The ALS Association is forging partnerships with industry and academia in a new drive towards clinical testing of possible therapeutics for amyotrophic lateral sclerosis (ALS). Already the effort, now formalized as TREAT ALS, is making an impact with new candidates entering clinical testing, notably ceftriaxone.
Researchers have made tremendous advances in the ALS field. We understand far more about the biological basis of the disease process. This knowledge has enabled design of laboratory models of the disease that have yielded innovative ideas and clinical candidates.
Design of patient trials in ALS has improved as well. Funding for ALS research has increased despite cuts elsewhere in the budget of the National Institutes of Health (NIH). The NIH is committed to finding a therapy for the disease.
Disease Process of ALSBasic research has uncovered mutations that can produce various motor neuron diseases. The search continues for additional genetic factors for ALS. Besides genes, environmental risk factors are sought by collaborative research. If risk factors were known, ALS might be addressed by preventative approaches, which work so well for cardiovascular disease.
The disease process of ALS is now understood to involve a variety of factors that affect motor neurons. Mutations in the SOD1 protein account for some inherited cases of the disease. Other aspects of function altered in dying motor neurons in ALS include excess excitation, inflammation, damage to the mitochondria that make energy for cells, and oxidative damage.
One approved drug exists for ALS. Riluzole prolongs life by about ten percent, according to post marketing studies. Can that modest effect be boosted?
Adequate Trial DesignSeveral potential new treatments have failed to demonstrate enough of a significant effect on the disease in clinical testing.
- Talampanel, which like Riluzole affects glutamate, may have had a hint of efficacy.
- Topiramate, a glutamate receptor blocker, at the dose tested apparently worsened muscle strength but had no other effect on measures of disease progression.
- Trophic factors, IGF-1 injected under the skin, may have provided some benefit, yet it may not have reached target tissue adequately.
- Creatine was not effective in two clinical trials, but the doses might have been too low.
- Vitamin E was not helpful in ALS at a high dose (See Clinical Trials).
- Celebrex was not effective, but it may not get into the brain sufficiently even at the highest recommended dose, which was tested.
- Tamoxifen appeared to benefit survival at the highest dose tested in a pilot study.
In all, 16 unique therapeutics have been tried over the past decade. These clinical trials moved the field forward towards better trial design. Therapy development in ALS is still hopeful and moving fast. A growing pipeline is feeding into trials of ALS therapeutics. Four trials are still ongoing for ALS, and four more are about to start.
How does one rule out a pathway or mechanism in ALS, just because a single drug at a particular dose does not work? Clinical trials need to be definitive tests that either rule out or admit a disease mechanism. Trials need sufficient background knowledge, and tight design to make sure a potential treatment gets where it should in the body, and to ensure it is safe. Placebos need to remain part of ALS clinical trials.
Ongoing TrialsFor updates on current clinical testing in ALS, please click here or visit the NIH clinical trials site. A Phase II trial in ALS patients of ONO 2506 was completed in
A record number of therapeutic strategies for ALS are poised to enter clinical testing. Trials for phenylbutyrate and ceftriaxone should begin in 2005. Meanwhile 23 potentially protective agents have been identified by drug screening in cooperation with the National Institutes of Neurological Disorders and Stroke (NINDS) and will be further tested in preclinical studies.
Ceftriaxone, Case in PointCeftriaxone is an illustration of the accelerating pace of ALS clinical testing. This drug, marketed for meningitis, was identified in a screen of drug libraries as having other possible actions that could benefit ALS patients. Of 1040 existing drugs tested, the class of antibiotics that includes ceftriaxone came up positive, in eight tests of relevance to ALS.
Researchers chose to work further with ceftriaxone because it enters the brain and it stays in the body for a day, which is relatively long lived for a drug. Ceftriaxone extended life for the mice that have the SOD1 mutation that is present in some inherited ALS. This drug will now enter clinical testing in the summer of 2005 in record time--eleven months to approval is the fastest time that the NIH has ever granted permission for clinical trial.
Ceftriaxone is effective in meningitis where it must enter the brain to work, but will it enter the nervous system adequately in ALS? How will extended use of the drug affect people? In meningitis it is only used for a few days. Kidney and liver safety, overall safety and efficacy must be demonstrated for ALS.
The first 60 patients to be enrolled will give data to answer these questions before more extensive testing continues in an additional 600 patients. This study design will expedite further testing provided the hard facts show that the drug is safe, and stays in the right tissues adequately.
Phenylbutyrate, AEOL 10150, and ArimoclomolAnother agent starting initial safety testing in ALS patients is phenylbutyrate, a drug approved for treating cancer (it is a histone deacetylase inhibitor). The agent is able to prolong function in animal models of ALS and other neurodegenerative disorders. This is a Veterans Administration study, funded by the VA and by the Muscular Dystrophy Association (MDA). Patients can enroll at eight sites, beginning in April of 2005.
Arimoclomol appears to protect motor neurons in animal models of ALS, and will enter clinical trials in 2005. It works by acting on heat shock proteins, protective factors within cells. AEOL 10150 is a porphyrin that acts as an antioxidant and will be entering initial clinical testing in ALS in 2005. Both of these agents are investigational drugs from biotech companies.
Gene Therapy with IGF-1The trophic factor, IGF-1, delivered by a gene therapy can prolong life in mice with the SOD1 mutation even if the therapy is given as symptoms appear. This gene therapy approach is scheduled to enter clinical testing. It will require many injections into various muscles of the body. The delivery system for the gene coding for IGF-1 is a virus that is taken up by the nerve endings from muscle.
Quality of LifeQuality of life in ALS should also be improved by a new treatment for pseudobulbar affect, an excess emotionality that is uncomfortable for both patients and caregivers. A trial of early intervention with nutritional and breathing support is also under way. People are living longer with ALS. Clinicians believe it is due to better care. Early intervention in nutrition and in pulmonary support may make a real difference in both survival and the quality of that survival. An NIH funded trial is enrolling patients to test objectively the effect of such early interventions.
Clinical trials for ALS are challenging due to the relative rarity of the disease, which makes it hard to gather study subjects. And there are now so many potential therapies to test. Yet an expanding network of dedicated ALS clinics nationwide may help provide sufficient patients to produce reliable data. ALS experts are collaborating to decide which therapeutics show the most promise, to enter these first and fast into testing. Progress is evident for so many factors that will undoubtedly influence favorably the potential for decisive clinical trials to find new, effective treatments, bringing hope for this tragic disease.
