NeuroVive Pharma updates on cyclosporine’s progress toward approval as a pharmaceutical for treating moderate to severe traumatic brain injury
Part 2: Addendum
Authors: Steve Campbell, Eskil Elmér, Mikael Bronnegard
Patient No. 1: German Boy Recovers After Severe Head Injury
Sometime in the 1990s, an anonymous 14-year-old German liver transplant recipient — regularly using cyclosporine to prevent tissue rejection — was hit by a car and suffered head injuries. By chance, an anaesthesiologist was at the scene when the accident occurred. He immediately examined the boy and suspected severe brain damage, later confirmed by an early Glasgow Coma Scale (GCS) score of three.
Although the worst was feared — children under 14 with a GCS below eight have a 28% mortality rate or have significant brain disability if they do survive — the patient not only survived but proceeded to make an amazing recovery. He was discharged from hospital five weeks later and was able to return to school after two months. He recovered unexpectedly well and is now an adult with a young son living in a town in northern Germany. The neuroprotective properties of cyclosporine were suspected in the recovery and the case was reported in a detailed case study published in the Journal of Neurosurgical Anesthesiology in 1998. The study concluded: “We conclude that neuroprotective properties of cyclosporine A [sic] may have been involved in the good recovery after severe brain injury in this 14-year-old patient.”
1. Gogarten W, Van Aken H, Moskopp D, et al. A case of severe cerebral trauma in a patient under chronic treatment with cyclosporine A [sic]. Journal of Neurosurgical Anesthesiology. 1998 10 (2): 101-105.
Cyclosporine Mitigates Heart Attacks in Proof-of-Concept Study
Mitochondria are present and producing effective energy in almost all cells in the body. It turns out that mitochondrial collapse and dysfunction may be associated with a variety of acute injuries, such as myocardial infarctions and also chronic diseases such as ALS, MS and other neurological disorders. In myocardial infarctions, reperfusion (re-opening) of the blocked artery can cause what’s called reperfusion injury, and extra damage and disability to the heart muscle, as well as increased mortality. The mechanism of action and process underpinning this additional damage to the heart muscle is the same as that affecting brain cells during traumatic brain injury. Mitochondrial protection in heart muscle tissue is one answer to moderating the long-term impact of heart attacks on health and lifestyle.
Every year, an estimated 500,000 people in the United States have a myocardial infarction. Infarct size is a major determinant of mortality. During myocardial reperfusion, the abruptness of the reperfusion can cause additional damage — a phenomenon called myocardial reperfusion injury. Studies indicate that this form of injury can account for up to 50% of the final size of the infarct. Focusing on reducing the additional infarct resulting from reperfusion would protect heart muscle and allow the patient to live longer and in better health after the initial attack.
Interestingly, a number of proposed interventions, e.g., ischemic post-conditioning, have been claimed to deliver cardioprotective benefits by acting on the opening of the mitochondrial permeability transition pore (the opening of which is directly inhibited by cyclosporine). CsA has been studied for its cardioprotective capabilities and found to be a potentially significant pharmaceutical for ameliorating long-term damage from heart attacks. As Gerczuk and Kloner noted in their recent (2012) review of the latest therapies to limit infarct size: “To date, cyclosporine is the most promising pharmacological post-conditioning mimetic.” 
A small proof-of-concept clinical study by Piot and his colleagues, published in the New England Journal of Medicine in 2008, found that the administration of CsA with the aim of inhibiting the induction of the mPT was associated with a 40% reduction in infarct size. An editorial in the same issue of the journal called for large, multi-centre studies to determine if this new treatment option can positively influence clinical outcomes. In addition, targeting the mPT “may also offer protection in other clinical contexts, such as stroke, cardiac surgery, and organ transplantation.” 
Following that lead, in April 2011, a European investigator-initiated, multi-centre phase III study of NeuroVive’s cyclosporine-based cardioprotection pharmaceutical (called CicloMulsion but it is the exact same product formulation as NeuroSTAT for TBI) in myocardial infarctions enrolled the first of 1,000 patients. With more than 700 patients enrolled (as of July 1, 2013) this study is expected to report results in early 2015.
1. Hausenloy D, Yellon D. Time to take myocardial reperfusion injury seriously. The New England Journal of Medicine. Comment. 2008; 359 (5): 518-520.
2. Gerczuk, P, Kloner R. An update on cardioprotection: A review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. Journal of the American College of Cardiology. 2012; 59 (11): 969-978.
3. Piot C, Croiselle P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. The New England Journal of Medicine. 2008; 359 (5): 473-481.
4. Hausenloy D, Yellon D. Time to take myocardial reperfusion injury seriously. The New England Journal of Medicine. Comment. 2008; 359 (5): 518-520.
5. NeuroVive Pharma news release www.neurovive.com.
Crossing the Blood–Brain Barrier
It is difficult for many drugs, including cyclosporine, to cross the blood–brain barrier. However, traumatic brain injury often causes the blood–brain barrier to open, permitting cyclosporine to reach those areas of the brain in which the need is greatest. However, in other conditions, such as stroke, the barrier does not open in the same way as in TBI. NeuroVive is conducting research to identify variants of cyclosporine that can penetrate the blood–brain barrier, with a view to being able to provide the brain with neuronal protection under conditions other than TBI. NeuroVive is also evaluating the possibility of administering cyclosporine directly to the brain fluid (e.g., through lumbar puncture).
In pre-clinical pilot studies, NeuroVive’s researchers demonstrated, in collaboration with scientists in the Army, that cyclosporine crosses the blood–brain barrier in prolonged seizures due to hyperactivity in the brain. In cases of stroke, scheduled cardiac surgery and cardiac arrest, the brain cannot yet be reached satisfactorily through intravenous therapy, since a method of increasing the passage of cyclosporine through the blood–brain barrier in these conditions has not yet been found. To this effect, in 2010 NeuroVive and the Dutch brain drug delivery company to-BBB entered into a joint program to develop therapies for stroke and other acute neurodegenerative diseases by combining their technologies.
NeuroVive is also conducting research to develop advanced cyclosporins, cyclophilin inhibitors, formulations, new chemical compounds, or small molecules that allow improved or free passage across the blood–brain barrier. The company is also researching and developing cyclosporine analogue molecules without immunosuppressive effects (called NICAMS for Non Immunosupressive Cyclosporine Analogue Molecules) that can be combined with new formulations and technologies.
1 Osherovich, L. Beating the brain’s bouncer. Science-Business eXchange. 2009; 2 (19): 1-4.
2 Email interview with NeuroVive CSO Eskil Elmér conducted by the lead author.
Pharmaceutical Approaches to TBI:
There are a number of TBI pharmaceuticals in a variety of stages of development. The most promising of these approaches are “multipotential,” targeting at least two or more secondary-stage injury mechanisms, including excitotoxicity, apoptosis, inflammation, edema, blood–brain barrier disruption, oxidative stress, mitochondrial disruption, calpain activation, and cathepsin activation.
The value of multipotential agents is that they have potential to modulate one or more of these multiple secondary injury factors, providing a great chance of achieving clinical value. Previously, more than 30 phase III clinical studies for single-factor targeted TBI pharmaceuticals failed to find significance. Multipotentials may have a greater chance of delivering a successful therapeutic result for TBI patients and ultimately recouping the costs of development and trials.
Promising pharmacological multi-potential agents fall under two categories: those that have been studied clinically and those that constitute emerging pre-clinical strategies. Clinically studied pharmaceuticals include the statins (targeting excitotoxicity, apoptosis, inflammation, edema), progesterone (excitotoxicity, apoptosis, inflammation, edema, oxidative stress), and cyclosporine (mitochondrial disruption, calpain activation, apoptosis, oxidative stress).
Emerging multi-potential neuroprotective agents showing promise in pre-clinical studies include diketopiperazines (apoptosis, calpain activation, cathepsin activation, inflammation), substance P antagonists (inflammation, blood–brain barrier, edema), SUR1-regulated NC channel inhibitors (apoptsis, edema, secondary hemorrhage, inflammation), cell-cycle inhibitors (apoptosis, inflammation), and PARP inhibitors (apoptosis, inflammation).[4, 5] McConeghy and et al’s review of neuroprotection pharmacologies in CNS Drugs  provides an excellent survey of the current state of pharmaceutical development strategies in TBI.
1. Loane J, Faden A. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences, 2010 Dec 31;(12):596–604.
2. Loane J, Faden A. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences, 2010 Dec 31;(12):596–604.
3. Loane J, Faden A. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences, 2010 Dec 31;(12):596–604.
4. Loane J, Faden A. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences, 2010 Dec 31;(12):596–604.
5. McConeghy K, Hatton J, Hughes L, Cook A. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs. 2012: 26 (7): 613-636.
NeuroVive Pharmaceutical AB, Medicon Village, 223 81 Lund, Sweden www.neurovive.com
Steve Campbell, BPE, MPE: North American communications consultant for NeuroVive Pharma AB. BPE and MPE are bachelor’s and master’s degrees in Physical Education, University of British Columbia.
Eskil Elmér, MD, PhD: Chief Scientific Officer for NeuroVive Pharma AB. Dr Elmér is associate professor of experimental neurology at Lund University (Sweden) and group leader of the Mitochondrial Pathophysiology Unit in the department of clinical neurophysiology. In addition, Eskil Elmér is a practising physician in the department of clinical neurophysiology at Skåne University Hospital in Lund, Sweden.
Mikael Bronnegard, MD, PhD: CEO of NeuroVive Pharma AB and is a pediatrician and assistant professor at the Karolinska Institutet.
All correspondence to lead author: Steve Campbell, Campbell & Company Strategies Inc., 23195 96th Avenue Box 770, Fort Langley BC Canada. O: 01 (604 888-5267), F: 01 (604) 888-5269. E: firstname.lastname@example.org.
Editor’s note: The views and opinions expressed in the articles contained in the International Neuro-Trauma Letter are those of the authors and contributors alone and do not necessarily reflect the views, policy or position of the International Brain Injury Association or all members of the NTL Editorial Board. The NTL is provided solely as an informational resource and the inclusion of any particular article does not establish or imply IBIA’s endorsement of its contents.