Amyotrophic Lateral Sclerosis is a fatal neurodegenerative disorder characterized by selective death of motor neurons in the brain and spinal cord. This leads to muscle weakness, atrophy, and gradual paralysis. At present, there is no effective therapy for the disease and patients usually die within 2-5 years after the onset of symptoms [1]. The only treatment currently in use for ALS patients is Riluzole, which extends the survival of the patients by approximately 3 months.

There are currently no precise measures of ALS disease progression that allow for short term monitoring of the disease and the assessment of treatment efficacy. In clinical trials, survival time is therefore used as the primary measure of effectiveness. This requires large numbers of patients over a long period of time, usually an average of well over a year. These factors make ALS clinical trials very expensive and constitute the main obstacle to phase II (proof of concept) clinical trials of novel drugs for the treatment of ALS. In order to make advances in the therapy of ALS, a more fine-grained measure of ALS disease progression is therefore crucial.

The Seeker is therefore interested in a biomarker that will allow robust assessment of disease progression in ALS. The proposed measure could be any biological correlate(s) of the disease, or a combination thereof, as long as it is suitable as a biomarker. Ideally, it would be highly sensitive, inexpensive, and easily performed in a clinical laboratory environment.

Objectives. An ALS biomarker is needed in order to enable a substantial reduction in the cost of ALS clinical trials, particularly Phase II/ proof of concept trials, and thereby accelerate therapy development for ALS. Currently, a typical proof of concept trial enrolls approximately 600 patients and lasts 15 months or longer, resulting in a total cost of at least 8-10 million USD. The objective of this challenge is to reduce this amount by at least 50%.

Thus, the aim is to find a biomarker that will reduce the cost of Phase II ALS proof of concept clinical trials to less than 5 million USD by shortening the duration of the trial, or reducing the number of patients required (or both). As an example: a biomarker that is powerful enough (power of 85% or better) to yield reliable results in a clinical trial in 200 patients over six months, or 150 patients over 9 months, would fulfill the definition of success (these numbers are given as an orientation and are based on a drug treatment effect size of 30%).

AWARD: up to $1,000,000 USD will be awarded for a validated functional ALS Biomarker that meets the desired requirements. Any biological correlate (e.g. body fluids, imaging, electrophysiological examination etc.) can qualify as a solution, as long as the Solver provides detailed description and statistically significant validation for it (experimental methods and conditions).

As an example, the validation could be based on clinical or experimental work, or on statistical analysis of existing trials data.

The Solver must provide statistically significant results as proof for the validity of the solution. All biological correlate(s) need to be thoroughly characterized. The description should also be accompanied by a solid scientific rationale supported by literature precedents. If Solvers are facing difficulties getting access to necessary information, they can approach the Seeker. The Seeker will help where warranted.

Technical Requirements:
There are a number of basic requirements that the proposed biomarker must address as a prerequisite to consideration for the award. In addition, we specify a list of "highly desirable" and "desirable" features for the biomarker which are not compulsory.

Basic Requirements

1. The biomarker must be able to serve as primary endpoint in a proof of concept clinical trial. This means the biomarker must provide a sensitive measure and be validated against a clinically meaningful outcome. Currently, the most widely accepted outcome for ALS phase III trials is patient survival time, defined as either (i) time to death or (ii) time to the first to occur of death or chronic ventilation. Therefore, validation must be conducted against one of these two definitions of survival time in ALS patients. Further, the biomarker must be predictive of future disease progression, as measured in ALS patients by the change in at least one of the following: the ALSFRS-R score, FVC, or muscle strength.
2. The biomarker will reduce the cost of Phase II ALS clinical trials to approximately 5 million USD. This means the biomarker must be powerful enough (power at least 85% to detect a 30% treatment effect at alpha 10% one-tailed or better) to either shorten the duration of a Phase II ALS trial, or reduce the number of patients required (or both). This will generally require evidence of a sufficiently small coefficient of variation.
3. The Solver must provide statistically significant results to prove the validity of his/her solution. Note that diagnostic sensitivity and specificity of the biomarker are not requirements for this challenge as long as the proposed measure correlates robustly with disease progression and survival in ALS patients.
4. The test should be feasible in an ALS center/trial setting.
5. All components of the test must be safe for human use. Any chemical agents used, for example, should be TSCA (Toxic Substances Control Act) and EINECS (European Inventory of Existing Commercial Substances) approved.

Highly Desirable Features:

1. The test is tolerated by 90% of ALS patient population.
2. The test should not cost more than 10,000 USD per patient per trial.
3. The biomarker predicts the impact of Riluzole on survival.

Desirable Features:

1. The biomarker will reduce the cost of Phase II ALS clinical trials below 2 million USD.
2. The biomarker can also be used as a diagnostic tool for early detection of ALS. In this case diagnostic sensitivity and specificity would be desirable data to submit.
3. The test does not cause undue pain or discomfort to the patients under testing. Some itching or local inflammation may be acceptable.
4. The test is as non-invasive as possible. Ideally, an easily obtainable body liquid is required, such as blood, urine or saliva (cerebrospinal fluid would also be acceptable, although less preferred).

All submissions must be in English and must conform to the following format:

1. General:
   The submission text must be 12-point type Arial or Times New Roman font. It can be single spaced. Figures, charts, tables, figure legends, and footnotes must be readily legible and incorporated into the overall page limits. Images must be no less than 10.5 and no more than 18.0 cm wide. Numbers, letters, and symbols should be no smaller than 6 point and no larger than 12 point. Composite figures must be preassembled. Each item should have a brief title. There must be an adequate border of at least 0.5 inches around each figure, chart or table. Page margins, in all directions, must be at least 0.5 inches. The complete application should be submitted as a PDF.
2. Maximum Length:
   The total submission package can be no more than 20 pages (not including references). No section may be longer than the limits provided below (if you have additional data that you can not fit into this format, please contact seeker).
3. Title and Abstract (1 page):
   Please submit a title and abstract for your proposal. The abstract should be no longer than 300 words and should summarize your proposed solution, the rationale and the methods on which it is based.
4. Background, introduction and rationale (1 page):
   Describe the background, introduction and rationale for your proposed solution, including relevant scientific literature.
5. Preliminary data from you and others (2 pages):
   Describe existing preliminary data from you and others as it relates to your proposed solution.
6. Main text (16 pages):
   Describe in detail your proposed solution and how it was realized. Be careful to explain in detail how your solution fulfills the basic requirements of the ALS Biomarker Prize challenge as specified above.
7. References (must be included but will not count toward 20 page limit):
   Use a standard scientific reference format including author, title, and full details of the source (such as journal name, volume, year, and page number).
8. Your completed package will adhere to the following format:
   Page 1: Title and abstract
   Page 2: Introduction, background and rationale
   Pages 3-4: Preliminary data
   Pages 5-20: Main text
   Pages xx-xx: References