Clinical Research Update. Spinal Muscular Atrophy Clinical Research Center. Columbia University Department of Neurology

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SMA Research Update – Providing Hope!




ISIS 396443-CS3A - A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients with Infantile-Onset Spinal Muscular Atrophy



**OPEN FOR ENROLLMENT**



Isis Pharmaceuticals, Inc. is conducting a Phase 1/2 clinical study of ISIS-396443 (ISIS-SMNRx) in patients with Infantile-Onset Spinal Muscular Atrophy (SMA Type 1). ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. In previously published results, researchers showed that ISIS-SMNRx produced sustained activity in mouse models of SMA and that adequate drug tissue concentrations were achieved in the spinal cord of non-human primates. The Phase 1/2 study of ISIS-SMNRx is a study designed to assess the safety, tolerability and pharmacokinetic profile (drug levels) of multiple doses of ISIS-SMNRx in patients with Infantile-Onset SMA (SMA Type 1). Approximately 8 infants will be enrolled in the study. The study consists of 2 groups, with 4 subjects in each group. In this study, ISIS-SMNRx will be administered by intrathecal delivery (that is, into the fluid filled space below the end of the spinal cord) 3 times over a period of approximately 3 months. The study will last for approximately 12 months, including appropriate follow-up.

To be considered for eligibility in the study, potential participants must:
  • Be between 21 days and 7 months (210 days) of age at screening
  • Birth between 35 and 42 weeks
  • Have a documented homozygous SMN1 gene mutation/ deletion. An infant can have any number of SMN2 gene copies
  • Not have a history of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments
  • Be able to follow all study procedures
  • Meet additional study-specific criteria
The study is being conducted in multiple centers within the United States. The Columbia University Medical Center is participating in the study to provide this opportunity to patients with SMA Type 1 in the United States.

If you would like more information about this study please contact Claudia Chiriboga, MD, MPH or Rosángel Cruz, MA, BS, at (212) 305-1336.



Spinal Muscular Atrophy (SMA) Biomarkers in the Immediate Postnatal Period of Development

Principal Investigator, Claudia Chiriboga, MD, MPH

**OPEN FOR ENROLLMENT**



Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants. Preclinical evidence strongly suggests that effective therapy must be delivered as early as possible to prevent disease progression. The Columbia University SMA Clinical Research Center is partnering with the NeuroNEXT clinical trial network is to conduct this study. The primary objective of this study is to identify biomarkers to better understand the disease and how it manifests and aid researchers to most effectively design and execute SMA clinical trials in infants.

What is a Biomarker?


A Biomarker is any laboratory measurement that reflects the activity or stage of a disease process. For example, cholesterol levels reflect heart disease risk. Biomarkers are being used effectively for cancer, diabetes, and heart disease to help determine whether new drugs are helping patients, and to better understand the diseases. The goal of the SMA Biomarker Project is to identify laboratory measurements that can be used in future SMA clinical trials.

What is involved in this study and how do I know if I qualify?


The study involves collecting information about your child’s development, immediately after birth up to 24 months of age. Children enrolled in this study will be required to come to the clinic every 3 months (or a maximum of 7 visits) and will undergo a number of procedures at each visit; these include, vital signs and motor function assessments, clinical exam, electrical impedance myography (EIM), compound motor action potential (CMAP) and blood draws. Infants 6 months of age and younger who have been diagnosed with Spinal Muscular Atrophy as well as, healthy infants are encouraged to participate.

To be considered for eligibility, infants with SMA must meet the following criteria:
  • Birth between 36 and 42 weeks inclusive of gestation
  • be between 0-6 months of age at the time of enrollment
  • have a documented homozygous SMN1 gene mutation/ deletion. An infant can have any number of SMN2 gene copies
  • be able to follow all study procedures
  • be healthy
  • not require breathing support for over 12 hours
  • not have a history of tracheostomy tubes and ventilator-dependency
  • Parents or guardians must be able to sign an informed consent prior to any study procedure being performed
Healthy control infants who meet the following criteria will be enrolled:
  • Birth between 36 and 42 weeks inclusive of gestation
  • Siblings of children with SMA must have had prior SMA genetic testing completed con-firming the infant is a healthy control
  • Principal investigator feels the family/infant is able and willing to comply with study procedures
  • Parent or guardian able to give informed consent
This study is being conducted by the SMA Clinical Research Center in collaboration with Ohio State University and fifteen other centers nationwide. If you would like more information about this study please contact Nicole Holuba, MSN at nh2282@columbia.edu or 212-304-5205.

To learn more about this study and its potential impact on the advancement of the understanding of SMA:




4-Aminopyridine (4-AP) in SMA: A Pilot Study in Ambulatory Patients


Principal Investigator, Claudia Chiriboga, MD, MPH

**OPEN FOR ENROLLMENT**



Fatigue is a common symptom in SMA with a resultant impact on physical function and quality of life; the precise mechanisms of fatigue in SMA are yet not understood. Currently, there is no treatment for SMA. There is evidence that 4-AP improves function in SMA animal models. Furthermore, in patients with multiple sclerosis, 4-AP was found to improve walking ability and diminish fatigue. This study is being conducted to see if 4-AP improves walking ability and endurance in adult patients with SMA Type 3. The purpose of the study is to determine whether treatment with 4-AP is associated with an increase in walking speed and endurance compared to placebo and whether the duration of treatment affects outcome.

The Columbia University SMA Clinical Research Center is currently recruiting SMA Type 3 individuals who are 18 years or older, have genetically confirmed SMA, and are able to walk without assistance for at least 25 meters.

The study will last for 21 weeks, and will require that subjects come for visits at the Columbia SMA Clinical Research Center 6 times. Each visit will consist of a series of tests that include motor function measures, a physical exam, questionnaires, and a test where the subject is asked to walk as far as they can in six minutes. Additionally at two visits needle EMGs will be performed. The main goal of the study is to see if individuals who take 4-AP (Ampyra) have improved walking speed and endurance.

To be considered for eligibility in the study, potential participants must:
  • be 18 years of age or older
  • have genetically confirmed SMA 3 (homozygous absence of SMN1 exon 7)
  • be free of major orthopedic deformities (i.e. scoliosis, contractures)
  • normal Cystatin C clearance (> 80 ml/min)
  • live within 75 miles of study site or deemed by staff able to reliably travel to CUMC for study visits
  • be able to provide informed consent
  • not have a history of seizures
  • meet additional study-specific criteria
If you are interested in participating, please contact Jonathan Marra at jdm2132@columbia.edu or 212-342-3022 for more information.



Biomaterial Collection and Banking for Translational Research in Spinal Muscular Atrophy


Principal Investigator: Wendy Chung, MD, PhD

**OPEN FOR ENROLLMENT**



SMA is an often severely disabling neuromuscular disease primarily affecting children. It causes muscle atrophy and weakness as well as frequent pulmonary, nutritional, and orthopedic complications. Many children with SMA eventually undergo surgery, most commonly for placement of feeding tubes and for scoliosis repair. These surgical procedures provide an opportunity to collect and bank small amounts of muscle and skin tissue to be used for research in SMA and related disorders. Similarly, children with disease other than SMA may undergo similar surgical procedures, providing an opportunity to collect muscle and skin samples from non-SMA control subjects. SMA is caused by a defect in the "Survival of Motor Neurons" (SMN1) gene. Researchers are hopeful to find a cure, because nature has provided humans with a second gene, almost a copy of the SMN1 gene. Normally, the second gene does not contribute much, but researchers think that its function can be increased by medications.

To learn more about the steps that lead to muscle weakness in SMA, skin and muscle samples are helpful to researchers working in the laboratory. This research aims to better understand the disease and to find and test potential treatments first in the laboratory and then ultimately in patients through clinical trials. Collecting samples from SMA and control subjects who undergo surgeries for clinical reasons provides an opportunity to gather important material for SMA research without more than minimal additional risk for the research participant undergoing surgery.

If you are interested in participating, please contact Nicole Holuba LaMarca at nh2282@columbia.edu or 212-305-5205



Ongoing Clinical Trials



ISIS 396443 - CS2: An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients with Spinal Muscular Atrophy.


Principal Investigator, Claudia Chiriboga, MD, MPH

**Ongoing/Closed for Enrollment**



Isis Pharmaceuticals, Inc. is conducting a Phase 1/2a clinical study of ISIS-396443 (ISIS-SMNRx) in patients with Spinal Muscular Atrophy (SMA). ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. In previously published results, researchers showed that ISIS-SMNRx produced sustained activity in mouse models of SMA and that adequate drug tissue concentrations were achieved in the spinal cord of non-human primates. The Phase 1/2a study of ISIS-SMNRx is a dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile (drug levels) of ISIS-SMNRx in patients with SMA. Approximately 24 children will be enrolled in the study - the study consists of 3 groups of patients with 8 patients in each group. In this study, ISIS-SMNRx will be administered by intrathecal delivery 2 or 3 times (into the cerebral spinal fluid) through an injection in the lower back into the fluid-filled space below the bottom of the spinal cord. The study will last for approximately 9 months.

To be considered for eligibility in the study, patients must:
  • be between 2 and 15 years of age
  • have genetic documentation of 5q SMA (homozygous gene deletion or mutation) and symptoms of SMA
  • not be required to use ventilator support
  • not be required to have a have a gastric feeding tube (where the majority of feeds are given by this route)
  • not have been hospitalized for surgery or a pulmonary event within the past 2 months or planned during the study
  • meet additional study-specific criteria
The study is being conducted in multiple centers within the United States. The Columbia University Medical Center is participating in the study to provide this opportunity to patients with SMA in the United States. If you would like more information about this study please contact Claudia Chiriboga, MD, MPh or Nicole Holuba LaMarca, DNP, MSN at (212) 304-5205.



ISIS 396443 – CS1: An Open-label, Escalating Dose Study to Assess the Safety, Tolerability and Dose-range Finding of a Single Intrathecal Dose of ISIS 396443 in Patients with Spinal Muscular Atrophy



**Completed/Closed for Enrollment**



Isis Pharmaceuticals, Inc. is conducting a Phase 1 clinical study of ISIS-396443 (ISIS-SMNRx) in patients with Spinal Muscular Atrophy (SMA). ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. In previously published results, researchers showed that ISIS-SMNRx produced sustained activity in mouse models of SMA and that adequate drug tissue concentrations were achieved in the spinal cord of non-human primates.

The Phase 1 study of ISIS-SMNRx is a dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile (drug levels) of ISIS-SMNRx in patients with SMA. Approximately 24 children will be enrolled in the study - the study consists of 4 groups of patients with 6 patients in each group. In this study, ISIS- SMNRx will be administered by intrathecal delivery (into the cerebral spinal fluid) through an injection in the lower back into the fluid-filled space below the bottom of the spinal cord.

To be considered for eligibility in the study, patients must:
  • be between 2 and 14 years of age
  • have a documented homozygous SMN1 gene deletion and symptoms of SMA
  • not have a gastric feeding tube
  • not be required to use ventilator support
  • not have been hospitalized for surgery or a pulmonary event within the past 2 months
  • meet additional study-specific criteria
The study is being conducted in multiple centers within the United States. The Columbia University Medical Center is participating in the study to provide this opportunity to patients with SMA in the New York tri-state region. If you would like more information about this study, please contact Jackie Montes at 212-342-5767 or jm598@columbia.edu.



Randomized, Controlled Clinical Trial of Exercise in Patients with Spinal Muscular Atrophy (SMA)


Principal Investigator: Darryl C. De Vivo, MD

**Ongoing/Closed for Enrollment**



The Columbia University SMA Clinical Research Center plans to recruit SMA Type 3 subjects to participate in a randomized trial of the effects of cardiovascular and strengthening exercising on people with SMA. Individuals who qualify for this study must be between the ages of 8 and 50, have genetically confirmed SMA, and be able to walk independently for at least 25 meters.

The study will last for 18 months, and will require that subjects come for visits at the Columbia SMA Clinical Research Center every 3 months. Each visit will consist of a series of tests that include motor function measures, a physical exam, questionnaires, an exercise capacity test which involves riding a stationary bicycle, and a test where the subject is asked to walk as far as they can in six minutes.

During the study subjects will be asked to closely follow a specific training regimen at some points and at other points they may be asked to exercise in the same manner they do normally. The exercises they will be asked to perform include biking on a stationary cycle and lifting hand weights. The main goal of the study is to see if individuals who participate in the exercise protocol have increases in their strength and/or function. If you are interested in participating, please contact Jackie Montes at 212-342-5767 or jm598@columbia.edu.



In-Home Pulmonary and Motor Function Monitoring in Spinal Muscular Atrophy


**Completed/Closed for Enrollment**



The purpose of this research study is to evaluate outcome measures for future clinical trials in patients with Spinal Muscular Atrophy (SMA) and to determine the feasibility, safety, and acceptability of in-home pulmonary and motor function monitoring in children with SMA. Please contact the Study Coordinator, Jonathan Marra at jdm2132@columbia.edu or 212-342-3022 for more information.



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