Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study of Autologous MSC-NTF Cells in Patients With ALS (NurOwn)

• Change in Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALS-FRS) slopes from the pre-transplantation period to the post-transplantation period between the treatment and placebo groups through 24 weeks post-transplantation. [ Time Frame: At all study visits: Visit 1 through visit 10 ]
• Change in SVC slopes from the pre-transplantation period to the post-transplantation period between the treatment and placebo groups through 24 weeks post-transplantation [ Time Frame: Visits 1,2,3,5,6,7,8,9,10 ]

• Change in Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALS-FRS) slopes from the pre-transplantation period to the post-transplantation period between the treatment and placebo groups through 24 weeks post-transplantation. [ Time Frame: At all study visits: Visit 1 through visit 10 ]
• Change in SVC slopes from the pre-transplantation period to the post-transplantation period between the treatment and placebo groups through 24 weeks post-transplantation [ Time Frame: All visits (1 through 10) ]

This is a multi-center, randomized, double blind, placebo controlled study to evaluate the safety and efficacy of autologous (self) transplantation of Neurotrophic factors-secreting Mesenchymal Stromal Cells (MSC-NTF, NurOwn™) in patients with ALS .

MSC-NTF cells are a novel cell-therapeutic approach which is expected to effectively deliver Neurotrophic factors, which are potent survival factors for neurons, directly to the site of damage.

The MSC-NTF cell therapy (NurOwn™) is based on transplantation of autologous bone marrow derived mesenchymal stromal cells (MSC), which are enriched from the patients' own bone marrow, propagated ex vivo and induced to secrete NTFs. The autologous MSC-NTF cells are back-transplanted into the ALS patient into the sites of damage, the spinal cord and the muscles.

NTFs are potent survival factors for embryonic, neonatal, and adult neurons and are considered potential therapeutic candidates for ALS. Delivery of appropriate NTFs to the immediate environment of afflicted neurons in ALS patients is expected to improve their survival and thus slow down disease progression and alleviate symptoms.

Previous open-label clinical trials have shown that MSC-NTF cells treatment was well tolerated and appears to be generally safe. Some initials indications of clinical benefit were also observed in some patients.

This multi-center, randomized, double blind, placebo controlled study will evaluate the safety and efficacy of a single combined intramuscular and intrathecal administration of MSC-NTF cells in early-stage ALS patients. Patients will be followed for approximately three months before transplantation with their autologous MSC-NTF cells or placebo. During this period of time, patient bone-marrow will be harvested and mesenchymal stromal cells will be isolated and expanded. Following treatment patients will be followed for a total of six months at monthly visits.

• Biological: Autologous MSC-NTF cells
  Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration
  Other Name: NurOwn
• Biological: Placebo
  Excipient administration by combined intramuscular and intrathecal administration

• Active Comparator: Autologous MSC-NTF cells
  Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration
  Intervention: Biological: Autologous MSC-NTF cells
• Placebo Comparator: Excipient
  Combined intramuscular and intrathecal placebo administration
  Intervention: Biological: Placebo

Inclusion Criteria

1. Males and females ages 18 to 75 years old, inclusive.
2. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria.
3. Disease onset, as defined by first reported occurrence of symptomatic weakness, spasticity, or bulbar symptoms, of more than 12 months and less than or equal to 24 months.
4. Current disease symptoms must include limb weakness.
5. ALSFRS-R ≥30 at the Screening Visit.
6. Upright slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at the Screening Visit.
7. Subjects must be taking a stable dose of riluzole for at least 30 days prior to enrolment or not be on riluzole, and not have been on it for at least 30 days prior to enrolment (riluzole-naïve subjects are permitted in the study).
8. Capable of providing informed consent and willing and able to follow study procedures, including willingness to undergo lumbar puncture.
9. Geographic accessibility to the study site and willingness and ability to comply with follow-up.
10. Women of child-bearing potential must agree not to become pregnant for the duration of the study. Women must be willing to consistently use two forms of contraceptive therapy throughout the course of the trial, and undergo a pregnancy test one week before bone marrow aspiration. Men must be willing to consistently use two forms of contraceptive if their partners are of child-bearing age.
11. Citizen or permanent resident of the United States.

Exclusion Criteria:

1. Prior stem cell therapy of any kind.
2. Inability to lie flat for the duration of intrathecal cell transplantation and/or bone marrow biopsy, or inability to tolerate study procedures for any other reason.
3. History of autoimmune disease (excluding thyroid disease) myelodysplastic or myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip fracture, or severe scoliosis.
4. Any unstable clinically significant medical condition other than ALS (e.g., within six months of baseline, had myocardial infarction, angina pectoris, and/or congestive heart failure), treatment with anticoagulants that, in the opinion of the investigator, would compromise the safety of patients.
5. Any history of malignancy including any malignancy affecting the central nervous system and melanoma, within the previous 5 years, with the exception of localized skin cancers (with no evidence of metastasis, significant invasion, or re-occurrence within three years of baseline).
6. Serum AST or ALT value >3.0 times the upper normal limit.
7. Serum creatinine value >2.0 times the upper normal limit.
8. Positive test for Hepatitis B, Hepatitis C, HIV.
9. Current use of immunosuppressant medication or use of such medication within 4 weeks of Screening visit (Visit 1).
10. Any history of acquired or inherited immune deficiency syndrome.
11. Exposure to any other experimental agent (off-label use or investigational) or participation in a clinical trial within 30 days prior to Screening Visit (Visit 1).
12. Use of non-invasive ventilation (NIV), diaphragm pacing system or invasive ventilation (tracheostomy).
13. Any history of either substance abuse within the past year, or unstable psychiatric disease according to PI judgment.
14. Placement or usage of feeding tube.
15. Pregnant women or women currently breastfeeding.