March 30, 2021 | Virtual Awards Program Visit www.clinicalresearchforum.org/2021Top10Awards to register. HONORING THE IMPORTANT WORK THAT WE ACCOMPLISH

On behalf of the Clinical Research Forum Board of Directors, thank you for supporting and celebrating the achievements of the 2021 Top Ten Clinical Research Achievement Awardees. As researchers around the globe are working around the clock to find ways to stop COVID-19, we are reminded by the great and important clinical and translational research that is done every day. Under tremendous pressure, the pandemic has inspired change, innovation, clinical work and research that has elevated our field. In the midst of this, many of the studies we will honor during the awards program surmounted great time constraints and made impressive discoveries without sacrificing the science and data that legitimizes our profession. In this context, I cannot emphasize enough the pride I feel for the amazing work of all our colleagues and for clinical research as a field. Not only has the nation been dealing with the pandemic, but recent tragic actions have surfaced social justice inadequacies and systemic racism in our culture. As clinical researchers, we are well versed in health disparities and the impact racism has on health. We believe that clinical research can make important contributions to social justice and health equity, as some of our Top Ten Clinical Research Achievement Awardees have shown so brilliantly. To that end, the CR Forum Board of Directors has put together a statement and an action plan to help make a difference. Racism is a disease Americans have failed to address for four hundred years. Racism is a public health crisis, and as such, requires an immediate plan to address its current terrible impact and a long-term sustainable plan to prevent its recurrence. I ask that you visit the Clinical Research Forum website to read the full statement and plan. Please join our community virtually on Tuesday, March 30 to celebrate this year’s Top Ten and continue these important discussions. I look forward to recognizing accomplishments from the past year and celebrating science.

Sincerely,

Harry P. Selker, MD, MSPH

2 BOARD OF DIRECTORS

Chair Vice Chair Harry P. Selker Herbert Pardes, MD MD, MSPH New York-Presbyterian Hospital Tufts Medical Center

Secretary/Treasurer William L. Lowe, Jr., MD, Northwestern University Feinberg School of Medicine

Members Robert M. Califf, MD, MACC Harry B. Greenberg, MD Arthur H. Rubenstein, MBBCh Verily Life Sciences Stanford University University of Pennsylvania School of Medicine Health System Barry S. Coller, MD The Rockefeller University Rebecca Jackson, MD Anantha Shekhar, MD, PhD The Ohio State University University of Pittsburgh School Anne B. Curtis, MD of Medicine University at Buffalo School Rainu Kaushal, MD, MPH of Medicine and Biomedical Weill Cornell Medicine Ex Officio Sciences Emma A. Meagher, MD Daniel E. Ford, MD, MPH Pamela Davis, MD, PhD Perelman School of Medicine, Johns Hopkins University Case Western Reserve University University of Pennsylvania School of Medicine Maurizio Fava, MD E. Albert Reece, MD, PhD, MBA John I. Gallin, MD Massachusetts General Hospital University of Maryland National Institutes of Health and Harvard Medical School School of Medicine

Schedule of Events

Tuesday, March 30 Extraordinary Impact on Health Award NEW 10:00 - 11:30 AM EST William Gruber, MD, FAAP, FIDSA, Virtual Program Senior Vice President Vaccine Clinical Research and Development, Pfizer, Inc. Welcome – Harry Selker, MD, MSPH Chair, Clinical Research Forum; Dean, Tufts Clinical Brett Leav, MD, Vice President of Clinical and Translational Science Institute, Tufts University Development, Public Health Vaccines, Moderna Presentation of the Top 10 Awards – Presentation of the Distinguished Clinical E. Albert Reece, MD, PhD, MBA Research Achievement Awards – Executive Vice President for Medical Affairs, UM E. Albert Reece, MD, PhD, MBA Baltimore, John Z. and Akiko K. Bowers Distinguished Presentation of the Herbert Pardes Clinical Professor and Dean, University of Maryland School Research Excellence Award – Herbert Pardes, MD, of Medicine Vice Chairman of the Board of Trustees, New York- Presbyterian Hospital Closing Remarks – Harry Selker, MD, MSPH 3 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

Anti-Selig-8 Antibody for Eosinophilic Gastritis and Duodenitis

Publication: Dellon ES, Peterson KA, Murray JA, ...Hirano I. Anti-Selig-8 Antibody for Eosinophilic Gastritis and Duodenitis. N Engl J Med. 2020 Oct22;383(17):1624- 1634. doi:10.1056/NEJMoa2012047. Summary: Eosinophilic gastrointestinal disorders are an under-recognized cause of gastrointestinal illness. Increasing in incidence for reasons that are unclear, eosinophilic GI disorders have no FDA-approved therapies. Dr. Dellon and his Evan Dellon, MD, MPH colleagues performed a randomized controlled trial of lirentelimab, an anti-Siglec-8 antibody, in patients with eosinophilic gastritis and duodenitis. This depletes and inhibits mast cells, which are thought to be critical in the pathogenesis of these diseases. After four monthly infusions, patients receiving the monoclonal antibody had an 86 percent reduction in mean counts from mucosal biopsies, compared to a nine percent reduction in controls. Additionally, treated patients experienced a 48 percent decrease in a standardized symptom score, compared to 22 percent in the placebo group. Both of these results were highly statistically significant. This study provides a potential therapeutic option for conditions afflicting thousands of patients, for whom other treatments were inadequate or too toxic for long-term use. It also provides proof-of-principle to advance our understanding of the pathogenesis of these conditions and their potential treatments. Given the significant challenges to treating EG and EoD, this study could significantly improve patient care. Author: Dellon ES, Peterson KA, Murray JA, Falk GW, Gonsalves N, Chehade M, Genta RM, Leung J, Khoury P, Klion AD, Hazan S, Vaezi M, Bledsoe AC, Durrani SR, Wang C, Shaw C, Chang AT, Singh B, Kamboj AP, Rasmussen HS, Rothenberg ME, Hirano I Institutions: University of North Carolina at Chapel Hill Funding: Supported by Allakos. The work of Drs. Khoury and Klion is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Dr. Murray’s work is supported in part by a grant (UL1 TR002377) from the National Center for Advancing Translational Sciences.

4 Evaluation of the Anti-SARS-Cov-2 Humoral Immune Response in a Cohort of COVID-19 Convalescent Individuals

Publication: Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, Agudelo M, Barnes CO, Gazumyan A, Finkin S, Hägglöf T, Oliveira TY, Viant C, Hurley A, Hoffmann HH, Millard KG, Kost RG, Cipolla M, Gordon K, Bianchini F, Chen ST, Ramos V, Patel R, Dizon J, Shimeliovich I, Mendoza P, Hartweger H, Nogueira L, Pack Christian Gaebler, MD M, Horowitz J, Schmidt F, Weisblum Y, Michailidis E, Ashbrook AW, Waltari E, Pak JE, Huey-Tubman KE, Koranda N, Hoffman PR, West AP Jr, Rice CM, Hatziioannou T, Bjorkman PJ, Bieniasz PD, Caskey M, Nussenzweig MC. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. 2020 Aug;584(7821):437-442. doi: 10.1038/ s41586-020-2456-9. Epub 2020 Jun 18. PMID: 32555388; PMCID: PMC7442695. Summary: In April 2020, during the peak of the novel coronavirus (COVID-19) pandemic in New York City, Dr. Gaebler and his team studied blood samples collected by the Michel Nussenzweig laboratory at Rockefeller University from 149 volunteers who had recovered from COVID-19. While ~75 percent of the individuals had IgG antibodies to the SARS-CoV-2 spike protein and the receptor binding domain (RBD) on the spike protein, the majority generated relatively poor plasma SARS-CoV-2 neutralizing activity as judged by a pseudo virus neutralizing assay developed by Dr. Paul Bieniasz at Rockefeller. The team was also able to identify individual B cells that bound an RBD peptide, and thus could determine from the DNA sequences that antibodies produced by different people had structural similarities. Most importantly, as a prelude to developing monoclonal antibodies (mABs) for therapy and prevention of COVID-19 from the B cells from these patients, they found antibodies that were extremely potent in neutralizing authentic SARS-CoV-2. Moreover, these antibodies could be grouped into ones that can bind simultaneously to the RBD, making it possible to pair such antibodies in ways that will make it much harder for the virus to escape by mutating the RBD. This study lays the groundwork for a major potential addition to resources against the COVID-19 pandemic. At the same time, by rigorously analyzing the antibodies that neutralize the virus at the genetic level, it provides important information for assessing antibody responses to the many vaccines under development. Authors: Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, Agudelo M, Barnes CO, Gazumyan A, Finkin S, Hägglöf T, Oliveira TY, Viant C, Hurley A, Hoffmann HH, Millard KG, Kost RG, Cipolla M, Gordon K, Bianchini F, Chen ST, Ramos V, Patel R, Dizon J, Shimeliovich I, Mendoza P, Hartweger H, Nogueira L, Pack M, Horowitz J, Schmidt F, Weisblum Y, Michailidis E, Ashbrook AW, Waltari E, Pak JE, Huey-Tubman KE, Koranda N, Hoffman PR, West AP Jr, Rice CM, Hatziioannou T, Bjorkman PJ, Bieniasz PD, Caskey M, Nussenzweig MC Institutions: Rockefeller University Funding: NIH grants: P01-AI138398-S1, 2U19AI111825, P50 AI150464, R01-AI091707-10S1, R37-AI64003 and R01AI78788. Caltech Merkin Institute for Translational Research, George Mason University Fast Grants, European ATAC consortium (EC 101003650), The G. Harold and Leila Y. Mathers Charitable Foundation, Robert S. Wennett Post-Doctoral Fellowship, National Center for Advancing Translational Sciences (National Institutes of Health Clinical and Translational Science Award programme, grant UL1 TR001866),Shapiro-Silverberg Fund for the Advancement of Translational Research and Howard Hughes Medical Institute

5 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

Genome-Wide Cell-Free DNA Mutational Integration Enables Ultra-Sensitive Cancer Monitoring

Publication: Zviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, Maloney D, Patel K, Liao W, Widman AJ, Wong P, Callahan MK, Ha G, Reed S, Rotem D, Frederick D, Sharova T, Miao B, Kim T, Gydush G, Rhoades J, Huang KY, Omans ND, Bolan PO, Lipsky AH, Ang C, Malbari M, Spinelli CF, Kazancioglu S, Runnels AM, Dan Landau, MD, PhD Fennessey S, Stolte C, Gaiti F, Inghirami GG, Adalsteinsson V, Houck-Loomis B, Ishii J, Wolchok JD, Boland G, Robine N, Altorki NK, Landau DA. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020 Jul;26(7):1114-1124. doi: 10.1038/s41591-020-0915-3. Epub 2020 Jun 1. PMID: 32483360. Summary: For many tumors, the chance of recurrence after initial treatment is quite high and scientists lack the ability to detect those recurrences early, when they are most treatable. Dr. Landau and his team identified that in solid tumor oncology, the need for advanced monitoring tools is extremely urgent. Dr. Landau and colleagues found that targeted sequencing approaches work only when circulating tumor DNA in blood samples includes sufficient fragments containing the targeted mutations yet in many cases, the tumor burden is much too low. In fact, standard targeted-sequencing techniques often miss small tumors that are evident on standard imaging scans. Even after cancer is diagnosed, medicine lacks sensitive tools to guide difficult therapeutic decisions such as adjuvant therapy. Sensitive cancer detection by blood biopsy can therefore transform care by enabling early detection and residual disease monitoring. Dr. Landau and his team replaced the prevailing paradigm of looking at a few DNA hotspots very thoroughly, with an innovative approach that detects minute amounts of tumor DNA by identifying mutations across the entire genome. The new method therefore involves the sequencing of all circulating DNA in a patient’s blood sample whole genome approach that boosts the effective sensitivity by one to two orders of magnitude. Thus, the novel DNA-sequencing strategy, powered by machine learning, may pick up even very low levels of tumor DNA in blood samples, potentially enabling the early detection of cancer recurrence after surgery or other treatments. The team demonstrated the method’s potential value with blood tests on patients who had melanomas, colorectal cancers and lung cancers. The results showed that the new technique can be used to detect blood-born tumor DNA even when it is much too sparse to be detected by existing methods, and many months or even years before recurrence is evident in imaging studies. This work will thus pave the way towards ultra-sensitive cancer detection, enabling transform cancer treatment in which therapeutic optimization is guided by real-time monitoring of tumor burden. Authors: Zviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, Maloney D, Patel K, Liao W, Widman AJ, Wong P, Callahan MK, Ha G, Reed S, Rotem D, Frederick D, Sharova T, Miao B, Kim T, Gydush G, Rhoades J, Huang KY, Omans ND, Bolan PO, Lipsky AH, Ang C, Malbari M, Spinelli CF, Kazancioglu S, Runnels AM, Fennessey S, Stolte C, Gaiti F, Inghirami GG, Adalsteinsson V, Houck-Loomis B, Ishii J, Wolchok JD, Boland G, Robine N, Altorki NK, Landau DA Institutions: Weill Cornell Medicine Funding: Supported by an EMBO long-term fellowship (ALTF 140-2016). D.A.L. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, the Pershing Square Sohn Prize for Young Investigators in Cancer Research and the National Institutes of Health Director’s New Innovator Award (DP2-CA239065). This work was supported by the Mark Foundation ASPIRE Award, the American Lung Association Cancer Discovery Award, the Daedalus Fund for Innovation and the Meyer Cancer Center.

6 Integrating Global Health with the Microbiome

Publication: Chen RY, Kung VL, Das S, Hossain MS, Hibberd MC, Guruge J, Mahfuz M, Begum KN, Rahman MM, Fahim SM, Gazi MA, Haque R, Sarker SA, Mazumder RN, Di Luccia B, Ahsan K, Kennedy E, Santiago-Borges J, Rodionov DA, Leyn SA, Osterman AL, Barratt MJ, Ahmed T, Gordon JI. Duodenal Microbiota in Stunted Undernourished Children with Enteropathy. N Engl J Med. 2020 Jul 23;383(4):321- 333. doi: 10.1056/NEJMoa1916004 PMID: 32706533 PMCID: PMC7289524 Jeffrey Gordon, MD Summary: Despite childhood malnutrition being the leading cause of death among those under five years old, current interventions have had limited success addressing this global heath challenges that is not due to food insecurity alone. This highlights the need for a more comprehensive understanding of mechanisms underlying malnutrition. One testable hypothesis is that proper assembly of the gut microbial community (microbiota), beginning at birth, is linked to healthy growth of infants and children. The role of the small intestinal microbiota is particularly enigmatic in part because of the difficulty in obtaining samples. Environmental enteric dysfunction (EED) is a disease of the small intestine characterized by a reduction in its absorptive area and chronic inflammation of the bowel wall. Most attempts to diagnose EED have relied on non-validated fecal and/or blood biomarkers. To examine the role of the small intestinal microbiota in the pathogenesis of EED and its relationship to stunting, 12-18 month-old Bangladeshi children who were stunted and failed a standard nutritional intervention underwent endoscopy to characterize their duodenal microbiota. The results revealed that duodenal levels of 14 different bacteria, present in >80 percent of children with biopsy-confirmed EED, were positively correlated with their stunting and gut inflammation. Furthermore, when young germ-free mice were colonized with duodenal bacteria cultured from these children, they developed features of EED in their small intestines. Together, these results provide evidence of a causal link between the small intestinal microbiota, EED and stunting, and identify new (microbial) therapeutic targets. The study of the duodenal microbiome and undernutrition reclassifies our understanding of gut physiology in children with stunted growth. Dr. Gordon and his team identify the duodenal microbiome as a plausible causal factor underlying stunting and pinpoints specific strains capable of transmitting enteropathy in a mouse model. Moreover, their proteomic analysis identified a swath of potential biomarkers and mechanistic drivers of stunted growth. Authors: Chen RY, Kung VL, Das S, Hossain MS, Hibberd MC, Guruge J, Mahfuz M, Begum KN, Rahman MM, Fahim SM, Gazi MA, Haque R, Sarker SA, Mazumder RN, Di Luccia B, Ahsan K, Kennedy E, Santiago-Borges J, Rodionov DA, Leyn SA, Osterman AL, Barratt MJ, Ahmed T, Gordon JI Institutions: Washington University School of Medicine in St. Louis Funding: Bill and Melinda Gates Foundation

7 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

ISCHEMIA Trial

Publication: Maron DJ, Hochman JS, Reynolds HR et al, for the ISCHEMIA Research Group. Initial Invasive versus Conservative Management of Stable Ischemic Heart Disease. N Engl J Med 2020; 382(15):1395-1407. DOI 10.1056/NEJMoa1915922. PMCID: PMC7263833 Summary: Ischemia of the heart occurs when cholesterol deposits narrow heart arteries and reduce blood flow to the heart muscle. Ischemia can cause chest pain, also known as angina. It is common for people who develop chest pain to have a David Maron, MD stress test, however, it is not clear how best to treat patients with ischemia who have abnormal results on a stress test. For this reason, the ISCHEMIA trial compared two standard treatments, invasive and conservative, to learn which is better. The invasive approach involves cardiac catheterization, a procedure to take video footage of the heart arteries, where then narrowed heart arteries can either be opened with a balloon and metal tubes called stents, or heart surgery can bypass the narrowed artery. The invasive approach also includes medicines (aspirin and cholesterol-lowering drugs) and lifestyle changes (like eating healthy food, exercising, and not smoking). The conservative approach involves treatment with medicines and lifestyle changes only. More than 5,000 people from 37 countries participated in the trial. Half were assigned to the invasive group and half were assigned to the conservative group. After an Judith Hochman, MD average of three years of follow-up, there was no overall difference between groups in major events like heart attack and death. People with angina (chest pain) who were assigned to the invasive treatment group had less angina, which improved their quality of life. With this information, patients and their doctors now understand that doing invasive procedures does not reduce the chances of a heart attack or dying, but does improve symptoms. The trial highlights the importance of using a validated instrument to assess patient-reported anginal symptoms, and provides critical information to use in shared decision-making between physician and patient when deciding whether or not to manage the disease with revascularization. Such decisions affect more than 9 million patients in the U.S. with stable angina, only one-third of whom take aspirin, statin, and beta-blocker (part of optimal medical therapy). In addition, this research has the potential to improve the management of millions of patients around the world. Authors: Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, Lopez-Sendon J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y Institutions: Stanford University School of Medicine and NYU Grossman School of Medicine Funding: Supported by grants (U01HL105907, U01HL105462, U01HL105561, and U01HL105565) from the National Heart, Lung, and Blood Institute, by Arbor Pharmaceuticals and AstraZeneca Pharmaceuticals, and in part by Clinical and Translational Science Awards (11UL1 TR001445 and UL1 TR002243) from the National Center for Advancing Translational Sciences. Devices or medications were provided by Abbott Vascular, Medtronic, St. Jude Medical, Volcano, Amgen, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Espero Pharmaceuticals, Merck Sharp & Dohme, Omron Healthcare, and Sunovion Pharmaceuticals.

8 Kisspeptin in the Evaluation of Delayed Puberty

Publication: Chan YM, Lippincott MF, Sales Barroso P, Alleyn C, Brodsky J, Granados H, Roberts SA, Sandler C, Srivatsa A, Seminara SB. Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2717–25. doi: 10.1210/clinem/dgaa162. PMID: 32232399; PMCID: PMC7282711. Yee-Ming Chan, Summary: Delayed puberty affects over two percent of children, and most children MD, PhD with delayed puberty have a condition called constitutional delay, a self-limited condition in which puberty is late to start but, once started, proceeds normally. However, some children with delayed puberty have a problem called idiopathic hypogonadotropic hypogonadism (IHH) and require medical treatment to go through puberty. Currently, there is no way to determine in advance which children have constitutional delay and which have IHH. As a result, children with IHH often experience significant delays in starting treatment, as they are often assumed to have constitutional delay and advised to wait for a puberty that will never come. The key biological innovation of this study was recognizing that giving a child with delayed puberty a dose of the hormone kisspeptin provides a glimpse into the future for that child. Kisspeptin is a key reproductive hormone that activates the reproductive endocrine Margaret Lippincott, MD system (the system of hormones that causes puberty to occur). In children with IHH, the reproductive endocrine system does not function properly, and puberty never occurs. However, in a child for whom puberty has not yet started and the reproductive endocrine system is still inactive, it can be impossible to determine whether the reproductive endocrine system is intact or not. By giving a dose of kisspeptin as part of a diagnostic test, the study was able to mimic the kisspeptin that the body would produce during puberty and thereby assess the integrity of the reproductive endocrine system. In this study, the children with delayed puberty who responded to kisspeptin all later entered puberty, demonstrating that their reproductive endocrine system was intact and that the kisspeptin-stimulation test could reveal this future potential. Conversely, the children who did not respond to kisspeptin did not enter puberty, demonstrating that the Stephanie Seminara, MD kisspeptin-stimulation test could also reveal when the reproductive endocrine system could not function properly. The kisspeptin-stimulation test cleanly distinguished children with constitutional delay from those with IHH. This major advance will allow children with IHH to receive prompt diagnosis and treatment and children with constitutional delay to receive appropriate reassurance. Author: Chan YM, Lippincott MF, Sales Barroso P, Alleyn C, Brodsky J, Granados H, Roberts SA, Sandler C, Srivatsa A, Seminara SB Institutions: Massachusetts General Hospital and Boston Children’s Hospital Funding: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01 HD043341, R01 HD090071, and P50 HD028138, NIH National Center for Advancing Translational Sciences grant UL1 TR001102, the Harvard Catalyst, Doris Duke Charitable Foundation award 2013110, the Charles H. Hood Foundation, the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, and the Robert and Laura Reynolds MGH Research Scholar Program

9 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

Remdesivir in COVID-19

Publication: November 5, 2020 N Engl J Med 2020; 383:1813-1826 DOI: 10.1056/NEJMoa2007764 Summary: More than 53 million children and adults have COVID-19 infections throughout the world. Although several therapeutic agents have been evaluated for the treatment of COVID-19, no antiviral agents have yet been shown to be effective. Dr. John Beigel and his team of researchers conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized John Beigel, MD with COVID-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was recovery time defined by either discharge from the hospital or hospitalization for infection-control purposes only. A total of 1,062 patients underwent randomization. In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo. The team’s data showed that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection. This study resulted in the first FDA-approved therapeutic for COVID-19, paving the way for more treatment options and greater access. Authors: Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Chien Lye D, Ohmagari N, O Myoung-don, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Clifford Lane H Institutions: National Institute of Allergy and Infectious Diseases, National Institutes of Health Funding: National Institute of Allergy and Infectious Diseases

10 Ruxolitinib for Treatment of Vitiligo

Publication: Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, Butler K, Kuo F, Sun K, Ji T and Howell MD, 2020. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. The Lancet, 396(10244), pp.110-120. Summary: Vitiligo is a disease of depigmentation, where the kills off the pigment cells, causing white spots on the body. Despite its high prevalence in about 0.5 to 2 percent of the population, not a single medication is currently FDA approved to repigment patients who suffer from vitiligo. Dr. Rosmarin and his team David Rosmarin, MD are helping meet the clinical need for reliable vitiligo treatments. Involving 26 centers in 18 states across the U.S., the study presents solid evidence for the efficacy and safety of a topical formulation of the Janus kinase (JAK) inhibitor, ruxolitinib. The team compared the use of a topical JAK inhibitor with that of a placebo cream, conducting the largest randomized controlled study ever done in vitiligo. The results showed that after one year of use of the medication, about half of the patients achieved 50 percent or more repigmentation for the whole body. Since the pathogenesis of the disease is superficial within the skin, a topical delivery system can be used instead of a systemic oral treatment, with a goal of minimizing side effects. Furthermore, JAK inhibition can also have pro-melanocytic effects which may counteract a further problem in the pathogenesis of vitiligo. The study offers strong evidence for a new understanding of the specific immune system mechanisms that cause vitiligo. The tested compound is already being used to treat the disorder. Based on this work, there are now multiple studies in earlier development evaluating JAK inhibitors for the treatment of vitiligo. The study has also helped to establish a pathway and trial design for others to follow to be able to determine if a vitiligo treatment is effective. Authors: Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, Butler K, Kuo F, Sun K, Ji T, Howell MD, Harris JE Institutions: Tufts Medical Center Funding: Incyte

11 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

Selumetinib in Children with Inoperable Plexiform Neurofibromas

Publication: Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Brigitte Widemann, MD Mar 18. Erratum in: N Engl J Med. 2020 Sep 24;383(13):1290. PMID: 32187457; PMCID: PMC7305659. Summary: Neurofibromatosis type 1 (NF1), is a progressive genetic disorder that affects 1 out of 3,000 individuals. One of the most devastating problems in NF1 is the development of tumors, plexiform neurofribomas, that typically grow in very young children. These tumors can cause compression of the airway, blindness, difficulty moving, disfigurement, and pain, which is difficult to control. In some cases, they can transform to an aggressive form of cancer. Unfortunately, for most patients, surgical removal is not feasible and there is no effective medical treatment for patients with NF1. Dr. Widemann’s team conducted phase I/II clinical trials of selumetinib, a specific MEK inhibitor, in children with inoperable plexiform neurofibromas, which were causing clinical problems such as pain, disfigurement and motor weakness. After a series of negative prior clinical trials with targeted therapies, selumetinib demonstrated unprecedented preclinical and clinical activity in NF1 plexiform neurofibromas. Selumetinib resulted in partial responses in 74 percent of patients and a progression free survival of 84 percent after three years on treatment. The team observed tumor shrinkage in the majority of patients, which was unprecedented compared to previous clinical trials. In addition, and most importantly, the majority of patients experienced improvement in pain, quality of life, or function and thus direct clinical benefit. Due to Dr. Widemann’s pivotal and pioneering work, selumetinib was approved by the Food and Drug Administration, and is now available as the first treatment to help children with NF1 across the United States. Authors: Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim AR, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC Institutions: Center for Cancer Research, National Cancer Institute Funding: Intramural Research Program of the National Institutes of Health

12 The CENTAUR Trial for ALS

Publication: Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman- Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Sabrina Paganoni, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz MD, PhD ME. N Engl J Med. 2020 Sep 3;383(10):919-930. doi: 10.1056/NEJMoa1916945. PMID: 32877582 Summary: ALS (Amyotrophic Lateral Sclerosis) is a fatal neurodegenerative disease. The lifetime risk of getting ALS is 1 in 400 and most ALS patients only live 2-4 years. The CENTAUR trial is the first trial to demonstrate positive effects of an investigational product on both functional outcomes and survival in people with ALS. ALS remains a uniformly fatal disease and the two FDA-approved medications only produce modest benefits. Dr. Paganoni and her team tested a new drug called AMX0035 in the CENTAUR trial. AMX0035, is a combination of two molecules (Sodium Phenylbutyrate and Taurursodiol) that each target a different molecular mechanism underlying ALS, endoplasmic reticulum stress and mitochondrial dysfunction, respectively. When combined in a fixed ratio in cell culture models of neurodegeneration they were found to have synergistic effects. The CENTAUR trial was the first trial to test this combination in people with ALS. Participants who took AMX0035 retained physical functions and lived longer than those who received placebo. Depending on the individual this could mean the difference between walking independently or needing an assistive device, or being able to feed themselves independently or needing a feeding tube. The team was able to see treatment effect in a relatively short period of time (six months). In addition, when the team followed trial participants for up to three years, they saw that patients who were originally assigned to AMX0035 lived longer than those who were given placebo (their risk of death was 44 percent lower). The results of this trial are currently being used to support a New Drug Application in several territories including the United States. This is the first time that a new drug is shown to have positive effects on both physical function and survival in ALS. Authors: Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME Institutions: Massachusetts General Hospital Funding: Supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association

13 CLINICAL RESEARCH FORUM HONORS

The Clinical Research Forum awards special honors to three studies that demonstrate excellence in clinical research and creativity and innovation in approach. The 2021 award recipients will be announced during the program. The Herbert Pardes Clinical Research Excellence Award

Named in honor of CR Forum board member Herbert Pardes for his profound impact on clinical research and academic medicine, this award, which comes with a $7,500 cash prize, is for the research study that best shows a high degree of innovation and creativity, advances science, and has an impact upon human disease. The Distinguished Clinical Research Achievement Awards

Presented to the top two studies that show creativity, innovation, or a novel approach that demonstrates an immediate impact on the health and well-being of patients. Each study will receive a $5,000 cash prize. Clinical Research Forum Award for Extraordinary NEW Impact on Health

The Clinical Research Forum acknowledges the incredible scientific achievement and effort of the many colleagues that have led to the successful development of the Pfizer and Moderna COVID-19 vaccines. The rapid development of these vaccines shows what clinical and translational research can accomplish at its best. These are the first RNA-vaccine constructs ever used for a major international vaccine. The researchers of both vaccines, along with the countless others who supported the effort, are to be commended, heralded and congratulated. This achievement is a demonstration of the research continuum from basic science, through translation into clinical research, to safe and effective vaccines to protect human health.

William C. Gruber, MD, Brett Leav, MD FAAP, FIDSA Vice President of Senior Vice President Clinical Development, Vaccine Clinical Research Public Health and Development, Pfizer, Inc. Vaccines, Moderna

14 2021 TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS FINALISTS

Congratulations to all of the 2021 Top Ten Award finalists.

• Artificial Intelligence Tools Assist in Treatment Planning by Improving and Standardizing Prostate Cancer Diagnosis and Grading Rajiv Dhir, MD, MBA, University of Pittsburgh • A Validated Predictive Algorithm of Post-Traumatic Stress Course Following Emergency Department Admission after a Traumatic Stressor Katharina Schultebraucks, PhD, Columbia University Irving Medical Center • Biologically Guided Discovery of Genetic and Functional Determinants of Human Infectious Disease Sagi Shapira, PhD, Columbia University Irving Medical Center •  Epidemiology, Clinical Course, and Outcomes of Critically Ill Adults with COVID-19 in New York City: Translational Science for Pandemic Severe Respiratory Viral Infection Max O’Donnell, MD, MPH, Columbia University Irving Medical Center • Preserves Beta-Cell Function and Reduces Insulin Use and Hypoglycemia in Youth with Recently Diagnosed Type-1 Diabetes: The Phase 2 TIGER Study Teresa Quattrin, MD, University at Buffalo • Measurement of SARS-Cov-2 RNA in Wastewater to Track Community Infection Dynamics Saad Omer, MBBS, MPH, PhD, FIDSA, Yale Institute for Global Health and Susan Dwight, Yale School of Public Health • Prevalence of SARS-Cov-2 Antibodies in a Large Nationwide Sample of Patients on Dialysis in the USA: A Cross-Sectional Study Shuchi Anand, MD, MS, Stanford University • Single Cell Analysis Defines Beta-Cell Failure in Type 2 Diabetes Klaus Kaestner, PhD, MS, Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania • The Impact of Sex on Gene Expression Across Human Tissues Barbara Stranger, PhD, Northwestern University Feinberg School of Medicine For full journal citations, please visit www.clinicalresearchforum.org.

15 ABOUT MEMBERSHIP

As a member of Clinical Research Forum, you will join a group of unified voices that support the broader interests and needs of clinical research, and educate policymakers on the nation’s investment in clinical research to benefit the health and welfare of its citizens. Opportunities are available year-round to convene leaders at the highest levels in academic institutions, the pharmaceutical industry,information technology industry, and government to communicate and draw upon their perspectives on big issues influencing clinical research. Learn more about joining this elite community at www.clinicalresearchforum.org.

ABOUT THE CLINICAL RESEARCH FORUM

The mission of Clinical Research Forum is to provide leadership to the national and clinical translational research enterprise and promote understanding and support for clinical research and its impact on health and healthcare. Membership is open to academic health and science systems (AHASs), as well as industry partners. For more information, visit www.clinicalresearchforum.org.

TOP TEN CLINICAL RESEARCH ACHIEVEMENT AWARDS

Recognizing the need to celebrate our nation’s clinical research accomplishments that involve both innovation and impact on human disease, the Clinical Research Forum conducts an annual competition to determine the ten outstanding research accomplishments in the United States. These major research advances represent a portion of the annual return on the nation’s investment in the health and future welfare of its citizens.

Clinical Research Forum 2001 K St NW Washington, DC 20006 2022 Top Ten Nominations Portal Opens: (202) 367-1176 www.clinicalresearchforum.org September 2021