Bio

Clinical Focus


  • Internal Medicine

Administrative Appointments


  • Assistant Professor of Medicine, Stanford University (1985 - 1993)
  • White House Fellow, Washington, DC (1993 - 1994)
  • Senior Consultant, The Advisory Board, Washington DC (1994 - 1995)
  • Director of Medical Affairs, Heartport - Redwood City, CA (1995 - 1999)
  • Healthcare Consultant, . (1999 - 2004)
  • Senior Director, Clinical Research, KAI Pharmaceuticals, Inc (2004 - 2007)
  • Co-Director, SPARK Program (2008 - Present)

Professional Education


  • Residency: Stanford University Internal Medicine Residency (1985) CA
  • Internship: Stanford University Internal Medicine Residency (1983) CA
  • Medical Education: Brown University School of Medicine (1982) RI
  • Board Certification: American Board of Internal Medicine, Internal Medicine (1985)
  • MA, Santa Clara University, Pastoral Ministries (2007)
  • MD, Brown University, School of Medicine (1982)
  • MBA, Stanford University-GSB, Health Management (1993)
  • BS, Brown University, Biological Sciences (1979)

Research & Scholarship

Clinical Trials


  • Ulinastatin for the Treatment of COVID-19 in Hospitalized Patients Not Recruiting

    The primary objective of this study is to evaluate the safety and efficacy of intravenous (IV) infusion of ulinastatin compared to placebo with respect to time to recovery, disease severity, need for ventilator support, and mortality in patients with COVID 19.

    Stanford is currently not accepting patients for this trial.

    View full details

Teaching

Stanford Advisees


Publications

All Publications


  • Mechanisms of Azetidine-2-carboxylic Acid (Aze)-Induced Oligodendrogliopathy In Vivo and In Vitro Sobel, R., Albertelli, M., Hinojoza, J., Eaton, M., Grimes, K., Rubenstein, E. OXFORD UNIV PRESS INC. 2020: 661
  • p38 MAPK inhibition: A promising therapeutic approach for COVID-19. Journal of molecular and cellular cardiology Grimes, J. M., Grimes, K. V. 2020

    Abstract

    COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

    View details for DOI 10.1016/j.yjmcc.2020.05.007

    View details for PubMedID 32422320

  • A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. Clinical therapeutics Sumi, E., Asada, R., Lu, Y., Ito-Ihara, T., Grimes, K. V. 2020

    Abstract

    PURPOSE: The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies.METHODS: Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies.FINDINGS: In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case.IMPLICATIONS: In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

    View details for DOI 10.1016/j.clinthera.2020.01.002

    View details for PubMedID 32008723

  • Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer. Translational oncology Knox, S. J., Jayachandran, P., Keeling, C. A., Stevens, K. J., Sandhu, N., Stamps-DeAnda, S. L., Savic, R., Shura, L., Buyyounouski, M. K., Grimes, K. 2019; 12 (11): 1525?31

    Abstract

    In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT.

    View details for DOI 10.1016/j.tranon.2019.08.006

    View details for PubMedID 31454725

  • Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries. Annual review of pharmacology and toxicology Parrish, M. C., Tan, Y. J., Grimes, K. V., Mochly-Rosen, D. 2018

    Abstract

    With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    View details for PubMedID 30208282

  • Human Chitotriosidase Does Not Catabolize Hyaluronan. International journal of biological macromolecules Danielson, B., Chen, C. H., Kaber, G., Mochly-Rosen, D., Grimes, K., Stern, R., Bollyky, P. L. 2017

    Abstract

    Humans express an enzyme that degrades chitin, called chitotriosidase, despite the fact that we do not produce chitin. One possible explanation for this is that chitinase also degrades hyaluronan, a polysaccharide that is abundant in human tissues and shares structural attributes in common with chitinase. The objective of this study was to determine whether human chitotriosidase is capable of hydrolyzing hyaluronan. Hyaluronan of various sizes under a range of pH conditions displayed no degradation when incubated with various chitinases over a period of 5 days, while commercial hyaluronidase readily digested the hyaluronan. Under the same conditions, recombinant chitinase but not our negative control chitinase, was able to digest chitosan. We conclude that human chitinase does not digest hyaluronan. Because chitin is a prominent component of certain fungi and insects, it seems likely that human chitinase evolved for roles in host defense rather than serving to catabolize the endogenous polymer hyaluronan.

    View details for PubMedID 29247734

  • Protein kinase C, an elusive therapeutic target? NATURE REVIEWS DRUG DISCOVERY Mochly-Rosen, D., Das, K., Grimes, K. V. 2012; 11 (12): 937-957

    Abstract

    Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications--including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder--were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.

    View details for DOI 10.1038/nrd3871

    View details for PubMedID 23197040

  • Myocardial salvage in acute myocardial infarction - Challenges in clinical translation JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Mochly-Rosen, D., Grimes, K. V. 2011; 51 (4): 451-453

    View details for DOI 10.1016/j.yjmcc.2011.08.002

    View details for Web of Science ID 000295302900006

    View details for PubMedID 21851825

  • Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction CIRCULATION Roe, M. T., Hartmann, F., LINS, J., Batchelor, W., Ruzyllo, W., Kochman, J., Armstrong, B., Buszman, P., Buszman, P., Leisch, F., Baran, K., Roubin, G., Zenni, M., Bilodeau, L., Caputo, R., Chu, A., Lombardi, W., Adamus, J., Hermiller, J., Darius, H., Krzeminska-Pakula, M., Saucedo, J., Simek, S., Zmudka, K., Farah, T., Hauptmann, K., Lee, D., Lemos, P., Rohrbeck, S., Moshage, W., Strasser, R., Albirini, A., Anderson, E., Bode, C., Caramori, P., Eaton, G., Hoffman, S., Huber, K., Khoury, S., Miller, J., Peterson, J., Porizka, V., Rivera, E., Roe, M., Schuster, P., Stasek, J., Zago, A. 2008; 117 (7): 886-896

    Abstract

    KAI-9803, a delta-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI).Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a "first-in-human," dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in (99m)technetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3.KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.

    View details for DOI 10.1161/CIRCULATIONAHA.107.759167

    View details for Web of Science ID 000253428100005

    View details for PubMedID 18250271

  • Recognition, diagnosis, and treatment of primary focal hyperhidrosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Hornberger, J., Grimes, K., NAUMANN, M., Glaser, D. A., Lowe, N. J., Naver, H., Ahn, S., Stolman, L. R. 2004; 51 (2): 274-286

    View details for DOI 10.1016/j.jaad.2003.12.029

    View details for PubMedID 15280848

  • GRANULOCYTE COLONY-STIMULATING FACTOR MOBILIZED PERIPHERAL-BLOOD PROGENITOR CELLS ACCELERATE GRANULOCYTE AND PLATELET RECOVERY AFTER HIGH-DOSE CHEMOTHERAPY BLOOD Chao, N. J., Schriber, J. R., Grimes, K., Long, G. D., Negrin, R. S., RAIMONDI, C. M., Horning, S. J., Brown, S. L., Miller, L., Blume, K. G. 1993; 81 (8): 2031-2035

    Abstract

    Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to "mobilize" peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P < .01) when compared with "nonmobilized" PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P < .001) when compared with "nonmobilized" recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving "mobilized" PBPC.

    View details for Web of Science ID A1993KY00500008

    View details for PubMedID 7682454

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