MICHAEL TOLENTINO, M.D.

Founder

Dr. Michael J Tolentino attended Deerfield Academy and received his honors Bachelor’s degree in computer science and organizational behavior from Brown University and his Medical degree from the University of Massachusetts. During college, he studied at Nanjing University in China. During high school and college, he worked at Harvard Medical School at the Schepens Eye Research Insitute in his fathers laboratory. His father (Felipe Tolentino MD) is one of the founders of the field of vitreoretinal surgery and was a partner of Charles Schepens the founder of the Schepens Eye Research Institute of the Harvard Medical School.

In the lab prior to college, he worked on perfluoronated carbons to be used on scleral contact lens (1) and on silicone oil for retinal detachment repair. He also worked at the National Eye Institute to develop an imaging system to monitor cataract formation for purposes of clinical trials. (2) In medical school he developed a model of glioblastoma multiforme in a rat and helped test an antibody-ricin linked toxin in this model. He also worked in the laboratory of the late Dr. Elliot Berson (Professor Harvard Medical School and Director of Berman Gund Laboratory), Thaddeus Dryja (Former Head Novartis Ophthalmology), and Michael Sandberg (Professor Harvard Medical School) on macular and retinal degeneration. In this Lab, he worked on developing electrophysiological devices such as the electroretinogram.

After medical school, he did a post-doctoral angiogenesis research fellowship at the Harvard Medical School with Dr. Judah Folkman, Anthony Adamis (Senior VP Global head of Ophthalmology/Immunology Roche), Joan Miller (Chair Harvard Medical School Ophthalmology), Patricia D’Amore (Director of SERI), and Robert D’Amato (Inventor of Revilimid). During this fellowship, he helped develop a xenograft model system to identify endogenous anti-angiogenic therapies. (3) This model was the basis for isolating angiogenic inhibitors such as endostatin and angiostatin. He then switched his research focus retinal disease by studying Verteporfrin (Photodynamic Therapy) and vascular endothelial growth factor (VEGF). He demonstrated that PDTs effect on vasculature was not a result of thermal damage. For VEGF, he demonstrated that VEGF was sufficient and necessary to produce all the findings of diabetic retinopathy and macular degeneration. (4-6)

It was during this time that he helped develop anti-vascular endothelial growth factor (VEGF) therapies such as Avastin, Lucentis Macugen and Eylea treatments used today for macular degeneration and diabetic retinopathy. Working with Napolean Ferrara (Inventor of Avastin and Lucentis) of Genentech, he was the first to administer Avastin in an animal model of human retinal disease. (7-8) In order to inject the precursor to Avastin into the eye, he identified the need to eliminate endotoxin by utilizing the limulus lysate assay to identify any presence of endotoxin in the Avastin preparation. The purification of Avastin and elimination of endotoxin allowed future clinicians the ability to inject Avastin a drug approved for cancer to be injected into the eye.

His work formed the basis for the founding of Eyetech a company that manufactured Macugen the first anti-VEGF therapy developed for retinal diseases. This work also served as the basis for Genentech’s Lucentis program and Regeneron’s Eylea program. In parallel, Dr. Tolentino also completed an ophthalmology residency at the Massachusetts Eye and Ear Infirmary/Harvard Medical, He then moved to Philadelphia where he finished a vitreo-retinal surgical fellowship while joining the ophthalmology and molecular biology faculty at the University of Pennsylvania.

Dr. Tolentino earned numerous awards and received several prestigious grants while at UPenn including the Heed/Knapp, AOS, Ron Michels, AUPO fellowships as well as RPB and K08 NEI research grants. His research focused on gene, cellular and stem cell therapies. He collaborated with Drs. Jim Wilson (Inventor of Ex Vivo Gene Therapy) and Jean Bennett (Inventor of Gene therapy (Luxturna) for LCA scientific foundation for Spark Therapeutics) on the development of regulatable adeno-associated gene therapy vectors to deliver anti-angiogenic therapies. (9-10) He invented a regulatable gene therapy AAV using a heat shock promoter that could be regulated by trans pupillary thermotherapy.

His major accomplishment is his invention of a new class of gene silencing molecules called small interfering RNA (siRNA). against anti-angiogenic targets. (11) He has 3 issued patents on the use of these molecules for treating neovascular diseases such as age related macular degeneration and cancer. (12-16) He was the first to demonstrate that the RNA interference mechanism worked in vertebrate organisms.

With these inventions Dr. Tolentino co-founded and served as the initial CEO for Acuity Pharmaceuticals where he raised 3 million dollars from friends and family and helped raise 21 million in venture funding (Psilos, Mitsubishi and J&J Development). He guided the company from invention, start up, clinical trials to exit. After the successful phase II trial of Bevasiranib for macular degeneration and diabetic retinopathy, Acuity pharmaceuticals merged with a publically traded company Exegenic, owned completely by the Miami Based Frost Gamma private equity group, to form OPKO health (NYSE: OPK) a publically traded biopharmaceutical company. This deal was valued at over 400 million. OPKO’s current market cap is over 2 Billion. (17) Dr. Phillip Frost is current CEO of OPKO health and also the Chairman of the Board of TEVA pharmaceuticals.
Dr. Tolentino is currently a practicing vitreoretinal surgeon specializing in the surgery and treatment of macular degeneration, diabetic retinopathy, retinal detachment, macular pucker, retinal vein occlusions. Patients travel from around the world and from other states to obtain treatment for their retinal conditions.

He is the former director and founder of the clinical research program at the Center for Retina and Macular Disease where he was a partner. The center became one of the largest retinal clinical trial centers in the world with over 120 retinal clinical trials in the last 7 years headed by Dr. Tolentino. He has been the top enrolling principal investigator for Phase I to III FDA registration and Phase IV trials for drugs such as Eylea, Lucentis, Verteporfrin, Macugen, Iluvien, Jetrea, AREDS II, Psvidia, Brolucizumab and SphingoMAB and has been involved in the approval process for several of these drugs. He has been involved in the early development of novel molecules such as eyedrops for AMD (GSK, Panoptica, Bayer), anti-PDGF (Ophthotech, Regeneron, Allergan), Anti-Complement antibodies (Novartis. Ophthotech, Genentech, Pfizer) TIE-2 manipulators(Aerpio, Regeneron), siRNA-VEGF(OPKO), Esbatech Molecule (Alcon), siRNA (Quark, OPKO), AntiSense (I-Cos, Isis) Anti-Amyloid(Pfizer), Squalamine, Sirolimus (Santen), Anti-Inflammatory(Xoma), DARPINs against VEGF (Allergan) and anti- C2/C5 (Pfizer) He has also helped develop devices such as the Foresee Home and microinfusion of anti-VEGF brolucizumab.

Dr. Tolentino is a frequent international lecturer on anti-angiogenic, retinal and macular therapies. He is currently lecturing on preventative strategies for delaying macular degeneration as well as on the history and state of the art management of macular degeneration and diabetic retinopathy. He has organized several ophthalmic education meetings in Florida as well as in other states. He is the co director of the Snowmass CME meeting in Aspen Colorado. He also serves on the faculty of University of Central Florida School of Medicine and is an Associate Clinical Professor and teaches advance ophthalmology course to medical students.

Dr. Tolentino has served on several scientific advisory panels and is or has been a consultant, advisor or speaker for several pharmaceutical companies including Merck, Bayer, Regeneron, Pfizer, Novartis, Genentech, Allergan, Eyetech, QLT, Bausch and Lomb/Valeant, Theravance, Thrombogenics and Glaxo Smith Kline. He served as the Chief Medical Officer for a stem cell company Cryotooth. He also served as founding CEO of Altiok Oncosystems a spin off Company from the Moffitt Cancer Center. He has also served as advisor to several biotech, device and startup companies including, Promedior, Eyelten, Ophthotech, LPath, Alimera, Eyesolutions, AMS Biotek, Panoptica, Sequenom, Arctic DX, Optherion, Occulogix, Clanotech, Asahi Medical, Sightpath, Theravance, Esight Eyewear and Notal Vision. He is also a consultant for the investment community and has recently consulted for Morganthaler, SSRI, and Gerson Lehrman Group. He has consulted for Soros Biotech Fund, and Healthcare Ventures in the past. He is currently on the speakers bureau for Bayer, Regeneron, Allergan, and Thrombogenic, but has been a speaker for Pfizer, Novartis, GSK, Eyetech and Genentech. He has given over 200 international lectures and talks.

He has published over 80 peer-reviewed papers, and over 100 publications in the field of anti-angiogenic, retinal and macular therapies. He is a former high skill high wage board member in the Lakeland economic development council. He is former vice chair of Applied Medicine for the Tampa Bay Partnership Business Plan Initiative. He is currently on the Foundation Board of the Florida Poly, He also has founded a mutual fund in the late 90’s called Physicians Investment Group and Co founded a hedge fund Phileo Securities.

He has started the Tolentino Eye Research Foundation to help develop preventative strategies against blindness that are often overlooked. With these foundations, he seeks to promote the need for protection against high energy visible light with biologic pigment (Melanin) impregnated lenses and to perform clinical research on macular pigment replacement therapy with organically derived supplement containing the optimal ratio of mezozeaxanthin, lutein and zeaxanthin (MACUHEALTH) supplementation.

He also evaluates technologies that claim to protect against blue light and rates these technologies based on their ability to filter the whole spectrum of blue light. From this research he works exclusively with TrueBlue Protection™ Technology whose technology is far superior to any other blue light filtering technology.

He recently founded one of the largest national ophthalmic groups in the United states with 30 doctors located in San Francisco, Tampa/Clearwater, Palm Beach/Miami Florida. The group called Vision Integrated Partners (VIP) is financed by the Firmament group (formerly McLarty Capital) a private equity group focused on small to medium market financing. This group will vertically integrate ophthalmic, clinical research, tele medicine and optometric services under one umbrella and will continue to grow organically and through acquisition.

In parallel to the founding of VIP, he has also founded the Blue Ocean Clinical Research Organization which will utilize the VIP locations as clinical trial centers. This will allow drug sponsors to stream line the execution of early stage or small clinical trials in ophthalmology by dealing with one umbrella organization which will reassure high patient recruitment, high patient retention, stringent FDA compliance, geographic separation of sites and exceptional data acquisition. Blue Ocean provides a seasoned team of clinical trialists who have been involved in over 100 trials in ophthalmology and a proven track record of high patient recruitment and strict study protocol compliance. For later stage Phase III and IV studies, Blue Ocean can provide rapid initiation, rapid patient recruitment and the ability to have several sites activated while dealing with only one organization.

Dr. Tolentino continues to see surgical and medical retina patients at The Macula Center, a VIP company, with offices in Clearwater, Lakeland and the Villages where he is a vitreoretinal surgeon as well as a partner.

He has won numerous awards:

1988 Sigma Xi (Science Honor Society)
1988 All American Scholar
1988 National Deans List
1989 Honors Graduate Brown University
1990 National Eye Institute Summer Research Grant
1990 National Heart, Lung and Blood Summer Research Grant
1993 Senior Scholar at Mass Eye and Ear Infirmary
1994-96 Research Prevent Blindness Unrestricted Grant
1995 ARVO Traveling Fellow for Retina
1999 Heed Ophthalmic Fellow
2000 AUPO fellow presenter
2000 Hernan Knapp-AOS Fellow
2000 Ronald G. Michels Vitreoretinal Fellowship
2001 Strathmore’s Who’s Who
2002 Charles Schepens Research Award Most Outstanding Research Paper
2003 AUPO fellow presenter Senior author
2003 Mentor for Alpha Omega Alpha Student Research Fellowship
2010 Lakeland Volunteers in Medicine Medical Researcher of the Year.
2012- Best Doctors
2012- Peoples Choice Award
2013 Subject Retention Award Regeneron Copernicus Study
2013 Investigator Recognition Award AREDS 2 Study
2014 Samaritan Touch Hero Award
2015 Top 5 Enroller Award Regeneron DME Vista Study
2015 Top 5 Screening Award Regeneron DME Vista Study
2015 Trial Runners Site of the Month Award for study DME-202 B
2016- Leading Physicians of the world.

He has received several prestigious grants including NIH – K08, R03, RPB Career development ward, AHAF.

He currently lives in Lakeland, Florida with his wife Agnes and 3 children. He is an avid skier, gardener and practitioner of Feng Shui.

References
1) Refojo MF, Leong FL, Friend J, Tolentino M. “ Perfluoro-1-Methyl Decalin as a potential oxygen carrier with fluid scleral lens. “ Invest Ophthalmol Vis Sci 1985, 26 (3); S144.
2) Datiles MB, Tolentino M, Sibug ME, Podgor M, Shumer J, Lee J. “ Cataract Progression Using the Zeiss Schiempflug Camera. “ Invest Ophthalmol Vis Sci 1990, 31 (4); S304.
3) Chen C, Parangi S, Tolentino MJ, Folkman J: A strategy to discover circulating Angiogenesis Inhibitors Generated by Human Tumors, Cancer Research. 1996, 55,pp 4230-4233.
4) Tolentino M, Miller J, Gragoudas E, Chatzistefanou K, Ferrara N, Adamis A. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a non-human primate. Arch Ophthalmol. 1996;114:964-70.
5) Tolentino MJ, Miller JW, Gragoudas ES, Jakobiec FA, Flynn E, Chatzistefanou K, Ferrara N, Adamis AP Intravitreal Injections of Vascular Endothelial Growth Factor Produce Retinal Ischemia and Microangiopathy in an adult primate. Ophthalmology. 1996;103:pp.1820-28.
6) Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA. Pathologic features of VEGF-induced retinopathy in the non-human primate. American Journal of Ophthalmology 2002 Mar;133(3):373-85.
7) Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Miller JW: Inhibition of Vascular Endothelial Growth Factor Prevents Retinal Ischemia-Associated Iris Neovascularization in a Nonhuman Primate, Arch Ophthalmol, 1996; 114, pp 66-71.
8) Tolentino MJ, Husain D, Theodosiadis P, Gragoudas ES, Connolly E, Kahn J, Cleland J , Adamis AP, Cuthbertson A, Miller JW. Angiography of fluoresceinated anti-VEGF antibody and dextrans in experimental choroidal neovascularization. Arch Ophthalmol 2000; 118(1)
9) Auricchio, A., Rivera, V., Clackson, T., Maguire, A., O’Connor, E., Tolentino, M., Bennett, J. & Wilson, J. Rapamycin-inducible Secretion of a Therapeutic Protein in the Eye After Transduction With Viral Vectors. Molecular Therapy 2002 Aug;6(2):238.
10) Auricchio A, Behling KC , O’Connor EE, Maguire AM, Bennett J, Wilson JM, Tolentino MJ. AAV-Mediated Retinal Transfer Of Anti-angiogenic Genes In A Murine Model Of Retinopathy Of Prematurity (ROP). Molecular Therapy 2002 Oct;6(4):490.
11) Reich SJ, Fosnot J, Kuroki A, Tang W, Yang X, Maguire AM, Bennett J, Tolentino MJ. Small interfering RNA targeting VEGF effectively inhibits laser induced choroidal neovascularization. Molecular Vision, 2003 May 30;9:210-6.
12) US Patent 7,148,342: Tolentino MJ, Reich SJ. Compositions and methods for sirna inhibition of angiogenesis.
13) US Patent 7,521,431 Reich SJ, Surace EM, Tolentino MJ. Compositions and methods for siRNA inhibition of HIF-1 alpha.
14) US Patent Application 20040248174 Reich SJ, Tolentino MJ. Compositions and methods for siRNA inhibition of angiopoietin 1and 2 and their receptor Tie2 .
15) US Patent Application 20060287259 Reich SJ, Tolentino MJ. Compositions and methods for combined therapy of disease.
16) US Patent Application 20040220129 Reich SJ, Tolentino MJ. Compositions and methods for siRNA inhibition of ICAM-1.
17) http://investor.opko.com/releasedetail.cfm?ReleaseID=279164