A Phase 2a Study of TPN-101 in Patients with C9ORF72 ALS/FTD (Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia)

1. Males or females * 18 years of age at the time of informed consent
2. Have documentation of a clinical genetic test demonstrating the presence of
a confirmed repeat expansion in the C9orf72 gene from a CLIA certified
laboratory
3. Body weight range of * 41 kg (90 lbs) to * 118 kg (260 lbs)
4. Score * 18 on the Mini-Mental State Exam (MMSE) at Screening
5. If female, must be postmenopausal (for at least 2 years), surgically
sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy),
or agree to use highly effective methods of contraception from Screening
through Week 52
6. If male, with a partner who is not postmenopausal (for at least 2 years) or
surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or
hysterectomy), the patient must agree that he and his partner will use highly
effective methods of contraception from Screening through Week 52
7. Able to perform all protocol-specified assessments, including
neuropsychological tests; and comply with taking study medication and the study
visit schedule, as judged by the investigator
8. Have a reliable caregiver to accompany the patient to all study visits.
Caregiver must be able to read, understand, and speak local language fluently
to ensure comprehension of informed consent and informant-based assessments of
the patient. Caregiver must also have frequent contact with patient (at least 3
hours per week at one time or at different times) and be willing to monitor the
patient's health and concomitant medications throughout the study
9. Able to understand and provide written informed consent at Screening
10. Agree to allow data sharing across observational longitudinal and
interventional studies using an encrypted global unique identifier (GUID) so
that potential prior or future data on biomarkers and disease progression can
be made accessible to the sponsor
11. Stable doses of all concomitant medications for 1 month prior to Screening
(e.g., edaravone, riluzole, dextromethorphan/quinidine, psychotropic
medications, cognitive enhancers, etc.)

For patients with ALS (with or without FTD):
12. Diagnosis of ALS (probable, possible, laboratory-supported probable or
definite) according to the World Federation of Neurology revised E1 Escorial
criteria
13. Onset of weakness within 3 years prior to Screening
14. SVC * 60% of predicted normal adjusted for sex, age, and height (from the
sitting position)
15. Able to perform reproducible pulmonary function tests
16. ALSFRS-R * 30 at Screening

For patients with FTD:
17. A gradual, progressive decline in behavior, language, or motor function
consistent with C9orf72 hexanucleotide expansion-related syndrome such as
behavioral variant FTD, primary progressive aphasia, or amnestic syndrome
18. CDR plus NACC FTLD global score of 0.5-2.0 at Screening

1. Presence of other significant neurological or psychiatric disorders
including (but not limited to) biomarker confirmed Alzheimer's disease;
dementia with Lewy bodies; prion disease; Parkinson's disease; multiple
sclerosis; a primary or severe psychotic disorder; severe bipolar or unipolar
depression; prior history of suicidal thoughts or behavior that are believed to
represent a current safety risk; seizure; brain tumor or other space-occupying
lesion; history of stroke; or history of severe head injury within the past 20
years
2. History of significant brain abnormality, including, but not limited to,
prior hemorrhage or infarct, cerebral contusion, encephalomalacia, aneurysm,
vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion
(e.g., abscess or brain tumor such as meningioma); symptoms or signs of
elevated intracranial pressure, e.g., symptoms or history of head injury or
abnormal funduscopic exam. If there is history or evidence on neurologic exam
suggesting possible subdural hematoma (SDH), patients should be fully
evaluated, including magnetic resonance imaging (MRI) if indicated, to exclude
significant, new SDH
3. Active alcohol, drug abuse or substance abuse, or any other reason that
makes it unlikely that the patient will comply with study procedures in the
opinion of the investigator
4. Clinically significant findings on Screening laboratory testing, physical
examination or vital signs that are not specific to ALS/FTD that could
interfere with the conduct of the study, the interpretation of the data, or
increase patient risk
5. Clinically significant intercurrent illness or medical condition (e.g.,
hematological, endocrine, cardiovascular, renal, hepatic, or gastrointestinal
disease) that would jeopardize the safety of the patient, limit participation,
or compromise the interpretation of the data derived from the patient
6. History of HIV infection, hepatitis B or hepatitis C, or any active infection
7. History of cancer within 5 years of Screening, with the exception of fully
excised non-melanoma skin cancers
8. Receipt of an investigational agent within 30 days or 5 half-lives prior to
Screening, whichever is longer
9. Prior treatment with any monoclonal antibody within 6 months of Screening
10. Receipt of systemic corticosteroids within 30 days prior to Screening
11. Any vaccination within 30 days prior to study drug administration
12. Has smoked or used tobacco products within 6 months prior to study drug
administration
13. Hypertension, defined as confirmed systolic blood pressure (SBP) > 170
mmHg and/or diastolic blood pressure (DBP) > 100 mmHg at Screening
14. Hypotension, defined as confirmed SBP < 90 mmHg and/or DBP < 60 mmHg
at Screening
15. Any major surgery within 4 weeks of Screening
16. Females who are pregnant (positive pregnancy test at Screening or prior to
administration of study drug), breastfeeding, or unable or unwilling to use
highly effective methods of contraception throughout the study
17. Contraindication to undergoing a lumbar puncture (LP) including, but not
limited to: inability to tolerate an appropriately flexed position for the time
necessary to perform an LP; international normalized ratio (INR) > 1.4 or
other coagulopathy; platelet count of < 120,000/*L; infection at the desired
LP site; taking anti-platelet or anti-coagulant medication within 30 days of
Screening (Note: aspirin is permitted); severe degenerative arthritis of the
lumbar spine; suspected non-communicating hydrocephalus or intracranial mass;
prior history of spinal mass or trauma
18. Allergy to any of the components of the study drug
19. History of any significant drug allergy (such as anaphylaxis or
hepatotoxicity)
20. Physical and laboratory test findings, including the following:
a. Evidence of organ dysfunction or any clinically significant deviation from
normal in physical examination, vital signs, ECG, or clinical laboratory
determinations beyond what is consistent with the target population
b. Clinically significant abnormality on 12-lead ECG prior to study drug
administration, confirmed by repeat testing
c. Total bilirubin, alanine aminotransferase (ALT), or aspartate
aminotransferase (AST) > 2 × upper limit of normal (ULN), confirmed by
repeat testing
d. Serum creatinine > 168*mol/L (1.9mg/dL), confirmed by repeat testing
e. Hematocrit < 35% for males and < 32% for females, absolute neutrophil
cell count of < 1500/*L
f. Clinically significant abnormal thyroid stimulating hormone (TSH) test
g. Abnormally increased number of white blood cells (> 7 cells/mm3) in the
CSF obtained at the Screening Visit; if there is evidence that the spinal tap
was traumatic, patients with > 7 cells/mm3 must be discussed with the
medical monitor to determine if they may be eligible
h. Hemoglobin A1C >7%, confirmed by repeat testing
i. Positive blood screen for HIV, hepatitis C antibody, or hepatitis B surface
antigen