Phase 2 Trial of Spheramine Shows Disappointing Results
In the first week of July 2008, Titan Pharmaceuticals, Inc., announced disappointing results from the Phase 2 trial of its symptomatic Parkinson's therapy Spheramine. The announcement came in the wake of results showing that the experimental drug had failed to meet clinical endpoints outlined for the trial. Only one week earlier, the company had reported positive five-year data from its Phase 1 open-label trial of the same treatment.
The Michael J. Fox Foundation spoke with David Standaert, MD, PhD, a member of the Executive Scientific Advisory Board of The Michael J. Fox Foundation, to gain a clearer understanding of the seemingly conflicting results, and what people with PD should take away from the news. Dr. Standaert is the John and Juanelle Strain Professor of Neurology and Director, Center for Neurodegeneration and Experimental Therapeutics, at the University of Alabama at Birmingham.
What is Spheramine?
Spheramine is a Parkinson's treatment derived from cells in the back of the eye, called human retinal epithelial cells. These cells have the ability to produce levodopa. Levodopa is the so-called "precursor" to dopamine, meaning it's a molecule that is converted into dopamine in the brain. (It's familiar to people with Parkinson's as the active ingredient in the gold-standard Parkinson's drug sold under the brand name Sinemet.)
To create Spheramine, researchers bind these retinal cells onto microscopic gelatin "beads" and surgically implant these beads in the putamen -- a part of the brain involved in the mechanisms that lead to Parkinson's disease.
Spheramine is not a disease-modifying or neuroprotective treatment -- it is a symptomatic therapy that cannot replace lost dopamine neurons. Rather, the concept is that the Spheramine essentially acts as a microscopic "levodopa factory" inside the brain. The factory relies on intact cells and systems of the brain to convert the levodopa produced by the Spheramine into dopamine. Ultimately this dopamine replaces the dopamine lost in PD and provides symptomatic relief.
When did Spheramine first enter clinical testing?
Before going into the clinic, Spheramine was tested extensively in animal models, where it appeared to be effective. The Phase 1, open-label trial of Spheramine began five years ago. This study was conducted at Emory University in Atlanta and enrolled six patients with moderate to advanced Parkinson's disease.
On June 24, 2008, at the Movement Disorders Society meeting in Chicago, Titan presented two different sets of recently updated results from this Phase 1 study. First they reported that no major new or unexpected safety concerns had emerged during the first five years of the study. And while efficacy results from an open-label, uncontrolled trial must always be taken with a grain of salt, the study also demonstrated reduced severity and frequency of symptoms measured against the Unified Parkinson's Disease Rating Scale (UPDRS), the standard validated tool used in PD clinical trials.
Second, Titan also reported on June 24 that Spheramine may contribute to enhanced health-related quality of life (HRQoL) in moderate to advanced PD. The enrollees were evaluated across a range of quality of life factors including mobility, stigma, activities of daily living, communication, bodily discomfort, cognition, emotional well-being, and social support for five years following Spheramine implantation. Overall, HRQoL scores improved for all patients from baseline at five years after surgery.
And what happened in Phase 2?
The Phase 2 trial of Spheramine completed enrollment with 71 patients in 2007. It was initiated by Titan and its partner Bayer Schering Pharma AG based on the one-year results from the Phase 1 study.
The Phase 2 trial was a multicenter, double-blind, randomized, sham surgery-controlled study to further evaluate safety and efficacy. In Phase 2, enrollees received bilateral surgery -- meaning Spheramine was injected on both sides of the brain. This was a difference from the Phase 1 trial, where the surgery was unilateral, or done only on one side of the brain.
On July 2, 2008, the company issued an SEC-required press release announcing that in Phase 2 Spheramine failed to meet its primary or key secondary endpoints, with no significant differences detected between the Spheramine and sham surgery (or placebo) arms of the study after 12 months of follow-up. The primary endpoint that the company needed to demonstrate was that Spheramine improved patients' Part III, or motor, scores on the UPDRS. As a result of the apparently disappointing results, Titan stopped the trial and Bayer has since pulled out of the development deal.
If everything went so well in Phase 1, why did the treatment fail at Phase 2?
I want to emphasize that the data from Phase 2 have not yet been published, so at this point we don't know exactly what happened. With that said, the bar was set very high for this trial to succeed. First, for any symptomatic therapy to gain regulatory approval, it must be demonstrated to offer significant benefits over the best symptomatic therapy we already have -- the drug Sinemet. In the case of Spheramine, the hurdle to approval is even higher because it requires brain surgery, which is by definition invasive and risky. Taken together, this meant Spheramine would have had to show truly major benefits over Sinemet in order for doctors and patients to consider it a desirable alternative to an orally administered pill.
Without seeing the clinical data, we can make some guesses as to what specifically occurred, but they are just guesses:
--It could be that there were significant differences between the patients enrolled for the Phase 1 trial and the Phase 2 trials, and that the treatment simply wasn't effective for the type of patients enrolled in Phase 2. It is also possible that the treatment helped some patients but not others, yet the overall average effect was not sufficient for the trial to be a success.
--Since the surgery was on only one side of the brain in Phase 1 but both sides in Phase 2, possibly this changed the way the treatment worked, and made it less rather than more effective. This may also have increased the rate of side effects.
--Some of the apparent effect in the Phase I trial may have been "placebo effect," improvement that results from the belief that a treatment has been administered. This is commonly observed in PD trials, and is the reason that sham surgery like that used in the Phase II study is important.
--Finally, Spheramine simply may not be as effective as the earlier (and much smaller) study suggested.
When will we see the data?
The company may publish the data in a peer-reviewed journal, and certainly all of us in the Parkinson's research and clinical community are hoping that they will. They aren't legally obligated to do so, and they have not yet announced their plans in this regard.
What is the likelihood of a future trial to determine whether any of the factors you've listed were at work in the Phase 2 trial, and whether Spheramine could still be a viable therapy?
Although the concept of putting a "levodopa factory" in the putamen remains attractive, I would say the odds of further trials of Spheramine itself are very low. Even if we eventually learn that Spheramine did benefit some of the patients involved, it's a treatment with significant risks and it would be hard to proceed unless there is a reliable way to identify those who will have a good outcome. From a prioritization point of view, other research avenues are likely a better use of limited resources.
Outcomes like this one are always frustrating, certainly for researchers, but much more importantly, for patients eagerly awaiting the results of every ongoing clinical trial. Unfortunately, this is one more reminder that just because an experimental therapy shows promising results in animal studies and then in an uncontrolled open-label Phase 1 trial, it is not necessarily going to pan out as a new treatment once studied in larger controlled trials.
The good news is that research into transformative therapies continues and there are many other irons in the fire. With the support of strategic partners like The Michael J. Fox Foundation, improved treatments for Parkinson's will be found, and that is what all of us in the research community continue to work toward with urgency.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.