ILLUMINATE-A study is an ongoing phase 3 trial to evaluate the efficacy and safety of lumasiran in adults and children >=6 years of age with PH1,The primary endpoint was the percent change from baseline to Month 6 in 24-hour urinary oxalate corrected for BSAKey secondary endpoints were proportion of patients with 24-hour urinary oxalate levels ULN at Month 6The following secondary endpoints were included in plans to control the overall type 1 error rate:Absolute change in 24-hour urinary oxalate corrected for BSA from baseline to Month 6Percent change in 24-hour urinary Ox/Cr ratio from baseline to Month 6 Percent change in plasma oxalate from baseline to Month 6 (changed from exploratory to secondary endpoint in Amendment 2)Proportion of patients with 24-hour urinary oxalate level at or below 1.5x upper limit of normal (ULN) at Month 6 (changed from below to at or below 1.5×ULN in Amendment 2)x Proportion of patients with 24-hour urinary oxalate level at or below ULN at Month 6 (changed from below to at or below ULN in Amendment 2)x Absolute change in plasma oxalate from baseline to Month 6 (changed from exploratory to secondary endpoint in Amendment 2) ILLUMINATE-B study is an ongoing phase 3, single-arm study to evaluate the efficacy, safety, PK and PD of lumasiran in children birth to <6 years of age with PH1The primary endpoint was percent change in urinary oxalate excretion, measured by Ox/Cr, from baseline to Month 6
Rivfloza
siRNA
肝乳酸脱氢酶（LDH）
代谢病
常规批准
1型或2型原发性高草酸尿症
FDA
2023
Primary EndpointThe primary endpoint, 24 h Uox AUC of percentage change from Baseline calculated from Uox data collected on Days 90, 120, 150, and 180, was analyzed using analysis of covariance with fixed effects for age category, eGFR category, and baseline 24 h urinary oxalate.key secondary endpoint was the percentage of patients with normal or near-normal Uoxother secondary endpointsthe percentage change in the summed surface area and number of kidney stones on kidney ultrasound from Baseline to Day 180, percentage change from baseline Pox(plasma oxalate) on Day 180, and the rate of change in eGFR.
Givlaari
siRNA
ALAS1
代谢病
加速批准
急性肝卟啉症AHP
FDA
2019
Primary. The primary endpoint was the annualized rate of porphyria attacks (AAR) that require hospitalization, urgent care visit, or in-home IV hemin administration.Secondary. Secondary endpoints included• urinary ALA in patients with AIP at 3 months. NOTE: Postbaseline ALA values measured within 3 days after hemin use during the 6 month DB period are treated as missing and excluded from analysis.• urinary ALA in patients with AIP at 6 months.• urinary PBG in patients with AIP at 6 months. NOTE: Postbaseline PBG values measured within 3 days after hemin use during the 6 month DB period are treated as missing and excluded from analysis. • annualized rate of administered hemin doses in patients with AIP over the 6-month DB treatment period• annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with any AHP over the 6-month DB treatment period• daily worst pain score as measured by Brief Pain Inventory-Short Form (BPI-SF) numeric rating scale (NRS) in patients with AIP over the 6-month DB treatment period• daily worst fatigue score as measured by Brief Fatigue Inventory-Short Form (BFI-SF) NRS in patients with AIP over the 6-month DB treatment period• daily worst nausea score as measured by NRS in patients with AIP over the 6-month DB period• change from baseline in the Physical Component Summary (PCS) of the SF-12 in patients with AIP at 6 months
Upstaza
AAV
AADC
罕见病
常规批准
芳香族 L-氨基酸脱羧酶缺乏症
EMA
2022
Achievement of key motor milestones at the 2-year time point was the primary measure of efficacy.• Proportion of patients achieving full head control, as measured using the Peabody Developmental Motor Scales – Second Edition (PDMS-2)• Proportion of patients able to sit unassisted, as measured using the PDMS-2• Proportion of patients able to stand with support, as measured using the PDMS-2• Proportion of patients able to walk with assistance, as measured using the PDMS-2The proportions calculated at 1-year post gene therapy were provided as supportive analyses. The secondary efficacy endpoints were:• Raw scores for the PDMS-2 total and subscales• Raw scores for the Alberta Infant Motor Scale (AIMS) total and subscales• Raw scores for the Bayley Scales of Infant Development – Third Edition (Bayley-III) total and subscales• Change from baseline in body weight• Neurologic examination findings with respect to muscle tone (i.e. floppiness), OGC episodes, dystonia, muscle power, and deep tendon reflex (DTR) response Immunogenicity Endpoints• Anti-adeno-associated virus serotype 2 (AAV2) optical density (OD) values.
Leqvio
siRNA
PCSK9
罕见病
常规批准
原发性高胆固醇血症
EMA
2020
co-primary efficacy endpoints were: Percentage change in LDL-C from baseline to Day 510 Time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 Three key secondary endpoints were defined in the protocol and statistical analysis plan: Absolute change in LDL-C from Baseline to Day 510.o The placebo-adjusted absolute change from baseline to Day 510 in LDL-C levelswas -68.9 mg/dL (p<0.0001). Time-adjusted absolute change in LDL-C from Baseline after Day 90 and up to Day 540.o Compared to placebo, the time-adjusted absolute change from baseline after Day 90 and up to Day 540 was -62.7 mg/dL (p<0.0001). Percentage change from Baseline to Day 510 in PCSK9, TC, Apo-B, and non-HDLC.o The placebo-adjusted percentage change in PCSK9 from baseline to Day 510 was -78.3% (p<0.0001).o The placebo-adjusted percentage change in TC from baseline to Day 510 was -31.8% (p<0.0001).o The placebo-adjusted percentage change in Apo-B from baseline to Day 510 was -36.1% (p<0.0001).o The placebo-adjusted percentage change in non-HDL-C from baseline to Day 510 was -42.4% (p<0.0001). EMA-co-primary efficacy endpoints were:percent change in LDL-C from baseline to Day 510 and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540The key secondary endpoints of the studies were:• Absolute change in LDL-C from baseline to Day 510• Time-adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540• Percentage change from baseline to Day 510 in PCSK9, total cholesterol, apolipoprotein B (Apo-B), and non-HDL-C.
Vyjuvek
HSV
COL7A1
罕见病
常规批准
营养不良型大疱性表皮松解症
FDA
2023
Primary Endpoint:The difference in proportion of complete wound closure (responder) in VYJUVEK treated and placebo-treated intra-subject primary wound sites at Weeks 22 and 24 or Weeks 24 and 26.• A responder was defined as having wounds that were closed for at least 2 consecutive weeks at defined timepoints.• Complete wound closure was defined as 100% wound closure from the exact wound area selected at baseline, specified as skin re-epithelialization without drainage.Key Secondary Endpoint:The difference in proportion of complete wound closure in VYJUVEK-treated and placebo-treated intra-subject primary wound sites at Weeks 8 and 10 or Weeks 10 and 12.
Strimvelis
体外修饰干细胞
腺苷脱氨酶（ADA）
罕见病
常规批准
重症联合免疫缺陷症
EMA
2016
Primary efficacy endpoint: Survival at 3 years post-gene therapy.Secondary efficacy endpoints (in hierarchical order):Key endpoints Change in the rate of severe infections (defined as infections requiring hospitalisation or prolonging hospitalisation). One-year change in T-lymphocyte counts (cells/L). One-year modification of the "systemic" metabolic defect, analysed by levels of purine metabolites in RBC.Other endpoints One-year change in the proliferative response to polyclonal stimuli. One-year change in thymic activity (T-cell receptor excision circles; TREC). Presence of genetically modified cells in the bone marrow compartment and presence of ≥10% genetically modified cells in peripheral blood lymphocytes. Lymphocyte ADA enzyme activity. One-year change in lymphocyte counts (cells/L). Recovery of physical growth. Need for reintroduction of PEG-ADA (in subjects previously treated with PEGADA). Antibody response to vaccination.
Luxturna
AAV
RPE65
罕见病
常规批准
RP
FDA
2017
primary efficacy endpoint: the median MLMT score change from Baseline to 1 Year 1 in the LUXTURNA treatment group as compared to the control group.Additional efficacy endpointsAnalysis of white light FST testing showed statistically significant improvement from Baseline to Year 1 in the LUXTURNA treatment group compared to the control group; The change in visual acuity from Baseline to Year 1 was not significantly different between the LUXTURNA treatment and control groups.
Zynteglo
体外修饰干细胞
β-珠蛋白
罕见病
常规批准
β-地中海贫血
FDA
2019
The primary efficacy endpoint was transfusion independence (TI), defined as weighted average hemoglobin (Hb) ≥ 9 g/dL without RBC transfusions for ≥12 months at any time after ZYNTEGLO infusion.Secondary endpoints included assessment of transfusion reduction, duration of TI, and iron overload and iron chelation parameters.
LYFGENIA
体外修饰干细胞
HbA
罕见病
常规批准
镰状细胞病
FDA
2023
The primary efficacy endpoint was complete resolution of VOEs (VOE-CR) between 6-18 months following LYFGENIA
CASGEVY
体外修饰干细胞
镰状细胞病，地中海贫血
FDA
2023
镰状细胞病(SCD)The primary efficacy outcome was VF12 response, defined as absence of protocoldefined sVOCs for at least 12 consecutive months within the 24-month follow-up period after CASGEVY infusion in Study 121. The key secondary endpoint was proportion of subjects who did not require hospitalization due to sVOCs for at least 12 consecutive months within the 24-month evaluation period (HF12) 地中海贫血The primary endpoint was the proportion of subjects who achieved transfusion independence (TI)12, defined as maintaining a weighted average Hb ≥ 9 g/dL without red blood cell (RBC) transfusions for at least 12 consecutive months any time after CASGEVY infusion during the 24-month followupThe key secondary endpoint was the proportion of subjects who achieved TI6
Waylivra
ASO
罕见病
常规批准
家族性乳糜微粒血症综合征（FCS）
EMA
2019
The primary endpoint was the percentage change in fasting TG from Baseline to the primary analysis time point at the end of Month 3, where the value was defined as the average of Week 12 (Day 78) and Week 13 (Day 85) fasting assessments.Secondary EndpointsThe secondary endpoints were rank prioritized and tested according to position in the hierarchy using asequential closed testing procedure:1. Treatment response rate, where a patient with fasting plasma TG < 750 mg/dL at the primary analysis time point (3 months) was defined as a responder. Only the subset of patients with baseline fasting plasma TG ≥ 750 mg/dL was included in this population2. Percent change from baseline to the 6-month time point in fasting TG3. Percent change from baseline to the 12-month time point in fasting TG4. Average of maximum intensity of patient reported abdominal pain during the treatment period5. Postprandial TG area under the curve (AUC)(0-9h) change from Baseline to on-treatment measures (between Week 13 and Week 19)6. Treatment response rate, where a patient who achieves fasting TG ≥ 40% reduction from Baseline at the primary analysis time point is defined as a responder7. Absolute change from Baseline to the primary analysis time point in fasting TG8. Frequency of composite of episodes of acute pancreatitis and patient reported abdominal pain during the treatment period9. Change from Baseline in hepatic volume as assessed by MRI at Week 52Exploratory endpoints included:• Percent change from baseline in fasting apolipoprotein B-48 (apoB-48) and chylomicron TG as measured in the primary analysis time point• Percent change from baseline in postprandial apoB-48 and chylomicron TG• Percent change from baseline in fasting apoC-III as measured in the primary analysis time point• Percent change from baseline in other fasting lipid measurements, including non-HDL-C, apoB,HDL-C, apoA-1, VLDL-C and LDL-C
Roctavian
AAV
F8
罕见病
附条件上市
血友病A
FDA
2022
The primary endpoint was revised to ABR (all bleeds).The primary objective was to assess the impact of ROCTAVIAN compared to FVIII prophylaxis on the number of bleeding episodesSecondary objectives included the following:• To assess the impact of ROCTAVIAN (compared to FVIII prophylaxis) on the number ofbleeding episodes requiring exogenous FVIII treatment in the EEP (i.e., treated bleeds in the EEP, as defined in the primary objective)• To assess the efficacy of ROCTAVIAN (compared to no treatment) defined as FVIIIactivity, as measured by the CSA at Week 104 following IV infusion of ROCTAVIAN• To assess the impact of ROCTAVIAN (compared to FVIII prophylaxis) on the usage ofexogenous FVIII replacement therapy in the EEP (as defined in the primary objective)• To assess the impact of ROCTAVIAN (compared to FVIII prophylaxis) on health-relatedquality of life (as assessed by the Haemo-QoL-A Total Score and Physical Functioning,Consequences of Bleeding, and Role Functioning domain scores) at Week 104 followingIV infusion of ROCTAVIAN
Hemgenix
AAV
F9
罕见病
附条件上市
血友病B
FDA
2022
Primary Efficacy Variables/Endpoints:Factor IX activity level at six weeks after dosing.Secondary Efficacy Variables/Endpoints:− Endogenous factor IX activity level at Week 6 and Week 52 post AMT-061 dose,− Remaining free of previous continuous routine prophylaxis during 52 weeks following AMT-061 dosing− Total usage of factor IX replacement therapy until 52 weeks following AMT-061 dosing (excluding ad hoc prophylaxis for invasive procedures),− Annualised bleeding rate(ABR) after 52 weeks of AMT-061 dosing (including a further break down of the frequency and percentage of spontaneous, traumatic, and joint bleeding events).Exploratory efficacy endpoints include joint health and QoL scores, correlation between AAV5 neutralizing antibodies titres and factor IX activity levels, and factor IX-protein-to-activity ratio in subjects without residual expression of non-functional factor IX protein.
Tegsedi
ASO
转甲状腺素蛋白（ATTR）
罕见病
常规批准
遗传性转甲状腺素蛋白淀粉样变性ATTR
EMA
2018
co-Primary efficacy endpoint：Changes from Baseline at Week 66 in: Modified Neuropathy Impairment Score +7 Norfolk QoL-DN Total Score Secondary efficacy measures：BMI; mBMI; Components of mNIS+7 (NIS and modified +7 composite scores ); Norfolk QoL-DN questionnaire symptoms domain score (Stage 1 subjects only) and physical functioning/large fiber neuropathy domain score (Stage 2 subjects only); GLS by ECHO; NIS +7 Tertiary efficacy measures：SF-36 questionnaire; Individual components of NIS; Individual components of modified +7; Individual domain scores of Norfolk QoLDN +7 (total score and individual components) Exploratory measures：ECHO parameters (except GLS); NT-proBNP Polyneuropathy Disability score NSC (total score and individual domain scores)
Onpattro
siRNA
转甲状腺素蛋白（ATTR）
罕见病
常规批准
遗传性转甲状腺素蛋白淀粉样变性ATTR
FDA
2018
co-Primary efficacy endpoint：Changes from Baseline at month 18 in: Modified Neuropathy Impairment Score +7 Norfolk QoL-DN Total ScoreSecondary Efficacy EndpointsThe study evaluated the difference between the study arms in the change from baseline in the following secondary efficacy outcome measures at 18 months: Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire; Neurological impairment score (NIS)-weakness (NIS-W) score; Rasch-built Overall Disability Scale (R-ODS) score; Timed 10-meter walk test (10-MWT, gait speed); Modified body mass index (mBMI); Autonomic symptoms questionnaire (Composite Autonomic Symptom Score[COMPASS 31]).
Amvuttra
siRNA
转甲状腺素蛋白（ATTR）
罕见病
常规批准
遗传性转甲状腺素蛋白淀粉样变性ATTR
FDA
2022
co-Primary efficacy endpoint：Changes from Baseline at month 9 in: Modified Neuropathy Impairment Score +7 and Norfolk QoL-DN Total ScoreSecondary and Other EndpointsNote that only 9 months of efficacy data for the HELIOS-A study were included with this application. Therefore, only the first two secondary endpoints at Month 9 for the HELIOS-A study, Norfolk QoL-DN and 10-MWT, were evaluated statistically for this application. The remaining pre-specified Month 18 secondary endpoints (mBMI, R-ODS) were evaluated at Month 9 as exploratory endpoints.The key secondary endpoint for the HELIOS-A study is the change in the Norfolk Quality of LifeDiabetic Neuropathy (Norfolk QOL-DN) score at 9 months. It is a clinically meaningful functional endpoint that is appropriate for use in this study. As discussed in Section 6.1.2, there was an improvement in the Norfolk QOL-DN score in the vutrisiran group, compared to a worsening in the external placebo group.The next secondary endpoint, the change from baseline at Month 9 in the 10-meter walk test (10-MWT), showed maintenance of gait speed in the vutrisiran group compared to mean worsening in the external placebo group at 9 months.Both Month 9 secondary efficacy endpoints for the HELIOS-A study had statistically significant results that support the efficacy of vutrisiran.
Wainua
ASO
转甲状腺素蛋白（ATTR）
罕见病
常规批准
遗传性转甲状腺素蛋白淀粉样变性ATTR
FDA
2023
co-primary endpoints: serum TTR reduction and the mNIS+7 score for the analysis at week 35.The secondary efficacy endpoint at the week 35 interim analysis was the change from baseline in the Norfolk QOL-DN at week 35.
Libmeldy
体外修饰干细胞
芳基硫酸酯酶-A
罕见病
常规批准
异染性脑白质营养不良
EMA
2020
primary endpoint is Gross Motor Function Measure score (GMFM) two years after treatment . co-primary endpoint was the ARSA activity (PBMC and CSF). A significant (≥2 SD) increase in residual ARSA activity measured in the BPBMC at two years as compared to pre-treatment values, was the aimedeffect size. Secondary endpoints included nerve conduction velocity (NCV), brain magnetic resonance imaging (MRI),gross motor function classification (GMFC-MLD, neuropsychological tests, neurological evaluations, survival, engraftment (lentiviral vector transduced cells, vector copy number [VCN]). The study included comparison to a natural history cohort (NHx) and where available untreated siblings.
Skysona
体外修饰干细胞
ABCD1
罕见病
加速批准
脑肾上腺脑白质营养不良
EMA/FDA
2021
Primary efficacy endpoint:Proportion of subjects who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 Visit (i.e. Month 24 MFD-free survival). MFDs were defined as:o loss of communicationo cortical blindnesso tube feedingo total incontinenceo wheelchair dependenceo complete loss of voluntary movementIn addition to experiencing any MFDs or death, the following events were also considered as a failureto meet the primary efficacy endpoint: requirement for rescue cell administration or an allo-HSCT, withdrawal from study, or lost to follow-up by Month 24. Secondary efficacy endpoints included MFD-free survival over time, Overall survival, Proportion of subjects who demonstrated resolution of gadolinium positivity on magnetic resonance imaging (MRI;i.e., GdE-) at Month 24, Time to sustained resolution of gadolinium positivity on MRI (i.e., GdE-). Sustained is defined as gadolinium resolution without a subsequent evaluation indicating
Exondys 51
ASO
DMD
罕见病
加速批准
杜氏肌营养不良症DMD
FDA
2016
Primary Efficacy Endpoint:The primary efficacy endpoint is the change from baseline in percent of dystrophin positive fibers as measured in the muscle biopsy tissue using immunohistochemistry (IHC) at Week 12 for groups 1 and 3a and at Week 24 for groups 2 and 3b.Key Efficacy Endpoints:1. Changes from Baseline in CD3, CD4, and CD8 lymphocyte counts in muscle biopsy tissue at Week 12 for groups 1 and 3a and at Week 24 for groups 2 and 3b.2. Changes from Baseline to Week 24 in 6-Minute Walk Test (6MWT).The following clinical assessments were described as exploratory endpoints in the protocol (Amendment 7, dated 07 January 2012), but are included as key secondary endpoints together with 6MWT in the SAP (dated February 20, 2012):• Timed 4 Step Test.• Maximum voluntary isometric contraction test (MVICT) to measure elbow flexion andextension, knee flexion and extension, and grip strength.• Timed 10-meter run from the North Star Ambulatory Assessment (NSAA).• NSAA total score.
Vyondys53
ASO
DMD
罕见病
加速批准
杜氏肌营养不良症DMD
FDA
2019
primary biological endpoint for Part 2 of the study was the change from Baseline to Part 2 Week 48 in dystrophin protein levels (in muscle biopsy samples) determined by Western blot. Secondary biological endpoints for Part 2 of the study include the change from Baseline to Part 2 Week 48 for the following:• Dystrophin intensity levels determined by immunohistochemistry (IHC)• Percent dystrophin-positive fibers as determined by IHC• Exon 53 skipping determined by measurement and sequence verification of exon 53 skipped mRNA Efficacy and Pharmacodynamics1. 6-minute walk test through Part 2 Week 144; primary efficacy endpoint was change from Baseline to Part 2 Week 1442. Forced vital capacity percent predicted (FVC-p) through Part 2 Week 144; Forced vital capacity percent predicted, maximum inspiratory pressure percent predicted, andmaximum expiratory pressure percent predicted were calculated. These secondaryefficacy endpoints were analyzed as change from Baseline to Part 2 Week 1443. Other endpoints included:• North Star Ambulatory Assessment• Leg Muscle Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy(fat content in lower leg muscle and skeletal muscle edema at the tibialis anterior)• Timed 4-step test• MoviPlate(a tool that measures the ability to produce repeated movements between 2 cylindrical target keys aligned in the sagittal plane.)• Performance Upper Limb• Pinch and Hand Grip• Pediatric Outcomes Data Collection Instrument• Actimetry (optional participation)
Viltepso
ASO
DMD
罕见病
加速批准
杜氏肌营养不良症DMD
FDA
2020
Primary endpoint• Change from baseline in the measurement Dystrophin Protein by Western Blot Analysis at week 25Secondary Endpoints• Induction of dystrophin protein in muscle measured by MS Induction of dystrophin protein in muscle measured by IF-labeled antibody detection on tissue sections• Induction of dystrophin mRNA in muscle measured by RT-PCR• Time function Tests:o Time to Stand (TTSTAND) (measured in seconds),o Time to Climb 4 stairs (TTCLIMB) (measured in seconds),o Time to Run/Walk 10 meters test (TTRW) (measured in seconds),• Six-minute Walk Test (6MWT) (measured in meters);• North Star Ambulatory Assessment (NSAA 17-item test) combined scale• Quantitative measures of strength were measured by CQMS (CINRG Quantitative Muscle System), and included: handgrip, isometric elbow flexion and extension, and knee flexion and extension (measured in pounds of pressure).• Viltolarsen PK on Day 1, week 5 and Week 24
Amondys 45
ASO
DMD
罕见病
加速批准
杜氏肌营养不良症DMD
FDA
2021
The primary efficacy endpoint is: Change from Baseline at Week 96 in 6MWTSecondary efficacy endpoints are: Change from Baseline at Weeks 48 or 96 in the quantity of dystrophin proteinexpression as measured by western blot of biopsied muscle tissue. Change from Baseline at Week 144 (Week 48 of the OL period) in 6MWT Change from Baseline at Weeks 48 or 96 in the intensity of dystrophin expression inbiopsied muscle tissue, as measured by immunohistochemistry (IHC). Ability to rise independently from the floor (without external support) at Week 96 and Week 144, as indicated by a North Star Ambulatory Assessment (NSAA) sub-score of “2” (without modification) or “1” (Gower’s maneuver). Time to loss of ambulation (LOA) from randomization through Week 96 and Week 144. Change from Baseline at Week 96 and Week 144 in:o NSAA total scoreo Forced Vital Capacity (FVC) % predicted
Elevidys
AAV
DMD
罕见病
加速批准
杜氏肌营养不良症DMD
FDA
2023
Primary Efficacy Endpoint for Study 301 Part 1• Change in NSAA Total Score Change from baseline to Week 52Secondary Efficacy Endpoints for Study 301 Part 1• Number of skills gained or improved on the NSAA• Quantity of micro-dystrophin protein at Week 12, as measured by western blot• Change from baseline to Week 52 on Time to Rise• Change from baseline to Week 52 on 100-MWR time• Change from baseline to Week 52 on Time to Ascend 4 Steps• Change from baseline to Week 52 on 10-MWR time• Change from baseline to Week 52 on the Stride Velocity 95th Centile (SV95C)• Change from baseline to Week 52 in PROMIS score in Mobility and Upper Extremity• Incidence of TEAEs• Incidence of SAE• Incidence of adverse events of special interest• Clinically significant changes in vital signs and findings on physical examination• Clinically significant changes in safety laboratory assessments, electrocardiogram,and echocardiogram
Qalsody
SOD1
罕见病
加速批准
肌萎缩侧索硬化（ALS）
FDA
2023
The primary efficacy endpoint for Study 101C :the change from baseline to Week 28 (Day 197) in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS. Each item is scored from 0 to 4, with higher scores representing greater functional abilities. The ALSFRS-R total score ranges from 0 (maximum disability) to 48 (no disability). The ALSFRS-R is an acceptable primary endpoint that is considered clinically meaningful to patientsKey Secondary Efficacy Endpoints for Study 101C:1.Change from baseline to Week 28 (Day 197) in slow vital capacity (SVC): The SVC measures the volume of air expired from the lungs in an unforced manner and is an acceptable endpoint measuring respiratory function in ALS. A decline in respiratory function is a direct result of the pathophysiology of ALS. 2.Change from baseline to Week 28 (Day 197) in handheld dynamometry (HHD) megascore to assess muscle strength, as measured by the HHD device: HHD is a quantitative measure of strength and is an acceptable endpoint in ALS. Because loss of strength is a hallmark of disease progression in ALS, a valid measurement of muscle strength may be an appropriate endpoint for treatments intended to increase or preserve muscle strength.3.Time to death or permanent ventilation (≥22 h of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days)4.Time to death
Spinraza
ASO
SMN2
罕见病
加速批准
脊髓性肌萎缩症SMN
FDA
2016
Primary efficacy endpoints of the study were as follows:• Proportion of motor milestone responders (Section 2 of the Hammersmith Infant Neurological Examination [HINE])• Time to death or permanent ventilation (≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event OR tracheostomy).Motor milestones were assessed as part of the neurological examination conducted by the neurologist at the study centre using Section 2 of the 3-part HINE. The assessments were performed at Screening, Day 64 predose, Day 183 predose, Day 302 predose, and Day 394. The subject’s ventilator or BiPAP use (number of hours/day) was recorded daily by the caregivers using a daily ventilator use diary for the duration of the study. This information was obtained during study visits and weekly telephone contacts.Secondary efficacy endpoints of the study were as follows:• Proportion of Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease (CHOP INTEND) responders.• Survival rate.• Percent of subjects not requiring permanent ventilation.• Proportion of compound muscle action potential (CMAP) responders.• Time to death or permanent ventilation in the subgroups of subjects below the study median disease duration.• Time to death or permanent ventilation in the subgroups of subjects above the study median disease duration.
Zolgensma
AAV
SMN1
罕见病
常规批准
脊髓性肌萎缩症
FDA
2019
co-primary endpoints:- survival at 14 months of age and- the proportion of patients who achieved functional independent sitting for ≥30 seconds at the 18 months of age study visit. Co-Secondary• The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate thin liquids (as demonstrated through a formal swallowing test) and to maintain weight (> third percentile based on World Health Organization [WHO] Child Growth Standards for age and gender) without need of gastrostomy or other mechanical or nonoral nutritional support at 18 months of age• The proportion of patients who are independent of ventilatory support, defined asrequiring no daily ventilator support/usage at 18 months of age, excluding acutereversible illness and perioperative ventilation, as defined above through assessment of actual usage data captured from the device (Phillips Trilogy)
