We are focused on developing therapies for serious neurological disorders for which only symptomatic (or palliative) therapies currently exist. All of these conditions rob their victims of productive and satisfying lives, as well as their human dignity. They include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease.
We are also targeting degenerative ocular diseases that result in serious vision impairment and blindness, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD) and glaucoma.
For each of our products, the gene for a therapeutic neurotrophic factor is delivered to the precise anatomical location where the major cell degeneration occurs in that particular disease. We employ our proprietary method of preparing adeno-associated virus (AAV) vectors for delivering the neurotrophic gene (see Gene Delivery Technology).
Once the therapeutic gene is inserted into the cell, the AAV vector quickly disintegrates and the cell's own biological machinery should then produce the therapeutic neurotrophic protein indefinitely.
Ceregene's pipeline currently includes four products at varying stages of development: CERE-110, CERE-120, CERE-135, and CERE-140.
CERE-120 is composed of an AAV vector carrying the gene for neurturin (NRTN), a naturally occurring protein known to repair damaged and dying dopamine-secreting neurons, keeping them alive and functioning normally. NRTN is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF). The two naturally-occurring molecules have similar biological properties, and both have been shown to benefit the midbrain dopamine neurons that degenerate in Parkinson’s disease and are responsible for the major motor impairments. CERE-120 is delivered by neurosurgical procedure in a highly targeted fashion directly to the affected area of the brain, which results in stable, long-lasting, local expression of NRTN. Thus, a single neurosurgical procedure is anticipated to provide therapeutic benefit for the remainder of the patient’s life.
The first CERE-120 study in persons with PD was completed in 2006. There were 12 participants in that study and CERE-120 was found to be safe and well tolerated. With five years of follow up after CERE-120 delivery, the early safety data seems to be holding up long term. Ceregene then conducted a larger, controlled Phase 2 study in 58 participants with PD at eight leading movement disorder centers in the United States. Participants were randomized (like the flip of a coin) to either receive CERE-120 or a similar “mock” (sham) surgical procedure without any treatment. Both patients and their neurologists were “blinded” to the treatment assignment, meaning they did not know whether the participant received CERE-120 or no treatment. One year after the surgery-based treatment, study results were analyzed but did not demonstrate a difference between CERE-120 and the control group in the ‘primary’ endpoint measuring various aspects of motor coordination, gait, tremor and stiffness (based on scale called UPDRS). However, CERE-120 did show a modest improvement on several other motor and quality of life (‘secondary’) endpoints at 12 months, including time spent in the “off” condition (unable to move) and activities of daily living. Importantly, CERE-120 demonstrated a statistically significant benefit on the primary endpoint (UPDRS score) at 18 months, as well as several additional secondary endpoints, though the magnitude of effect was modest. No measure showed an advantage to the group of patients who underwent surgery without receiving treatment (though they did not worsen either).
Despite only modest improvements in participants receiving CERE-120, several findings from the completed Phase 2 study provided encouragement and important insight into ways to enhance CERE-120 effects. First, CERE-120 delivery appeared safe, with follow up of more than two years for those enrolled in Phase 2, and over 4 years for those enrolled in Phase 1. Second, analyses of two brains from CERE-120-treated participants (who died of other causes) demonstrated unexpected deficiencies in the degenerating neurons with implications for how to dose CERE-120 in future studies. These data showed that CERE-120 produced neurturin in the terminal ends of the degenerating neurons (located in the brain area call the putamen) where CERE-120 was injected. However, surprisingly, no neurturin was seen in the cell bodies of these same neurons (located further away in a part of the brain called the substantia nigra). This suggested that the degenerating neurons no longer had sufficient capacity to transport the neurturin from their terminals (where CERE-120 was producing it) to their cell bodies (where it must exist in order for the cell’s repair genes to be turned on). Thus, these data informed investigators that in order to achieve the maximum benefit of CERE-120, it must be injected directly into the substantia nigra, in addition to the putamen.
Refinements in dosing of CERE-120 were then implemented to enhance and accelerate the effects of neurturin on dopaminergic neurons in PD. Going forward, CERE-120 is being administered to both the substantia nigra (in the brainstem, an area in the back of the brain) as well as the putamen (in the middle of the brain). This dosing regimen was successfully employed in a recently completed Phase 1 study in six PD participants. Based on favorable safety data, Ceregene is now initiating a new controlled Phase 2 trial in 10 leading movement disorder centers in the USA to determine if the new dosing of CERE-120 remains safe and improves efficacy in PD. Approximately 52 people with PD will be assigned (randomly, like the flip of a coin) to either receive CERE-120 or undergo a similar (mock) surgery without treatment (or even an injection). All participants will be followed in clinic for at least 15 months to assess potential benefits and any safety concerns.
Whereas no human study has yet confirmed the beneficial effects seen in animals who received neurotrophic factors such as neurturin or GDNF, better understanding of dosing parameters provide additional confidence that it still might be proven to be beneficial for PD. The new clinical trial is designed to answer this question.
See Newsroom section for related press releases.
CERE-110 is composed of an AAV vector carrying the gene for nerve growth factor (NGF). NGF is a naturally occurring neurotrophic factor that has profound protective and restoring effects on cholinergic neurons in the brain. These neurons are particularly vulnerable in Alzheimer’s disease (AD) and are strongly implicated as playing a key role in the memory loss and other cognitive disorders characteristic of the early phases of AD. CERE-110 is selectively delivered to these neurons by a neurosurgical procedure. Interim data from a Phase 1 clinical trial of CERE-110 for AD revealed that after nearly three years of follow-up, the administration of CERE-110 was well tolerated. Ceregene has initiated a multi-center, controlled Phase 2 clinical trial in collaboration with the Alzheimer’s Disease Cooperative Study (ADCS).
CERE-140 carries the gene for neurotrophic factor 4 (NT4) within one of our proprietary gene delivery vectors. NT4 is a neurotrophic factor that benefits many cells in the retina and thus may prove useful for treating ocular diseases. It is closely related to another neurotrophic factor, brain-derived neurotrophic factor (BDNF), which has shown promise in several animal models of retinal degeneration of the eye. CERE-140 is delivered to the retina via an injection of our proprietary gene delivery technology. In nonclinical studies, we have shown CERE-140 to protect against retinal degeneration and lost function in several animal models of retinitis pigmentosa. We are extending these studies while also evaluating the safety of CERE-140 in anticipation of initiating testing of CERE-140 in human patients with retinal degeneration. A single injection into each eye is expected to provide therapeutic benefit for the lifetime of the patient. While our initial clinical effort will be directed toward retinitis pigmentosa, it is likely that CERE-140 might also provide novel and important benefits to patients with wet and dry age-related macular degeneration (AMD) as well as glaucoma.
CERE-135 carries the gene for insulin-like growth factor (IGF-1), delivered to the muscles and nerves of ALS patients via our proprietary gene delivery technology. IGF-1 is known to enhance the function and provide protective support of motor neurons that originate in the spinal cord and control all of our muscles. Degeneration of these motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and is directly or indirectly responsible for the death of all ALS patients. Still in nonclinical research, we are working with our collaborators to enhance the biological characteristics and targeted delivery of CERE-135 to assure maximum safety and efficacy prior to advancing to human clinical trials.