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Re: What is next in ALS clinical trials?

Like numerous other neuroscientists, I share many of the sentiments expressed by Dr. Sorenson in his editorial regarding clinical trials in ALS. [1] The study by Miller et al. adds TCH346 to a long list of therapeutics for neurological diseases that earns the ‘promising’ label in pre-clinical tests, only to fail in human trials. [2]

While Sorenson notes the difficulties of performing an appropriately powered human trial, more emphasis needs to be placed on the proper performance of pre-clinical tests in animal models of disease. There is a universal failure to apply the same rigorous standards used for planning and executing human trials toward pilot trials in animal models. Has anyone read a report in which data from an animal trial is subjected to an intent-to-treat analysis? Or in which the primary outcome measures are pre-specified rather than chosen post-hoc?

Institutional animal care and use committees (IACUCs) already review proposed animal tests, mostly to ensure humane treatment. They are not equipped to assess trial design itself. However, we do not need to create the equivalent of IRB review for animal testing protocols. Journals and granting agencies should take the lead in encouraging scientists to apply more rigorous standards to the design and reporting of animal trials including:

• Pre-specify the number of animals to be tested, based on power calculations and predicted drop-out rates.

• Pre-specify primary and secondary outcome measures.

• Disclose methods of blinding.

• Account for all the animals included and excluded from analysis (e.g., excluded due to post-surgical infection).

• Clearly define differences noted during or after the trial as post-hoc analysis with all the caveats. Journals should give more consideration to publishing the results of ‘negative’ animal tests, as long as they are appropriately conducted.

Of course, such rigorous, pre-specified analyses cannot and should not be applied to all spheres of basic bench research. But hopefully, this approach can strengthen the findings of pre-clinical testing in animal models of disease.

If a potential therapeutic can muster these standards, then perhaps it could truly earn the label of ‘promising’ when applied to human clinical trials.

References

1. Sorenson EJ. What is next in ALS clinical trials? Neurology 2007;69:719-720.

2. Miller R, Bradley W, Cudkowicz M, et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007;69:776–784.

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Re: Reply from the editorialist / Harel

I agree with Dr. Harel that pre-clinical animal screening studies should be held to the same standards as human clinical trials.

While blinding of the animals is unlikely an issue, blinding of the examiners is an issue. This and other potential sources of bias are problematic without rigorous methods and data scrutiny. These biases may partially explain why some agents are successful in animal trials but have failed when advanced to human trials, where more rigorous surveillance of the methods and data are applied.

We will have substantive treatments to offer those with ALS only through coordinated efforts of the ALS scientific community to establish the mechanisms of cell death and to perform well designed pre-clinical animal studies followed by high quality phase I through III human clinical trials.

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Re: Reply from the authors/ Harel

We agree with Dr. Harel regarding the need for more rigorous pre-clinical trials in animal models of ALS. However, we wish to point out that the SOD1 mouse model has potential limitations because it is based on only one pathogenetic mechanism. We need other animal models that are based on different mechanisms relevant to ALS including: excitotoxicity, neuroinflammation and mitochondrial dysfunction.

We would add the following to Dr. Harel’s list of reporting suggestions:

• Outlining genetic background, gender and litter matching which can confound studies

• Evaluating treatment after disease onset, to more closely parallel the human situation,

• Quantitating the human mutant transgene copy number to control disease severity

• Quantitating weight loss which is an important predictor of survival in human disease. An extensive treatment of this subject was recently published. [3]

Reference

3. Ludolph AC, Bendotti C, Blaugrund E, et al. Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: Report on the 142nd ENMC international workshop. Amyotroph Lateral Scler. 2007;8:217-223.

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Re: What is next in ALS clinical trials?

I read the editorial by Sorenson and the manuscript by Miller and colleagues with great interest. [1,2] Although the study was negative, the study design is novel and may help future trials. As outlined in the editorial, this is not the first negative trial in ALS and probably not the last.

A problem with potential ALS treatments is that often the molecular targets are wrong. As is the case with this drug, the therapeutic targets often deal with late stage cell death pathways but fail to recognize that in most neurodegenerative diseases, cell death is a late phenomenon.

One of the earliest phenomena seen in neurodegenerative diseases is distal axonal degeneration; a unique example is in ALS. [3] The molecular mechanisms that play a role in disease pathogenesis and lead to distal axonal degeneration are likely to be different than the late stage cell death pathways, and treatments aimed at preventing cell death are not likely to succeed. Drug development programs need to consider this and develop drug screening tools and programs aimed at preventing these earlier processes.

For a motor unit, it really does not matter even if it was prevented from dying but allowed the distal axonal degeneration to take place. For example, a recent study showed that prevention of apoptotic cell death does not prevent motor denervation in an animal model of ALS. [4]

If future treatments are to succeed, we need to focus on the events that occur early in disease pathogenesis and concentrate on axon degeneration as the step to intervene. This approach is likely to succeed not only in ALS but other neurodegenerative diseases such as peripheral neuropathies. [5]

References

1. Sorenson EJ. What is next in ALS clinical trials? Neurology 2007;69:719-720.

2. Miller R, Bradley W, Cudkowicz M, et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007;69:776-784.

3. Fischer LR, Culver DG, Tennant P, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 2004;185:232-240.

4. Gould TW, Buss RR, Vinsant S, et al. Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci 2006;26:8774-8786.

5. Hoke A. Neuroprotection in the peripheral nervous system: rationale for more effective therapies. Arch Neurol 2006;63:1681-1685.

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Re: Reply from the editorialist / Hoke

I thank Dr. Hoke for his correspondence. As he correctly points out, most of the recent molecular targets for ALS clinical trials modulate end-stage neurodegeneration.

This strategy is problematic as cellular dysfunction and death may already be committed at this point. However, a major disadvantage currently exists in targeting the more upstream pathways. This disadvantage is that we currently do not know which pathway or pathways are pathogenic. It is possible, or even likely, that there is no one set of pathways that lead to the motor neuron disease phenotype.

Given this possibility, it is unlikely that one treatment directed at a very early pathway in the disease process will benefit all patients, many of whom may not share the same aberration. Dr. Hoke mentions axonal degeneration as the earliest pathological phenomena and suggests this should be targeted instead. While it is possible that axonal degeneration may be the earliest pathogenic process yet identified, it is also possible that axonal degeneration is reactive. Intervention at this point may also be ineffective in prolonging motor neuron function and survival.

There is a fundamental lack of understanding into the pathophysiology of this disease at the molecular level.

Unfortunately, it is not until this process is better understood that significant and meaningful treatments for the ALS population will be developed.

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Re: Reply from the authors/ Hoke

We appreciate the comments of Dr. Hoke about our article and our novel study design.

We agree that carefully selecting the proper targets for therapy is important. Advances in improving the selection process will be very beneficial. Among these targets, antiapoptotic agents are promising and antiapoptotic strategies have resulted in prolonged lifespan in the SOD1 mouse model. [6,7]

Among other hypotheses, the work on distal axonal degeneration is interesting yet it is unclear which of these processes are primary. There are pathological studies of human phrenic nerve tissue from ALS patients showing abundant motor neuronal death with only scant distal axonal degeneration. [8]

A relationship between the two processes has been shown in an SOD1 Bax-deficient mouse model where distal axonal degeneration is Bax dependent. [4] Further information is needed to better understand the early, upstream events in the cell death pathway and to better define targets in the apoptotic process.

We believe that intervening at a very early phase in the apoptosis cascade and neuronal degeneration may be an effective step that should be considered at this stage of our understanding of programmed cell death.

References

6. Guegan C, Przedborski S. Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest. 2003;111:153-161.

7. Pasinelli P, Belford ME, Lennon N, et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004;43:19-30.

8. Bradley WG, Good P, Rasool CG, Adelman LS. Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis. Ann Neurol. 1983;14:267-277.