Neuralstem Announces Topline Results Of Phase II ALS Trial


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GERMANTOWN, Md., March 12, 2015 /PRNewswire/ -- Neuralstem, Inc. (NYSE MKT: CUR) announced top line data from the Phase II trial of NSI-566 spinal cord-derived neural stem cells under development for the treatment of amyotrophic lateral sclerosis (ALS). The study met primary safety endpoints. The maximum tolerated dose of 16 million transplanted cells and the surgery was well tolerated.

Secondary efficacy endpoints at nine months post-surgery indicate a 47% response rate to the stem cell treatment, as measured by either near-zero slope of decline or positive slope of ALSFRS score in seven out of 15 patients and by either a near-zero decline, or positive strengthening, of grip strength in seven out of 15 patients. Grip strength is an indicator of direct muscle strength of the lower arm. ALSFRS is a standard clinical test used to evaluate the functional status of ALS patients. The average ALSFRS score for responders at 9 months after treatment was 37. Non-responders scored an average of 14. These scores represent 93%, versus 35%, of the baseline score retained, respectively, by the responders versus non-responders at 9 months, which is a statistically significant difference. As measured by an average slope of decline of ALSFRS, responders' disease progression was -0.007 point per day, while non-responders' disease progression was -0.1 per day, which was again statistically significant. Lung function as measured by Seated Vital Capacity shows that responder patients remained within 94% of their starting scores, versus 71% for non-responder patients. The trial met its primary safety endpoints. Both the surgery and cells were well-tolerated, with one patient experiencing a surgical serious adverse event.

"In this study, cervical intervention was both safe and well-tolerated with up to 8 million cells in 20 bilateral injections," said Karl Johe, PhD, Neuralstem Chief Scientific Officer. "The study also demonstrated biological activity of the cells and stabilization of disease progression in a subset of patients. As in the first trial, there were both responders and non-responders within the same cohort, from patients whose general pre-surgical presentation is fairly similar. However, we believe that through the individual muscle group measurements, we may now be able to differentiate the responders from the non-responders.

"Our therapy involves transplanting NSI-566 cells directly into specific segments of the cord where the cells integrate into the host motor neurons. The cells surround, protect and nurture the patient's remaining motor neurons in those various cord segments. The approximate strength of those remaining motor neuron pools can be measured indirectly through muscle testing of the appropriate areas, such as in the grip strength tests. We believe these types of endpoints, measuring muscle strength, will allow us to effectively predict patients that will respond to treatment, adding a sensitive measure of the therapeutic effects after treatment. Testing this hypothesis will be one of the primary goals of our next trial." The full data is being compiled into a manuscript for publication.

"We believe the top-line data are encouraging," said Eva Feldman MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System, and an unpaid consultant to Neuralstem. "We were able to dose up to 16 million cells in 40 injections, which we believe to be the maximum tolerated dose. As in the first trial, the top-line data show disease stabilization in a subgroup of patients. Perhaps equally as important, we believe the top-line data may support a method of differentiating responders from non-responders, which we believe will support our efforts as we move into the next, larger controlled trial expected to begin this summer."

"The top-line data look very positive and encouraging. If this proportion of patients doing well after treatment can be corroborated in future therapeutic trials, it will be better than any response seen in any previous ALS trials," said site principal investigator, Jonathan D. Glass, MD, Director of the Emory ALS Center. "Elucidating which factors define a patient who may have a therapeutic response to the stem cell treatment will be the next key challenge. We are hopeful that a set of predictive algorithms can be established to help pre-select the responders in our future trials."

"We were very excited to participate as a site in this clinical trial," said Merit Cudkowicz, MD, Chief of Neurology, Massachusetts General Hospital and Co-Chair of the Northeast ALS Consortium (NEALS). "We are hopeful with respect to the top-line results and we need to move swiftly and safely forward to confirm the responder effect and identify people who might benefit from this treatment approach."

The open-label, dose-escalating trial treated 15 ambulatory patients, divided into 5 dosing cohorts, at three centers, Emory University Hospital in Atlanta, Georgia, the ALS Clinic at the University of Michigan Health System, in Ann Arbor, Michigan, and Massachusetts General Hospital in Boston, Massachusetts, and under the direction of principal investigator (PI), Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. Dosing increased from 1 million to 8 million cells in the cervical region of the spinal cord. The final trial cohort also received an additional 8 million cells in the lumbar region of the spinal cord.

The company anticipates commencing a later-stage, multicenter trial of NSI-566 for treatment of ALS in 2015. Neuralstem has received orphan designation by the FDA for NSI-566 in ALS.

About Neuralstem

Neuralstem's patented technology enables the production of multiple types of central nervous system stem cells in FDA GMP commercial quantities. These stem cells are under development for the potential treatment of central nervous system diseases and conditions.

Neuralstem's ability to generate human neural stem cell lines for chemical screening has led to the discovery and patenting of compounds that Neuralstem believes may stimulate the brain's capacity to generate neurons, potentially reversing pathologies associated with certain central nervous system (CNS) conditions. The company has completed Phase Ia and Ib trials evaluating NSI-189, its first neurogenic small molecule product candidate, for the treatment of major depressive disorder (MDD), and is expecting to initiate a Phase II study for MDD and a Phase Ib study for cognitive deficit in Schizophrenia in 2015.

Neuralstem's first stem cell product candidate, NSI-566, a spinal cord-derived neural stem cell line, is under development for treatment of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). The primary endpoints were met in Phase II. In addition to ALS, NSI-566 is also in a Phase I trial in chronic spinal cord injury at UC San Diego School of Medicine. NSI-566 is also in clinical development to treat neurological diseases such as ischemic stroke and acute spinal cord injury.

Neuralstem's next generation stem cell product, NSI-532.IGF, consists of human cortex-derived neural stem cells that have been engineered to secrete human insulin-like growth factor 1 (IGF-1). In animal data presented at the Congress of Neurological Surgeons 2014 Annual Meeting, the cells rescued spatial learning and memory deficits in an animal model of Alzheimer's disease.

Cautionary Statement Regarding Forward Looking Information:
This news release contains "forward-looking statements" made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements relate to future, not past, events and may often be identified by words such as "expect," "anticipate," "intend," "plan," "believe," "seek" or "will." Forward-looking statements by their nature address matters that are, to different degrees, uncertain. Specific risks and uncertainties that could cause our actual results to differ materially from those expressed in our forward-looking statements include risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Neuralstem's periodic reports, including the annual report on Form 10-K for the year ended December 31, 2013 and Form 10Q, for the period ended September 30, 2014.

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SOURCE Neuralstem, Inc.


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And then there's this.....

Dive Brief:

In a phase II clinical trial, only 47% of patients treated with Neuralstem's surgical stem-cell therapy responded to therapy, meaning they experienced stabilization of muscle function in the short term.

Neuralstem has not been entirely forthcoming about the results of the trial. Instead, they chose to release results from the 15 ALS patients enrolled, which simply compared responders versus nonresponders, The Street reports.

One of the secondary endpoints was response to therapy as measured by ALSFRS score, which measures muscle function. (A previous version of this post referred to this as the primary endpoint—that was actually safety). Subsequent analysis shows that therapy, known as NSI-566 did not significantly improve muscle function in ALS patients (CLARIFICATION: it did not significantly improve for patients in the entire aggregate of the trial, not just the ones who actually responded to the treatment). The stock was down 14% on the news.

Dive Insight:
Failure to disclose full results of a clinical trial is generally a bad sign, and efforts to hide clinical trial data are becoming increasingly difficult—especially given the focus on clinical trial transparency.

Neuralstem's comparison of responders versus nonresponders is considered wishy washy and led the market to discount the stock partly on lack of transparency. Nonetheless, Neuralstem plans to continue investigating the therapeutic potential of NSI-566, which is a cocktail of neural stem cells, in patients with ALS.


GERMANTOWN, Md. (TheStreet) -- Neuralstem (CUR - Get Report) is providing an overly optimistic picture about its surgical stem-cell therapy for amyotrophic lateral sclerosis (ALS), the degenerative and fatal nerve disease.

Instead of disclosing the results from all 15 ALS patients enrolled in Neuralstem's phase II study of NSI-566, the company decided to only release a comparison between the patients who responded and those who didn't respond. Of course, the seven responders in the study showed more stabilization or improvements in muscle function compared with the eight patients deemed non-responders.

The scientific term for this conclusion is, "Duh."

When you work backwards and do some simple math on the muscle performance of all 15 ALS patients in the Neuralstem study, the results aren't very encouraging. Neuralstem chose to stay mum on this more customary analysis.

Neuralstem shares are down 14% to $3.21 in Thursday trading.

Roll up your sleeves, and let's take a closer look at Thursday's Neuralstem announcement.

The phase II study enrolled 15 ALS patients. All underwent surgery during which NSI-566, a cocktail of neural stem cells, was injected into the spine. The goal of this study was to show that these stem cells could engraft into the spine, regenerate nerves and improve muscle function and breathing in ALS patients. All 15 patients in the study underwent surgery and transplantation with NSI-566, so there's no control arm to compare against.

In Thursday's announcement, Neuralstem said the NSI-566 phase II study achieved its primary endpoint of safety because the surgery and transplantation were well- tolerated. Only one patient experienced a serious surgical adverse event. No other details were provided.

On the more interesting secondary efficacy endpoints, Neuralstem said seven of the 15 patients, or 47%, responded to the stem cell therapy when they were assessed nine months after surgery. Response is defined as a slowing or improvement in the slope of the ALSFRS score over the nine months. ALSFRS measures muscle function in ALS studies, so a flattening or positive slope means patients are stabilizing or improving.

The average ALSFRS score for responders at nine months after treatment was 37 and these patients retained 93% of their baseline ALSFRS score, Neuralstem says.

The remaining eight ALS patients in the study did not respond to NSI-566 therapy. After nine months, their average ALSFRS score was 14, which represents just 35% retention of their baseline scores, the company says.

If we do some simple math, the baseline ALSFRS scores for responders and non-responders was 40, which is in line with other ALS studies.

Here's Neuralstem's conclusion: "As measured by an average slope of decline of ALSFRS, responders' disease progression was -0.007 point per day, while non-responders' disease progression was -0.1 per day, which was again statistically significant."

Responders benefited more than non-responders. Thanks, Neuralstem, but this analysis is not very helpful because the company can't identify patients who will respond to NSI-566 before they undergo the extensive surgical surgery required to transplant the stem cells into the spine.

If you can't preselect responding patients, it's important to know how all the patients taken together performed following surgery and implantation of the NSI-566 stem cell therapy. Neuralstem doesn't disclose this analysis in Thursday's release, but you can figure it out on your own.

I did the rough math, and this is what you get: For all 15 ALS patients in Neuralstem's phase II study, baseline ALSFRS score of 40 fell to 25 after nine months of follow-up. A lower ALSFRS score means worsening of muscle function in ALS patients over time. If you graphed the ALSFRS score over nine months, the slope would be negative. Taken together, Neuralstem's NSI-566 did not improve muscle function in ALS patients.

Did NSI-566 slow the rate of ALS disease progression? Unknown because Neuralstem's study lacks a control arm. However, if you compare these cumulative results to results from a natural history study of ALS patients known as Pro-Act, it looks like NSI-566 performed worse. Caveat: Cross-trial comparisons are imperfect.

Neuralstem and the investigator who conducted the phase II study say they are encouraged by the results enough to justify starting another clinical trial. ALS is a terrible disease with no cure, so there's no reason for Neuralstem to give up. A competitor, Brainstorm Cell Therapeutics (BCLI), is doing the same.

But ALS patients and investors deserve a more complete airing of the results from this phase II study of NSI-566. False hope serves no one well. A Neuralstem spokeperson says the company intends to present or publish additional data from the phase II study at a later date. Let's hope they do.