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Current Drugs in Development

CCM Clinical Research in the News

October 2017 - New Therapeutic Target. UCSD researchers identify Thrombospondin 1 (TSP1) as a possible therapeutic to inhibit CCM lesion development. Read more

September 2017 - Dr. Awad's team at the University of Chicago develops biomarker tools to facilitate the success of future clinical trials. Read more about plasma and imaging biomarkers.

August 2017 - BioAxone BioSciences is awarded an additional $1.5M in NIH funding to accelerate their drug development program for BA1049. Read more.

May 2017 - New Therapeutic Target. Researchers at U Penn discover a connection between gut bacteria and CCM disease severity. Read more in a NYTimes article and our Newsletter.

January 2017Recursion Pharmaceutics is featured in MIT Tech Review. Read more.

November 2016 - Preclinical Studies. Rock inhibition with Fasudil or simvastatin improve CCM disease severity in treated mice. Read more.

March 2016Atorvastatin Therapy in CCM: A proof of Concept Phase I/II Trial is planned and seeking funding. Read more.

February 2016 – BioAxone BioSciences Inc. Announces NIH/SBIR Fast Track Grant to Develop BA-1049 for Treatment of Cerebral Cavernous Malformations/AngiomaRead more.

October 2015Recursion Pharmaceuticals obtains orphan designation for CCM. Read more.

 

CCM Drug Pipeline

The interactive tool below lists medications 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.

To receive ongoing notifications about clinical drug trials and patient enrollment, please register at www.Angioma.org/registry.

 


 

Pre-Clinical

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.

 

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in vitro

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.

 

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Animal Models

In CCM disease research, a variety of animal models are used, including c. Elegans (worms), zebrafish, and mice.

 

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Phase I

Phase I clinical trials are typically quite small, may likely use healthy volunteers, and are focused on determining safety of a new drug.

 

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Phase II

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.

 

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Phase III

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).

 

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Rho Kinase Inhibitors

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. This is because in CCM lesions Rho Kinase is overactive. Studies have shown that inhibiting (blocking) Rho Kinase function can fix leaky blood vessels and limit the formation of new lesions.

Several Rho Kinase inhibitor are of interest to CCM researchers. Statin drugs (cholesterol-lowering drugs) are often referred to as ‘dirty drugs’ because they affect so many signaling systems, including Rho Kinase. Fasudil is a more specific Rho Kinase inhibitor that currently is approved for use for other conditions in Japan, and BA-1049 is a brand new chemical inhibitor that is being developed specifically for CCM treatment.

 

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Superoxide Dismutase

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, superoxide dismutases, like Tempol.

 

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Inflammatory Inhibitors

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. 

 

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Beta Blocker

Beta blockers are a class of drugs used to lower blood pressure and are used to manage heart attacks and improve blood flow. 

 

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Fasudil

Fasudil is a Rho Kinase inhibitor. Targeting the Rho Kinase protein is important in CCM disease because in CCM lesions this protein is overactive and is a molecular cause of leaky blood vessels. In mice, it has been shown to decrease the number of CCM lesions (presumably by blocking the formation of new lesions), and to decrease iron deposition (related to lesion bleeding).

Need to determine long term safety concerns with this drug before moving to human trials. Other Rho Kinase inhibitors are underdevelopment and may be better clinical candidates. (e.g. BA-1049)

Fasudil is approved for short-term treatment of Cerebrovasospasm in Japan. It has no approved uses in the United States.

References:

www.ncbi.nlm.nih.gov/pubmed/22034008

www.ncbi.nlm.nih.gov/pubmed/20308363

 

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ZOCOR (Simvastatin)

Simvastatin is most widely known for its cholesterol-lowering effects. Additionally, it acts as a Rho Kinase inhibitor. In cell and mouse-based models, simvastatin has been shown to decrease permeability (leakiness) between blood vessel cells. However, there have been no conclusive studies done to treat mice with the drug to investigate its effect on lesion development and/or bleeding.  

In Mice, simvastatin is shown less effective than Fasudil at inhibiting lesion development and prolonging life, but equally effective in blocking chronic hemorrhage. 

A small human clinical trial to investigate the effects of simvastatin on lesion permeability, as measured by permeability MRI, has finished recruitment and is currently analyzing data. This study was done at the University of New Mexico as part of the Brain Vascular Malformations Consortium.

References:

www.ncbi.nlm.nih.gov/pubmed/27879448

www.ncbi.nlm.nih.gov/pubmed/19151728

 

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LIPITOR (Atorvastatin)

The Atorvastatin drug is of interested to CCM researchers because is also has Rho Kinase inhibiting properties (with potential effects on bleeding and/or lesion development), and is known to be a very strong statin drug.

A safety and efficacy human trial with Atorvastatin treatment is planned to begin in late 2016. This study will investigate the safety of long-term treatment and potential effects on bleeding, as measured by iron deposition.

 

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TEMPOL

Tempol is a superoxide dismutase – it 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 Tempol.

Tempol 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.

References:

www.ncbi.nlm.nih.gov/pubmed/25486933

www.ncbi.nlm.nih.gov/pubmed/24291398

www.ncbi.nlm.nih.gov/pubmed/26795600

 

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Vitamin D3

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.

References:

www.ncbi.nlm.nih.gov/pubmed/25486933

www.ncbi.nlm.nih.gov/pubmed/26861901

 

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BA-1049

BA-1049 is a specific Rho Kinase inhibitor being developed by a pharmaceutical company, BioAxone. This molecule is in early stages of development and a collaborative team recently received an NIH Small Business and Innovation Research (SBIR) grant to develop this drug for CCM treatment. The grant will support dosing studies in mice, safety in human, and lead investigators to a phase II treatment trial. 

Reference:

http://bioaxonebio.com/wp-content/uploads/2011/05/BioAxone-Announces-NIH-SBIR-Fast-Track-Grant-to-Develop-BA-1049-for-Treatment-of-Cerebral-Cavernous-Malformation-Angioma.pdf

 

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Lescol & Reclast Combined Therapy

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

 

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Sulindac

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

 

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B-Cell Depletion Therapy

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

 

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Propranalol

Propanalol is a beta-blocker that has been used successfully to a treat giant infantile brain cavernoma as well as two adult women with symptomatic and bleeding CCM lesion. Further studies are needed to confirm these observations and investigate further use of this drug for CCM patients.

References:

www.ncbi.nlm.nih.gov/pubmed/20413807

www.ncbi.nlm.nih.gov/pubmed/26578351

 

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Gut Bacteria Modification

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, the UPenn research team was able to reduce the number of CCM lesions by 95-100%. Studies are ongoing to determine if human patients share a similar pattern of bacterial composition correlating to lesion number or disease severity.

References:

www.ncbi.nlm.nih.gov/pubmed/28489816

 

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Thrombospondin1 (TSP1)

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.

References:

www.ncbi.nlm.nih.gov/pubmed/28970240

 

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Zocor Lipitor Fasudil BA-1049 Tempol Sulindac Metabolites B-cell Depletion Therapy Vitamin D3 Propanalol preclinical in vitro animal Phase I Phase II Phase III RHO Kinase Inhibitors Superoxide Dismutase Beta Blocker Inflammatory Inhibitors