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Treatments in Development
The interactive tool below lists medications and other treatments that are currently under investigation in academic and industry labs for the treatment of CCM. Click on labels to read more about each medication and to learn about the phases of drug development.
Medicines for CCM may be developed with a variety of purposes in mind. For CCM, we need treatments that will:
- Stabilize blood vessels to reduce oozing and the risk of hemorrhage
- Prevent re-hemorrhage after an acute hemorrhage
- Shrink lesions or remove them without surgery
- Prevent lesions from coming back after surgery
- Remove iron deposits in the brain and spinal cord left behind by hemorrhage
- Prevent systemic effects of familial CCM
- Stop familial CCM from being passed to the next generation
Each potential treatment in the pipeline may address one or more of these treatment needs.
At least initially, until there is a cure, some medicines may be more appropriate for some people with the illness than others. For example, a specific medicine might be best suited for those with familial CCM, or, conversely, for those with sporadic CCM. Preferences and tolerances may also play a role. Some people may be more sensitive to side effects. Or, some may want or need a medicine that is used for just a short time while others may want ongoing protection that requires staying on a medicine for a longer time. We will need many choices.
CCM Treatment Pipeline
Proof of Concept & Preclinical Entities
Drug research that occurs before testing in people is termed ‘pre-clinical.’ During this stage of testing, researchers investigate the function of the drug as well as toxicity and dosing.
Latin for, ‘outside of the body,’ in vitro research typically refers to that which does not include animals, but may include cell and chemical-based assays.
In CCM disease research, a variety of animal models are used, including c. Elegans (worms), zebrafish, and mice.
Phase I clinical trials are typically quite small, may likely use healthy volunteers, and are focused on determining the safety of a new drug.
Phase II clinical trials are larger studies of patients for whom the drug intends to treat, can be placebo-controlled, and aim to investigate the effectiveness of the new drug.
Phase III clinical trials are even larger trials that aim to confirm effectiveness, monitor side effects, and may compare to other approved treatments (if available).
Rho Kinase and its associated signaling molecules are involved in regulating important cellular processes including proliferation and maintaining/changing cell shape. Drugs targeting the Rho Kinase protein are of interest for CCM treatment because in CCM gene mutations cause overactivity of Rho Kinase. Studies in mice have shown that inhibiting (blocking) Rho Kinase function can fix leaky blood vessels and limit the formation of new lesions. Several Rho Kinase inhibitors are of interest to CCM researchers and one is currently in trials. In addition to lowering cholesterol, statin drugs affect the Rho Kinase signaling pathway. Atorvastatin is a statin drug currently in a Phase I/II trial to test its effects on cavernous malformation with symptomatic hemorrhage. BA-1049 is a new Rho Kinase Inhibitor being developed by Neurelis specifically for cavernous malformations.
Oxidative stress refers to a state in which the cell has an overabundance of reactive oxygen species (ROS). ROS are naturally occurring molecules that need to be kept at a regulated level to avoid damaging the cell. A variety of molecules can detoxify ROS including REC-994 being developed by Recursion. REC-994 is in Phase II trials in the United States.
Inflammation is a normal way that the body protects itself or responds to injury. However, too strong an inflammatory response can also contribute to disease, as is the case with CCM; therefore, inflammation may become a drug target.
Beta blockers are a class of drugs used to lower blood pressure and are used to manage heart attacks and improve blood flow.
The Atorvastatin drug is of interest to CCM researchers because, in addition to its cholesterol-lowering effects, it also has Rho Kinase inhibiting properties. A safety and efficacy human trial with Atorvastatin treatment began enrolling in the summer of 2018. This study will investigate the safety of long-term treatment and the potential effects on bleeding, as measured by iron deposition. For more information, visit our Atorvastatin Trial Page. [Reference: https://clinicaltrials.gov/ct2/show/NCT02603328]
REC-994 targets molecules in the body that have become superoxides because of the activity of reactive oxygen species (ROS) and may be damaging to cells. The role of ROS in CCM is beginning to be understood at a biological level. We know that CCM gene mutations cause an increase in ROS, which are targeted by REC-994. REC-994 is able to reduce blood vessel leakiness in cell and mouse models of CCM. Furthermore, treatment of mice with the drug decreases lesion size and number. Recursion Pharmaceuticals is developing this drug for cavernous malformation treatment and the drug is currently in Phase II trials. [References: www.ncbi.nlm.nih.gov/pubmed/25486933, www.ncbi.nlm.nih.gov/pubmed/24291398, www.ncbi.nlm.nih.gov/pubmed/26795600]
CCM lesions have a high level of leakiness due to improper structural connections between neighboring blood vessel cells. Treatment of CCM cells with vitamin D3 can trigger signaling within the cells to stabilize those cellular junctions. Vitamin D3 is able to reduce blood vessel leakiness in cell and mouse models of CCM. Furthermore, treatment of mice with the drug decreases lesion size and number. There is no clinical evidence that Vitamin D3 alters the course of disease in human patients. However, low vitamin D levels are correlated with a more aggressive disease course. The CCM disease community has no formal recommendation to treat CCM with vitamin D, though experts agree that supplementation for individuals with low Vitamin D levels is recommended. [References: www.ncbi.nlm.nih.gov/pubmed/25486933, www.ncbi.nlm.nih.gov/pubmed/26861901, www.ncbi.nlm.nih.gov/pubmed/26861901]
Propranolol is a beta-blocker that can be used to treat infantile hemangiomas. Several reports in the medical literature describe successful treatment of a giant infantile brain cavernoma, as well as two adult women with symptomatic and bleeding CCM lesions. Further studies are ongoing to investigate the biological effects of propranolol in CCM patients. A clinical trial to investigate the effects of propranolol treatment for CCM completed enrollment at multiple centers across Italy in late 2019. The trial will run for 2 years, through 2021. Outcome data should be available in late 2022. [References: www.ncbi.nlm.nih.gov/pubmed/20413807, www.ncbi.nlm.nih.gov/pubmed/26578351, https://clinicaltrials.gov/ct2/show/NCT03589014]
Mouse studies have shown a connection between naturally occurring gut bacteria (the microbiome) and CCM disease severity. These studies used genetically engineered mice that rapidly develop a high number of lesions. By modifying the composition of the microbiome (reducing the number of gram-negative bacteria), the University of Pennsylvania research team was able to reduce the number of CCM lesions by 95-100%. Further investigations into the gut-brain connection unveiled the importance of the mucous layer of the gut. It is required in sufficient quantity to keep bacteria in the gut. Stripping the layer either due to CCM3 genetic mutation or by the consumption of high levels of emulsifier results in increased passage of gram-negative bacteria to the bloodstream. It is recommended that all cavernous malformation patients protect their gut lining by consuming a diet low in processed foods and emulsifiers. This recommendation is particularly important for CCM3 patients. Studies are ongoing to determine if human patients, similar to mice, exhibit a similar pattern of bacterial composition correlating to lesion number or disease severity. [References: www.ncbi.nlm.nih.gov/pubmed/28489816, www.ncbi.nlm.nih.gov/pubmed/31776290]
Proof of Concept and Pre-Clinical Entities
BA-1049 is a specific Rho Kinase inhibitor developed by a pharmaceutical company, BioAxone Biosciences, and now licensed by Neurelis, a company that plans to take the medicine to human trials. Working in collaboration with researchers at Duke and the University of Chicago, BA-1049 has been shown to reduce lesion volume and hemorrhage in mouse models. [Reference: www.ncbi.nlm.nih.gov/pubmed/31446620]
In and around CCM lesions, there is a strong inflammatory system response that includes the localization of B-cells (those that produce antibodies and contribute to inflammation). B-cell depletion therapy includes treatment with specific antibodies to get rid of these cells from the body. This type of therapy has been successful in several cancers and auto-immune conditions. In CCM mice, B-cell depletion therapy has been able to stop the maturation/progression of lesions and also decrease Rho Kinase activity and iron deposition (a marker of bleeding). [References: www.ncbi.nlm.nih.gov/pubmed/27086141, www.ncbi.nlm.nih.gov/pubmed/24864012, www.ncbi.nlm.nih.gov/pubmed/19286587]
The Thrombospondin1 protein is a known inhibitor of angiogenesis (blood vessel growth). Recent reports indicate that in the context of a CCM1 mutant mouse, the TSP1 protein volume is reduced; thus, allowing for unregulated blood vessel growth. In these mouse models, treatment with TSP1 blocks the development of CCM lesions. Because of its involvement in angiogenesis, TSP1 has been a target for cancer research. A fragment of the large TSP1 protein, called 3TSR, has been developed for cancer therapy. The 3TSR molecule was used in the CCM1 mouse studies to prevent lesion development. [Reference: www.ncbi.nlm.nih.gov/pubmed/28970240]
In a high-throughput screen of FDA-approved drugs and a CCM cellular model, Yale researchers identified a combined treatment with fluvastatin and zoledronate as a potential CCM treatment. In models of CCM3 deficient mine, the combined therapy is able to significantly prevent the development of CCM lesions and extend the lifespan of the CCM3 animals. Related to other statin medications, fluvastatin is used to treat high cholesterol and is sold under the common brand name Lescol. Zoledronate is sold under the brand name, Reclast, and is currently used to treat progeria, multiple myeloma, breast and prostate cancer, hypercalcemia, and osteoporosis. [Reference: https://www.ncbi.nlm.nih.gov/pubmed/28500274]
The development of CCM lesions involves cells changing behavior (endothelial-to-mesenchymal transition EndMT), which is controlled by signaling involving TGF-B/BMP and its downstream effectors, B-catenin. Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has been used to treat cancer (outside of the USA). This drug has many cellular actions, one of which is to block the function of B-Catenin. Treatment of mice with this drug leads to decreased number and size of CCM lesions. References: www.ncbi.nlm.nih.gov/pubmed/26109568, www.ncbi.nlm.nih.gov/pubmed/23748444, www.ncbi.nlm.nih.gov/pubmed/26839352]
Fasudil is a Rho Kinase inhibitor that is approved for the treatment of vasospasm in Japan. The drug is not approved for use in the United States. Mouse treatment studies with this drug showed it could reduce lesion burden and hemorrhage. Further Rho Kinase research focuses on statin drugs and the development of a new generation of more specific inhibitors. [Reference: https://www.ncbi.nlm.nih.gov/pubmed/22034008]
The cholesterol-lowering drug, simvastatin, was the first Rho Kinase inhibitor identified as a possible human therapeutic for CCM. However, mouse studies and a small pilot human trial did not replicate the promising results from the cell studies. The clinical trial treated half the study cohort with simvastatin and half with placebo, then measured brain permeability. The findings showed no statistical difference between the control and test groups, though the study was very small. Future statin research will likely focus on other drugs, including atorvastatin. [References: https://www.ncbi.nlm.nih.gov/pubmed/27879448, https://www.ncbi.nlm.nih.gov/pubmed/31643041]
The MEKK3-KLF pathway is regulated by the CCM proteins. When one of the CCM genes is mutated, the result is a chemical imbalance with too much MEKK3-KLF signaling and resulting in CCM lesions. The cancer drug, Ponatinib, is known to inhibit this pathway. In mice, Ponatinib blocks signaling and prevents lesion development. Even though these are promising results, this drug has too many side effects for long-term treatment. However, the study provides an interesting proof of concept to develop a new MEKK2-KLF signing inhibitor. [References: https://www.ncbi.nlm.nih.gov/pubmed/30417093]
These molecules are drugs structurally designed to model Fasudil, but with improved structural elements for increased ROCK inhibitory effects. Developed by Cervello Therapeutics, these molecules are in IND-enabling studies.