Translational Medicine

CURRICULUM VITAE

Timothy P. O'Neill, Ph.D. RAC

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Regulatory Affairs Specialist

Cardiovascular, Respiratory, Gastrointestinal and Neuropharmacologist Email: *.******@*******.***

Skill Set

• Regulatory Affairs Certified (RAC)

• Regulatory Submissions (PIND, IND, NDA)

• Translational Medicine

• Clinical Development

• Pharmaceutical Project Leadership

• Cardiovascular Pharmacology/Physiology

• Gastrointestinal Pharmacology/Physiology

• Neuropharmacology/Toxicology

• Respiratory Pharmacology/Physiology

• Contract research (contract labs, University collaborations)

• Clinical Laboratory Medicine

Pharmaceutical Industry Experience

Medpace

1 Apr 2019 – 15 April 2020. Senior Manager, Regulatory Affairs. Responsible for o Strategic consulting on regulatory strategies

o Review of regulatory documents on behalf of client companies o Arrange and represent clients at FDA meetings

o Training of Regulatory Affairs Project Managers and Associates 8 Oct 2012 – 1 Apr 2019. Manager, Regulatory Affairs. Responsible for: o Strategic consulting on regulatory strategies

o Preparation and submission of regulatory documents on behalf of client companies o Arrange and represent clients at FDA meetings

Achievements

Led development of Pre-NDA Meeting/Successful NDA Filing and Approval o Developed efficient and effective regulatory strategies for several projects including gap analyses, and risk mitigation o Contributed the nonclinical sections to the Pre-NDA meeting request and briefing document o Wrote nonclinical (2.6's) written summary sections o Worked with Team and FDA Project Manager to get acceptable responses to our Pre-NDA questions. o Addressed FDA questions during 30-day safety review Led successful EOP2 meeting

o Led the meeting between FDA and Sponsor

o Authored all non-CMC sections of the Request Letter and Briefing Document o Edited Mod 3 sections, compiled entire submission (300+ pages) o Made last-minute changes during Publishing/Printing process o Worked closely with the FDA Project Manager to coordinate the initial submission of the briefing document and subsequent changes to the meeting

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Timothy P. O'Neill, Ph.D. RAC

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Led several successful IND filings for small molecules, biologics, and a therapeutic cancer vaccine o Authored Mods 2.4 and 2.5, cover letter, bridging tox study synopsis o Edited 2 clinical study protocols, Mod 3 sections, Mod 4, Mod 5 sections o Arranged, chaired Team meetings

o Addressed FDA information requests during 30-day safety review Led Development of several Pre-IND request/information packages o Led development of PIND meeting request/packages o Chaired Team meetings

o Authored cover letters

Regulatory Strategy Development

o Reports comparing US and EU requirements for Biosimilars. o Leveraged this information to develop responses to refusal from Russian MOH to allow clinical trials in psoriatic arthritis and rheumatoid arthritis, leading to trial approval. o Compiled ROW regulatory queries/responses for all Medpace clinical studies; work with IT to develop an internal regulatory intelligence database

Camargo Pharmaceutical Services

2009 -31 Sep 2012. Senior Research Scientist. Responsible for: o Strategic consulting on regulatory strategies

o Preparation and submission of regulatory documents on behalf of client companies o Arrange and represent clients at FDA meetings

o Develop nonclinical strategies, study designs and provide oversight of nonclinical studies on behalf of clients o Preparation of risk assessments for regulatory filings. Achievements

Led successful NDA filing for a program with both US and European studies o Authored all non-CMC sections of Module 2

o Compiled all Module 4 and 5 Sections

o Authored draft, annotated draft labeling

Prepared 2 IND filings, 3 PIND filings

o Draft clinical protocol synopsis

o Work with team write, finalize protocols for IND-opening studies o Develop, write General Investigative Plan, Investigator Brochure o Author all non-CMC sections of Module 2

o In conjunction with CRO develop, finalize nonclinical study protocols and reports. o Led nonclinical development, wrote all nonclinical pharmacology/toxicology sections for a successful IND filing o Led 3 successful PIND meetings including developing overall strategy and writing regulatory, clinical pharmacology, clinical efficacy and safety, and nonclinical sections. o Promotion to Senior Research Scientist

Procter & Gamble, Procter & Gamble Pharmaceuticals 2006 – 2009 Leader of internal team charged with identifying, evaluating, and providing technical support for in-licensing opportunities for upper gastrointestinal disorders. 2005 – 2006 Chair of the internal team responsible for identifying and in-licensing external opportunities for cardiovascular therapeutics.

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1997 – 2006 Project Leader for 5 projects to identify novel therapeutic approaches for heart failure. One of these efforts advanced to clinical development and the results were presented at the 2005 Annual Meeting of the American College of Cardiology (PREMIER Trial, late-breaking trials session). A manuscript on this trial has been accepted for publication in the Journal of the American College of Cardiology. Established and supervised small animal cardiac laboratory for to develop and utilize models of ventricular dysfunction and remodeling in mice, rats, and hamsters in vivo

(echocardiography, left ventricular cannulation, central and regional hemodynamics in anesthetized preparations, telemetry, metabolism cages). Managed 3 outside research studies to determine effects of matrix metalloproteinase inhibitors in model of heart failure (results presented at the 2000, 2002, and 2003 Annual Meeting of the AHA and Heart Failure Society of America). Also managed 3 outside research studies in small animals. Two of these were to determine the effect of novel therapeutics in rodent heart failure models, while the other was to determine the effect of a novel therapeutic on the development and progression of atherosclerosis. 1994 – 97 Lead in vivo Biologist for Heart Failure. Established and supervised small animal cardiac laboratory for study of novel compounds on cardiac function ex vivo (isolated, working heart) and in vivo (left ventricular cannulation, central and regional hemodynamics in anesthetized preparations). Responsibility for training and managing 2 research associates. Managed three outside research studies, two determining alterations in ionic currents in myocytes from cardiomyopathic hamsters and the other to examine the effect of drug treatment on survival and exercise performance in cardiomyopathic hamsters.

1992 - 94 Lead in vivo Biologist for Asthma. Established and supervised laboratory for testing the effects of novel compounds on pulmonary function and pulmonary inflammation in anesthetized

(pulmonary function) and conscious (inflammation) mice. Inflammatory models involved both immunologic and non-immunologic pro-inflammatory stimuli. Responsibility for training and managing 2 research associates. Also managed outside research studies to determine drug effects in sheep model of allergic respiratory disease.

1989 - 92 Project Leader for Respiratory Pharmacology. Established and supervised laboratory for determining effects of novel compounds on airway function and respiratory reflexes. Responsibility for training and managing 2 research associates. Managed 2 outside research projects to determine drug effects in on airway reflexes in healthy animals and a clinical study of the effect of upper respiratory infection on airway reflex sensitivity. Was also invited to speak at the first conference on Cough and Other Airway Reflexes and write a review article in area of expertise (see Invited Reviews, below).

1985 - 89 Toxicologist. Established and supervised laboratory for determining direct and neurally-mediated effects on cardiovascular function of novel therapeutics. Included measuring arterial pressure, heart rate, regional blood flows and cardiac output in conscious and anesthetized rats. Also involved managing 2 outside research projects, results of which were published. Also responsible for identification and validation of contract laboratories for neurotoxicity testing. Patents

Gilbert, S.A., Mizoguchi,H. Charest,R.P., O'Neill, T.P. and Smith, R.L. Use of loperamide and related compounds for treatment of respiratory tract symptoms. U.S. Patent 5,116,847, May 26, 1992. O'Neill, T.P., Kasting, G.B., and Kupps,T.L. Use of vanilloids for the prevention of lesions due to herpes simplex infections., U.S. Patent 5,461,075, October 24, 1995. Published Abstracts

1. O'Neill, T.P., and Haigler, H.J. Alpha-adrenoceptors in a nociceptive pathway in the mesencephalic reticular formation of the rat. Fed.Proc. 41: 1765, 1982.

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2. Haigler, H.J., and O'Neill, T.P. Morphine: blockade of neuronal firing evoked by norepinephrine (NE), acetylcholine (Ach), and a nociceptive stimulus. Fed.Proc. 41: 1302, 1982. 3. O'Neill, T.P., and Haigler, H.J. Effects of microinotophoretically-applied alpha1

- and alpha2

-adrenoceptor

agonists and atnagonists on neruonal firing evoked by a nocious stimulus. Fed.Proc. 42: 382, 1983. 4. O'Neill, T.P., and Brody, M.J. Role of the median preoptic nucleus (MnPO) in the response to centrally-acting pressor agents. Fed.Proc. 43: 310, 1984.

5. O'Neill, T.P., and Brody, M.J. Hemodynamic effects evoked by electrical stimulation of the arcuate nucleus

(AN). Soc.Neurosci.Abstr. 10: 32, 1984.

6. Brody, M.J., O'Neill, T.P., Porter, J.P., Bonham, A.C., and Needleman, P. Baroreflex-dependant hemodynamic effects of synthetic atriopeptins. Hypertension 6: 783, 1984. 7. O'Neill, T.P., and Brody, M.J. Hemodynamic effects produced by arcuate stimulation are mediated in part through a projection to paraventricular nucleus. Fed.Proc. 44: 1553, 1985. 8. Brody, M.J., O'Neill, T.P., and Portis, L.R. Do angiotensinergic projections mediate the pressor effects produced by electrical stimulation of the subfornical organ. Fed.Proc. 44: 1553, 1985. 9. Thoren, P., Morgan, D., O'Neill, T.P., Needleman, P., Mark, A., and Brody, M.J. Atrial natriuretic factor activates vagal afferents in rats. Fed.Proc. 44: 1886, 1985. 10. Mark, A.L., Thoren, P., O'Neill, T.P., Morgan, D., Needleman, P., and Brody, M.J. Atriopeptins stimulate cardiac sensory receptors with vagal afferents in rats. Clin.Res. 11. O'Neill, T.P. Differential effects of capsaicin derivatives on arterial pressure in rats. Soc.Neurosci.Abstr. 12: 646, 1986.

12. Bennett, T., Gardiner, S.M., and O'Neill, T.P. Treatment of adult Wistar rats with synthetic capsaicin reversibly inhibits vasopressin-mediated recovery of blood pressure following acute hypotension. J.Physiol. 398: 58P, 1988.

13. O’Connell,F., Thomas, V.E., Studham, J.M., O’Neill, T.P., Fuller, R.W., and Pride, N.B. Capsaicin cough sensitivity increases during upper respiratory tract infection. Thorax 48: 1074, 1993. (Also presented May, 1993 at American Thoracic Society Meeting, Anaheim, CA). 14. DeMuth, J.P., Rosa, L.R., Margulies, K.B., O’Neill, T.P., Doersen, C.-J.W. Quantitative RT-PCR analysis of calcineurin mRNA abundance in end-stage human heart failure by the fluorogenic 5’ nuclease (TaqMan) Assay. J.Cardiac Failure 6:30, 2000

15. O’Neill, T.P., King, M.K., Coker, M.L., Goldberg, A.T., Morrison,A.E., Holder,J.R., Gunasinghe, H.R., Mukherjee, R., Wendt, K.A., Zile, M.R., Spinale, F.G. Selective matrix metalloproteinase inhibition influences LV geometry and myocardial structure in developing congestive heart failure. Circ. 102:II-292, 2000.

16. King, M.K., Coker, M.L.,Goldberg, A.T., Morrison,A.E., McElmurray, J.H., Gunasinghe, H.R., Mukherjee, R., Wendt, K.A., O’Neill, T.P., Zile, M.R., Spinale, F.G. Selective matrix metalloproteinase inhibition influences LV geometry and myocardial structure in developing congestive heart failure. Circ. 102:II-452, 2000.

17. Kawamoto, R. M., Suzuki, G., Morita, H., O’Neill, T. P., Sabbah, H. N. Matrix Metalloproteinase 2 and 9 Activity Is Increased in Dogs With Progressive Left Ventricular Failure. Circ. 104 (17): II-738, 2001. 18. Mukherjee, R., Brinsa, T. A., Thornton, J. L., Yarbrough, W.M., Sample, J. A., Dowdy, K. B., O'Neill, T. P., Escobar, G. P., Spinale, F. G.. Selective Matrix Metalloproteinase Inhibition Influences Regional Myocardial Geometry and Reduces LV Dilation Following Myocardial Infarction. Circ. 106(19): II-266, 2002. CURRICULUM VITAE

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19. Henry, C. E., Doersen, C. W. Zwolshen, J. M., Cabrera, E.J., Peterson, K. T., Pozzi, M. E., Harrod, K.J., Deutsch, A. J., DeMuth, J. P., Stevens, P.J., Varbanov, A. R., Kawamoto, R.M., and O'Neill, T. P. Effects of volume overload on cardiac remodeling and gene expression. FASEB J. 17 (5):A847, 2003. 20. Henry, C. E., Pozzi, M. E., Cabrera, E.J., Zwolshen, J. M., Harrod, K.J., Peterson, K. T., Kawamoto, R.M., Deutsch, A. J., Doersen, C. W. and O'Neill, T. P. Effects of Captopril on cardiac remodeling and pro- inflammatory pathways in a rat arteriovenous fistula model of volume overload. FASEB J. 17 (5):A846, 2003. 21. Cabrera, E.J., Peterson, K. T., Henry, C. E., Pozzi, M. E., Zwolshen, J. M., Harrod, K. J., Deutsch, A. J., Doersen, C. W., Kawamoto, R.M., and O'Neill, T. P. Altered levels of TNF- receptors in a heart failure model of volume overload. FASEB J. 17 (4):A527, 2003. 22. Yarbrough, W.M., Sample, J.A., Jukherjee, R., McLean, J.E., Hendrick, J.W., Escobar, G.P., Dowdy, K.B., Mingoia, J.T., O’Neill, T.P., Spinale, F.G.j Selective inhibition of matrix metalloproteinase species favorably modifies left ventricular remodeling post myocardial infarction. J.Card.Fail. 9 (No. 5 Suppl.): S26, 2003 23. Sabbah, H.N., Morita, H., Suzuki, G., Sharov, V.G., Todor, A., O’Neill, T.P. PG-530742, a novel matrix metalloproteinase inhibitor, improves left ventricular function and attenuates remodeling in dogs with chronic heart failure. J.Am.Coll.Cardiol. 43 (Suppl. A):22A, 2004. Full Publications

1. O'Neill, T.P., and Haigler, H.J. Characteristics of adrenoceptors in a nociceptive pathway in the mesencephalic reticular formation of the rat. J.Pharmacol.Exp.Ther. 222: 555-561, 1982. 2. Haigler, H.J., and O'Neill, T.P. Interactions of morphine with putative nociceptive neurotransmitters in the mesencephalic reticular formation. Life Sci. 32: 759-769, 1983. 3. O'Neill, T.P., and Haigler, H.J. Effects of clonidine on neuronal firing evoked by a noxious stimulus. Brain Res. 327: 97-103, 1985.

4. Thoren, P., Mark, A.L., Morgan, D., O'Neill, T.P., Needleman, P., and Brody, M.J. Activation of vagal depressor reflexes by atriopeptins inhibits renal sympathetic nerve activity. Am.J.Physiol. 251 (Heart Circ.Physiol. 20): H1252-H1259, 1986.

5. O'Neill, T.P., and Brody, M.J. Role for the median preoptic nucleus in centrally-evoked pressor responses. Am.J.Physiol. (Regulatory Integrative Comp.Physiol.): R1165-R1172, 1987. 6. Gardiner, S.M., Bennett, T., and O'Neill, T.P. Synthetic capsaicin reversibly impairs vasopressin-mediated blood pressure recovery. Am.J.Physiol. (Regulatory Integrative Comp.Physiol.): R1429-R1435, 1989. 7. Neubecker TA, Coombs MA, Quijano M, O'Neill T.P., Cruze CA, Dobson RL. Rapid and selective method for norepinephrine in rat urine using reversed-phase ion-pair high-performance liquid chromatography-tandem mass spectrometry. J.Chromatogr.B.Biomed.Sci.Appl. 1998;718:225-233. 8. Kuhlenbeck D.L., O'Neill T.P., Mack C.E., Hoke, S.H.I., Wehmeyer, K.R. Determination of norepinephrine in small volume plasma samples by stable-isotope dilution gas chromatography-tandem mass spectrometry with negative ion chemical ionization. J.Chromatogr.B. 2000;738:319-330. 9. King, M.K., Coker, M.L.,Goldberg, A., Morrison, A.E., McElmurray, J.H., Gunasinghe, H.R., Mukherjee, R., Zile, M. R.., O’Neill, T.P., Spinale, F.G. Selective matrix metalloproteinase inhibition with developing heart failure. Effects on left ventricular function and structure. Circ.Res. 2003;92:177-185. 10. Yarbrough, W.M., Mukherjee, R., Escobar, G.P., Mingoia, J.T., Sample, J.A., Hendrick, J.W., Dowdy, K.B., McLean, J.E., Lowry, A.S., O’Neill, T.P., Spinale, F.G. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation 2003; 108:1753-1759. CURRICULUM VITAE

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11. Apple, K.A., Yarbrough,W.M., Mukherjee, R., Escobar,P., Mingoia, J.P., Sample, J.A., Hendrick,J. W., Dowdy, K.B., MacClean, J.A., Stroud, R.E., O’Neill, T.P., Spinale, F.G. Selective targeting of matrix metalloproteinase inhibition in post-infarction myocardial remodeling. J. Cardiovasc.Pharmacol. 2006; 47:228- 235.

12. Kaiser R.A., Lyons, J.M., Duffy, J.Y., Wagner, C.J., McLean, K.M., O’Neill, T.P., Pearl, J.M., Molkentin, J.D. Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion. Am.J.Physiol. 2005, 289:H2747-H2751.

13. Morita, H., Khanal, S., Suzuki, G., Imai, M., Todor, A., Sharov, V.G., Goldstein, S., O’Neill, T.P., Sabbah, H.N. Selective matrix metalloproteinase inhibition attenuates the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am.J. Phsyiol. 2006, 290:H2522-H2527. 14. Hinkle, R.T., Lefever, F.R., Dolan, E.T., Reichart, D.L., Zwolshen, J.M., O’Neill, T.P., Maloney, K.G., Ferreira, L.F., Musch, T.I., Poole, D.C., Isfort, R.J. Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals. BMC Musculoskelet Disord. 2011 Jan 14;12:15. doi: 10.1186/147*-****-**-**. Invited Reviews

1. Brody, M.J., O'Neill, T.P., and Porter, J.P. Role of central catecholaminergic systems in pathogenesis and treatment of hypertension. J.Cardiovasc.Pharmacol. 6 (Suppl. 5): S727-S741, 1984. 2. Brody, M.J., Alper, R.H., O'Neill, T.P., and Porter, J.P. Central neural control of the cardiovascular system. in: Handbook of Hypertension, Vol. 8: Pathophysiology of Hypertension - Regulatory Mechanisms. A. Zanchetti and R.C. Tarazzi, eds. Elsevier Science Publishers, pps. 1-25, 1986. 3. Brody, M.J., O'Neill, T.P., and Porter, J.P. Role of paraventricular and arcuate nuclei in cardiovascular regulation. in: Central and Peripheral Mechanisms of Cardiovascular Regulation. A. Magro, W. Osswald, D. Reis, and P. Vanhoutte, eds. Plenum Press, pps. 443-464, 1986. 4. O'Neill, T.P. Mechanism of capsaicin action: recent learnings. Respiratory Medicine 85:35-42, 1991. Education

University of Vermont,

Burlington, Vermont A.A.S. Medical Technology

S.U.N.Y. at Buffalo,

Buffalo, New York B.S., Biochemical Pharmacology

Emory University,

Atlanta Georgia M.S., Ph.D., Pharmacology

Appointments

Predoctoral Trainee, Dept. of Pharmacology, Emory University Postdoctoral Trainee, Cardiovascular Center, University of Iowa Postdoctoral Fellow, Dept. Of Pharmacology, University of Iowa CURRICULUM VITAE

Timothy P. O'Neill, Ph.D. RAC

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Society Memberships

Heart Failure Society of America 1997-2006 Functional Brain-Gut Research Group 2006-2009

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