An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS) (VALOR (Part C))

• ClinicalTrials.gov Identifier: NCT02623699
• Recruitment Status: Completed
• First Posted: December 8, 2015
• Results First Posted: July 28, 2023
• Last Update Posted: July 28, 2023
• Sponsor: Biogen
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Biogen

Study Description

Brief Summary:

The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of tofersen in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation.

The secondary objective of Parts A and B of this study is to evaluate the effects of tofersen on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of tofersen.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Tofersen; Drug: Placebo	Phase 3

Detailed Description:

This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of tofersen. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of study and Part C is the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3.

The study completed on 16 Jul 2021. In total, the study enrolled 176 participants, of which 108 enrolled in Part C.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 176 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
• Actual Study Start Date: January 20, 2016
• Actual Primary Completion Date: July 16, 2021
• Actual Study Completion Date: July 16, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Part A-SAD: Combined Placebo; Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Part A-SAD: Cohort 1: Tofersen 10 mg; Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part A-SAD: Cohort 2: Tofersen 20 mg; Participants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part A-SAD: Cohort 3: Tofersen 40 mg; Participants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part A-SAD: Cohort 4: Tofersen 60 mg; Participants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Placebo Comparator: Part B-MAD: Combined Placebo; Participants will be administered tofersen-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Part B-MAD: Cohort 5: Tofersen 20 mg; Participants will be administered tofersen 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part B-MAD: Cohort 6: Tofersen 40 mg; Participants will be administered tofersen 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part B-MAD: Cohort 7: Tofersen 60 mg; Participants will be administered tofersen 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 6.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: Part B-MAD: Cohort 8: Tofersen 100 mg; Participants will be administered tofersen 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Placebo Comparator: Part C-Pivotal: Placebo; Participants will be administered tofersen-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Part C-Pivotal: Tofersen 100 mg; Participants will be administered tofersen 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY

Outcome Measures

Primary Outcome Measures :

1. Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A: First dose up to Day 63; Part B: First dose up to Day 289 ]
   An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.
2. Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Part A: Up to Day 57; Part B: Up to Day 169 ]
   Clinical laboratory assessments included hematology, chemistry, and urinalysis.
3. Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Part A: Up to Day 57; Part B: Up to Day 169 ]
   The criteria for clinically significant vital sign abnormalities include: Temperature: >38 degree Celsius (°C) or an increase from baseline of ≥1°C; Pulse: >120 beats per minute (bpm) or an increase from baseline of >20 bpm, <50 bpm or a decrease from baseline of >20 bpm; Systolic blood pressure (BP): >180 mmHg or an increase from baseline of >40 mmHg, <90 mmHg or a decrease from baseline of >30 mmHg; Diastolic BP: >105 mmHg or an increase from baseline of >30 mmHg, <50 mmHg or a decrease from baseline of >20 mmHg.
4. Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Part A: Up to Day 57; Part B: Up to Day 169 ]
   Clinically significant physical examination abnormalities included weight decreased.
5. Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Part A: Up to Day 57; Part B: Up to Day 169 ]
   Clinically significant neurological examination abnormalities included hyporeflexia.
6. Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: Part A: Up to Day 57; Part B: Up to Day 169 ]
7. Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) [ Time Frame: Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85 ]
8. Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85 ]
9. Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) [ Time Frame: Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 ]
10. Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 ]
11. Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) [ Time Frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 ]
12. Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 ]
13. Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) [ Time Frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 ]
14. Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 [ Time Frame: Baseline, Week 28 (Day 197) ]
    The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression.

Secondary Outcome Measures :

1. Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline [ Time Frame: Day 85 ]
   Total CSF SOD1 protein ratio to baseline was calculated.
2. Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline [ Time Frame: Week 28 (Day 197) ]
   Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
3. Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline [ Time Frame: Baseline, Day 197 (Week 28) ]
   NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
4. Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 [ Time Frame: Baseline, Week 28 (Day 197) ]
   Vital capacity was measured by means of an SVC test, administered in the upright position.
5. Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 [ Time Frame: Baseline, Week 28 (Day 197) ]
   Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength.
6. Part C: Time to Death or Permanent Ventilation [ Time Frame: Baseline up to Week 28 (Day 197) ]
   Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days).
7. Part C: Time to Death [ Time Frame: Baseline up to Week 28 (Day 197) ]
8. Part C: Number of Participants Experiencing AEs and SAEs [ Time Frame: First dose up to Day 236 ]
   An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria: Part A and B

• Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
• A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator.
• If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Key Exclusion Criteria: Part A and B

• History of or positive test result for human immunodeficiency virus.
• History of, or positive test result at Screening, for hepatitis C virus antibody.
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study.
• Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed.
• Current enrollment in any other interventional study.
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

Key Inclusion Criteria: Part C

• Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
• If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
• Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Key Exclusion Criteria: Part C

• History of or positive test result for human immunodeficiency virus.
• Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention).
• Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
• Current enrollment in any other interventional study.
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine.
• Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

United States, Arizona

Barrow Neurological Institute

Phoenix, Arizona, United States, 85013

United States, California

University of California San Diego Medical Center

La Jolla, California, United States, 92093

California Pacific Medical Center

San Francisco, California, United States, 94115

United States, Florida

Mayo Clinic in Florida

Jacksonville, Florida, United States, 32224

University of Miami School of Medicine

Miami, Florida, United States, 33136

Bioclinica Research

Orlando, Florida, United States, 32806

United States, Georgia

Emory University Hospital

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States, 60611

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, Minnesota

Mayo Clinic - Rochester

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Nebraska

Neurology Associates, P.C.

Lincoln, Nebraska, United States, 68506

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, Ohio

The Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44106

United States, Oregon

Providence ALS Center

Portland, Oregon, United States, 97213

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company

Knoxville, Tennessee, United States, 37920

United States, Texas

Methodist Neurological Institute

Houston, Texas, United States, 77030

Australia, New South Wales

Westmead Hospital

Westmead, New South Wales, Australia, 2145

Belgium

UZ Leuven

Leuven, Belgium, 3000

Canada, Alberta

University of Calgary - Health Sciences Centre

Calgary, Alberta, Canada, T2N 1N4

Research Site

Edmonton, Alberta, Canada, T6G 2G3

Canada, Ontario

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada, M4N 3M5

Canada, Quebec

Montreal Neurological Institute

Montreal, Quebec, Canada, H3A 2B4

Denmark

Bispebjerg Hospital

Copenhagen, Denmark, 2400

France

Hopital Pitie Salpetriere

Paris, France, 75651

Germany

University of Ulm

Ulm, Baden Wuerttemberg, Germany, 89081

Italy

ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin

Torino, Italy, 10126

Japan

The University of Tokyo Hospital

Bunkyo-Ku, Japan

Research Site

Fukuoka-shi, Japan

Research Site

Kagoshima City, Japan

Research Site

Shinjuku-ku, Japan

Research Site

Suita-Shi, Japan

Korea, Republic of

Research Site

Yangsan-si, Gyeongsangnam-do, Korea, Republic of, 50612

Research Site

Seoul, Korea, Republic of, 04763

Poland

Research Site

Warszawa, Poland, 01684

United Kingdom

Research Site

London, Greater London, United Kingdom, SE5 9RS

Research Site

Sheffield, South Yorkshire, United Kingdom, S10 2HQ

Sponsors and Collaborators

Biogen

Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director; Biogen

  Study Documents (Full-Text)

Documents provided by Biogen:

Study Protocol  [PDF] June 17, 2021

Statistical Analysis Plan  [PDF] August 14, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.

Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02623699
• Other Study ID Numbers: 233AS101; 2015-004098-33 ( EudraCT Number )
• First Posted: December 8, 2015
• Results First Posted: July 28, 2023
• Last Update Posted: July 28, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
• URL: https://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Biogen:

IONIS-SOD1Rx; SOD1; ALS

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases