Hurdles in conducting of cell therapy trials for acute neurological conditions

by Alexey Bersenev on October 20, 2013 · 0 comments

in neurology

Acute neurological conditions, such as stroke and traumatic brain injury (TBI) is an attractive target for cell therapy. Success of pre-clinical models allowed to move to clinical trials relatively quickly. Industry also sees a great opportunity in this direction. For example, Athersys and Cytomedix have active ongoing Phase 2 trials. However, the trials did not progress as fast as expected. There are many barriers in conducting of such trials. In this post, I’m going to overview some of these hurdles. I used the following sources: (i) talk by Charles Cox from MSC2013 conference, (ii) article by Sean Savitz and (iii) analysis of recent Cytomedix press release.

1. Slow enrollment
This is probably the biggest problem in stroke and TBI trials. Sean Savitz team, which assesses autologous bone marrow mononuclear cells in acute ischemic stroke, discussed practical barriers in patient enrollment. A single most important obstacle is natural variation in clinical course, means possible significant fluctuations in patient condition after signing a consent form. The patients, which unexpectedly rapidly deteriorated or recovered, should be excluded from the study, even after bone marrow aspiration:

In our study, it was not always predictable which patients would require hemicraniectomy by the time window for enrollment. Some patients with large infarcts fell out of the study after consent was obtained due to neurological dete- rioration and the need for surgical decompression.

A 55-year-old woman was consented for the trial after receiving IV t-PA, but she improved to such an extent that she fell below the range of clinical deficits to remain in the study and was deemed to be a screen failure.

A 64-year-old woman initially treated with t-PA, consented for the clinical trial at 24 h after stroke. She subsequently developed intra- cerebral hemorrhage and deterioration to such an extent that she exceeded the study’s clinical severity criteria and was then deemed a screen failure.

So, tPA (tissue plasminogen activator) – a standard of care in ischehmic stroke, can contribute significantly to fluctuation of clinical course. Yet another contributor is anticoagulation therapy (ex: heparin). Significant number of stroke patients are required therapy by anticoagulants. These patients can not undergo such invasive procedures as bone marrow harvest. Another exclusion criteria is potential risk of hypotension from sedation during bone marrow harvest.

So, due to rapid fluctuation in clinical course, there is a big screening failure and exclusion rate after singing consent form. The situation could be even worse with TBI patients. Charles Cox said that in their trial, only 1 patient get enrolled out of 100 screened. One interesting example that he gave was about patients, which were injured while allegedly committing a crime – while team consented them in emergency room and aspirated marrow, they didn’t know about it. But if those patients turned into prisoners, the follow-up is not possible and they should be excluded from the trial.

2. Thin business model
The business model for autologous cell therapy in acute neurological conditions is very slim. The autologous business model is complicated by: emergency of condition, fluctuation of patient condition, high liability in decision making (Go/ No Go), a requirement of big multidisciplinary team effort and other factors. So, it’s not very attractive for investors.

A month ago, US-based company Cytomedix announced a halting of their Phase 2 stroke trial, involved autologous bone marrow-derived ALDH+ cells. One of the major reasons was a very slow enrollment:

RECOVER-Stroke began enrollment in 2011. At the time of the Aldagen acquisition in February 2012, only six patients had been enrolled…
A year after the deal, in March 2013, the number had grown to only 26 patients. As of today, the company tells us 39 patients have been enrolled. The original plan was to enroll 100 patients in a 60:40 randomization between ALD-401 and the control.

It was probably a good business decision for them. It demonstrates how difficult to handle such long-term and complex autologous trials. In this case, the Athersys business model, which commercializes “off-the-shelf” allogeneic stem cell product, is much more attractive and promising. The trend to move to allogeneic is also visible in academic trials.

3. Trial design
The difficulties with enrollment, screening failures and decision “on a fly” to exclude some patients, led to significant expansion of exclusion criteria in U of Texas stroke trial. The list of exclusion criteria now composed of 26 positions. Yet another big problem in trial design is setting primary end points when moving to Phase 2. Due to acuity and fluctuation of patient condition, it’s hard to determine the real effect of cells:

For an acute patient initially enrolled into a cell therapy trial who then shows deterioration in the next few days and requires hemicraniectomy, it may be difficult to determine if morbidity is solely associated with the surgical procedure or if the bone marrow harvest and/or cell infusion has some contribution.

4. Organizational issues
Currently, in US, only big reputable medical centers can afford such trials. As Carles Cox mentioned: “Infrastructure – must have the most robust clincial system in place”. In such acute conditions, a multidisciplinary team of professionals must work as a whole highly coordinated entity. A little mistake can cost a life of patient or “kill the trial”. The medical center should be equipped by good imaging facility and GMP manufacturing facility. Cox said about GMP: “If you don’t have one – get it!” Of course, GMP is required if you decide to manufacture cells “in house”.

Yet another consideration is competing clinical trials. In big medical centers one patient could be a “good candidate” for few clinical trials. One of exclusion criteria in Savitz-led trial is “current participation in any interventional research study”. This consideration is especially important for TBI, where patients get in emergency room with multiple traumas and few teams could “compete” for their inclusion in different trials.

The funding is a big problem for such trials. Due to possible slow enrollment, it’s hard to predict how long the trials going to last. Maintenance of facilities (imaging, GMP, pathology…) is enormously expensive. Due to nature of disease and a lot of “decisions on a fly”, it’s hard to calculate the exact cost of the trial. Charles Cox recommended to have a few funding sources as a “portfolio”. Once you started a trial, you don’t want it to die in the middle due to financial problems.

So, there is a high burden of internal logistics and a lot of possible unanticipated cost. These organizational issues could be also applied to many other cell therapy trials.

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