Cerebroprotection As An Approach for Ischemic Stroke Care

Patrick Lyden, MD, PhD

Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide.¹ Typical treatments to restore blood flow have involved emergency intravenous medications, namely recombinant tissue plasminogen activator (TPA), endovascular procedures, and other methods such as carotid endarterectomy, angioplasty, and stents.

Time is extremely valuable in the stroke treatment paradigm, and the math is simple: the sooner treatment begins, the better odds of recovery. Despite advances in acute treatments for stroke, these approaches are restricted to causative recanalization and restoration of cerebral blood flow, and thus, have no impact on brain protection, or what those in the field like to call ‘cerebroprotection’.²

Despite the advances in acute treatments for stroke, development of cerebroprotective agents has been a challenge thus far. "Ischemia is multifaceted, there’s a lot of things happening in parallel," stroke expert Patrick Lyden, MD, PhD, told NeurologyLive^®. "The idea that you could turn it off with 1 magic bullet targeting 1 enzyme was not true. Now, we have a lot of agents that are able to protect not only neurons, but glia and endothelium. The term ‘cerebroprotection’ tries to capture that notion that it’s not just about neurons, it’s not just about neuroprotection, but it’s about protecting the brain or ‘cerebroprotection.’"

Lyden, a professor of physiology and neuroscience at the Zilkha Neurogenetic Institute in the Keck School of Medicine at the University of Southern California, has written several papers on the emergence of this concept. He believes, like many others, it will take a combination of therapies and targets to truly have a significant impact on preserving brain health following ischemic stroke.

A Look at the Pipeline

To date, hundreds of potential cerebroprotective/neuroprotective drugs have shown promising preclinical evidence; however, none of them have been successfully transferred to daily clinical routines. There are several emerging concepts being tested, including therapeutic hypothermia, ischemic conditioning, targeting 3K3A-activated protein C (APC), nitric oxide, stem cells and extracellular vesicles (EVs), and the microbiota-gut-brain axis.²

There are several promising neuroprotective candidates in the pipeline, including nerinetide (NoNO Inc) and sovateltide (Pharmazz Inc). Nerinetide, a 20–amino-acid peptide that prevents the postsynaptic density protein 95 from attaching to the NMDA receptor subunit, had its efficacy and safety evaluated in a large-scale, placebo-controlled phase 3 study called ESCAPE-NA1 (NCT02930018). The trial featured 1105 adults with disabling stroke who had an Albera Stroke Program Early CT Score greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography.

Sean Savitz, MD

Results from ESCAPE-NA1 showed no treatment benefit on the primary end point of functional outcome; however, investigators did observe evidence to support a modification of nerinetide treatment effect by usual care of alteplase treatment in an exploratory analysis.³ In the no alteplase stratum, nerinetide was associated with improved outcomes, whereas no observed benefit was found in the alteplase stratum, with the absolute risk difference slightly (but not significantly) favoring placebo. All told, 49.8% (113 of 227) of those without alteplase receiving placebo achieved a modified Rankin Scale (mRS) score 0-2, whereas 59.3% (130 of 219) receiving nerinetide achieved mRS score 0-2 (adjusted rate ratio, 1.18; 95% CI, 1.01-1.38).

The results of ESCAPE-NA1, despite not meeting the originally intended benefit, still represented encouragement for the development of other neuroprotective drugs, as well as negated some of the "hopeless perception in the field of neuroprotective drug development," as noted in a 2021 editorial by Xin-Fu Zhou, PhD, MS, of the University of South Australia. He added that excitotoxicity, oxidative stress, apoptosis, and autophagy all are excellent targets for the development of such therapies.⁴

On nerinetide, stroke expert Sean Savitz, MD, believes this is an intelligent approach to cerebroprotection. "We’re talking a story that’s more than 10 years in the making, where they’re blocking the detrimental signaling pathways that are activated by glutamate. And they’re doing it in a way that only blocks the detrimental signaling, but also doesn’t interfere with any of the other processes and signaling that glutamate mediates in the brain as part of normal functions."

Sovateltide, an agonist of the g-protein coupled endothelium B receptors, is also currently being evaluated as a potential medication to treat cerebral ischemic stroke. In a phase 3, double-blind, placebo-controlled trial, a significantly higher proportion of patients treated with the therapy achieved improvements of at least 2 points on mRS (76.1% vs 52.8%; P = .005), and a greater number of participants showed at least a 6-point improvement in National Institute of Health Stroke Scale score (82.1% vs 64.3%; P = .019) than placebo.⁵

Following those positive results, Pharmazz Inc, the developer of sovateltide, announced an FDA clearance for a large-scale phase 3 trial assessing the agent in 444 patients with acute cerebral ischemic stroke. That trial, announced in February 2023, is intended to be used as potential pivotal efficacy evidence to support a future new drug application.⁶

Savitz, who is a professor of neurology and director of the Institute for Stroke and Cerebrovascular Disease at the University of Texas Health Science Center at Houston, added that, “the most promising [agents] are ones that are trying to block the ischemic pathophysiology very early on after a stroke occurs. Once these molecular mechanisms are activated or unleashed, they can lead to the ultimate death or dissolution of neurons and other brain cells."

"Right now, there’s a whole bevy of different [approaches]," Lyden noted. "There are some molecules that target multiple cells—agents that act on blocking thrombin, which has a receptor in the brain (the protease activated receptor), and those are found on neurons and glia and endothelial cells. Some other enzyme processes like Rho kinase are blocked in multiple cells. The idea is to find something that, if it’s a single enzyme, maybe it occurs in multiple cells and is a multiple targeted strategy, or to find something like uric acid, that may act in multiple different ways in the brain to protect multiple cells."

Uric acid, a chemical created when the body breaks down substances called purines, has emerged as a potential therapy to enhance recovery from ischemic stroke. A 2023 preclinical study led by Lyden tested 6 candidate therapies, including uric acid, based on prior research showing evidence that they could potentially treat stroke. In animal models, uric acid was the only candidate that passed the efficacy boundary through all phases of analysis. The other interventions, which included 4 drugs approved by the FDA to treat other conditions and remote ischemic conditioning, an experimental medical procedure, were dropped after the second or third evaluation.^7,8

That research, conducted by the NIH’s Stroke Preclinical Assessment Network (SPAN), is ongoing, and is expected to expand to include more testing sites and evaluate 5 additional cerebroprotective approaches. The SPAN design and infrastructure present a unique and innovative method to stroke research that could be used in similar preclinical, multi-laboratory studies in other disease areas.

Remaining Questions

Finding the right approach to cerebroprotection remains the biggest question of them all. “Nobody knows what the best combination is,” Lyden said. “Synergism isn’t just taking 2 things and putting them together, you have to show that the combination is stronger than the drugs by themselves. Combinatorial therapy is standard in oncology. They do this routinely. For some reason, in neurology, it’s not done. In my opinion, there’s no doubt it’s the way in the future, where we’re going to have to find synergistic combinations of drugs that tackle multiple places."

Lyden, who’s written a publication on synergism in stroke, remarked that the timing of these combination approaches matters as well. "A drug that benefits the neurons maybe should be given early, but a drug that benefits the glia maybe should be given later, after some time. Sometimes people talk about a combination therapy ‘cocktail,’ or putting it all together at once. My idea is not a cocktail, but more of a wine pairing. There’s an early drug, a drug in the middle, and a drug at the end that is just right so it pairs perfectly with the pathophysiology evolving over time."

There are several other questions that will need answering over the coming years, including whether certain cerebroprotective approaches improve clinical outcomes, as well as whether cerebroprotection can only work if administered at the earliest stages. "How do we integrate that type of therapy with our standard-of-care reperfusion? Because the major focus, particularly in public health care, is to identify these ischemic stroke populations as quickly as possible, and get them to a center where they can receive IV thrombolytics, and if they quality mechanical, endovascular thrombectomy," Savitz added. He notes that it will be critical for the field to identify productive ways to incorporate these agents without interfering in currently used standard of care treatments.

Traditionally, research has shown that treating patients with stroke within the 4.5-hour window of their last well known will lead to better outcomes and prognosis, hence the phrase “time is brain.” Going forward, the field will need to answer questions about the timing of these treatment approaches, especially if they are combinatory as anticipated, and how far out their treatment effects may truly last. In recent years, clinicians have identified more patients that benefit from reperfusion, with some seeing benefits out to 24 hours after stroke.

"Does that mean cerebroprotection/neuroprotection could work for some of those patients if they have an underperfused brain but yet still had salvageable tissue?" Savitz asked. "We’ve got lots of big questions to answer. Could any of these types of approaches for cytoprotection work days after injury? They may be working on glutamate excitotoxicity, or other proximal events. There’s even been some really interesting studies looking at anti-inflammatory or immunomodulatory approaches, even cell-based therapies are working potentially in this fashion. You could also say that they are involved in the protection of cells one way or another."

He added, "I think the field is very bright looking forward with regards to these types of questions."

REFERENCES
1. Haupt M, Gerner ST, Bahr M, Doeppner. Neuroprotective strategies for ischemic stroke–future perspectives. Inter J Mol Sci. 2023;24(5):4334. Doi:10.3390/ijms24054334
2. Diaz-Tejedor E, Gutierrez-Fernandez M. Why do we say ‘neuroprotection’ in stroke when we mean ‘brain protectionor cerebroprotection’? Eur Stroke J. 2019;4(3):281-282.
3. Hill MD, Goyal M, Menon MK, Nogueira RG, et al. Efficacy and safety of nerinetide for the treatment of acute ischemic stroke (STROKE-NA1): a multicentre, double-blind, randomized controlled trial. The Lancet. 2020;395(10227):878-887. doi:10.1016/S0140-6736(20)30258-0
4. Zhou XF. ESCAPE-NA1 Trial brings hope of neuroprotective drugs for acute ischemic stroke: highlights of the phase 3 clinical trial of nerinetide. 2021;37(4):579-581. Doi:10.1007/s12264-020-00627-y
5. Clinical phase 3 trial results demonstrating sovateltide’s efficacy to treat acute cerebral ischemic stroke presented at the international stroke conference 2023. Pharmazz. February 10, 2023. Accessed February 27, 2023. https://www.prnewswire.com/news-releases/clinical-phase-iii-trial-results-demonstrating-sovateltides-efficacy-to-treat-acute-cerebral-ischemic-stroke-presented-at-the-international-stroke-conference-2023-301741886.html
6. Pharmazz Inc announces US FDA clearance for a phase 3 clinical trial of sovateltide (PMZ-1620) in acute cerebral ischemic stroke patients. Pharmazz. February 13, 2023. Accessed February 27, 2024. https://www.prnewswire.com/news-releases/pharmazz-inc-announces-us-fda-clearance-for-a-phase-iii-clinical-trial-of-sovateltide-pmz-1620-in-acute-cerebral-ischemic-stroke-patients-301744465.html
7. Researchers develop new method to identify potential stroke therapies. National Institutes of Health. September 20, 2023. Accessed February 27, 2024.https://www.nih.gov/news-events/news-releases/nih-researchers-develop-new-method-identify-potential-stroke-therapies
8. Lyden PD, Diniz MA, Bosetti F, et al. A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke. Science Translational Med. 2023;15(714). doi:10.1126/scitranslmed.adg8656