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Biomarker assay development to expedite ALS experimental therapeutic advancement

Periodic Reporting for period 1 - DEALS (Biomarker assay development to expedite ALS experimental therapeutic advancement)

Reporting period: 2015-05-01 to 2015-10-31

The unique Dutch SME Treeway B.V. was founded in 2012 by two highly experienced and successful entrepreneurs that both have been diagnosed with amyotrophic lateral sclerosis (ALS). It is Treeway’s mission to eradicate ALS from the face of the earth by speeding up ALS research and bringing new therapies on the market as soon as possible. Treeway already has one new therapy in clinical development, which has recently received EMA’s Orphan Medicinal Product Designation.

ALS is a rare disease that is characterised by muscle spasticity and rapidly progressive weakness due to muscle wasting. This results in difficulties in walking, moving, speaking, swallowing, and breathing. Most ALS patients die from respiratory failure within three years. ALS diagnosis currently is mainly aimed at excluding other diseases with similar symptoms. As a result there is a 9–14-month delay between symptom onset and final diagnosis of ALS. For similar reasons, there is also a lack of accurate and practical diagnostic tests for monitoring the benefit of potential therapeutic interventions for ALS. This is severely slowing down the progression of clinical drug development in this field.

As ALS drug developer, Treeway will greatly benefit from the availability of a (combination of) quick diagnostic assay(s) to be used in monitoring therapeutic efficacy in clinical trials. In addition, the ALS diagnostic tool will be instrumental for (speeding up) the initial diagnosis of the disease, determining the stage of the disease, and selecting and stratifying patients for clinical studies on novel ALS therapeutics.

Therefore, within DEALS, Treeway will perform a mostly paper study to investigate the technical and economic feasibility of developing a quick and reliable diagnostic tool. These developments will be based on known and detectable biomarkers of the disease. Economic benefit will stem from the ability of the assays to enable earlier diagnosis and to speed up clinical drug development; per one month gained in development time for a new ALS drug, about €25 million additional revenues can be foreseen.
The main result achieved is the overall outcome of the feasibility study. The outcome is that the foreseen developments for the DEALS diagnostic tool are both technically as economically feasible. Importantly, the economic feasibility is in part determined by Treeway’s mission, and thereby linked to the benefit Treeway will have from the diagnostic. This benefit includes the usefulness of the diagnostic for the ALS drug development at Treeway. The diagnostic will make it easier to select the most suitable patients for clinical trials, and will make monitoring disease development during the trial easier and quicker. These features will significantly reduce the costs of such clinical investigations. The economic benefit from selling the diagnostic tool to third parties (patients, physicians, drug developers) can also be significant. Despite high development costs, the return on investment purely based on sales is foreseen within 2 years after market entry.

Therefore, the diagnostic developments will not be considered as economically feasible for just any party. However, specifically for the party Treeway the developments are considered worthwhile. Based on this analysis, Treeway has decided to take the developments forward. Treeway aims to receive support from the SME instrument phase 2 to fund the initial steps for the clinical validation of the selected biomarkers, and is drafting an application with the acronym DEALS2. Such financial support will forward developments to a point where the significant additional funds required to reach market entry can be attracted from external parties (e.g. investors, co-development partners).
Science is starting to unravel the mechanisms behind ALS and its progression. It is now mainly a matter of efficiently leveraging these research findings into drug development strategies. The availability of an efficient diagnostic tool to measure the effects of novel therapeutics will have a huge impact on the swift development of new ALS treatment options.

This SME instrument phase 1 project (DEALS) has evaluated the technological and economic feasibility for developing an ALS diagnostic tool. As discussed above, the development was rated as feasible for the specific party Treeway.

The diagnostic will importantly impact the costs of clinical drug development in ALS (by Treeway and by other drug developers). The costs of an ALS clinical trial are around 6M€. Although ALS is an orphan disease, the numbers of patients currently necessary per trial are relatively high (at least 200) as the patient population is heterogeneous and the primary endpoint currently is subjective. Demonstration of efficacy is therefore very difficult. The ability to more quickly assess efficacy will lower costs due to:
- shorter studies, requiring less man-hours
- shorter periods for patients to take medication and thus less experimental drug required
- clear quantitative read-out allowing for interim analysis that may lead to earlier termination of an investigational trial when too little efficacy is seen
- due to improved diagnosis and staging of patients smaller patient groups will be required per study
- the possibility to perform exploratory proof-of-concept studies
In addition, there is a potential enormous gain in reducing development time as the value of the IP-protected time of a marketed drug is huge; for an orphan drug this may be as much as €0.6 to €2.5 billion per month. For an ALS therapeutic we currently conservatively estimate this value to amount to at least 25M€ per month. Therefore, even a limited reduction in the time needed to assess efficacy will have a significant economic impact on the ALS drug developers.

Furthermore, the diagnostic tool developed here will support the initial diagnosis and staging of ALS. Worldwide neurologists receive >100.000 patients per year that are diagnosed with ALS. Especially as effective therapeutic options will become available, monitoring the progress of all these patients, detecting the drug’s effectiveness and if dose-adjustments are in order, will become highly important. As such, Treeway (and other drug developers) may opt to develop its novel ALS drugs with the DEALS diagnostic tool as companion diagnostic. This may significantly add to the market reach of this tool.
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