The Enterprisers: Life Science Leadership In Action
Not everyone knows someone with a spinal-cord injury. I did. We met as teenagers, shared a few years as friends but lost touch when I drifted to the opposite end of the country. Then, one day, I picked up the phone and heard through his girlfriend’s sobs that he had broken his neck in a swimming accident and was paralyzed from the mid-chest down. When I later visited him and spent some nights on his couch, I could hear him crying out in the morning, “Why me?” But, tough as nails, he remained a great human being to the end, and after tripling his predicted lifespan, he died just two years ago, more than three decades after his accident.
Through all of that time, we looked for a significant breakthrough in preventing or restoring lost function due to spinal-cord injury (SCI). Once, for an article based on my friend’s suggestion, I interviewed Chris Reeve at his home in New York and came away inspired with new hope. That was 16 years ago, and everyone who lives with such a condition is still waiting for the same breakthrough — that is, perhaps, until now.
It seems necessary to share all of the above as context for this article — the story of InVivo Therapeutics. It is not only because extraordinary claims require equal caution, but also because I have never seen such a bold and ambitious approach to treating, dare I say healing, one of the worst injuries anybody can sustain. InVivo’s development of a tiny scaffold inserted into the injury site also takes me into new territory, because I have spent most of my career covering pharmaceuticals rather than devices. But the company’s story merits attention in “The Enterprisers” both for its ambitious goal and its means for reaching it.
Spinal-cord injury is a rare condition — in the United States, it affects fewer than 300,000 total patients, or about one in every 1,000 people, with only about 12,500 new patients per year. Unless already wealthy or financially secure, SCI patients tend to live on the economic margins, with mercurial granting of Medicaid benefits and medical attention, except for the most severe cases. Countless discoveries, inventions, and treatment approaches for SCI have percolated out of various labs and institutions over the years, yet so far no company has succeeded in commercializing a transformative treatment. A near exception was a program for the neurogenesis agent Sygen (bovineextracted monosialoganglioside), which had the sponsorship of the Italian company Fidia, but its clinical development stalled in the United States.
InVivo has followed the startup path, dedicating itself entirely to gaining FDA approval and practical adoption of its approach as the standard of care for U.S. patients. Its lead product, the Neuro-Spinal Scaffold, placed by an innovative surgical approach into the spinal cavity caused by the injury, may arrest further tissue death and create a “neuro-permissive” environment, friendly to nerve healing and regrowth. The FDA has given the product fasttrack status as a Humanitarian Use Device (HUD) and allowed InVivo to convert a pilot study into a pivotal clinical trial. A second, related program still in the research stage at the company, Bioengineered Neural Trails, would add an infusion of neural stem cells in a biomaterial at the injury site.
The first 24 hours after an SCI event is a critical window for intervention. When vertebrae break, the shattered pieces push into the spinal cord and cause hemorrhaging, swelling, reduced blood flow, and ischemia necrosis. The trauma begins to kill and liquefy the innermost neurons or grey matter cells, which are surrounded by neural white matter cells inside the spine. Unimpeded, the necrosis will hollow out the entire area, creating a dead zone that thoroughly disconnects the spinal cord below the injury from the cord above.
To preserve as much of the connection as possible, the Neuro-Spinal Scaffold procedure must take place as early as possible after injury. In InVivo’s first, five-patient study, researchers were encouraged to treat within the 24-hour window but in some cases found it practically impossible to do so. Nevertheless, one of the patients in the study who showed significant improvement received treatment at 80 hours, and if approved, the Neuro-Spinal Scaffold procedure could be used up to 96 hours post-injury.
In the procedure, the surgeon first siphons off the dead, liquefied cells, then inserts the highly porous biopolymer scaffold into the resulting cavity, where it gives support and protection for the remaining nerve tissue and allows natural regrowth, hopefully to restore basic functions such as bladder and bowel control. One of the polymers is PLGA (poly lactic-co-glycolic acid), a biodegradable structure for cell regrowth; the other is poly-L-lysine, to promote cell adhesion. The scaffold thus propels appositional healing, in which new neurons sprout and strengthen connections across the periphery of the injury by detouring around it.
With the aim of promoting extensive regrowth and even reconnection of nerve channels to the brain, Bioengineered Neural Trails would employ a patented device to make a longitudinal injection of stem cells incorporated into an injectable scaffold soft gel for the treatment of patients with chronic spinal cord injuries. Past stem-cell treatments have used multiple trans-spinal injections plagued by reflux and poor cell distribution. To avoid those faults, the longitudinal method leaves a clean line of cells along the path of healing.
From Academe To Enterprise
InVivo’s technology originated in the laboratory of Robert Langer at MIT, which has been a prolific source of life sciences inventions and startups. “Bob has spawned about 30 companies out of his lab and holds more medical patents than anyone else in the world — and more patents generally than anyone except Thomas Edison,” says Mark Perrin, InVivo’s chairman and CEO.
When Perrin joined the company two years ago, it was trying to advance two main programs at once — hydrogel drug delivery and spinal injury. He soon came to see the dual focus as diluting company efforts and distracting it from the novel “sweet spot” in its portfolio: the Neuro- Spinal Scaffold. At the time, he says, the company’s management was somewhat in disarray, with all the chief officers in only interim assignments. The situation gave him the opportunity to apply his business and commercial background — at Burroughs Wellcome, Lederle, and a number of smaller companies such as COR Therapeutics — to building his own team and steering InVivo in a new direction.
Perrin went after even more industry experience. He recruited Tom Ulich, M.D., former head of preclinical development at Amgen, as chief scientific officer; Lorianne Masuoka, M.D., formerly of Cubist, as chief medical officer; and Tamara Joseph, also from Cubist, as general counsel. He also terminated the drug-delivery program and concentrated the company’s efforts on SCI. On a practical level, that meant raising enough cash to fund operations and accelerating clinical development of the Neuro-Spinal Scaffold.
At that point, the FDA had given the green light to the company’s small pilot study in humans, a significant step following the extensive preclinical development in rodent and primate models. The study involved five patients with complete thoracic injury — total paralysis below the site of injury, in the thoracic region directly below the neck. Complete-injury patients have the highest rating, AIS A, on the American Spinal Injury Association’s (ASIA) Impairment scale (AIS). Incomplete injury, where patients have some feeling or function below the injury site, carries the rating AIS B through AIS D, and AIS E represents normal function. Conversion from a higher to a lower score, as from AIS A to B or C, thus represents improvement in the paralysis.
Perrin says the FDA initially wanted InVivo to study patients sequentially — treating one patient at a time, waiting three months, and evaluating the results before treating the next. “But after completing the process with Patient 2, after we had established a good dialogue between the new members of our team and the FDA, the agency agreed to concurrent enrollment for Patients 3, 4, and 5. That probably took a good year off the early development program.”
With the HUD designation, the scaffold is traveling the HDE (humanitarian device exemption) pathway. “HDE sounds like an orphan drug designation, and that is the comparable regulatory pathway for devices, but with a big difference — rather than running a placebocontrolled trial to show significance, all you need to do is show probable benefit,” Perrin says. “So it’s a classic risk-benefit analysis, and we must demonstrate a benefit outweighing the risk.”
What InVivo needed was an agreement with the agency on an “objective performance criterion” to support its probable benefit claim. Fortunately, some relevant benchmarks already exist in the form of large historical patient databases: the European Multicenter Study about Spinal Cord Injury (EMSCI), the Spinal Cord Injury Model System (SCIMS), and the Sygen clinical trial. EMSCI showed a conversion rate of 15.6 percent at six months; SCIMS, 15.5 percent at 12 months; and the Sygen trial, 12.9 percent at six months. Thus, the estimated baseline recovery rate is between 12 to 15 percent.
Besides movement and feeling, including sexual function, the most critical losses in SCI are bladder and bowel control — the separate but related abilities to recognize and prepare for when the body needs to “go.” Adapting and responding to the resulting incontinence can become almost a full-time preoccupation for patients. Fortunately, in the rare cases when SCI patients improve, bladder control and bowel control are often among the first functions to return. It appears conversion by treatment may follow the same pattern.
Among the first five patients treated with InVivo’s scaffold, one converted to AIS C and another to AIS B at one month and a third to AIS B at six months. The first patient regained bowel and bladder function and has experienced ongoing, and one could say dramatic, return of sensation and movement below the injury. The second patient to convert continued to regain sensory function through month six. A fourth patient remained AIS A but showed significant recovery of bowel and bladder function through month 12.
“We have a video of the first patient’s surgery and a video of the patient walking at 12 months,” says Perrin. “He is walking with braces, but he’s walking. Dr. Nick Theodore, one of the world’s thought leaders in this field, did the surgery in October 2014 at the Barrow Neurological Institute in Phoenix, the largest neurological center in the United States. The patient was a young gentleman involved in a motocross accident, completely paralyzed from T11 down. At one month, he had improved to AIS C already, and at three months, he began to get recovery of function in his hips, and at six months, in his knees, and he was then able to lift his legs against gravity. At 12 months, in addition to walking up to a quarter mile with braces, he had regained function in his ankles and had complete bowel and bladder function.”
Trial By Inspire
Based on such results, the FDA granted the company’s request to expand the pilot study to a 20-patient trial that would include the first five patients already tested, with a six-month primary endpoint of conversion from complete to incomplete injury status, or from AIS A to AIS B or better. Bending the normal bounds of acronyms somewhat, InVivo dubbed the trial INSPIRE (InVivo Study of the Probable Benefit of the Neuro-Spinal Scaffold for Safety and Neurologic Recovery in Subjects with Complete Thoracic AIS A Spinal Cord Injury). The objective performance criterion for the study is 25 percent or more of the patients in the study demonstrating an improvement of at least one ASIA Impairment Scale (AIS) grade by six months post-implantation. The conversion rate for the first five patients in the study was 60 percent.
Of course, this is thoracic, not cervical SCI. My friend’s injury was low in the cervical region, so although he had total paralysis from the top of the chest down, he also had partial impairment of his arms and hands, and, most important in everyday life, he could not oppose his thumbs to achieve a firm grasp. Chris Reeve’s injury was at the very top of the spine, so his paralysis extended all the way down from there. Generally speaking, in SCI, the higher in the spine, the more serious the injury — more and more nerve channels join the spinal cord as it approaches the brain. It is literally a simpler matter to show treatment benefits in the lower body than higher up, even though the upperbody gains may be more dramatic.
But InVivo seems ready to take on the next challenge. The company plans to initiate a second study with the Neuro-Spinal Scaffold in mid-2016, this time treating acute cervical SCIs in expanded populations — and again using the HDE path. It may also take the premarket approval (PMA) route for further expansion and acceleration of the scaffold program. A trial designed for PMA approval would allow the company to test the scaffold in all acute SCI patients, even those with incomplete injuries, and it could put the product on the FDA’s Expedited Access Pathway (EAP) for devices, similar to the Breakthrough Therapy Designation on the drug side. With EAP, the FDA could grant a PMA for the device based on a two-phase study — one that meets certain criteria before approval and delivers confirmatory data post-approval.
“There is a big difference between cervical and thoracic injury,” says Perrin. “If you can gain an inch in the thoracic spine, there’s a lot of real estate there, so you may only get another area of feeling one level down. But, in the cervical spine, if you gain one level, it could make a huge difference, such as taking the patient off a ventilator or restoring the hand grasp. So the endpoints will be quite different in the cervical trial than in the thoracic trial, with ventilator dependency and hand grasp the two biggest additions.”
At present, SCI patients receive the same initial treatment my friend experienced 36 years ago, decompression, or external stabilization of the spine with rods and bolts, which does not address the necrotic process in the spinal cord itself. “What was so attractive to me about InVivo was that, among all the therapeutic categories in which I had worked before, I had never seen another one like SCI, where patients have no good treatment options to improve their lives,” Perrin says.
My friend loved to dream. When he slept and dreamt, he could walk and run and feel his entire self as most of us do. And when awake, he would dream about taking a trip in the space shuttle, where he would be free of the awful force of gravity on a paralyzed body. But most of all, he dreamed about a way to heal spinal-cord injury, even if it would only apply to the newly injured and not to himself. I believe he would share in the excitement over InVivo’s approach as do the people at the Christopher & Dana Reeve Foundation. Where before there was only hope, the company may succeed in bringing progress.