Below is an open letter from LPI researcher Joe Beckman to ALS patients who are interested in hearing more about the next steps of his groundbreaking finding released last week that halted the progression of ALS in mice.
Please accept my apologies for writing a general note. The response has been overwhelming and heartbreaking. I have been working as a basic scientist on ALS for 23 years now. I have come to know many patients and family members and appreciate what you are going through. I want to assure you that many researchers and clinicians are focused on all aspects of this terrible disease and the research community is making progress in many ways. Ours is one study in mice, but I believe this drug will soon start clinical tests. There is no guarantee of success, but I would like to share what I can.
Progress towards clinical trials
The most important question underlying so many of the emails and phone calls I’ve been getting is how to enroll in a clinical trial. When trials are approved, information will be made available on the National Institute of Health’s clinical trials searchable database, http://www.clinicaltrials.gov/. You can search for “ALS” in this database and we will also alert you on the Linus Pauling Institute Facebook page as well.
My lab works with mice trying to understand the disease. We have no involvement with clinical trials and neither should we, as we have a potential bias in the success of the compound. Those conducting trials will be blinded with respect to treatment regime so they can objectively measure how patients progress. This is critical for finding a cure of ALS, no matter what the drug or treatment.
The past three years
It was about three years ago that we had the first evidence that Copper-ATSM offered remarkable protection in a very specific mouse model of ALS. We first replicated the experiment as fast as we could to be sure we had not made a mistake. We compared our results with those of my colleagues and friends in Melbourne, Australia. The benefit of Copper-ATSM in treating mouse models of ALS and Parkinson’s was discovered by Drs. Crouch, Barnham, Roberts (a former Ph.D. student with me) and others at the Florey Institute there. They have taken the lead in developing the compound for Parkinson’s and ALS. Their license was granted to a newly-formed company called Procypra, based in the USA, which is developing Copper-ATSM for treatment of Parkinson’s disease and ALS. Procypra also will have no say in which patients receive treatment during clinical trials, but is working hard to make the drug available to test in patients.
In the summer of 2014, coincidently at the same time the Ice Bucket Challenge was underway, it was clear that we had achieved a remarkable and reproducible protection in the familial SOD-based mouse model. Though still too early for publication, we contacted the NIH, the ALSA, the Northeast ALS Consortium (NEALS), the Prize4Life and the FDA. We traveled to a variety of ALS meetings to present the preliminary findings. We made contact with Procypra and provided our results with the hopes that they would be committed to developing the drug for ALS as well as Parkinson’s (which is a much bigger market). They are and were in fact already committed.
I also want to be clear that I have no financial connection with or support from Procypra. I am in frequent contact with the CEO and traveled to help pitch the case for developing Copper-ATSM. I may undertake a joint venture in the future. Our work has not been conflicted by commercial interests, though we have worked hard to move the development forward as fast as possible.
The FDA are in fact the “good guys” and a critical safeguard for patients
I want to assure you that the FDA has been and is being very helpful in the process. What some patients might consider to be time-wasting regulations are absolutely necessary steps in the process. You may have heard of the recent deaths in France for another “safe” experimental drug in a phase I trial, which illustrates the importance of following the steps carefully for developing the drug. I can assure you that Copper-ATSM is being moved down the path already and should be in human safety testing in a few months. Approval will be a ways away, as the risks versus benefits are determined.
The first step in a clinical trial is called a Phase I safety study where the drug is given to healthy volunteers. It appears likely that the Phase I trial for Copper-ATSM will be done with ALS patients in Australia first and within the USA a few months later. If Copper-ATSM is tolerated, the trial may be allowed to continue into a Phase II efficacy trial. These will be followed by larger phase III trials that really determine whether the drug is effective. This path is the best way to test a drug for a deadly disease. Copper-ATSM is being developed for international use as rapidly as possible.
The challenges of making Copper-ATSM
There are several important things to understand about making a drug for clinical testing and key milestones required by the FDA. For example, we were able to make about a pound (500 g) of the drug in my laboratory for testing in mice. This was a lot of work, but our procedures were not appropriate for making clinical grade material for humans. For example, we found that mixing with copper forms an impurity that is very hard to eliminate, make the drug unstable in storage and likely to cause acute copper toxicity. Copper ATSM is now commercially available for research purposes, but I urge the ALS community not to take this compound from outside non-pharmaceutical suppliers.
Making the compound for human studies has shown that the synthesis is not a simple scale up. (Imagine making 5 tons of this chemical each year—that is a rough guess of what would be needed to treat 420,000 ALS patients worldwide—a challenge but a good one to have if the drug works.) Then comes the complex questions of establishing how to formulate the Copper-ATSM as a pill, how much to give, and how often. These are just a few of the challenges that must be overcome before starting a clinical trial or producing a drug for human use.
Above all, we do not want to cause harm from unintended consequences. Copper-ATSM is remarkably safe in mice and rats, but humans handle copper differently. And too much copper is toxic. Some humans will respond to the drug differently than others, so researchers will determine whom and why.
It is important to know that copper supplements will not work and can easily become toxic. The online Micronutrient Information Center from the Linus Pauling Institute (http://lpi.oregonstate.edu/mic) contains peer-reviewed information on copper and other micronutrients that you might be considering.
Our success in treating a mouse model is based on a type of human mutation that causes only 2-7% of ALS cases. One of the most vigorously debated issues in our discussions with ALS leaders is whether Copper-ATSM will work in non-SOD based ALS cases. As a biochemist, I believe that it could work in sporadic SOD (the vast majority of cases), but there is no evidence that it will (or won’t). However, the drug will be tested in both types of ALS patients and we should know the answer in several years.
Copper-ATSM has the appropriate properties to reach the key target in ALS—motor neurons in the spinal cord—when taken orally. It is undergoing extensive safety testing, and much of the necessary background work has been done to proceed to human trials. Our mouse experiments have provided a compelling rationale for why the drug works in the form of ALS involving SOD mutations (about 3% of patients). We need to determine whether the risks of taking Copper-ATSM outweigh its putative benefits we infer from the mouse experiments. We have to learn how to best use it to treat ALS in humans.
As a final note, I have been highly impressed with the recent progress and commitment of the ALS clinical community in testing and developing a wide variety of treatments for ALS, as well as the scientific progress in understanding the disease. When I started 23 years ago, so little was known and we were probing in nearly complete darkness. Many people are spending their careers on this disease now.
A note about the actual publication
If you would like to read the paper itself (and I hope you do), it is freely available here: dx.doi.org/10.1016/j.nbd.2016.01.020
To see why we are so excited about the results, compare the number of days on the x-axis of Fig. 1 compared to Fig. 3 and you will see the protective effect. All humans have CCS like the mice shown in figure 1, which gives us hope that the drug could work in human ALS patients. The rest of the paper provides some insights into why the drug works. This is not evidence it will work in humans, but offers hope and the promise that it is worth testing carefully in humans.
With best regards,
Joe Beckman, Ph.D.
The Burgess and Elizabeth Jamieson Chair in Healthspan Research at
the Linus Pauling Institute
University Distinguished Professor of Biochemistry and Biophysics
Director, Environmental Health Sciences Center