Clear Vascular

Clear Vascular, Inc. is a clinical stage company.  The company has developed an injectable, targeted radiopharmaceutical agent, Tin-Annexin, for imaging and therapy of inflammatory tissues, initially targeting vulnerable and unstable plaque. This is produced at a cGMP facility along with other radioisotope-based products.

Phase 1 (Safety) human clinical imaging studies and Phase 2 have been completed. Atherosclerotic therapy studies have shown statistically significant therapeutic effects on vulnerable plaque in a number of animal models.

Clear Vascular, Inc. (CVI) is a clinical stage company that was formed in 2005 by Dr. Gilbert Gonzales (CEO) and has been supported by equity and equity-sparing funding .  The Company’s aims are to image and treat vulnerable plaque and other vascular inflammatory diseases. The commercial manufacturing of tin-117m, initially using reactors in Russia, was developed under the Initiative for Proliferation Prevention (IPP) program in collaboration with the US Department of Energy and Brookhaven National Laboratory.  This early work validated the imaging and therapeutic effects predicted for tin-117m.

Under this IPP program a proton accelerator method of producing the tin-117m at higher specific activities was then developed in collaboration with the Institute for Nuclear Research near to Moscow.  This production method has been demonstrated to be transferable to a number of institutions in the USA and elsewhere where the product could be made at will.

Innovative work by Dr. Nigel Stevenson led to a new tin-117m production method using alpha particles and a cadmium-116 target.  This is now the primary method that is routinely used to manufacture the tin for the clinical trial product.

In conjunction with this, the development of our primary product, Tin-Annexin, has led to numerous pre-clinical and clinical trials that have demonstrated the viability of not only imaging the vulnerable and unstable plaque but, more importantly, therapeutically treating the conditions.

Studies

PRE-CLINICAL STUDIES

• Normal mouse and rabbit BD and atherosclerotic rabbit BD, therapy and imaging studies
• Pig and rabbit stent therapy studies
• Normal mouse sterile abscess and pK studies
• Preliminary and validating Apo-E mouse therapy studies
• Rat toxicity studies

HUMAN CLINICAL TRIALS:

CAROTID 1 (Safety Study)

• Imaging and pathology on 6 CEA subjects
• 500 µCi cGMP dose to determine dosimetry for Carotid #2 study
• Identification by U/S and histology of VP
• Binding to VP

CAROTID 2 (Low Dose Study)

• Imaging and pathology on 9 CEA subjects
• 3 mCi cGMP dose
• Identification of VP by U/S, histology and autoradiograph
• Binding to VP specific inflammatory cells
• Binding and imaging of AAA
• Imaging studies with the therapeutic markers on CEA subjects

R&D Studies (CMC):

SBIR 1 (completed 2012) [Agency: DOE; Grant $150k]

• Developed separation chemistry for alpha Sn-117m production
• Developed chelation and conjugation of Sn-117m to annexin
• Verified yields, calculation of economics and modeling the scale-up of production capacity

SBIR 2 (2013-2015) [Agency: DOE; Grant $1M]

• Optimize separation chemistry
• Optimize linking of Sn-117m to several targeting molecules
• Detailed calculations, verification and planning for commercial scale production of high specific activity Sn-117m
• Develop existing CMC production capabilities for larger scale production
• To develop, support and provide an adequare future supply of high specific activity Sn-117m to groups and projects performing R&D work with this isotope

Technolgy

CVI has developed proprietary technology and methods to produce:

• High specific activity Tin-117m (Sn-117m) radiochemical
• Applications in imaging and therapy
• Tin-Annexin ([Tin-117m]-DOTA-Annexin) to detect and treat vulnerable plaque in cardiac, carotid and other locations in the body
• Tin-117m can be electroplated onto stents or wires for a number of applications

Products

PRIMARY PRODUCT

The primary product is composed of three components – tin-117m, a linker molecule DOTA and the targeting molecule annexin V.

• Tin-117m (Sn-117m) is a unique radioisotope that can be used to both image and treat vulnerable plaque, cancers, rheumatoid arthritis, and other medical problems.  Propriatary technology for the production of high specific activity Sn-117m is central to all our products.  More information is available here.
• DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a chelating agent used to contain the Sn-117m in the product.  The Amino Benzyl DOTA bifunctional version used in the product allows the DOTA-[Sn-117m] to be attached to a targeting molecule (annexin).
• Annexin V is a naturally occuring protein that attaches to inflamatory cells in the body.  More information is available here.

OTHER PRODUCTS

Tin-117m is also electroplated onto stents or wires for a number of applications. More information is available here.

PRODUCTION

The production of [Sn-117m]-Annexin is performed under cGMP in our suites located at our contract manufacturing partners, IsoTherapeutics, in Angleton, TX. 

Intellectual Property

CLEAR VASCULAR HAS A cGMP PROCESS SUPPORTED BY EXTENSIVE IP PROTECTION

• High Specific Activity Sn-117m (Tin-117m) material produced on linear accelerators and cyclotrons, patented processes, targetry and chemical processing
• CVI developed and owns (patented) and has exclusive licenses in CV for the only two viable methods of commercial production
• CVI routinely manufactures Sn-117m for its own use (clinical trials) and also for collaborators.  Clear Vascular has a cGMP process and product (~90 manufacturing procedures with ~30 support procedures) used in the clinical trials
• CVI has two dedicated cGMP suites to manufacture the product
• Extensive filed/licensed/issued patents and additional trade secrets; some IP through US DOE, Brookhaven National Laboratory, Initiative for Proliferation Prevention and others

Applications

Tin-117m is applicable to multiple medical conditions:

• Vasculopathy
• Oncology  (Serene Oncology, LLC)
• Rheumatology  (Rheumco, LLC)
• Ophthalmology
• Other  (SnIP Holdings, Inc.)

References

Recent Presentations and Publications:

• “Simultaneous Localization and Treatment of Vulnerable Plaque by Tin-117m Conversion Electrons: First-in-Human Results”, R. Virmani, TCT (‘Innovations’ session): (Oct 22, 2012).
• “Paving the Way to Personalized Medicine: Production of Some Promising Theragnostic Radionuclides at Brookhaven National Laboratory” , S.C. Srivastava, Semin. Nucl. Med. Vol 42, 151-163 (2012).
• “Tin-117m-DOTA-Annexin for Imaging and Treating Vulnerable Plaque”, G.R. Gonzales, ICRT (WARMTH), Finland (2012).
• “Paving the Way to Personalized Medicine for Treatment of Cancer and Other Inflammatory Disorders”, S.C. Srivastava, ICRT (WARMTH), Finland (2012).
• “Production and Applications of Very High Specific Activity Sn-117m”, N.R. Stevenson, et al., ACS New Orleans (April 2013).
• “Sn-117m Labeled Annexin for Vulnerable Plaque”, J. Simon, et al., ACS New Orleans (April 2013).
• “Production and applications of very high specific activity Sn-117m and labeled chelates/molecules”, N.R. Stevenson, et al., ISRS, Korea (May 2013).
• “Theragnostic potential of Sn-117m for the molecular targeting and therapy of vulnerable plaque”, S.C. Srivastava, et al., SNMMI, Vancouver (June 2013).
• “Targeting of vulnerable plaque using [tin-117m]-DOTA-annexin”, H.W. Strauss, et al., SNMMI, Vancouver (June 2013).
• “Production and Applications of High Specific Activity Sn-117m-DOTA-Annexin”,  S.C. Srivastava, J. Narula, H.W. Strauss, G. Gonzales, WIPR 2013: Latest Progress in the Field of RadioImmunoTherapy, France (July 2013).
• “Simultaneous imaging and treatment of vulnerable plaques with tin-117m-DOTA-Annexin”, S.C. Srivastava, J. Narula, H.W. Strauss, G. Gonzales, WIPR 2013: Latest Progress in the Field of RadioImmunoTherapy, France (July 2013).
• “Manufacturing and integrated medical imaging of high specific activity [Sn-117m]-annexin in cardiovascular disease”, N. R. Stevenson, et al., IAEA International Conference on Integrated Medical Imaging in Cardiovascular Disease, Vienna (Sept. 2013).
• “Sn117m-DOTA-Annexin as a novel vulnerable plaque tracer. First time in humans trial.”, R. Jaimovich, et al., IAEA International Confernce  on Integrated Medical Imaging in Cardiovascular Disease, Vienna (Sept. 2013).
• “Preparation and Evaluation of Sn-117m Annexin For Vulnerable Plaque”, J. Simon, et al., 8^th International Conference on Isotopes, Chicago (August 2014)
• “Methods of Producing High Specific Activity Sn-117m with Commercial Cyclotrons”, N. R. Stevenson, 8^th International Conference on Isotopes, Chicago (August 2014). Journal of Radioanalytical and Nuclear Chemistry: Volume 305, Issue 1 (2015), Page 99-108 (DOI: 10.1007/s10967-015-4031-7)
•  “Enabling simultaneous imaging and treatment with the theragnostic radionuclide Tin-117m”, S.C. Srivastava, TERACHEM 2014, Italy (Sept. 2014)
• “A Novel Sn-117m Colloid for Radiosynovectomy”, S.C. Srivastava, et al, SNMMI, San Antonio (January 2015) – Submitted
• “Homogeneous Sn-117m Colloid – A Novel Radiosynovectomy Agent”, S.C. Srivastava, et al, ICRT (WARMTH), Austria (May 2015) – Submitted
• “Homogeneous Sn-117m Colloid Radiosynovectomy Results in Rat Models of Joint Disease”, C.A. Doerr, et al, SNMMI, Baltimore (June 2015) – Submitted

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