Ceregene today announced disappointing results from its second Phase 2 trial of CERE-120, an experimental gene therapy treatment for Parkinsonís disease (PD). CERE-120 was designed to deliver neurturin, a specialized protein known as a trophic factor, into the brain. The hope was that it might heal diseased brain cells, helping to slow the progression of the disease, a therapeutic effect suggested in pre-clinical studies of neurturin.
CERE-120 did not reach its primary endpoint in this study, unfortunate news which makes it unclear if it will remain in development. Still, there is a lot to be learned from Ceregeneís research that could have important implications for developing similar trophic factor therapies for PD moving forward.
The Michael J. Fox Foundation (MJFF) spoke with Chief Scientific Advisor/neurturin co-discoverer Gene Johnson, PhD, and senior associate director Jamie Eberling, PhD, to understand what these results could mean for Parkinsonís patients.
MJFF: What are trophic factors and why should Parkinsonís patients care?
Jamie Eberling: Trophic factors are proteins that are critical to the development of our brain in early life, and then keep mature brain cells healthy. In Parkinsonís disease (PD), dopamine neurons in the brain die ó this death is what leads to the motor symptoms of the disease. Laboratory studies have shown that dying cells exposed to trophic factors can be rescued. If we could recapitulate this scenario in the brains of people with Parkinsonís, we could potentially have our first disease-modifying treatment for the disease.
MJFF: Explain the results that Ceregene is announcing today.
JE: In short, this is unfortunate news for the Parkinsonís community and Ceregeneís therapy, called CERE-120. The trial did not demonstrate statistically significant efficacy for its primary endpoint, which was an improvement in patient scores according to the Unified Parkinsonís Disease Rating Scale.
The study did show some statistical benefit according to a secondary endpoint ó self-reported daily diaries from patients that asked them to assess their own motor function throughout the course of the day. The trial also continued to show that the drug is safe. Still, the fact they didnít meet the primary endpoint makes it unclear if CERE-120 will remain in development.†
While itís certainly discouraging that the study didnít achieve its primary endpoint, scientists will be able to continue to analyze the data and learn from the patients who took part in the study. This should help them to learn a lot more about the potential for trophic factor therapy for PD.†
MJFF: This was actually Ceregeneís second phase 2 study of CERE-120. Can you tell us more about the history?
Gene Johnson: Itís not easy to get trophic factors into the human brain, as they donít readily cross the blood-brain barrier. After many years and significant investment, Ceregene developed a technique to deliver neurturin via gene therapy. Throughout the development process, including in clinical studies, they have continued to tweak this technique. The two phase two trials aimed to study differences in how long participants were treated with the drug, as well as where the neurturin was delivered into the brain.
JE: The first trial was 12 months long. At 12 months, the results showed that CERE-120 was not more beneficial to patients than a placebo, which was disappointing. But the researchers continued to evaluate the data, and at the 15-month mark they saw promising indications of therapeutic benefit in the volunteers who had received the treatment.
So while the trial was considered inconclusive, researchers were encouraged enough to design a second trial in which the primary outcome was at 15 months instead of 12 months.
GJ: The second study also introduced a second brain target for where to deliver the neurturin. In the first study, Ceregene concentrated on delivering neurturin to a region of the brain called the putamen. In this second study, it was delivered into two areas of the brain called the substantia nigra and the putamen, and the dose delivered into the putamen was increased.
A lot of work has gone into finding the most promising method for delivering neurturin into the brain, and where to put it. But based on this weekís results, we still havenít found the way to replicate the promising pre-clinical findings in a clinical setting.
MJFF: So what does this mean for CERE-120?
JE: This was a pivotal trial, not just for Ceregene as a company, but for trophic factors as a potential therapy for Parkinsonís disease more broadly. The reality is that future investment in CERE-120 is unlikely. But itís important to realize that there are still a lot of unknowns. For example, the fault may lie not with neurturin itself, but with the delivery method. The protein may still not have made it into the right areas of the brain to provide therapeutic benefit.
Scientists continue to investigate where and how to deliver trophic factor therapy in PD. Itís possible that we still havenít found the best means of delivery, and that this could have a big impact on the future success of these therapies in development. †
MJFF: Are there any plans to continue studying the volunteers who received treatment in this trial?
JE: Yes ó and this is an important point. Ceregene has agreed to have the Foundation work with the clinical sites to conduct long-term observational studies of the participants.
As you may know, when most clinical trials end, participants stop taking the investigational medicine. But in a gene therapy trial, the therapy will always continue to be present in the brains of those who underwent the study procedure.†For this reason, there is still a lot that can be learned from those who received CERE-120.
MJFF: Does this outcome change MJFFís position on trophic factors overall?
JE: Neurturin is not the only trophic factor in development. Just because it failed, doesnít mean the others will as well. We need to wait for results of other studies before making any definitive conclusions about the future of the field, on the whole.
As readers know, MJFF is focused entirely on prioritizing research that is close or critical to practical relevance in patientsí lives. In a case like this, one concern is that companies can become reluctant to invest in even highly scientifically promising work if it has faced a public setback. Weíll continue to closely monitor results from other projects so that we can help potential funders gain a realistic and unbiased assessment of trophic factorsí continuing promise for patients.
MJFF: Tell us about some of the other trophic factors in development.
GJ: Many patients are familiar with a trophic factor similar to neurturin called GDNF (glial cell-derived neurotrophic factor). It is in Phase 2 clinical testing with a company called MedGenesis Therapeutix, in collaboration with the United Kingdomís Cure Parkinsonís Trust and Parkinsonís UK (MJFF has also supported MedGenesis in related work).
Like Ceregene, this company is looking to improve the method for delivering the trophic factor in the brain. MedGenesis is looking to do so by improving the hardware they use to implant, and then monitor, the effect of the trophic factor. MedGenesisí approach would work through chronic intermittent delivery of GDNF into the putamen through a pump system. Ceregene, on the other hand, was testing a one-time surgical approach.
Two other trophic factors in pre-clinical development for PD are CDNF (conserved dopamine neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor). Both have been shown to have interesting effects in a laboratory setting. Itís possible that down the road, either of these could prove to be as good, or even better, than GDNF or neurturin, but for now we just donít know. The research is yet to be done. The scientific community currently knows more about CDNF than it does MANF. Ongoing pursuit of both is warranted.
Some companies are working on non-surgical approaches to trophic factor therapy. Phytopharm recently completed a study to determine if oral delivery of their medication Cogane might incite the brain to produce more trophic factors on its own. Unfortunately, this trial returned negative results.
Itís also possible successful trophic factor therapy might require that patients be treated earlier in the disease, when there are likely more neurons remaining in the brain that could respond to the treatment. In the later stages of the disease, some scientists have hypothesized, there may not be enough healthy neurons left in the brain for the trophic factor to take effect. To date, trophic factor clinical studies have only investigated people at the later stages of Parkinsonís. It remains to be seen if trials in early stage patients will happen.
MJFF: What does this mean for the overall pursuit of a disease-modifying treatment?
JE: There are several other disease-modifying approaches for Parkinsonís drugs nearing clinical testing that are unrelated to trophic factors. We remain hopeful that one of these other types of approaches could lead to the treatments the Parkinsonís community needs.
Itís also possible that the field will continue to think about trophic factors in other ways. For example, we know that trophic factors are released during exercise, and we also know that exercise is good for people with PD. Better understandings of this link could contribute to how we target these proteins in the future.
Stay tuned for information about a planned Hot Topics Webinar to discuss the results and answer questions.†