ4のアルツハイマー病と一致する患者、ステージ3の患者の80%及びステージ4の患者の20%を含むように層別化)。ADUHELMの効果は、アルツハイマー病患者を対象とした二重盲検、無作為化、プラセボ対照、用量設定試験(試験3, NCT 01677572)(アミロイド病変の存在が確認されており、病期3及び病期4のアルツハイマー病と一致する、前駆期又は軽度の認知症の病期にある患者で、 43%が病期3の患者、 57%が病期4の患者として登録されている)と、その後の任意の用量盲検、長期継続投与試験でも裏付けられた。
The efficacy of ADUHELM was evaluated in two double-blind, randomized, placebo-controlled, parallel group studies (Study 1, NCT 02484547 and Study 2, NCT 02477800) in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease, stratified to include 80% Stage 3 patients and 20% Stage 4 patients). The effects of ADUHELM were also supported by a double-blind, randomized, placebo-controlled, doseranging study (Study 3, NCT 01677572) in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and prodromal or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease, with an enrolled distribution of 43% Stage 3 patients and 57% Stage 4 patients), followed by an optional, dose-blind, long-term extension period.

試験1及び2では、患者をADUHELM低用量(ApoEε4保有者及び非保有者それぞれ3 mg/kg又は6 mg/kg)、 ADUHELM高用量(10 mg/kg)又はプラセボの4週ごとの投与に無作為に割り付けて18ヵ月間投与した後、任意の用量盲検長期継続投与期間を設けた。
In Studies 1 and 2, patients were randomized to receive ADUHELM low dose (3 or 6 mg/kg for ApoE ε4 carriers and noncarriers, respectively), ADUHELM high dose (10 mg/kg), or placebo every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period.

いずれの試験でも、最初の漸増期間は最大目標用量まで6ヵ月間とした。試験開始時、 ApoEε4キャリアは高用量群では最初に最大6 mg/kgまで漸増し、その後10 mg/kgに調節した。
Both studies included an initial titration period of up to 6 months to the maximum target dose. At the beginning of the study, ApoE ε4 carriers were initially titrated up to a maximum of 6 mg/kg in the high dose group, which was later adjusted to 10 mg/kg.

研究1と2では、患者は、CDRグローバルスコア0.5、RBANSススコア≤85及びMMSEスコア24~30で登録した。試験3では、総合CDRスコアが0.5又は1.0, MMSEスコアが20~30の患者を登録した。アルツハイマー病に対する承認された併用療法(コリンエステラーゼ阻害薬及びN-メチル-D-アスパラギン酸拮抗薬メマンチン)の有無にかかわらず患者を登録した。
In Studies 1 and 2, patients were enrolled with a Clinical Dementia Rating (CDR) global score of 0.5, a Repeatable Battery for Assessment of Neuropsychological Status (RBANS) delayed memory index score ≤ 85, and a Mini-Mental State Examination (MMSE) score of 24-30. In Study 3, patients were enrolled with a global CDR score of 0.5 or 1.0 and an MMSE score of 20-30. Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease.

試験1及び2は計画された完了前に終了した。本治験の評価項目は、事前に規定した統計解析計画書に基づいて解析した。
Studies 1 and 2 were terminated prior to their planned completion. Study endpoints were analyzed based on the prespecified statistical analysis plan.

Study 1

In Study 1, 1638 patients were randomized 1:1:1 to receive ADUHELM low dose, ADUHELM high dose, or placebo. At baseline, the mean age of patients was 71 years, with a range of 50 to 85 years.

A subgroup of 488 patients were enrolled in the amyloid PET substudy; of these, 302 were evaluated at week 78. Results from the amyloid beta PET and CSF biomarker substudies are described in Figure 1 and Table 4.

Figure 1: Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid Beta PET Composite, SUVR and Centiloids) in Study 1
Table 4: Biomarker Results of ADUHELM in Study 1

The primary efficacy endpoint was the change from baseline on the CDR-Sum of Boxes (CDRSB) at Week 78. In Study 1, treatment with ADUHELM high dose demonstrated reduced clinical decline, as evidenced by a statistically significant treatment effect on change from baseline in CDR-SB compared to placebo (-0.39 [-22%], p = 0.0120), as shown in Figure 2 and Table 5. The estimate of the treatment effect favored ADUHELM across all prespecified subgroups of interest.

Figure 2: Line Plot of Primary Efficacy Endpoint (Change From Baseline in CDR Sum of Boxes) in Study 1

Secondary efficacy endpoints included the change from baseline in MMSE score at Week 78, the change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13 items) (ADAS-Cog 13) at Week 78, and the change from baseline in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL-MCI) score at Week 78. In Study 1, statistically significant differences from placebo were observed in the ADUHELM high dose group on all secondary efficacy endpoints evaluated. The estimate of the treatment effect favored ADUHELM across most prespecified subgroups of interest for the secondary efficacy endpoints. The Neuropsychiatric Inventory-10 item (NPI-10) was the only tertiary endpoint that assessed efficacy. The results of the high dose group, compared to placebo, are presented in Table 5.

Differences from placebo observed in the ADUHELM low dose group numerically favored ADUHELM but were not statistically significant.

Table 5: Clinical Results of ADUHELM in Study 1

Study 2

In Study 2, 1647 patients were randomized 1:1:1 to receive ADUHELM low dose, ADUHELM high dose, or placebo. At baseline, the mean age of patients was 71 years, with a range of 50 to 85 years.

A subgroup of 585 patients were enrolled in the amyloid PET subgroup; of these, 374 were evaluated at week 78. Results from the amyloid beta PET and CSF biomarker substudies are described in Figure 3 and Table 6.

Figure 3: Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid Beta PET Composite, SUVR and Centiloids) in Study 2
Table 6: Biomarker Results of ADUHELM in Study 2

No statistically significant differences were observed between the ADUHELM-treated and placebo-treated patients on the primary efficacy endpoint, the change from baseline in CDR-SB  score at 78 weeks.

Study 3

In Study 3, 197 patients were randomized to receive a fixed dose of ADUHELM 1 mg/kg (n=31), 3 mg/kg (n=32), 6 mg/kg (n=30), 10 mg/kg (n=32), titration of ADUHELM to 10 mg/kg over 44 weeks (n=23), or placebo (n=48) for 12 months. At baseline, the mean age of patients was 73 years, with a range of 51-91 years.

Results from the amyloid beta PET substudy are described in Figure 4 and Table 7.

Figure 4: Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid Beta PET Composite, SUVR and Centiloids) in Study 3
Table 7: Biomarker Results of ADUHELM in Study 3

Clinical assessments in Study 3 were exploratory. Results for clinical assessments were directionally aligned with the findings from Study 1, with less change from baseline in CDR-SB and MMSE scores at 1 year in the ADUHELM 10 mg/kg fixed-dose group than in patients on placebo (CDR-SB: -1.26, 95% CI [-2.356, -0.163]; MMSE: 1.9, 95% CI [0.06, 3.75]).

16 包装・保存及び取扱い上の注意(HOW SUPPLIED/STORAGE AND HANDLING)

16.1 How Supplied

ADUHELM (aducanumab-avwa) injection is a preservative-free, sterile, clear to opalescent, and colorless to yellow solution. ADUHELM is supplied one vial per carton as follows:

170 mg/1.7 mL (100 mg/mL) single-dose vial (with red flip cap) – NDC 64406-101-01

300 mg/3 mL (100 mg/mL) single-dose vial (with blue flip cap) – NDC 64406-102-02

16.2 保存および取扱い方法(Storage and Handling)

未開封バイアル(Unopened Vial)
  • 光を避けるため使用するまで元の箱に入れて保管すること。Store in original carton until use to protect from light.
  • 2℃~8℃(36°F~46°F)で冷蔵保存する。Store in a refrigerator at 2°C to 8°C (36°F to 46°F).
  • 凍結させたり振盪したりしないこと。Do not freeze or shake.
  • 冷蔵保存ができない場合、ADUHELMは、25℃(77°F)までの室温で3日間、光から保護するために元のカートンに入った状態で保管してもよい。If no refrigeration is available, ADUHELM may be stored unopened in its original carton to protect from light at room temperature up to 25°C (77°F) for up to 3 days.
  • 希釈前に、未開封のADUHELMのバイアルを取り出し、必要に応じて冷蔵庫に戻してもよい。遮光した冷蔵庫から取り出した総時間は、室温~24℃ 25(77°F)で時間を超えてはならない。Prior to dilution, unopened vials of ADUHELM may be removed from and returned to the refrigerator if necessary, when kept in the original carton. Total combined time out of refrigeration with protection from light should not exceed 24 hours at room temperature up to 25°C (77°F).

17 患者への情報提供(PATIENT COUNSELING INFORMATION)

FDA承認済みの患者用添付文書(医薬品ガイド)を読むよう患者及び/又は介護者に助言すること。
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

アミロイド関連画像異常(Amyloid Related Imaging Abnormalities)

ADUHELMがアミロイド関連画像異常又は 「ARIA」 を引き起こす可能性があることを患者に説明すること。ARIAは、脳の一部に一時的な腫れがみられることが最も多く、通常は時間の経過とともに解消される。一部の患者では、脳の内部や表面に小さな出血斑がみられることもある。脳の領域に腫れがある人のほとんどは症状を経験しないが、一部の人は頭痛、錯乱、めまい、視覚の変化、悪心などの症状を経験することがあることを患者に説明する。これらの症状が発現した場合は担当医師に報告するよう患者に指示すること。医療提供者がARIAをモニタリングするためにMRIスキャンを実施することを患者に通知する[警告及び使用上の注意(5.1)参照]。
Inform patients that ADUHELM may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, or nausea. Instruct patients to notify their healthcare provider if these symptoms occur. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)].

過敏症反応(Hypersensitivity Reactions)

ADUHELMが血管浮腫及び蕁麻疹を含む過敏症反応を引き起こす可能性があることを患者に説明し、過敏症反応が発現した場合は担当医師に連絡するよう患者に説明すること[警告及び使用上の注意(5.2)参照]。
Inform patients that ADUHELM may cause hypersensitivity reactions, including angioedema and urticaria, and to contact their healthcare provider if hypersensitivity reactions occur [see Warnings and Precautions (5.2)].

MEDICATION GUIDE

ADUHELM™ (AD-yew-helm)

(aducanumab-avwa)

injection, for intravenous use

ADUHELMについて知っておくべき最も重要な情報は何か?(What is the most important information I should know about ADUHELM?)

ADUHELMは以下のような重篤な副作用を引き起こす可能性がある。ADUHELM can cause serious side effects, including:

アミロイド関連画像異常「ARIA」 。ARIAは一般的な副作用で、通常は症状を引き起こさないが、重篤になることがある。脳の一部に一時的な腫れがみられることが最も多く、通常は時間の経過とともに消失していく。腫れを伴う脳の表面や内部に小さな出血斑がみられる場合もある。脳の一部の領域が腫れても、ほとんどの場合は症状がみられないものの、一部の患者では以下のような症状がみられることがある。
Amyloid Related Imaging Abnormalities or “ARIA”. ARIA is a common side effect that does not usually cause any symptoms but can be serious. It is most commonly seen as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain with the swelling. Although most people with swelling in areas of the brain do not have symptoms, some people may have symptoms, such as:

  • headache
  • confusion
  • dizziness
  • vision changes
  • nausea

ADUHELM治療開始前と治療中に、担当の医療提供者が磁気共鳴画像法(MRI)スキャンを実施し、ARIAの有無を確認する。
Your healthcare provider will do magnetic resonance imaging (MRI) scans before and during your treatment with ADUHELM to check you for ARIA.

上記のいずれかの症状がある場合は、すぐに医療提供者に電話するか、最寄りの病院の救急治療室に行くこと。
Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.

ADUHELMとは?(What is ADUHELM?)

  • ADUHELMは、アルツハイマー病の治療に用いられる処方薬である。ADUHELM is a prescription medicine used to treat people with Alzheimer’s disease.

小児におけるADUHELMの安全性及び有効性は不明である。It is not known if ADUHELM is safe and effective in children.

Before receiving ADUHELM, tell your healthcare provider about all of your medical conditions,

including if you:

  • are pregnant or plan to become pregnant. It is not known if ADUHELM will harm your unborn baby. Tell your healthcare provider if you become pregnant during your treatment with ADUHELM.
  • are breastfeeding or plan to breastfeed. It is not known if aducanumab-avwa (the active ingredient in ADUHELM) passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while receiving ADUHELM.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive ADUHELM?

  • ADUHELM is given through a needle placed in your vein (intravenous (IV) infusion) in your arm.
  • ADUHELM is given every 4 weeks. Each infusion will last about 1 hour.

What are the possible side effects of ADUHELM?

ADUHELM can cause serious side effects, including:

  • See above “What is the most important information I should know about ADUHELM?”
  • Serious allergic reactions. Swelling of the face, lips, mouth, or tongue and hives have happened during an ADUHELM infusion. Tell your healthcare provider if you have any of the symptoms of a serious allergic reaction during or after ADUHELM infusion.

The most common side effects of ADUHELM include:

  • swelling in areas of the brain, with or without small spots of bleeding in or on the surface of the brain (ARIA)
  • headache
  • fall

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

General Information about the safe and effective use of ADUHELM.

Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. You can ask your pharmacist or healthcare provider for more information about ADUHELM that is written for health professionals. For more information, go to www.aduhelm.com or call at 1-833-425-9360.

What are the ingredients in ADUHELM?

Active ingredient: aducanumab-avwa

Inactive ingredients: L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, Lmethionine, polysorbate 80, and water for injection

Manufactured by: Biogen Inc., Cambridge, MA 02142, U.S. License #1697

参照

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf

-エビデンス全般

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