A pipeline beginning with the development phases of CBT101
Advancing from rare to societal disease
The Ceres Brain therapeutics pipeline features CBT101 as a drug candidate approaching clinical development and a number of additional candidates under preclinical development. Our streamlined approach enables the seamless application of technical and disease-area expertise, ensuring the swift progression of candidates to the clinical stage.
Focus on CBT101
Ceres's first drug candidate, CBT101, is a creatine prodrug incorporated into a specialized and highly innovative formulation, patented as a unique “composition of matter”.
The intelligent chemical structure of the creatine prodrug enables passive diffusion through cell membranes, bypassing the need for the creatine transporter, acting as a "gatekeeper."
Despite the inherent instability of the creatine prodrug, the formulation, presented as a particulate emulsion, serves to stabilize it and ensure sprayability.
The sprayability is crucial as CBT101, to avoid blood degradation, is administered intra-nasally, utilizing the nose-to-Brain pathway, specifically the Nose-to-Neurons route, to reach the brain cells. In this process, CBT101 leverages the Nose-to-Neurons physiological pathway, made possible by the distinctive anatomy of the nasal cavity featuring olfactory and trigeminal nerve bundles at the surface of the nasal epithelium.
Thus, after being sprayed into the nasal cavity, CBT101 enters olfactory and trigeminal neurons, travels toward their origins, and subsequently diffuses from neuron to neuron throughout the brain's various regions, releasing creatine as the active principle.
CMC
Drug Substance
The drug substance component of CBT101 is a creatine ester (DCE). DCE, utilized as a creatine prodrug, is synthesized from creatine and an alcohol. It exhibits well-defined particle shape and characterized morphology, and it remains stable under ambient conditions.
In neurons, the DCE is hydrolyzed in Creatine and Alcohol.
Drug product
The drug product, CBT101, comprises DCE formulated into a highly innovative particulate emulsion. This specific formulation guarantees the stability of DCE and ensures its sprayability in accordance with the relevant guidelines.
The formulation is patentet with its composition precisely defined, and its quality control attributes have been determined. The particles of the drug substance are also thoroughly characterized.
GMP batches of both the drug substance and drug product have already been manufactured.
The creatine prodrug enables passive diffusion through cell membranes, bypassing the need for the creatine transporter, acting as a "gatekeeper."
Program 1: CBT101 in the Creatine Transporter Deficiency
Creatine Transporter Deficiency syndrome (CrTD) is a rare monogenic cause of X-linked intellectual disability resulting from mutations in the creatine transporter gene SLC6A8 (Xq28). This condition arises due to a defective membrane protein, the creatine transporter, causing inadequate creatine transportation in neuronal cells and leading to impaired energy metabolism.
Clinically, CrTD is characterized by severe global developmental delay, intellectual disability, prominent speech/language delay, autistic behavior, movement disorders, and seizures. The estimated prevalence of CrTD is 1/50,000 people.
To date, no prevention or treatment options exist for CrTD, rendering it an orphan disease. Individuals diagnosed with CrTD may require the coordinated efforts of a team of specialists.
This collaborative approach ensures a comprehensive and holistic focus on symptoms. Occupational, speech, and physical therapists may be necessary to improve developmental disabilities, and behavior therapy can address behavioral problems. Additionally, in cases of repeated seizures, patients may receive anticonvulsants.CBT101 has demonstrated its efficacy in Creatine Transporter Deficiency through an extensive set of preclinical experiments conducted on patient cells and specific animal models (i.e., SLC6A8 KO mice from two different teams and cynomolgus monkeys).
These experiments were assessed using state-of-the-art technologies, including Mass Spectrometry and 18F-FDG PET Scan.
A comprehensive set of preclinical results (most of them being published or under publication) affirms the effectiveness of the CBT101 approach, establishing a full proof of concept after 10 and 30 days of nasal dosing. Key findings include:
Successful delivery of creatine into the brain, particularly into neurons both in KO and WT rodents,
Enhanced brain plasticity, evidenced by an increased set of biomarkers (CREB, PSD95, BDNF) in KO mice,
Elevated brain metabolism in KO mice, as demonstrated by functional imaging (18F-FDG PET scan),
Improved cognition and behavior in KO mice, substantiated by cognitive tests such as Novel Object Recognition and beam walking tests.
Thanks to this results, CBT101 obtained Orphan Drug Designation (ODD) from both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for Creatine Transporter Deficiencies and other creatine deficiencies. ODD status streamlines the development process, lowering regulatory fees, facilitating access to specific grants, and expediting the time to market.
Program 2: CBT101 in Parkinson’s disease
Parkinson's disease (PD) is a chronic neurodegenerative disorder of the central nervous system primarily affecting motor control. It is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra of the brain.
Classic symptoms of Parkinson's disease include tremors, muscle rigidity, bradykinesia (slowed movements), and balance issues, which can significantly impede daily activities.
Parkinson's disease has been associated to mitochdondria failure in dopaminergic neurons. Mitochondria serve as the cellular powerhouses, producing ATP, the cellular energy unit. Alterations in mitochondrial function have been observed in the cells of individuals with Parkinson's disease. These mitochondrial dysfunctions may contribute to the oxidative stress and progressive cell death characteristic of the disease.
Current therapeutic approaches primarily focus on symptom management, utilizing medications to increase dopamine levels in the brain.
Ongoing research aims to enhance our understanding of the underlying mechanisms of the disease to develop more targeted treatments.
Both the National Institute of Neurological Disorders and Stroke and the scientific literature have highlighted the significant role of creatine in modulating mitochondrial dysfunction. Creatine has been identified as a potential disease-modifying agent for Parkinson Disease.
However, creatine faces challenges in efficiently distributing into the brain, particularly within dopaminergic neurons, mainly due to creatine transporter playing the role of a gatekeeper (Lowe M., 2015).
In this context of neurological diseases involving dopaminergic disorders such as Parkinson's disease, enhancing creatine delivery to dopaminergic neurons could be beneficial.
However, developing strategies to bypass or facilitate creatine passage through the blood-brain barrier is a significant challenge in current research.
Ceres-Brain's drug candidate, CBT102 will to address this challenge. Ceres strives to slow down or halt mitochondrial dysfunction and mitophagy, ultimately impeding the progression of the disease. This approach aims to improve patients' motor symptoms and cognition.
Other R&D programs
Through collaborations with research organizations such as CEA, Ceres is involved in and supports several R&D programs in the areas of brain diseases currently without treatment. The objective will be to have a pipeline of development programs for the future years.