CEO Christian Wandersee explains the hurdles and hopes when developing drugs for traumatic brain injury, a devastating condition for which there is no existing drug treatment

What is your background?As co-founder of Vasopharm, I joined the company in 1999, serving as managing director and CFO from January 2000 to July 2004. In August 2004 I became CEO.

Having graduated with a Masters degree in Business Administration from the University of Wuerzburg and writing my thesis about the Vasopharm spin-off I was asked by the founders to join the company as managing director. It was naturally a quite unusual start for a professional career but I was convinced that the company possesses 'drugable targets' and should change their strategy from acting as a service provider for the pharmaceutical industry to a drug developer. The original founders supported the idea and that is how it all started. The combination of a highly ethical environment combined with the world of venture capital as well as the opportunity to build a company seemed like a very attractive job profile for me. I have to admit however that this was not my initial plan to start a professional career but I have never regretted my decision.

What is the history of the company? What is the main drive behind  the business?

Vasopharm is focused on treatment of traumatic brain injury (TBI) through highly specific, allosteric inhibition of inducible nitric oxide synthase (iNOS) that is formed in response to brain trauma and damage to the blood brain barrier.
Vasopharm was founded as a spin-off from the University of Wuerzburg Medical School by Harald Schmidt, MD, PhD, Professor of Pharmacology and Toxicology, and Ulrich Walter, MD, Professor of Clinical Biochemistry and Pathobiochemistry.
TBI is the leading cause of death and disability in young adults in  the developed world. It results in more lost working years  than cancers, stroke and HIV/AIDS combined. The majority  of patients are young adults and suffer life-long disabilities – it is a huge burden for patients and their relatives as well to the healthcare  systems worldwide.

Tell us about VAS203. How does it work? What is the history of  the idea?

Our lead asset, VAS203 (Ronopterin), is currently in a 220 patient European Phase III trial that aims to confirm the positive data from a Phase II study in which VAS203 was the only product that has shown a (2 point) improvement in the extended Glasgow Outcomes  Score, equivalent to seeing patients move from requiring constant  care at home to being able to return to work.
VAS203’s approach is to target inducible nitric oxide synthase (iNOS), which is generated in response to trauma and results in very high local concentrations of NO, leading to severe inflammation in the brain tissue increasing intracranial pressure and also the formation of free radicals and reactive oxygen species which are highly neurotoxic. VAS203 blocks the inflammatory response by selectively inhibiting iNOS, without disrupting the actions of other NOS isoforms which are necessary for normal brain function.

The VAS203 programme began in 2006 as our CSO, Dr Frank Tegtmeier, had been involved in stroke and TBI drug development at Janssen-Cilag, Germany (a J&J company) before he joined Vasopharm. The goal was to develop a drug which under normal conditions does  not enter the brain tissue but will reach the area of risk in case of a  breakdown of the blood brain barrier as a result of a severe traumatic  brain injury.

What unmet needs is VAS203 aiming to address?

There is currently no drug available which has been demonstrated to improve either acute or long-term consequences of TBI. Current therapies rely on ‘physical’ interventions (cooling, osmotic agents or craniectomy) to maintain control of Intra Cranial Pressure (ICP). Unfortunately all of these approaches, whilst potentially lifesaving, confer significant consequences in the patient. There is strong demand from physicians for a pharmaceutical agent to manage the inflammatory process in the injured brain. In our phase II (NOSTRA II) study we demonstrated that our compound – Ronopterin – had a statistically significant effect in both acute and long-term measures of recovery in moderate and severe TBI patients when used in addition to current standard of care.

What are some of the drug’s unique features and why are they important?

Because the iNOS enzyme which is the target for Ronopterin is synthesised in the brain in response to trauma there is no substrate  for the drug to affect for the first six (approx.) hours post-TBI. As a result there is a window to allow for these, frequently poly-traumatic, patients to be stabilised in the ICU before treatment  commences. The infusion of Ronopterin is started 6 to 18 hours after  the TBI is incurred. The drug material is very easy to handle  requiring only reconstitution with injectable water to produce  a pH neutral, isotonic infusion. It has a multi-year shelf life at  room temperature.

Why are there are no other drug treatments for traumatic brain injury?

There are two components to a traumatic brain injury, first the damage caused by the impact itself and second the damage resulting from subsequent inflammatory processes in the brain. It is only the latter that might be treatable with a pharmacological intervention.

The inflammatory cascade is multifactorial and changes over time. There have been numerous previous attempts to treat TBI with a whole range of agents but none has demonstrated significant acute or long-term improvements in recovery. We believe that the release of excessive levels of NO by iNOS is at the root of not one but several components of damage resulting from the inflammatory process. NO is implicated in increased blood brain barrier permeability, pro-inflammatory signalling, excitatory amino acid release, mitochondrial stress and the formation of free radicals and peroxynitrites, all of which can result in neurotoxicity. Inhibition of iNOS function can potentially impact all of these different components of the inflammatory response following TBI. That is one aspect of the failure of previous trials in TBI.

The other is the nature of the injury itself and subsequent trial design. Every brain injury is specific to the individual, there is no ‘before injury’ baseline to compare to. Patients are often poly-traumatic (many TBI’s are traffic accident related) and the injury itself is dynamic. Thus rigorous inclusion/exclusion criteria are vital, escalation protocols between centres must be matched and the outcome rating scale must be consistent. The Vasopharm team has tried to learn as much as possible from past failures to design a trial in which it is possible to demonstrate success.

What are currently some of the biggest challenges when developing new treatments for traumatic brain injury?
Possibly the hardest thing to overcome in trying to develop a new treatment for TBI, is the history of the indication itself. There have been many, many trials of numerous treatment options, both pharmacological and physical and none has shown statistically significant improvement in long-term outcome. The trials are expensive, complex and recruitment tends to be slow.

The big pharmaceutical companies are increasingly absent from acute brain injury trials, they have been too badly burned in the past (particularly in stroke) and have reservations about committing to new trials. The major life science VCs know it is unlikely that they will be able to have a reasonable exit of a TBI company until final clinical data is available, making the timeline too long. So we are left with either academic studies or the rare situation where a small company can persuade long-term, highly committed investors to support expensive and time-consuming trials. We are very lucky to have the long-term focused and committed investor support that we do.