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The NINDS Spinal Muscular Atrophy (SMA) Project

The NINDS Spinal Muscular Atrophy (SMA) Project
Completes Discovery Phase of Therapeutics Development Program


In pursuit of its mission to reduce the burden of neurological disease, the National Institute of Neurological Disorders and Stroke (NINDS) established the Spinal Muscular Atrophy (SMA) Project, a networked contracts program to accelerate the development of therapeutic candidates for SMA. SMA is a neurodegenerative disease with variable severity ranging from limited motor neuron loss and normal life expectancy (Type III) to progressive infantile paralysis and death (Type I).

The NINDS chose SMA because of its impact on patients and families, and because basic research on SMA had provided a strategy for therapeutics development. SMA results from the loss of function of a single gene, the Survival Motor Neuron 1 (SMN1) gene that encodes the SMN protein. Increasing production of SMN protein from a "back-up" copy of the gene, the SMN2 gene, offers an attractive treatment strategy. The SMN2 back-up gene mostly produces a less stable truncated form of the protein, the "delta7" SMN protein, and small amounts of full-length and stable SMN protein. At the time when the SMA Project was initiated, researchers had already identified compounds that could increase SMN protein production from the SMN2 gene in patient cells cultured outside the body.

From its inception, the SMA Project was advised by a panel of senior experts from industry, academia, the NINDS and the U.S. Food and Drug Administration. With the guidance of this Steering Committee, the Project established a preclinical drug development effort, modeled after those conducted by large pharmaceutical companies, by funding a core group of industry contract research organizations (CROs) and partners in academia. Under supervision of NINDS scientific staff, a primary contractor organization (SAIC) managed day-to-day activities of the Project, and a Lead Development Team with extensive pharmaceutical industry experience interpreted results and planned next steps. This drug discovery strategy of contracting out specific development activities is referred to as a virtual drug discovery and development model, and is widely used by biotechnology companies, academic researchers, and other NIH programs.

Early on, the SMA Project decided to focus on small molecule drugs, rather than gene therapy, stem cells or biologics. Indoprofen was chosen as the starting point for a medicinal chemistry program after a systematic review of FDA approved drugs that had demonstrated activity in SMA-relevant assays and models. Previous studies, as part of the NINDS-sponsored Drug Screening Consortium, had shown that indoprofen could significantly increase SMN expression in a human reporter gene assay and in fibroblast cells derived from SMA patients. In addition, the increase in expression observed with indoprofen treatment translated into improved in utero survival in a very severe mouse model of SMA.  

The Project adopted a multi-tiered system for compound synthesis and testing, which is referred to as a drug development "testing funnel" because the number of compounds decreases as the testing for desired drug properties advances. The goals of the medicinal chemistry optimization effort for indoprofen included increasing the potency and brain penetrance of the drug and eliminating its inhibitory activity on cyclooxygenase, which had previously been found to be a liability for clinical use. 

Over a 5-year-period, the SMA Project synthesized and screened more than 1,400 analogs of indoprofen. Of the compounds screened in tier 1 assays, over 150 were selected for further characterization and advanced to the next tier of the testing funnel. This included several assays to measure increases in SMN protein levels in patient fibroblasts, and assessments of compound bioavailability, genotoxicity and safety profiles.

Key Accomplishments and Findings

Potential SMA Therapeutic Candidate. Among the indoprofen series of compounds, one analog in particular, ALB-111, emerged as a potential drug candidate for SMA. After two key in vitro assays had shown that ALB-111 could increase cellular SMN protein levels, and the compound was shown to have relatively good brain penetration, ALB-111 was tested in vivo in two different SMA mouse models, the moderately affected C/C mice and Arthur Burghes' more severely affected delta7 mice. The SMA voluntary organizations had played a key role in the development of these two SMA animal models. Significant increases in SMN protein levels were observed in the liver and—to a lesser extent—the brain of C/C mice treated with ALB-111 for 15 days.

SMA Project researchers at PsychoGenics performed a hind-limb strength test on delta7 mice and observed a significant improvement in animals treated with ALB-111 compared to controls in three of four trials. Treatment with ALB-111 did not, however, alter body weight, survival or gravitationally directed movement in these severely affected SMA mice, which have an average lifespan of only about 12 days. SMA Project researchers also conducted toxicity and pharmacokinetic analyses of ALB-111 and found that the compound has good drug and safety properties, and could be delivered orally to patients. The main hurdle of ALB-111 has been its limited solubility. A consultant of the SMA Project recently devised a formulation approach to improve the solubility and oral availability of the compound. ALB-111 is now at the late lead compound stage of the preclinical drug development process.

Industry Adoption of ALB-111. Starting in July 2012, the NINDS initiated discussions with several pharmaceutical and biotechnology companies to determine whether ALB-111 meets their technical requirements as a late-stage lead compound, and if so, to identify a partner to conduct the next steps of preclinical drug development.

Compound Library. SMA Project medicinal chemists developed a 1,400+ patent-protected compound library that could be rich in biological activities. NINDS is seeking to grant an exclusive license for either the entire platform, or to license subsets of compounds. NINDS is offering interested parties the opportunity to test these molecules, which are available in plate format, in their own assays and to pursue further drug development under a Material Transfer Agreement. 

Other Outcomes. NINDS conceived the SMA Project as a pilot program to expedite therapeutics development.  Lessons from the SMA Project have guided the design of other drug development programs at the NIH, including the NIH Blueprint Neurotherapeutics Grand Challenge. Furthermore, NINDS’ choice of SMA for this pioneering effort has helped catalyze increased interest in SMA therapy development. Development of a variety of candidate drugs and biologics targeted to SMA is now underway at several pharmaceutical and biotechnology companies, as well as in multiple academic laboratories. Clinical trial resources, diagnostic screening tests and biomarkers are being developed to facilitate clinical trials of candidate therapeutics for the disease.

Community Involvement. The SMA voluntary organizations and patient advocate community played a key role in the establishment of the SMA Project in 2003 and have supported it strongly ever since. Throughout its duration, these groups lent their scientific expertise to the Project, and made a number of critical assays and tools available that helped move it forward. The present status of the Project is that a late-stage lead compound has been developed that may be of interest to a pharmaceutical/biotechnology company, to further develop and take into clinical trials. The NINDS actively encourages feedback and input from the SMA community regarding the path forward.

NINDS contact information:

Amelie K. Gubitz, Ph.D.
Program Director, Neurodegeneration
6001 Executive Blvd., Room 2154
Bethesda, MD 20892
Tel: (301) 496-5680

Last updated December 23, 2013