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Regenerative Clinical Trial Director: Do It for the Science

The latest CureCast will drop soon, featuring Monica Perez, a clinician-scientist at the Shirley Ryan AbilityLab in Chicago. She’s talking to hosts Matthew Rodreick, executive director for U2FP, and Jason Stoffer, U2FP Cure Advocacy Network co-director, about an important clinical trial she is leading to test an injectable regenerative drug on people with spinal cord injury – including those with chronic injuries.

This blog is a plug for the podcast, so be sure and tune in on Soundcloud, Apple, or Spotify. This is also a closer peek at the trial itself, and a call-out to potential participants.

The words chronic and clinical trial are seldom paired in a pharmacologic/regenerative SCI study. This trial is a rarity, so interest is expected to be strong. But meeting the trial requirements and actually being enrolled, that’s the challenge. 

The chronic part of the trial began in September with a plan to enroll 20 patients. (Recruitment for the subacute phase hasn’t started but will include 20 newly injured participants -- 10 days to 49 days post injury).

As with any clinical study, the NVG-291 trial has inclusion and exclusion criteria. To be eligible here, one must be an incomplete tetraplegic (C7 or higher) with the ability to volitionally initiate at least one step on one leg (without body weight support). What’s more, one needs to be in Chicago at least 5 days a week. For 84 days. And there’s this: the trial is randomized, and placebo controlled, meaning that half the participants will not get the drug but will get dummy shots instead, and no one knows which until it’s over.

So, you might be thinking: you want me to be in Chicago, in the winter, for three months, on my own tab, and I might not even get the real treatment?

Monica Perez makes the case on the podcast for why you should – for the sake of the science. To see for real if this peptide works. To do that, each participant's experience must be as close to exactly the same as possible, in the same place, tightly controlled for injury level, functional ability and response to accompanying physical therapy, and for measuring changes in spinal cord electrical activity. 

There must be a placebo group because it’s well known that thinking one has been given a drug changes peoples’ response to it – the placebo effect is often very significant and therefore must be ruled out.

Perez, with her soft Chilean accent and kindly manner, goes over trial exclusions in her CureCast interview. She makes a convincing case if you believe in the scientific method, and if you’ve seen other SCI trials fall short because they were so unfocused and equivocal in outcome.

The Drug
The study drug is called NVG-291; the letters derive from the name of the Vancouver start-up company NervGen that has license to the drug and who is paying for the trial (with a big boost from a $3.2 million Wings for Life grant). If you’ve been following us for the last few years this drug will be familiar. It’s what people call “Jerry’s peptide,” Jerry as in Silver, the Case Western neuroscientist who’s worked on SCI regeneration for 40+ years and who has presented about his work to regenerate spinal cord nerves many times at U2FP’s annual Science and Advocacy Symposium (2011, 2012, 2013, 2014, 2017, 2019).

(Note: Monica Perez presented her work at the 2022 Symposium. NervGen has also presented at the event and have been a sponsor since 2018). 

Silver’s primary hypothesis is that the scar formed after SCI contains sticky sugar molecules called chondroitin sulfate proteoglycans (CSPGs). Injured nerves typically start to grow but CSPGs stop them in their tracks. Might there be some way to clear away these inhibitors? Bingo. Silver discovered a way to neutralize CSPGs using a peptide: it ties them up and allows the body’s natural repair process to occur, bypassing the roadblock. In preclinical models, this resulted in functional growth, including plasticity, regeneration and remyelination.

Two Silver lab animal studies published in Nature (2015) and Experimental Neurology (2018) showed that NVG-291 treatment of animals with a serious spinal cord injury resulted in what NervGen described as “recovery of multiple neurological functions, including motor, sensory, autonomic and cognitive functions ….and significant recovery in mobility and/or bladder function.”

Silver said this to a reporter from Health Europa: “The recovery that we’ve seen in laboratory rats is nothing short of spectacular, especially with high doses. Our rats have gone from being completely paralyzed to walking again without any apparent impairment.” Independent researchers in Europe replicated the results, he says, using doses 50 times higher than he used, without side effects.

Silver’s lab this month published results showing fine digit and upper extremity recovery in chronic SCI animals treated with NVG-291. A beneficial effect has also been shown in models of multiple sclerosis, stroke, and brain injury.

Let’s Try This in People!
It became clear to Silver and the NervGen team that the peptide should be tried out in humans. 

The company worked for two years on the trial design. Trial protocols mirror the results of animal studies. That’s why the dose is daily for 84 days, for example. And that’s why only incomplete cervical injuries are being tested. 

Clinical trials set what are called outcome measures. What is the intended result of the study? Normally this would be the measured changes in the physical realm, e.g. strength or function. The NVG-291 trial will quantify motor function changes, including walking speed and upper extremity dexterity, but not as the primary outcome. 

Here the main target will be whether the spinal cord sends stronger electrical signals from the brain to below the lesion site. As she tells it, this is where Perez, an electrophysiologist, comes in. She says in the podcast that she joined the trial because Silver called her and asked her to – because she works at a major SCI clinical center and knows how to measure spinal cord signal traffic. 

To further understand decisions made in the trial design, and its various enrollment requirements, we’ll bring in NervGen’s chief medical officer, Daniel Mikol, MD, PhD.

I posed some hypothetical questions that a potential trial participant might ask.

Why such a long dosing period?
Mikol: Preclinical studies in SCI animal (rat) models have always administered NVG-291 as a daily subcutaneous injection for 7-8.5 weeks. The positive effect of NVG-291 became apparent (separating from placebo) within the first few weeks in the preclinical studies, particularly in the chronic SCI model. In this clinical trial, NVG-291 will be administered as a daily subcutaneous injection for 12 weeks, i.e. longer than in animal studies. This duration of treatment should be sufficient to evaluate an efficacy signal of NVG-291 in this proof-of-concept trial, particularly given the emphasis on electrophysiological measures, which are sensitive, objective measures of motor connectivity.

Why not let patients stay home, arrange with a local clinic to administer the drug? There is no specialization required for getting a shot. We would come in to SHAL for the electrophysiology measures only.  
Perez talks about this in the podcast: there is a physical therapy arm to the study that if delivered at the center will yield a more consistent, more objectively quantified result.

The trial recruitment data says the primary outcome is evidence of an electrical signal, and not just restored function. So why not widen the inclusion requirements to all incomplete SCI?
Mikol: While the use of electrophysiology is an innovative aspect of this proof-of-concept trial, we also seek to understand the effects of NVG-291 on clinical measures as well, which requires a somewhat homogeneous population (in this case, cervical SCI) to be enrolled.  When the data are eventually analyzed, results on both the electrophysiological and clinical outcome measures will be analyzed together. 

The target population is motor incomplete as the animal models are motor incomplete models. If NVG-291 shows efficacy in this study population, NervGen would be interested in understanding the potential of NVG-291 to treat other SCI populations.

What is the electrophysiology part about? You are measuring two spinal cord pathways?
Mikol: In humans, the corticospinal tract is the most important pathway controlling voluntary movement. The overarching objective of the clinical trial is to evaluate the effect of treatment on change in motor connectivity of the corticospinal tract, as reflected by change in motor evoked potential amplitudes.

The trial will also measure change in maximal voluntary contractions and latencies, the latter of which may change if NVG-291 has an effect on remyelination, which has been demonstrated in animal studies.

The reticulospinal pathway is not commonly evaluated in electrophysiological laboratories but is relevant [in this trial] because this is an important pathway for motor control in rats. This pathway, which can be activated by an acoustic startle in humans, influences the coordination of gross movements such as locomotion and balance, and in rodents is an important pathway controlling locomotion. Given the positive effects of NVG-291 in animal studies, we felt it was important to understand the potential effect of NVG-291 on this pathway in humans also, although again, it is the corticospinal pathway that is more important for voluntary motor control in humans.

I might want to participate if I knew that even getting the placebo I could be assured of getting the drug at some point. Any plans for that?
Mikol: Currently the protocol does not allow for NVG-291 treatment of placebo-treated subjects after completion of the trial. However, this is something we are definitely considering under a separate protocol, if the placebo-controlled study demonstrates efficacy of NVG-291.

How about help with finances, or at least housing?  
Mikol: We are looking into ways to provide support to potential qualifying subjects, such as temporary housing close to SRALab.

For more detail about the trial, see the NervGen website. The trial is being managed by DP Clinical (full disclosure: the SCI program manager, Jim Hamer, is on the U2FP board of directors).

One more thing: Perez admits that the trial team could have included the SCI lived experience perspective more insistently, from the get-go. We agree. Some recruitment issues might have been mitigated with full community participation.


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