Design and Testing of ZMapp Manufacturing Challengessocietyformolecularfarming.org/sites/default/files/Zeitlin_Haydon .pdf · Ebola Virus Disease • Transmitted by contact with body

Design and Testing of ZMapp™

&

Manufacturing Challenges

Larry Zeitlin - Mapp Biopharmaceutical, Inc.

Hugh Haydon - Kentucky BioProcessing, Inc.

June 2015

Copyright 2015 Mapp and KBP 1

• Founded in 2003 to develop

antibody drugs for the

prevention and treatment of

infectious diseases

• Focusing on unmet needs in

global health and biodefense

• 20 employees

Mapp: Developing Antibody Drugs for

Global Health and Biodefense


Ebola Virus Disease

• Transmitted by contact with body fluids

• Mortality rates as high as 90%

• Causes viral hemorrhagic fever

– Massive destruction of organs, vascular

damage and hemorrhage

• Identified as bioweapon threat with the

potential for aerosol dissemination

• No licensed vaccines or treatments

Source: CDC 3

27,049 11,149

Total Cases Deaths

2014-2015 Ebola Outbreak (WHO data as of 5/24/15)

4

ZMappTM Development Timeline

< 2013 Focus on MB-003

Post Exposure Treatment

< 2013 2015


2004: Funding from DARPA



0

50

100

150

200

250

300

350

400

450

1

ug

/g

13F6 13F6 6D8 13C6 13C6

Pre-magnICON magnICON

6D8

2006: Collaboration with Icon

Genetics


History of antibody therapy for Ebola

1995: During an outbreak in the Democratic Republic of the Congo, 7 of 8 patients survived disease after treatment with whole convalescent blood Mupapa K, et al.; International Scientific and Technical Committee (1999). J Infect Dis 179(suppl 1):S18–S23.

2007: Polyclonal anti-serum did not protect non-human primates Jahrling PB, Geisbert JB, Swearengen JR, Larsen T, Geisbert TW. J Infect Dis. 2007 Nov 15;196 Suppl 2:S400-3

2007: Potent neutralizing monoclonal antibody did not protect non-human primates Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, Jahrling PB, Parren PW, Burton DR. PLoS Pathog. 2007

2012: Success with purified

polyclonal IgG and mAb cocktails

mAb cocktail Species

Days treatment

initiated post-infection

Dosing every 3 days

(# doses)

% Survival (n)

MB-003 Rhesus 1 50 mg/kg (4) 67% (3)

MB-003 Rhesus 2 50 mg/kg (4) 67% (3)

ZMAb Cyno 1 25 mg/kg (3) 100 (4)

ZMAb Cyno 2 25 mg/kg (3) 50 (4)

MB-003 = c13C6 + c6D8 + h13F6 ZMAb = 4G7 + 2G4 + 1H3


< 2013 Focus on MB003 Post Exposure Treatment

December 2013 Identification of

ZMappTM

< 2013 2015


Dosing 3 days post-infection


Group A = c13C6 + c2G4 + c4G7 (n=6) Group B = c13C6 + 1H3 + c2G4 (n=6) Group C = PBS or control IgG (n=2)

ZMappTM Antibodies Binding to Ebola

12

Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Murin C et al. Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17182-7

June 2014

Therapeutic

window NHP study



ZMappTM

January-February 2014

Production of research lot of

ZMappTM

< 2013 2015


ZMappTM treatment initiated

3, 4, or 5 dpi

A = Dosing days 3, 6, 9 B = Dosing days 4, 7, 10 C = Dosing days 5, 8, 11

c13C6 + c2G4 + c4G7 Copyright 2015 Mapp and KBP 14

June 2014

Therapeutic window

NHP study

September 2014 Contract with

BARDA


December 2013 Identification of ZMappTM mAbs

January-February 2014 Production of research lot

of ZMappTM

August 2014 eIND use of

ZMappTM

August 2014 cGMP production

initiated

< 2013 2015


BARDA Contract

(HHSO100201400009C)

IND-enabling activities Submit IND Manufacture 6 lots of GMP ZMappTM Drug Substance - demonstrate consistency


June 2014

Therapeutic window

NHP study

September 2014 Contract with BARDA

October 2014 1st GMP campaign

completed




of ZMappTM

August 2014 eIND Use of ZMappTM


initiated

December 2014

2nd GMP campaign completed

< 2013 2015

January 2015 3rd GMP campaign

completed

March 2014 4th GMP

campaign completed


Fill and Finish at Baxter


Pharmacology/toxicology

(SRI International; NIAID)

- Human Tissue Cross Reactivity Testing - 21-Day Multiple Intravenous Dose Toxicity Study of ZMappTM Administered on Days 1, 3, 7, 11, 16, and 21 with Toxicokinetic Assessment in Sprague Dawley Rats Followed by a 49 Day Recovery

- 50 or 100 mg/kg/injection - well tolerated - mild changes to the liver which resolved by end of the

recovery period (effects similar to marketed pharmaceuticals); not clinically dose limiting


June 2014

Therapeutic window

NHP study

September 2014 Contract with BARDA

October 2014 1st GMP

campaign completed




of ZMappTM

August 2014 eIND Use of ZMappTM


initiated

December 2014

2nd GMP campaign completed

< 2013 2015

January 2015 3rd GMP

campaign completed

February 2015 IND

Submission


Investigational New Drug (IND)

Application

- Rolling submission to the pre-IND - IND submitted February 3, 2015 - OK to proceed received February 5, 2015 - OK to proceed received by NIAID February 6, 2015 for

their Phase 2 RCT Master Protocol


Clinical Efficacy Study Principal Investigator: Richard T Davey, M.D. (NIAID)

ClinicalTrials.gov Identifier: NCT02363322

• “A Multicenter Randomized Safety and Efficacy Study of Putative Investigational Therapeutics in the Treatment of Patients with Known Ebola Infection” • Designed to establish the safety and efficacy multiple therapeutics

• ZMappTM is the first to be evaluated • Randomized and controlled to a current optimized standard-of-care (oSOC) • Adaptive trial design with frequent interim monitoring to facilitate the

following: • dropping of poorly performing arms • introduction of new candidate therapies • modification of current oSOC

• Sponsored by the National Institute of Allergy and Infectious Diseases • Sites in the U.S., Liberia, and Sierra Leone; site(s) expected soon in Guinea • Primary Outcome Measure: Mortality at Day 28 • Secondary Outcome Measures:

• Clinical and virology effects of treatment • Adverse events • Plasma viral load


Continued plans for development

• NHP dose reduction

• Allometric scaling and PK modeling (Gates Foundation)

• Continuing manufacture (BARDA)

• BLA enabling activities (BARDA)

• Additional manufacturing systems being explored (BARDA)


KBP: A Leader in Production of

Plant Expressed Proteins


=

“The platypus is among nature's most unlikely animals. In fact, the first scientists to examine a specimen believed they were the victims of a hoax. The animal is best described as a hodgepodge of more familiar species: the duck (bill and webbed feet), beaver (tail), and otter (body and fur). Males are also venomous.”

“National Geographic”


ZMapp™ May 2007

Initial KBP/Mapp collaboration

April 2010 Blue Angel Project

with US DoD

September 2008 Development

Agreement with Bayer / ICON

March 2011 ~10 Million

Doses cGMP protein

October 2007 GENEWARE®

Technology Acquired

April 2006 KBP begins operation

KBP Timeline

2006 2014


Blue Angel

• Designed in Response to 2009 H1N1 Pandemic

• Demonstration Project to Test Speed & Utility of NB System

• Invested in Product Development and Manufacturing Capacity

• Resulted in Live Fire Test


Program Inception

Plant Growth Facility Groundbreaking

First Vector Construct Test Results

Plant Growth Shell Completed

Downstream Process Development Begins

Down Select to Target Construct

Production of Material for Mouse HAI Testing

Plant Growth Facility Qualification Completed

Vector Selected- Downstream Process Defined

QA/QC Documents Completed

Plants for Production Seeded

2010 April May June July Aug

2011 Sept Oct Nov Dec Jan Feb Mar

KBP Blue Angel Timeline

~10 million doses of cGMP HA protein produced and released

• Designed to provide controlled conditions for the growth and harvest of transformed plants

• Facility is 55,000 SQFT with a capacity of 672 tables holding 30,240 plant trays. Each tray holds 104 plants (~3.1 million plants)

• Automated plant movement system allows for movement, irrigation, lighting and environmental control (temperature and humidity, air movement) of trays for plant growth

Plant Growth Facility


February / March 2014

NHP study

September 2014 Contract with U.S. Government

for ZMapp Development

October 2014 cGMP campaign

completed

ZMapp Development



alternative mAbs

January 2014 Initial production of small

quantity of ZMapp

August 2014 Emergency Use of

ZMapp


initiated

December 2014 Second cGMP

campaign completed

February 2015 Phase 1 / Phase 2 Clinical

Trial

< 2013 2015


©Kentucky Bioprocessing Inc. Not to be used without permission

Autumn 2014


Hand off to Liberian Ambassador BARDA Visits

Dr. Brantley and Delegation

Congressional Leadership

Lessons Learned/Challenges Consistent Manufacturing vs. Production for R&D

• Consistent Manufacturing is an Entirely Different Challenge

• QA & and Particularly QC Become More Complex (More Assays and Capacity Limitations)

• Identifying, Managing and Training Personnel

• Logistics and Materials Management

• ZMapp™ Circumstances NOT the Recommended Approach


Other Lessons Learned

• Regulatory Concerns with System Unfounded?

• Manufacturing is a Grossly Undervalued/Appreciated Part of Product Development

• There is Almost 100% Probability that Bench Scale Processes Will Not Transfer

• More Large Scale Manufacturing Capacity is Needed if NB Platform is to Realize its Potential



Acknowledgements Mapp

Miles Brennan Jane Ennis

Tom Furman Marty Hynes

Thomas Moench Tara Nyhuis

Michael Pauly Ken Payie

Kevin Whaley Natasha Bohorova

Ognian Bohorov

KBP Barry Bratcher Hugh Haydon

Ernie Hiatt Ashley Johnson

Josh Morton Jennifer Poole

ICON Genetics Yuri Gleba

Victor Klimyuk

USAMRIID John Dye

Jeffrey Froude J. Trefry

Defyrus Jeffrey Turner

Ragon Institute Galit Alter

Bronwyn Gunn

PHAC/U. Winnipeg Gary Kobinger Xiangguo Qiu

IRF Lisa Hensley

Peter Jahrling Gene Olinger James Pettitt

BOKU Herta Steinkellner

TSRI

Zach Bornholdt Marnie Fusco

C. Daniel Murin Erica Ollmann Saphire

IBT M. Javad Aman

Frederick Holtsberg

SRI (NIAID) James Bakke

Travis Harrison Bonnie Mai Jon Mirsalis

(Michael Kurilla) (Ramya Natarajan)

KBI Tim Kelly

Baxter (BARDA FFN) Alyson Norrick, Jamey Jarman

Damaris (Dee) Lee Trent Cox Kelly Roby

Wendy Saffell-Clemmer

BARDA Gary Disbrow

Stephen Morris Robin Robinson Chia-Wei Tsai

FDA Debra Birnkrant

Lu Borio Robert Kosko

Sohail Mosaddegh

NIAID Richard Davey

Cliff Lane Jerome Pierson

John Tierney

Funding BMGF (Steve Hadley)

NIAID (Pat Repik) AI58345, AI72915, AI109762 DTRA (Erin Reichert) HDTRA1-13-C-0018

BARDA (Chia-Wei Tsai) HHSO100201400009C


Acknowledgements (cont.)


Fraunhofer Icon Genetics

Medicago Novici

Planet Biotechnology Protalix

Amgen Dupont

Genentech Merck