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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 treatment of CCM. Click on labels to read more about each medication and to learn about the phases of drug development.
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 safety of a new drug.
Phase II clinical trials are larger studies of patients for whom the drug intends to treat, may be placebo controlled, and aim to investigate the effectiveness of the new drug.
Phase III clinical trials are even larger trials that aims 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 an 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 angioma with symptomatic hemorrhage.
Oxidative stress refers to 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 (Tempol).
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 summer 2018. This study will investigate the safety of long-term treatment and potential effects on bleeding, as measured by iron deposition. For more information, visit out 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 angioma treatment. [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 enrolling at multiple centers across Italy in late 2019. The trial will run for 2 years, through 2021. [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 blood stream. It is recommended that all cavernous angioma 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. Working in collaboration with researchers at Duke and University of Chicago, BA-1049 has 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 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 cell 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 (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 sold under the common brand name of 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 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 new generation and 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 the 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 and 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.