TRANSCRIPT OF PROCEEDINGS IN THE MATTER OF: ) ) BACTERIOPHAGE THERAPY: ) SCIENTIFIC AND REGULATORY ISSUES ) PUBLIC WORKSHOP ) (This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation as to its accuracy.) Pages: 301 through 532 Place: Rockville, Maryland Date: July 11, 2017 HERITAGE REPORTING CORPORATION Official Reporters 1220 L Street, N.W., Suite 206 Washington, D.C. 20005-4018 (202) 628-4888 [email protected] 301 BEFORE THE DEPARTMENT OF HEALTH AND HUMAN SERVICES U.S. FOOD AND DRUG ADMINISTRATION IN THE MATTER OF: ) ) BACTERIOPHAGE THERAPY: ) SCIENTIFIC AND REGULATORY ISSUES ) PUBLIC WORKSHOP ) Room 1D-13 NIAID Conference Center 5601 Fishers Lane Rockville, Maryland Tuesday, July 11, 2017 The parties met, pursuant to the notice, at 8:30 a.m. MODERATOR: RYAN RANALLO, Ph.D. NIAID PARTICIPANTS: BISWAJIT BISWAS, Ph.D. Naval Medical Research Center Frederick, Maryland ANDREW CAMILLI, Ph.D. Tufts University BRECK DUERKOP, Ph.D. University of Colorado MICHAEL KURILLA, Ph.D. Office of Biodefense, Research Resources, and Translational Research NIAID Heritage Reporting Corporation (202) 628-4888 302 PARTICIPANTS: (Cont'd.) TIMOTHY LU, MD, Ph.D. Massachusetts Institute of Technology JAMES REGEIMBAL, Ph.D. U.S. Naval Medical Research Unit Lima, Peru ROY STEVENS, DDS Temple University SCOTT STIBITZ, Ph.D. Center for Biologics Evaluation and Research, FDA STUART TYNER, Ph.D. Walter Reed Army Institute of Research PAUL TURNER, Ph.D. Yale University MICHAEL ZAPOR, MD, Ph.D. Walter Reed Army Institute of Research Heritage Reporting Corporation (202) 628-4888 303 C O N T E N T S SESSION 3: Future Directions PAGE The Potential Therapeutic Use of Bacteriophages 305 as Adjuncts or Alternatives to Antibiotics, Michael Zapor and Stuart Tyner Phage Receptors and Resistance Mechanisms in 328 Enterococci, Breck Duerkop Using Phage to Select for Evolution of 350 Reduced Virulence in Pathogenic Bacteria, Paul Turner Engineering Phage and Phage Products to Disrupt 378 Enterococcus faecalis Biofilms, Roy Stevens Engineered Phages for Diagnostics and Therapeutics 398 Timothy Lu Prophylactic Use of Bacteriophages Against 431 Cholera, Andrew Camilli Rapid Emergence of Phage-Resistant Bacteria during 456 Phage Therapy of a Terminally Ill Patient Who Was Infected with Multidrug-resistant A. baumannii, Biswajit Biswas Phage Therapy Against MDR Strains: Overcoming 477 the Double-edged Sword of Phage Specificity, James Regeimbal Panel Discussion Session 3 speakers, with Scott Stibitz, FDA/CBER 513 Concluding Remarks, 527 Michael Kurilla, NIAID Heritage Reporting Corporation (202) 628-4888 304 1 P R O C E E D I N G S 2 (8:30 a.m.) 3 DR. RANALLO: Good morning, everybody. 4 Sorry about that. Good morning. I hope everybody's 5 up. Okay. So we're going to start on time today. My 6 name is Ryan Ranallo, I'm a program officer here, at 7 NIAID, and I'm going to be your moderator for the 8 entire day today, something the organizing committee 9 didn't tell me before they signed me up for this. 10 Nevertheless, hopefully we'll get through it all day 11 today. 12 So one thing that I wanted to just note is 13 how in two years, how things have changed 14 significantly since the last time we've held a phage 15 therapy meeting, and so, with that, I think we have a 16 couple of large buckets of topics today, phage 17 engineering being one of them, and essentially looking 18 at phage for different uses, including, you know, 19 transmission and decolonization. 20 So, with that -- oh, the only other thing I 21 would say is if you have any questions about whether 22 or not your slides have been loaded for speakers, 23 please check in the back. Marcus has been great all 24 day yesterday, and certainly today as well. So for 25 the first talk, it's a tag team talk of Col. Zapor and Heritage Reporting Corporation (202) 628-4888 305 1 Lt. Col. Tyner. 2 Col. Zapor is the deputy commander of 3 operations at the Walter Reed Army Institute of 4 Research, and Lt. Col. Tyner, who I first met actually 5 when I was a post-doc at NCI and -- in Building 37, is 6 the director of bacterial diseases branch, which just 7 actually happens to be my old department where I spent 8 10 years at Walter Reed working on enteric vaccines. 9 So, without further ado, I'm going to introduce Col. 10 Zapor and Lt. Col. Tyner for our first talk. 11 DR. ZAPOR: Okay. Good morning, everybody. 12 Thanks to the organizers for inviting me to speak at 13 this conference. Unfortunately, I'm only here for the 14 morning session because of conflicting obligations, as 15 well as secondary to car problems, but -- so I'll be 16 here until lunch and then depart after that. 17 As you heard, I'm splitting my 30-minute 18 block with a colleague, Lt. Col. Tyner, so I'll be 19 cognizant of the fact that I have 15 minutes to speak 20 to ensure that he has 15 minutes as well. 21 So the purpose of this talk, I was asked to 22 speak about potential therapeutic indications for 23 bacteriophages and first thought we would kind of 24 address some of the limitations of the current -- 25 antibiotics and the current problems. Heritage Reporting Corporation (202) 628-4888 306 1 So antibiotics of course have been the 2 mainstay of therapy in the -- for the treatment of 3 infections for decades, but there have been some 4 unintended consequences. Everybody of course is 5 familiar with the issue of the emergence of multidrug- 6 resistant organisms, in some cases extremely drug- 7 resistant organisms, or even pan drug resistance. 8 Moreover, antibiotics, as effective as they 9 are, are not 100 percent specific. In the parlance of 10 my profession, we unfortunately see considerable 11 friendly fire, especially with the broad-spectrum 12 antibiotics such as the carbapenems, and so oftentimes 13 the antibiotics are effective in eradicating the 14 intended target, but have the unintended consequence 15 of killing benign, or even beneficial, bacteria as 16 well. 17 This is evidenced, for example, by the 18 emergence of C. diff colitis in patients who are on 19 broad spectrum antibiotics. 20 Other limitations with antibiotic use of 21 course include the emergence of drug resistance. I've 22 already spoken to that. Some types of infections are 23 less amenable to treatment than other types. So 24 infections which involve abscesses or other sequestra, 25 antibiotics generally don't penetrate abscess fluid Heritage Reporting Corporation (202) 628-4888 307 1 very well, some less well than others. Rifampin works 2 fairly well, but there are many other antibiotics that 3 are inactivated in abscess fluid. Aminoglycosides 4 come to mind. 5 Additionally, the presence of a foreign body 6 can make infections difficult to treat. Foreign body 7 -- we've seen a considerable number, a very large 8 number, of war wounded coming back from Iraq and 9 Afghanistan status post blast injuries with retained 10 foreign bodies. Some of these can be removed 11 surgically, some cannot. Some are intentionally left 12 in place. 13 Each of these FBs becomes a potential nidus 14 for infection. They get colonized with bacteria, 15 oftentimes bacteria that elaborate glycocalyces or 16 make a biofilm, and there are very few antibiotics 17 that can reliably sterilize biofilms. 18 Other considerations include patient anatomy. So I 19 gave the analogy or offered the example of war 20 wounded. Patients who have had blast injuries 21 oftentimes have interruptions in their blood supply, 22 they have interrupted vasculature, and all the tissue 23 prior, distal to the injury becomes ischemic, starved 24 for oxygen, starved for blood, and antibiotics can 25 only work where they're delivered, and if antibiotics Heritage Reporting Corporation (202) 628-4888 308 1 are not delivered to vascularized, oxygenated tissue, 2 then they don't work very well. It's very common for 3 us to see patients who have ischemic limbs, necrotic 4 tissue, retained foreign bodies, and antibiotics just 5 don't work very well. More often than not the 6 intervention of choice for those patients is cold 7 steel, for example, amputation, rather than medical 8 therapy alone. 9 And then there are other considerations such 10 as the rapid metabolizers. We know that there are 11 some patients who just inherently metabolize and 12 inactivate antibiotics and other drugs more rapidly 13 than other patients. 14 And then we always have to be cognizant of 15 patients who have drug allergies or some other 16 contraindication to antibiotics. So, examples that 17 come to mind, beta lactam allergies, which are fairly 18 common, nephrotoxicity associated with 19 aminoglycosides, associated with vancomycin and so 20 forth. 21 So, for all these reasons, antibiotics, as 22 effective as they are, as reliable as they have been, 23 they do have their limitations, and, as a consequence, 24 we're forced to explore alternatives. 25 So what are some of the pros and cons of Heritage Reporting Corporation (202) 628-4888 309 1 using phages as therapy? This is a table I put 2 together with which you may or may not agree. In the 3 pro column for phages there's long history of use. 4 Everybody knows that phage has been used in Eastern 5 Europe for many years, and at one point in time early 6 in the 20th Century, phages of course were available 7 by prescription in this country.