Earliest Time Frame of Potential SCI Therapies
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey
Many people have been asking about potential time frames of therapies that are under development for spinal cord injury. There are too many unknowns to predict when therapies will be available. However, it is possible to estimate what the minimum time requirements are for treatments that are currently under development, assuming that all goes well. If there are any problems, of course, the development will be slowed down substantially or stopped.
Let me first define some terms for people who might not be familiar with clinical trials. Phase 1 refers to clinical trials that are primarily concerned with demonstrating safety and feasibility. Such trials often do not have controls and are not sufficiently powered (i.e. have enough subjects) to demonstrate efficacy. Phase 2 refers to clinical trials that are optimizing therapies, looking for efficacy. If the trial is sufficiently powered to show efficacy, they are called Phase 2b. Phase 3 trials are “pivotal trials” intended to demonstrate efficacy of an optimized therapy.
Several assumptions were made in the following analyses. First, all goes well in the trials, i.e. the trials don’t run into any trouble in terms of safety and all the trials show positive results. Second, adequate financial resources are available for preclinical and clinical studies. Many treatments may fall out of the following list. Nevertheless, with sufficient therapeutic options available for trial, one or more the therapies should show significant benefit with acceptable risk. The rate-limiting step is funding and not therapeutic options.
Earliest Possible Times for Pivotal Results
Brief description of therapies (potential mechanisms, company)
• Treadmill training (restoration of locomotion, many companies). Several groups have shown that intensive treadmill training can restore locomotor function to 20-40% of patients with incomplete SCI. Robotic devices (Lokomat, etc.) may be approved by next year.
• Fampridine SR (improve conduction in the spinal cord, Acorda). Several phase 2 trials indicate that 4-AP can improve motor and sensory function in as many as 30% of people with chronic spinal cord injury. A pivotal trial is underway with spasticity as the endpoint.
• Peripheral nerve bridging to bladder (reinnervate bladder). The approach to reinnervating the bladder is already being tried in China. If phase 2 trials start in 2003, phase 3 in 2004-2005, pivotal results may be available in 2005.
• Peripheral nerve bridge of spinal cord injury site coupled with a growth cocktail (to stimulate regeneration, Cheng in Taiwan). This approach is being carried out in Taiwan by Henreich Cheng. He has already done over 50 patients in combined phase 1 and phase 2. A pivotal phase 3 may be planned for 2003-2004.
• AC electrical currents (stimulate regeneration, Purdue or Traxon). Phase 1 trials have started for subacute spinal cord injury at Purdue and chronic spinal cord injury in Dublin (Traxon). Phase 2 trials in 2003 and possibly pivotal results by 2004.
• Lumbar L2 stimulation (activate locomotor center and accelerates locomotor training, possibly Medtronics). Two groups have conducted phase 2 trials showing that L2 lumbar stimulation accelerates locomotor recovery. If phase 3 trials start in next year, we should have pivotal results by 2004.
• Activated macrophages (growth factors delivery, Proneuron). Phase 1 trials are now being done. Phase 2 trials in 2003. Phase 3 in 2004-2005. Pivotal results in 2005 but only for subacute spinal cord injury. So far, Proneuron does not have plans for using activated macrophages for chronic SCI.
• AIT-082 (stimulates axonal growth and stem cell proliferation). Phase 2 trials by Neotherapeutics are underway. Results should be available by 2003 and phase 3 trials (if the company gets funding) may start in 2003 and pivotal results may be available by 2004 but only for subacute SCI.
• Inosine (stimulates axonal growth and sprouting, Boston Life Science Inc). Preclinical trials are being done now. Recent safety studies have been completed. Assuming phase 1 studies start in 2001, phase 2 studies in 2002, and phase 3 in 2003-2004, pivotal results may be available by 2005.
• Copaxone (stimulates antibodies to myelin-basic protein and lymphocytes). Preclinical trials indicate beneficial effects on subacute SCI. Because this drug is already approved for MS, this can go directly to phase 2 in 2003, possibly phase 3 in 2004-2005 with pivotal results by 2005.
• Rolipram (phosphodiesterase 4 blocker stimulate regeneration, Filbin). Preclinical trials are underway. Rolipram is already being tested in phase 2 trial for MS. If Rolipram goes to phase 2 in spinal cord injury in 2004, phase 3 in 2005-2006, pivotal results may be available by 2006.
• Nogo receptor blockers (stimulates axonal regeneration and sprouting, Biogen). Preclinical trials just reported. If confirmed, phase 1 trials perhaps by 2003, phase 2 trials in 2004, phase 3 trials in 2005-6, we may get pivotal results by 2006.
• Fetal stem cells (stimulates regeneration and sprouting). Phase 1 trials alrady completed in Russia and underway in China. If this goes into phase 2 by 2003 in China and phase 3 in 2004-2005 in the U.S., we may get pivotal rsults by 2006.
• Fetal olfactory ensheathing glia (stimulates regeneration and sprouting). Phase 1 trials already completed in Russia and underway in China. If this goes into phase 2 by 2003, phase 3 in 2004-2005, we may get pivotal results by 2006.
• M1 antibody therapy (enhances remyelination of the spinal cord). Preclinical trials are largely completed. A phase 1 trial is planned for 2003, phase 2 in 2004, and phase 3 in 2005-6, with pivotal results in 2006.
• Porcine olfactory ensheathing glia (stimulates regeneration and sprouting, Alexion). Preclinical trials completed. If this goes into phase 1 trials in 2003, phase 2 trials in 2004, phase 3 trials 2005-2006, we may get pivotal results by 2007.
• Adult human olfactory ensheathing glia autografts (stimulates regeneration and sprouting). Preclinical trials completed. If this goes into phase 1 in 2003, phase 2 in 2004, phase 3 in 2005-2006, we may get pivotal results by 2007.
• Adult bone marrow human stem cells (provide a bridge for axonal growth and remyelination). Preclinical trials are continuing. If this goes into phase 1 in 2003, phase 2 in 2004, phase 3 in 2005-2006, we may get pivotal results by 2007.
• Adult neural stem cells (provide a bridge for axonal growth and remyelination). Preclinical trial are continuing. Phase 1 trial has been proposed. If phase 1 starts 2003, phase 2 in 2004, phase 3 in 2005-2006, we may get pivotal results by 2007.
• Chondroitinase (breaks down chondroitin-6-sulfate proteoglycans to allow axonal regeneration). Preclinical results for subacute SCI in 2002. If a company picks this up, phase 1 trials are possible in 2003, phase 2 in 2004, and pivotal results by 2006. In preclinical results for chronci SCI in 2003, this may lead to phase 2 in 2004, and pivotal results by 2007.
• IN-1 (antibody that blocks Nogo to stimulate axonal regeneration and sprouting). If preclinical studies completed in 2003, phase 1 probably will start in 2004, phase 2 in 2005, and phase 3 in 2006-2007 with possible pivotal results by 2008.
• Recombinant C3 toxin blockade of rho GTPase (enhances axonal growth in the presence of growth blockers, Bioaxone). Preclinical studies suggest that this treatment will stimulate axonal regeneration. These are continuing. Phase 1 trials may begin by 2004, phase 2 in 2005, and phase 3 in 2006-2007, with pivotal results in 2008. Pivotal results for chronic SCI may take a year or two longer, i.e. 2009.
• Therapeutic vaccine (produces antibodies and activate lymphocytes). Preclinical studies suggest that myelin basic protein may have positive effects on subacute SCI. Phase 1 trials may start in 2004, phase 2 in 2005, and phase 3 in 2006-2007 with pivotal results by 2008.
• Cell transplant + growth factors (bridge injury site and stimulate regeneration). The cell transplants may be OEG, fetal stem cells, adult stem cells, etc. Growth factors may include any of the treatments such as neurotrophins, rolipram, AIT-082, chondrotinase, etc. These combination therapies will probably start in 2007 once the cell transplant data comes in. Pivotal data for combination cell transplant and growth factor trials may be available within 2 years after the growth factors have been shown to be effective.
• Embryonic stem cell therapies (replacement of neurons). Preclinical studies suggest that embryonic stem cells can replace neurons in the spinal cord. However, due to restrictions in funding and supply of embyronic stem cells by the U.S. government, I am assuming that phase 1 and 2 trials of embryonic stem cell therapies will not start until overseas studies show sufficiently positive results to force the government to relax their restrictions or the current administration changes policies in 2008. In such a case, pivotal trial results may become available by 2012.