Drug Company Working Group Meeting Attracts Professionals from Academia and Industry to Discuss Therapeutic Opportunities for ALS

In April, at The American Academy of Neurology Annual Meeting in New Orleans, The ALS Association brought together an overflow crowd of researchers, industry executives, and many others, all with the common purpose of finding new treatments for ALS. The meeting of the ALS Drug Company Working Group organized by the Research and Public Policy Departments of The ALS Association was standing room only, an indication of the broad interest in the research and drug development world in developing treatments for the disease.

“Our purpose for the meeting was to encourage those in the field and those thinking of getting into it, to talk with each other, and to share ideas and strategies for fighting ALS. That's what will help us move ahead,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.

The latest news on the trial of antisense therapy against SOD1 was discussed by Frank Bennett, Ph.D., of Isis Pharmaceuticals, which is developing the drug for treatment of familial ALS due to SOD1 mutations. Final results of the trial were then presented the following day by Timothy Miller, M.D., Ph.D., of Washington University in Saint Louis. In this double-blind trial, antisense molecules that bind to SOD1 messenger RNA were injected into the spinal cord in 21 patients.

The intent of the treatment is to shut down production of SOD1 and alter the progression of the disease in familial ALS. However, Dr. Bennett said that the trial was meant to establish safety, not test efficacy, and the drug was given only once, rather than multiple times over a prolonged period, as would likely be needed to have an effect on disease progression. Additional studies would be needed to determine the efficacy of this treatment.

Drs. Bennett and Miller reported that the trial showed that single doses appeared to be safe with the most important side effects related to the delivery of the drug, not the activity of the drug once inside the spinal cord. Because it is delivered by lumbar puncture (injection into the intrathecal space surrounding the spinal cord), treatment is associated with an increased risk of headaches, nausea, and vomiting.

Tests performed on patients showed that the drug achieved the predicted levels in the cerebrospinal cord and in the blood. “This was an important trial for studying the intrathecal delivery of antisense oligonucleotides,” Dr. Bennett said, as it was the first time that the procedure had been performed.

Dr. Miller noted that the antisense molecule targets all types of mutations of SOD1, rather than being mutation-specific, which would increase its potential utility if it turns out to be effective. Some evidence suggests that normal SOD1 may be involved in sporadic ALS, and that lowering it may be therapeutic. If so, Dr. Bennett said, antisense therapy may be helpful. He also noted that antisense directed against the C9ORF72 gene may be therapeutic if it is shown that the disease it causes is due to a new toxic substance, rather than the absence of normal protein from the gene.

Steve Han, M.D., Ph.D., of Massachusetts General Hospital in Boston, and the Department of Stem Cell and Regenerative Biology at Harvard University, discussed progress toward the development of ALS models using induced pluripotent stem cells (iPS cells) from patients with ALS.

In this system, cells are taken from the skin of a patient, grown in a lab dish, and then, by application of a cocktail of growth factors, transformed into iPS cells, which multiply to make many millions of cells. These cells can then be transformed into motor neurons. The value of this system is to rapidly create many identical cells for study in the lab, all of which contain the same genetic mutation that caused the patient's ALS. These cells can be used to learn more about what causes disease and to screen drugs as potential therapies. The lab has developed iPS cell lines with mutations in SOD1, TDP-43and FUS and has begun development of lines with C9ORF72 and the ALS risk factor ataxin-2.

FUS (Fused in Sarcoma) is currently a major target of research in the lab. The FUS protein binds RNA, the messenger cells used to translate genes into proteins. It is normally found in the cell's nucleus, but the mutations that cause ALS relocate it to the cytoplasm in the cell's periphery. The more FUS is mislocalized, the earlier the disease begins and the more severe it is, Dr. Han said.

Dr. Han is currently comparing cell lines from two different sources with different FUS mutations to understand more about how specific mutations affect neurons. One notable feature in FUS mutants is their effect on so-called stress granules. These structures appear in cells in response to stress and are thought to be part of a protective response. In some FUS mutants, though, these granules, which are in the cytoplasm, appear to be adversely affected by the presence of FUS. Dr. Han is investigating the details of that effect, which may lead to better understanding of how the mutant causes disease in motor neurons.

The ALS Association invited Steve Perrin, Ph.D., of the ALS Therapy Development Institute, to update the group on TDI's development of a therapeutic strategy targeting the body's immune system. Their work in mouse models has identified an immune pathway that appears to overactivate a certain type of T cell (one major type of immune cell), which carries a receptor called CD40. This activation leads to inflammation, which is thought to contribute to the disease process in ALS. TDI has worked to develop an antibody that blocks CD40, preventing activation of the T cell and increasing survival in mice. The antibody itself doesn't get into the central nervous system but may exert part of its beneficial effect by preventing other immune cells, called macrophages, from crossing into the central nervous system where they may do damage.

Currently efforts are underway to develop a human antibody against the CD40 ligand. However, TDI demonstrated that the same pathway can be intervened by using an oral drug called fingolimod, which may have benefit in ALS patients. This drug, trade name Gilenya, was recently approved by the Food and Drug Administration for the treatment of multiple sclerosis. TDI is in early stages of planning a trial to test this compound in ALS. There are concerns about safety based on data from the use of the drug in multiple sclerosis. Dr. Perrin noted that the trial, which is still in the early planning stages, may require 24-hour monitoring of heart function to determine if treatment causes the heart irregularities seen in a small proportion of MS patients.

Mark Boutin, Executive Vice-President and Chief Operating Officer of the National Health Council (NHC), discussed the MODDERN Cures Act (HR 3497), legislation endorsed by The ALS Association and introduced in Congress by Representative Leonard Lance (R-NJ).  The bill would help accelerate the search for a treatment for ALS and other diseases by removing the barriers that limit medical innovation and by providing incentives to develop new treatments and diagnostic tools.

He noted that despite increases in federal spending for medical research, the rate of new drug approvals has not increased. “Money is not the only barrier to development of new therapies,” Boutin said. As important are four barriers that inhibit the interest of pharmaceutical companies from taking risks in the development of new therapies. Addressing these barriers could rapidly change the development landscape.

The first barrier, and the most important, is the problem of “intellectual property.” In the large majority of cases, it is difficult or impossible to obtain a patent on a potential therapy (this is true for all disorders, not just ALS). “We see this again and again,” said Boutin. Patents expire after a certain number of years, and the clock begins ticking not when the therapy is marketed, but at the beginning of a clinical trial development program.

The development of a new drug, particularly for ALS, can take 15-20 years, reducing the potential return on investment; thus, many are not begun. The MODDERN Cures Act would create a new legal class of drugs called “dormant therapies,” which are those therapies that show promise in treating a disease with unmet medical needs, like ALS, but which have weak or no patent protection.  Such dormant therapies would be afforded a period of “data exclusivity,” which offers incentives for development similar to those of patents.  However, unlike patents, the period of data exclusivity would begin at the time of FDA approval so that manufacturers are not penalized for pursuing treatments for diseases like ALS that can take 15 or more years to develop.

The other barriers relate to the ability to develop biomarkers and other diagnostic tools that can help speed treatment development by informing whether or not and in whom a drug may be effective much earlier in the development process.  Even effective medicines work in an average of only 60% of patients because of genetic differences between individuals that affect response to the drug.

“We have few effective tools to determine who a medicine will work for,” Boutin continued. Even when a diagnostic test is developed to determine differential response, it may take years to obtain the necessary medical coding from the government to allow reimbursement for the test. 

Nevertheless, the reimbursement is often too little to support the cost of the test. Regulatory and statutory changes included in MODDERN Cures could encourage development of such tests, speed the ability to obtain a reimbursement code, and better match reimbursement to costs. The National Health Council and The ALS Association are working with Congress, the FDA, the White House and industry to enact the legislation as soon as possible.

“These are the kinds of efforts that we need to move our search for new treatments forward,” Dr. Bruijn said. “That is what all of us are focused on.”