“The accident was a horrible thing - but that horrible thing made Chris, at the end of his life, Superman. It's a happy irony if there is such a thing. I'm proud to have known him.”
Morgan FreemanYesterday, Neuralstem announced that the FDA approved our spinal cord injury trial (SCI). It’s hard not to think of Chris Reeves at a time like this. I actually met him once, at a dinner party in London in 1979. He was filming the second Superman movie, a remarkably quiet and unassuming young man given his enormous physical gifts and burgeoning fame. That he is synonymous now with the effort to cure spinal cord injury is a tribute to the efforts he put into his foundation’s work from the time of his accident until his death.
Our approved trial is a Phase I trial to treat chronic spinal cord injury. For this trial, chronic is defined as one to two years out from the injury. The patients will be “complete” paralysis patients, which means no sensory or motor function from the point of the injury “down.” We will not be treating cervical injuries (the type Christopher Reeves had) in the first group of patients, but thoracic injuries; think of it as from the chest down. As with our ALS trial, the FDA would like us to establish the safety of our surgical route of administration in the back below the cervical region before moving “up” there.
The earlier, now-abandoned Geron trial to treat SCI was aimed at acute patients, that is: very close to the accident in time. We will be conducting such a trial later this year in Seoul Korea, but I would like to focus on this chronic paralysis trial today. There are several important points to consider to fully understand the impact of this trial.
First, the approval by the FDA itself. I believe it shows a growing comfort level with our spinal cord cells and our surgical route of administration. We will be using the same NSI-566 spinal cord product that we have been using in the now complete ALS phase one trial. In many respects those ALS patients are more fragile than the patients we will be treating in this trial. And after 18 surgeries, there were no SAE’s (serious adverse events) related to either the cells or the surgery.
We also showed compelling evidence in the ALS trial that the cells we transplanted survived for the life of the patients, regardless of the length of time the patients were on special drugs to suppress their immune systems. We have always thought that only transient immune suppression would be required for our cells to optimize their survival. This is important because these are powerful drugs and often the side effects from these drugs can be worse than the ailments they are meant to cure. The FDA is allowing a transient (3 months as tolerated) regiment here acknowledging comfort again with what has been demonstrated in the ALS trial.
Next, I would like to talk about how we think our cells can help these patients. A helpful analogy for me is to think of the spinal cord as a pipe that comes down from the brain through the spine. And inside that pipe are countless wires transmitting the signal from the brain through the spinal cord, which then innervates our body. When there is a “break” in that connection, when all the wires are severed, no signal can get through and all motor and sensory function below the point of the break is lost. These patients are referred to as “complete” as opposed to partial. These are the patients with whom we are starting.
In the ALS patients, even though our cells are integrating and synaptically connecting to host cells, there is no “break” in any circuitry descending from the brain. The benefit to the patients is provided by the nutrients that our cells pump into the areas of transplantation, which nurture and protect the remaining motor neurons and nurse some sick cells back to health. In chronic SCI, we are actually trying to “bridge the gap” with new circuitry provided by our cells. This will be the world’s first such trial.
The previous abandoned trial by Geron worked under a different theory. Again, thinking about wires coming down through the pipe, Geron’s theory was that “all” the wires weren’t really broken. They believed that some were left intact, but that the myelin (like the rubber coating on an electrical wire) was knocked off, no longer allowing smooth transmission of the signal through the wire. There has never been a consensus that in fact this is the case, but never the less Geron believed it and proceeded based on that belief. The company stated publicly that it thought it was too “hard” to rewire, or bridge the gap with new neurons. The cells they put in were meant to try to remyelinate those (hopefully present) remaining wires and restore the signal below the injury. There is also a trial currently ongoing in Switzerland attempting remyelination as a mechanism of action to treat these patients with different cells.
We do not believe it is “too hard,” and our goal here is in fact to “bridge the gap” with new circuitry. A recent peer-review publication this past fall reported exactly that outcome in an animal model of spinal cord injury using our cells. This data combined with the data from our successful ALS Phase I, is the basis for our belief that we can help these patients.
Again, as the FDA gets more comfortable with our technology, the trial designs become more streamlined. With four sites operating, and reduced wait times between surgeries, we believe that we can complete the surgeries and the 6 months data collection periods all within one year.
Of course, also as with the ALS trial, we are required to start with a small dose in the first trial with optimal larger doses reserved for later trials. But people thought we would never see a therapeutic effect in the ALS trial with the initial dose, and we believe we clearly have. So I am hopeful here too. We now know from the ALS trial that the cells survive and do what we expected them to do, long term, in the patients. It is a question now of optimizing the dosage and placement and doing large enough trials to statistically power a conclusion about efficacy. I believe spinal cord injury will prove out the same way. The cells will do their jobs. It is a question of how many, where, and finding out just how much we can help the patients.
When I met Christopher Reeves, he walked up to me, stuck his hand out and introduced himself and said “I’m famished, let’s eat.” I never met him again, before or after his accident. From what I have read about him though, he attacked all life that way, head on with no pretense, even after his accident. As Mr. Freeman’s poignant quote highlights, he was an inspiration to many people, and I can’t help but think he would approve of the way we are attacking SCI
Sentiment: Strong Buy
"You never want a serious crisis to go to waste"
- Rahm Emanuel (attribution)
Posted: February 27th, 2013
As callous and cold hearted as this sounds, it is a political truism. There are some systems, some bureaucracies that are so gridlocked, or so moribund that only the urgency that comes from dealing with a crisis can create enough momentum to make progress. The FDA held a hearing on Monday to allow the ALS community to voice their opinions on how to proceed with ALS research. While it is unclear exactly what precipitated the calling of this hearing, the failure of the Phase III Biogen “dex” trial to treat ALS patients has perhaps, finally created a “crisis” mode at the FDA. The audience was able to assure the FDA that they are already in crisis mode.
In emotional and chilling testimonies, patients and their families spoke of living with and dying from ALS. Parents wept for their children, dead and alive. Speaker after speaker, from patients to care givers to clinicians to researchers, echoed the same themes. The FDA needs to redefine “risk” for this patient population; using their existing model is not “protecting” these people from anything, it is killing them. The FDA needs to allow broader access to drugs for this population if these drugs can improve the quality of life for patients, regardless of whether or not it can impact survival. And finally, the FDA needs to dramatically speed up the entire process; no one has a moment to wait. And, in what I confess was a moment of immense pride personally, Ted Harada (patient 15 of in ALS trial) stood up and excoriated the FDA for slowing down a trial and a therapy that held enormous potential for ALS patients. “Just look at me” he said, in more than words. In his testimony, Ted proposed that it is time that the FDA did the right thing and treat this process with the same urgency that the ALS community feels. He spoke with passion, elegance and conviction.
But to me, the most chilling and important testimony came from our site principal investigator at Emory, Dr. Jonathan Glass. Dr. Glass is a clinician with one of the largest ALS practices in the U.S. who has seen over a thousand ALS patients in his career. He is also a world class scientist and researcher who knows first-hand what our experience with the FDA has been like in the Neuralstem trial. In short, Jon speaks here with more experience and authority than anyone else in the field, in the world, literally. Add to that, the fact that outside of our trial, Jon will have to go before the FDA many more times throughout his career and you can understand that criticizing them over “one” experience could have lasting reverberations. But such is his conviction and dedication to his patients, and to science, that he felt compelled to speak truth to power. We should all be thankful.
What Jon said was basically this; Neuralstem has completed 18 surgeries over an artificially long, but agreed upon timeframe to demonstrate that both our cells and the intraspinal surgery route of administration are safe. We did just that beyond any question. Ten experts at NIH have reviewed the data from the first trial, and our proposed Phase II protocol, and found it worthy of millions of dollars of NIH funding. Yet the FDA, without the expertise or experience in the field that the NIH can harness, continues to place arbitrary hurdles in our way, and demand an inappropriately slow time frame for the dosing of patients in the next trial.
The problem is easy to fix, Dr. Glass added. The FDA merely needs to admit when they don’t have the expertise to deal with a subject, and borrow it from another government agency that does; in this case the NIH. They should rely on the NIH scientific and medical vetting at a level the FDA doesn’t have the resources to produce. This is no time for “turf” wars or false egos, people are dying. Furthermore, all the FDA needs to do to speed up the process is talk to us. As Jon said, we are constantly “guessing” where they will be on any particular issue, and waiting the statutory 30 days for responses to every question.
In a recent presentation at the New York Stem Cell meeting, I said that the FDA was not the enemy. They are not. They are under resourced, and in our particular case, without experience or expertise. However, more to the point, they are trying to work from a model which simply isn’t applicable to this disease. At the pace they are currently suggesting we proceed, even if we are right and our therapy works; almost every ALS patient alive today will be dead before it is approved. The ALS community deserves better. We all deserve better.
Had I said these things first, it would have sounded like just another CEO whining about the FDA being “tough.” We all owe Dr. Glass a debt of gratitude for not just his service to the ALS community, but his willingness to speak up. None of these problems are insurmountable. Let us hope that the FDA takes the opportunity that this crisis presents to change the way they approach our trial, and any other novel therapy that has the potential to help this population. I will conclude as Jon started, reminding everyone that we are all on the same team here.
Sentiment: Strong Buy
“A scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents simply die off. Science progresses one funeral at a time.”- Max Planck 1918(Nobel Prize winner for discovery of the quantum theory of physics)Posted December 31, 2012As 2012 draws to a close, I would like to reflect on the “bigger picture” of Neuralstem’s technology, and how we fit into the scheme of things from a historical perspective. Stepping back, just a bit, enables a clearer picture than sometimes emerges from the noise and chaos of the constant stream of evaluations and opinions we are all bombarded with. And when we step back and see how many of the other stem cell technologies have fallen into irrelevance (they never die as Dr. Planck observed) we can also better understand where we are on our path.When Dr. Johe discovered our neural stem cell technology, we thought the advantages were obvious. These are the cells that actually “become” the brain and spinal cord. They are physiologically relevant. We don’t have to “trick” them into becoming what they are supposed to become, nor do we rely on some unknown “black box” effect inside the patient (often referred to as the micro environment) for the cells to do what they are supposed to do. Additionally, they have a mitotic capacity (doubling ability in dishes) of roughly a billion, billion fold expansion. Without the negative effects of immortalization, we could create an almost unlimited source of cells from a single donated tissue. Finally, the cells had no “ABO” markers, nor any histochemical markers. They were in essence, one size fits all as far as the immune system was concerned. All of this has now been verified and validated in humans in our first trial using our spinal cord cells to treat ALS.Of course there have been skeptics, and critics, as there should have been. Any novel world class science will encounter much opposition. For a while people believed that all manner of cells from fat cells to bone marrow cells could be turned into neural cells for transplantation into patients to treat degenerative nerve diseases. Of course they really couldn’t and very few people still push any of these “adult stem cell” technologies for CNS (central nervous system) indications. The proponents of these theories haven’t died, but faded into irrelevance, an ideas’ way to die. The cells may indeed have therapeutic uses, but not in the CNS.
Sentiment: Strong Buy
Then of course there were embryonic stem cells. These cells clearly could be “pushed” down various fate paths, and hopefully turned into any type of cell, including and even first, neural cells. The decision by Geron to simply abandon the technology says all one has to know about how that turned out. In the interim labs and companies came up with innumerable schemes to “trick” various early stage cells into acting like Embryonic cells without having to go through the growth stages and destruction of embryos that caused so much controversy. Again, despite initial high hopes (and much hype) none of these technologies proved either safe or reliable enough to move forward into humans.This phase was followed by the rush to “IPS” cells. We were told that a patients’ own skin cells could be turned “back” in time and then pushed to a fate like a neural cell. Again of course, they proved unsafe and unreliable, and when one reads about “IPS” cells now, it is always couched in terms of genomic research. They do offer great progress there, but they will never be a transplantation therapeutic into the CNS.So as Dr. Planck noted almost 100 years ago, “truth will out” (to borrow the phrase from another author of whom I am very fond) over time. But one’s critics will never acknowledge it. So Neuralstem alone now from all these other technologies is moving forward with promising cell therapeutics in the CNS in humans. We have completed the world’s first intra spinal injection trial of neural stem cells in ALS patients and demonstrated that the surgery and route of administration is safe; that the cells survive long term in the patients despite patients going off their immune suppressant drugs; and that even at very low doses we can see a treatment effect in some patients.In 2013 these same cells will go back into ALS patients in greater doses; and in multiple trials throughout the world. They will also go into spinal cord injury patients in several countries across the globe; and even into stroke patients in China.We have much work to do of course, to show efficacy and safety in large numbers. As those of you who follow this page well know, the first trial was not statistically powered to show anything but a proof of principle that such a thing is feasible. But we believe the trial has showed much more. And looking at it in perspective, it is a clear step forward. Unlike all of these other technologies that have had their “15 minutes of fame”, ours has moved through all of the pre clinical technical, legal, regulatory and manufacturing issues; and completed a successful first in human trial. And of all of those technologies mentioned, ours alone is moving into multiple indications across the globe and in the U.S. in both first in human and advanced trials for CNS indications.I believe that 2013 will be a seminal year in the development of our cell therapies; but it shouldn’t surprise anyone. Looking back, one can see the path very clearly, as one technology moves forward while others fall by the wayside. We do not expect our critics to capitulate. As Max Planck so insightfully observed almost a hundred years ago; they will never see the light. But as he also knew, the weight of the evidence will eventually make them simply irrelevant.A happy and healthy new year to all.
Sentiment: Strong Buy