Vyriad — Hazardous Materials Safety Interpretation

Page 1U.S. Department of Transportation 1200 New Jersey Avenue, SE Washington, DC 20590 Materials Safety Pipeline and Hazardous MAR 2 O 2018 Administration Mr. Jon Harrington Director of Manufacturing Operations Vyriad 221 1st Avenue SW, Suite 102 Rochester, MN 55902 Reference No. 17-0076 Dear Mr. Harrington: This letter is in response to your July 24, 2017, email requesting clarification of the Hazardous Materials Regulations (HMR; 49 CFR Parts 171-180) applicable to infectious substances. Specifically, you currently offer for transportation two live viruses: 1) Vesicular stomatitis virus (Indiana), or VSV, as a Category A infectious substance, and 2) Measles, as a Category B infectious substance. You ask if the HMR provide any exceptions for biological products as defined in § 173.134(a)(2), and if so, whether they may be used for live viruses stored for manufacturing purposes. The answer to both of your questions is yes. As prescribed in § 173.134(b)(6), a biological product, including an experimental or investigational product or component of a product, subject to Federal approval, permit, review, or licensing requirements, such as those required by the Food and Drug Administration of the U.S. Department of Health and Human Services or the U.S. Department of Agriculture Animal and Plant Health Inspection Service (APHIS), is not subject to the requirements of the HMR as a Division 6.2 material. Since APHIS granted you a permit to import and transport the VSV, it is not subject to the requirements of the HMR as a Division 6.2 material. However, because the Measles virus is not transportation in commerce. Live viruses stored for manufacturing purposes are also eligible for the exceptions provided by § 173.134 of the HMR I hope this information is helpful. Please contact us if we can be of further assistance. Sincerely, / Hear roster T. Glenn Foster Chief, Regulatory Review and Reinvention Branch Standards and Rulemaking Division#

Page 2stevens 8173.134 Defentions Dodd, Alice (PHMSA) 17:0076 From: INFOCNTR (PHMSA) Sent: Tuesday, July 25, 2017 4:29 PM To: Hazmat Interps Subject: Attachments: FW: clarification for shipping 2017-05-04_600390_Permit_Cover_TO.pdf Hi Alice, Please submit this as a letter of interpretation. Mr. Harrington spoke with Breanna. Please let me know if you have any questions. Thanks, Jodi From: Jon Harrington [mailto:jharrington@vyriad.com] Sent: Monday, July 24, 2017 4:13 PM To: INFOCNTR (PHMSA) < INFOCNTR.INFOCNTR@dot.gov> Subject: clarification for shipping Requesting a formal letter of interp. Dear DOT, This is a repeat message. I wanted to add a read receipt to make sure you received the information. I am looking for some clarification for the shipping of two biological products. Vyriad is conduction clinical trials using two different types of viruses for treating cancer. 1. Measles: MV-NIS MV-NIS is a live, tissue culture adapted measles virus engineered to express the human thyroidal sodium iodide symporter (NIS). The virus was constructed by inserting the NIS gene (cDNA) into a full - length infectious molecular clone of an attenuated Edmonston lineage measles virus (MV- tag). This virus is not a vaccine. MV-NIS propagates on Vero cells with kinetics equivalent to the parental strain of virus. It propagates selectively in human cancer cells that it infects by binding preferentially to CD46, a membrane protein that is overexpressed in tumor cell lines. The virus is directly cytopathic to tumor cells leading to the formation of multinucleated syncytia that die by apoptosis. MV-NIS infected 1#

Page 3tumor cells express NIS, a membrane ion channel that actively transports iodide into cells. Radioiodine uptake by cells expressing NIS provides the basis for in vivo radioiodine imaging that can reveal the profile of MV-NIS gene expression and the location of MV-NIS infected cells during virus spread elimination. 2. VSV(Vesicular stomatitis virus): VSV-IFN B -NIS VSV-IFN B-NIS is a live virus engineered to express both the human interferon ß gene and the thyroidal sodium iodide symporter (NIS). The virus was constructed by inserting the gene for human IFN downstream of M gene and the NIS gene (cDNA) downstream of the gene for the G protein into a full- length infectious molecular clone of an Indiana strain VSV. This virus is not a vaccine. VSV-IFN B-NIS propagates on BHK cells with similar kinetics to the parental strain of virus and can be grown to high titers. It propagates selectively in human cancer cells since many of them cannot mount an effective antiviral response mediated via the IN pathway. However, IFN production from infected cells will serve to protect non-cancer cells from the effects of the virus. As a result, the virus is directly cytopathic to tumor cells leading their rapid lysis with amplification of the virus. VSV-IFN B -NIS infected tumor cells also express NIS, a membrane ion channel that actively transports iodide into cells. Radioiodine uptake by cells expressing NIS provides the basis for in vivo imaging with 99mTc pertechnetate or radioiodine I-123 that can reveal the time dependent profile of VSV-IN B -NIS gene expression and the location of VSV-IFN B -NIS infected cells during virus spread and elimination. Currently we are shipping 2mL dosages to clinical trials sites using Category B requirements for the measles virus and Category A requirements for the VSV. Vyriad is required to make sure clinical trial sites have a permit for receipt of VSV material through Aphis (see attached). Using Category A and B shipping containers are a very costly method of shipping for a startup company like ours and would like to explore alternatives if possible. Does this material qualify as an exception $173.134? If the material qualifies for an exemption, what classification can we use to ship the materials? Additionally, we have measles and VSV materials stored for manufacturing purposes. Can we ship this material under the same exemption? I appreciate your time and consideration. How long does the evaluation process normally take? I would like to relay the approximate timeline to my CEO. Kindest Regards, Jon Harrington Director of Manufacturing Operations 2#

Page 4= VYRIAD 221 1st Ave SW, Suite 102, Rochester, MN 55902 O: 507.722.0231 | M: 608.698.5331 | jharrington@vyriad.com | www.vyriad.com Notice: E-mails and attachments sent from this address may be confidential. I very rarely make a mistake but would appreciate you letting me know if you get this note as a mistake. After letting me know, please do not print, distribute or copy the material but permanently delete the message and attachments. You can achieve this by deleting the message from your deleted or trash folder. Shredding is effective but not recommended. 3#

Page 5USDA United States griculture epartment o Health Inspection Animal and Plant Vyriad Jonathan Harrington Service 221 Ist Ave. SW, Suite 102 Services Veterinary Rochester, MN 55902 Import and Export National Center for Thursday, May 4, 2017 4700 River Road Unit 2, Mailstop 22, Dear Jonathan Harrington: Riverdale, MD 20737 Cub. 1A07 our USDA Veterinary Permit 133771 to import and/or transport controlle aterials, organisms and vectors accompanies this cover letter 01) 851-330 X (301) 851-22 organisms, or vectors accompanies this cover letter. Your USDA Veterinary Permit to import and/or transport controlled materials, Reviet the permlt carton new pratated segund anguago nay have changed to Please note the following: • Review the import permit for errors. Should you identify any errors, •lease contact our office immediatelv •A copy of the permit must accompany every shipment. De Not send the permit back to this office. For frequently asked questions, permit process and updates, our office with visit: www.aphis.usda.gov/animal-health/organisms-vectors. Contact any questions or concerns by email at: ov@aphis.usda.gov or telephone at 301-851-3300, option 3. Sincerely, APHIS Safeguarding Animal Health An Equal Opportunity Provider and Employer APHIS is an agency of USDA's Marketing and Regulatory Programs Federal Relay Service 1-800-877-8339 (Voice/TTY/ASCI/Spanish)#

Page 6Dr. Troy Bigelow Organisms and Vectors, Senior Staff Officer National Import Export and Select Agents re: application number 17095116#

Page 7ANIMAL AND PLANT HEALTH INSPECTION SERVICE U.S.DEPARTMENT OF AGRICULTURE PERMIT NUMBER RIVERDALE, MARYLAND 20737 VETERINARY SERVICES 133771 UNITED STATES VETERINARY PERMIT FOR IMPORTATION file:///D:/netpub/wwwroot/Epermits/images/ Research AND TRANSPORTATION OF CONTROLLED MATERIALS AND DATE ISSUED ORGANISMS AND VECTORS 05/04/2017 DATE EXPIRES 05/04/2018 NAME AND ADDRESS OF SHIPPERS) CC: Vyriad Jon Harrington Service Center, MN (St. Paul, MN) VB-LPD (Ames, IA 221 Ist Avenue SW, Suite 102 DA (Rockville, MD Rochester, Minnesota 55902 UNITED STATES Jonathan Harrington NAME AND ADDRESS OF PERMITTEE INCLUDING ZIP CODE AND TELEPHONE NUMBER U.S. PORTS) OF ARRIVAL TRANSPORT PERMIT 221 lst Ave. SW, Suite 102 Vyriad 362) 1483 Rochester, Minnesota 55902 507-289-0944 / 608-698-5331 TOLD DAT ONE HAH RITUAL! MODE OF TRANSPORTATION ANY AS REQUESTED IN YOUR APPLICATION, YOU ARE AUTHORIZED TO IMPORT OR TRANSPORT THE FOLLOWING MATERIALS Recombinant oncolytic Vesicular stomatitis virus (Indiana) - Purified, vialled tissue culture-derived virus preparations of recombinant VSV-IFND-NIS RESTRICTIONS AND PRECAUTIONS FOR TRANSPORTING AND HANDLING MATERIALS AND ALL DERIVATIVES THIS PERMIT IS ISSUED UNDER AUTHORITY CONTAINED IN 9 CFR CHAPTER 1. PARTS 94,95 AND 122. THE AUTHORIZED MATERIALS OR THEIR DERIVATIVES SHALL BE USED ONLY IN ACCORDANCE WITH THE RESTRICTIONS AND PRECAUTIONS SPECIFIED BELOW (ALTERATIONS OF RESTRICTIONS CAN BE MADE ONLY WHEN AUTHORIZED BY USDA, APHIS, VS).[ • Adequate safety precautions shall be maintained during shipment and handling to prevent dissemination of disease. oWith the use of this permit I, Jonathan Harrington, Permittee, acknowledge that the regulated material (s) will be imported/transported within the United States in accordance with the terms and conditions as are specified in the permit. The Permittee is the legal importer/recipient [as applicablel of regulated article(s) and is responsible for complying with the permit conditions. The Permittee must be at least 18 years of age and have and maintain an address in the United States that is specified on the permit; or if another legal entity, maintain an address or business office in the United States with a designated individual for service of process; and serve as the contact for the purpose of article(s). **Note: Import/Permit requirements are subject to change at any time during communications associated with the import, transit, or transport of the regulated the duration of this permit. •***Materials shall be consigned directly to the permittee address specified above. continued on subsequent page (s)..... BEAR THE PERM BEST THE PORT OF ENTRY, BILL OF LADING, AIRBILL OR OTHER DOCUMENTS ACCOMPANYING THE SHIPMENT SHALL SIGNATURE Troy Bigelow TITLE Senior Staff Veterinarian NO. LABELS National Import Export Services VS FORM 16-6A (MAR 95) Replaces VS Form 16-3A and 16-28 which are obsolete Page 1 of 2#

Page 8U.S. DEPARTMENT OF AGRICULTURE APHIS / VETERINARY SERVICES, RIVERDALE, MARYLAND 20737. ATTACH TO U.S. VETERINARY PERMIT - 133771 RESTRICTIONS AND PRECAUTIONS: (continued from Permit Form VS 16-6) •Work shall be limited only to laboratory studies and or human clinical trials. This permit does NOT authorize direct or indirect exposure of or inoculation into domestic or goats, swine, and horses). This permit DOES authorize direct and indirect exposure of and laboratory livestock (including but not limited to: birds/poultry/eggs, cattle, sheep, inoculation into other animal species and for human clinical trials. All exposed animals be held only in isolated facilities with insect and rodent control program in effect. • Packaging, containers, and all equipment in contact with the imported products shall be sterilized or considered a biohazard and must be disposed of accordingly. • Pens, sterilized or considered a biohazard and be disposed of accordingly. cages, bedding, waste, and dead animals in contact with these materials shall be • This permit authorizes the transport of this material into your research and development licensed establishment must be approved by the Center for Veterinary Biologics (CVB). facilities. Introduction of this material into the production areas of your USDA, APHIS, Storage locations, movements, and use within your licensed premises must be reported to • Imported material, clinical trials and animal trials may be subject to regulations enforced by the United States Food and Drug Administration (FDA). Importer must contact the Division of Import Operations and Policy at Area Code (301) 796-0356. •THIS PERMIT IS VALID ONLY FOR WORK CONDUCTED OR DIRECTED BY YOU OR YOUR DESIGNEE IN YOUR MATERIAL (S) MUST BE SHIPPED/CONSIGNED DIRECTLY TO THE ADDRESS OF THE PERMITTEE OR TO THE PRESENT U.S. FACILITY OR APPROPRIATELY INSPECTED LABORATORY. THE AUTHORIZED IMPORTED ADDRESS OF THE ADDITIONAL PERMITTEE(S) AS IDENTIFIED ON THIS PERMIT. (MATERIALS SHALL NOT BE MOVED TO ANOTHER U.S. LOCATION, OR DISTRIBUTED WITHIN THE U.S., WITHOUT USDA, APHIS, VS, NIES AUTHORIZATION.) ++EXCEPTION++ Material is authorized to be distributed to human clinical trial sites, animal testing sites, and biorepository, but Jonathan Harrington, Vyriad, retains responsibility for compliance to the permit. Locations shall be recorded and made available to the USDA upon request. • This permit only authorizes exposure to animals for trials associated with development of animal trial requirements must be available to the USDA upon request. Animal trials of any a human product per direction and guidance of the FDA. Documentation from FDA on FDA are not authorized. Contact the Center of Veterinary Biologics for information regarding type for development of an animal product, animal related vaccine or derivative thereof development of animal vaccines or products. • This permit does not exempt the permittee from responsibility for compliance with any other applicable federal, state, or local and regulations. •A copy of this permit must be included with the shipping documents. Page 2 of 2#