Clinical

NurOwn® in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or motor neuron disease, is a progressive neurodegenerative disease that afflicts tens of thousands of patients around the world. As motor neurons die, patients become progressively weaker land lose motor function; when the muscles controlling breathing are affected, patients will require ventilator support. For most patients, the disease leads to death within 3 to 5 years of diagnosis. There is currently no available treatment to stop or reverse its progressive course.

Our ALS program is currently testing MSC-NTF cells ALS patients after we showed the cells can have a benefit in the human DOD1 transgenic mouse model of ALS. 

We have completed two single-arm studies in ALS patients, conducted in Israel at Hadassah Medical Center, and have also completed a 48 patient randomized, double-blind, placebo-controlled phase 2 trial at three prestigious medical centers in the United States at Mayo clinic, MGH (Massachusetts General Hospital) and UMass (University of Massachusetts).

Location

Design

n

Status

Phase 1/ 2 Israel Single-arm, single dose in IM and IT cohorts 12 Completed
Phase 2a Israel Single-arm, single ascending dose, IM and IT 14 Completed
Phase 2 United States Randomized, placebo-controlled, double-blind, single dose IM and IT 48 Completed
Phase 2 Israel Single arm, repeat doses, IT only Up to 24 Submitted to Israel Ministry of Health (MoH)

Phase 1/ 2 Study from Hadassah

A total 12 ALS patients enrolled in two cohorts of six subjects each, in this phase 1/ 2 study conducted at Hadassah Medical Center. One cohort consisted of late-stage patients who received cells via IT administration, and the second cohort consisted of earlier-stage subjects who received IM administration. No serious adverse events were associated with MSC-NTF cells administration. The vast majority of the observed adverse events were transient and low-grade. Subjects in the IT cohort, but not the IM cohort, showed a substantial improvement in the rate of progression of the ALSFRS-R score for the six months after treatment compared to the three month run-in period. Subjects in both cohorts had a lower progression rate in the post-treatment period compared with the run-in period assessed by forced vital capacity (FVC), a measure of lung function.

Conclusion

This study showed IT and IM administration of MSC-NTF cells to be safe and well-tolerated, and showed signs of clinical impact.  In particular, subjects who received IT administration had improvements in the rate of disease progression for the six months following treatment for both ALSFRS-R and FVC, and the magnitude of benefit was clinically meaningful.

Results from this study were presented at the 2013 American Academy of Neurology.

Phase 2a Study from Hadassah

The second Israeli study was a single-arm dose escalation phase 2a trial, also conducted at Hadassah Medical Center. A total 14 early-stage ALS patients enrolled in three dosing cohorts low, mid and high dose), and received a single administration of MSC-NTF cells both IT and IM. No serious adverse events were associated with administration of MSC-NTFs and as in the phase 1/ 2 trial, the vast majority of the observed adverse events were of grade I-II and transient. Subjects in this study also showed a substantial improvement in the rate of progression of the ALSFRS-R score and FVC for the six months after treatment compared to the three month run-in period

Conclusion

This study showed simultaneous IT and IM administration of MSC-NTF cells to be safe and well-tolerated, with subjects receiving IT doses as high as 140 million cells and IM doses of 48 million cells. Subjects in this study experienced clinically meaningful improvements in the rate of disease progression for the six months following treatment for both ALSFRS-R and FVC.

Results from this study were presented at the 2015 American Academy of Neurology.

Pooled Analysis of Both Studies

From the onset, it was clear that the systematic results would be seen with IT. This piece-wise linear regression model revealed a statistically significant improvement in the rate of FVC progression (p=0.036, n=15) and a nearly significant improvement in the rate of ALSFRS-R progression (p=0.052, n=15) for those with complete follow-up.

Measure

Baseline

Change per Month (slope)

% Improvement

Run-in

3 months

6 months

3 months

6 months

ALSFRS-R
Phase 1/2 (IT, n=6) 24.8 -1.56 -0.98 -0.28 37% 82%
Phase 2a (IT+IM, n=14) 39.9 -1.41 -0.78 -0.60 45% 57%
Pooled, per protocol (n=15) -1.2 -0.6 (p=0.052) 50%
FVC (% predicted)
Phase 1/2 (IT, n=6) 59.5% -3.48% -4.35% -2.30% -25% 44%
Phase 2a (IT+IM, n=14) 87.3% -2.60% -0.70% -0.86% 73% 67%
Pooled, per protocol (n=15) -5.2% -1.2% (p=0.036) 77%

U.S. Clinical Trial in Amyotrophic Lateral Sclerosis

Our first US study was a multi-center, randomized, double-blind, placebo-controlled clinical trial in ALS that enrolled 48 early-stage ALS patients, randomized 3:1 to receive treatment versus placebo. In October of 2015, our last patient was treated. In November 2015, the study Data Safety Monitoring Board (DSMB) conducted a planned comprehensive interim analysis involving data from all sites and had no concerns regarding participant safety to date and approved the study to go forward without modification. The top line results from this study were released on July 18, 2016 .