Every couple of years we explore the research pipeline for therapies to treat acute spinal cord injury. Of course this may be of little or no interest to those already dealing with paralysis, but it is hugely important to clinicians around the world, desperate for treatments to minimize damage in newly injured patients.
SCI starts with sudden impact on the cord, which immediately destroys critical nerve circuits. But there is so much more damage to come: a progressive cascade of tissue injury follows in the minutes, hours and even weeks after the initial blow.
Researchers and doctors have been aware of this secondary wave of damage for many years, and have been tantalized by the possibilities of many, many experiments aimed at stopping disruption from inflammation, oxidation, neurotransmitter toxicity, cell death and so on. A lot of these therapies were reported to work in animals. To date, however, not a single neuroprotective treatment has been FDA-approved for acute SCI.
A heavy steroid called methylprednisolone (MP) was studied in the 1980s and 1990s; until about 25 years ago, MP was the de facto standard of care for acute SCI. It appeared to reduce inflammation and improve recovery. But data began to pile up that MP also caused damage to patients -- respiratory, urinary tract, and wound infections, hyperglycemia, gastrointestinal hemorrhage -- which exceeded any potential benefit. The neurosurgery literature recommended against the routine administration of methylprednisolone but left it up to attending doctors to decide. Indeed, MP is still in use, but far less so than in years past.
According to Michael Fehlings, a neurosurgeon researcher from Toronto, MP may get a second wind. AO Spine (a community of spine surgeons advancing international spine care) will soon release guidelines for MP, recommending a 24-hour course of MP within eight hours of injury for some patients. “I definitely think there is a role for MP in the acute management of SCI,” Fehlings told me.
Where are we now? Fehlings is the man. In a recent paper in the journal Neurosurgery, he and his collaborators summarized the pipeline for acute SCI, citing numerous potential therapies in various stages of development.
Among the clinical trials for acute SCI is the drug riluzole, now being tested in a Phase II/III randomized controlled trial in patients with cervical injuries, and supported in part by the Reeve North American Clinical Trials Network. Another in a Phase II/III stage is hypothermia (cooling) within six hours of injury. Miami Project studies have shown positive results. A third acute trial we’ve heard a lot about is the Asterias study of embryonic stem cells, injected two to four weeks after injury, and also only in cervical injuries.
A Phase III trial you can’t avoid hearing about if you follow SCI therapy development is the INSPIRE trial from InVivo Therapeutics, a small company that constantly cranks out press releases about its activities. The company developed a dissolvable polymer implant that is inserted inside the spinal cord within 96 hours of injury. So far, 11 patients have been enrolled. The company says eight have converted from complete to incomplete injuries (AIS A to AIS B). Says InVivo, “The AIS conversion rate observed in the INSPIRE study to date is considerably higher than published rates observed in a range of SCI natural history databases that are all below 25 percent.”
Anti-Nogo is a go: a 52-patient trial is expected to begin soon in Europe for a drug that blocks the inhibitory effect of myelin debris in the acutely injured spinal cord. This work continues three decades of work from the Martin Schwab lab in Zurich (a member of the Reeve International Consortium on Spinal Cord Injury). Earlier trial results have not been reported but Schwab told a recent science meeting that anti-Nogo showed promise in primate models. “The monkeys treated with the anti-Nogo antibody recovered function in their hands, very well.” The animals also regained bladder function, a result that was not expected. Schwab thinks his antibody boosts growth of spared spinal circuits, and that allows the spinal cord make adjustments on its own.
Here’s a trial that hasn’t revealed results, but is a stark reminder how brutal the biotech business can be: Magnesium may decrease excitotoxicity (e.g. excess glutamate; similar action as riluzole) and may also be anti-inflammatory. The New York biotech Acorda Therapeutics ran a Phase 1 study of a magnesium-based drug they called AC105. Preclinical studies showed that Mg treatment enhanced tissue sparing and promoted behavioral recovery. A 15-patient clinical trial concluded two years ago; results are unknown and AC105 is not listed on the Acorda developmental pipeline. This past week the company was hit with painful news: patents the company held for its top selling drug, Ampyra, were invalidated by a U.S. District Court, opening the door for competition from generics ten years sooner than expected. Acorda says it will appeal but meantime, the workforce will be cut by 20 percent. The company says it wants to focus on promising therapies for Parkinson’s Disease, which probably leaves the 105 drug in limbo.
In the next blog report we will look at a Phase II/III trial recruiting participants with SCI within 72 hours of injury. It involves a drug called cethrin, which may offer a double benefit – neuroprotection and enhanced regeneration. The story behind this compound, and that of Lisa McKerracher, who discovered it, are a case study in perseverance and resolve.