June 11, 2015 Michael Pensiero, VTRB A workshop sponsored by the Division of AIDS and the Global HIV Vaccine Enterprise

Transcription

1 HIV Envelope Manufacturing Workshop June 11, 2015 Michael Pensiero, VTRB A workshop sponsored by the Division of AIDS and the Global HIV Vaccine Enterprise

2 Presentation Outline HIV Env Protein Manufacturing status Why is the Manufacturing Success so low? Current versus Proposed Manufacturing Models Workshop goals and expected outcome NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 2

3 Status Quo: HIV Env Protein Vaccines We acknowledge that the field has had few manufacturing successes to date since the RV144 results in Success defined as vialed released product: Barouch/JnJ Collaboration: first vialed trimeric protein (2 doses vialed) NVD: grams each of 2 gp120 products 3

4 Were these successes Optimal? In terms of cost control, time to delivery, deliverables, availability of the product, etc? Dan Barouch/Crucell/J&J started late in 2009 Release 4Q14 NVD/DAIDS/BMGF for the P5 (Pox-Protein Public- Private Partnership) started in 2010, HIV gp120s selected in mid Release 4Q14-ongoing NO NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 4

5 Status Quo: HIV Env Protein Vaccines Why do we have such a low manufacturing success rate? What can the field do in aggregate in increase the success rate? 5

6 Backdrop of HIV Env Proteins as Vaccines Designed by nature to be in low abundance vs Mabs Manufacturing follows mg/l vs gm/l Complex molecule, which is half sugar by mass Despite many promising candidates, it is not clear what the correct immunogen should be. Without a true correlate choices have to be made with unverified metrics Layered on top is the DEMAND that is ever increasing Multiple immunogens may be needed to elicit breadth Likely many protein platforms (scaffolds, trimers, peptide/lipid complexes, etc) will need to be tested before identifying an optimal regimen NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 6

7 Every protein is unique it is NOT plug and play VACCINE HIV ENV PROTEINS? Traditional Upstream and Downstream PD Manufacturing Box $$$$$

8 Every protein is unique but there may be a better way to approach the need! Build the car, not a better cart!

9 Current Models for Development is the Primary Reason for Low Success 9

10 Current Operating Models Vaccine Concept NIH de-risks Early engagement of industry partner Product Champion NIH funds Grantee with research concept Industry Partner + CMO Experienced and engaged Rapid and targeted troubleshooting Frequent and detailed attention and communication with CMOs Selection of qualified CMOs Person-in-Plant Detailed Tech Transfer Plan Analytical Development and Scale-Down Models CMO Multiple abrupt starts and stops Inexperience of CMO Viral Vaccine Experience is Lacking Lack of expertise in process development needed for troubleshooting Technology Transfer Gaps Lack of understanding of Analytics 10

11 Reality: Current Operating Model Vaccine Concept Product Champion Early engagement of industry partner highly unlikely Grantee with research concept reality Industry Partner + CMO CMO Obstacles: Critical path issue Limited access to: Trade Secrets, IP Platforms, BRs, Analytics Realizing this is the most likely path, how can we gain learning efficiencies moving forward and translate that into acceleration? Major Obstacle: Slow accumulation of learning efficiencies 11

12 Protein Manufacturing Portfolio Product P5 Clade C bivalent gp120s (1086.C and TV.1) MHRP gp145 Clade C protein Haynes (CHAVI-ID) CH505TF gp120s (CH505TF, w.58, w.73, w.100) Barouch (IPCAVD) gp140 Clade C fold-on trimer and gp140 mosaic fold-on trimer Lu (IPCAVD) tetravalent gp120s Moore (CHAVI-ID/IAVI) Clade A BG505 SOSIP trimer Leo Stamatatos (IPCAVD) clade C gp TMC-scaffolded IHV FL-SC, Clade B eod-gt8 60mer (Schieff) MPER656-GTH1 liposome (Haynes) Clade B gp120 (B Δ11) Wyatt NFL trimer Source/CMO NVD / Renstchler (Germany) MHRP / Avid (San Diego, CA) CHAVI-ID/DHVI / KBI (Durham, NC) BIDMC /Crucell/JnJ / Gallus (Princeton, NJ) UMass / Waisman (Madison, WI) CHAVI-ID/IAVI/Catalent TBD/IPCAVD Catalent/Profectus KBI OR Paragon IDRI CHAVI-ID/DHVI/KBI (Durham, NC) VDRG Product Available 4Q14 Vialed and Released 3Q15 3Q15 (CH505TF), 4Q15 (other 3) gp140 Clade C Vialed 3Q14; Mosaic TBD 3Q TBD TBD TBD TBD Funding Legend DAIDS BMGF Joint NIAID/DAIDS/VRP/VTRB Most Proteins fit the without Industry Partner Model CONFIDENTIAL 12

13 Summary of Current Models for HIV Env Manufacturing The 2 Current Models: 1. A product champion partnered with Industry ensures: Subject matter expertise with USP, DSP and formulation Understand manufacturability Quality Assurance Oversight from raw materials to product release Dedicated team to rapidly mobilize necessary resources when deviations/failures occur Industry Project Management to follow the day-today activities INFRASTRUCTURE 2. The approach of cobbled together grants, contractors, CMOs VTRB and VxPDC (BMGF/IAVI) staff. the N is small for learning efficiencies the learning curve is steep, slow and expensive NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 13

14 High Level Lessons Learned Moving Forward HIV Env Specific Issues: Molecule is biologically complex Translational issues: Translating from research to manufacturing is a technical hurdle Not a regulatory issue No need to invent exploratory or experimental INDs Not a GMP issue yes scale up issue More CMOs ALONE are not the answer Non-vested team, a la carte mentality, B team variable Communication/PM Issues: Multiple stakeholders involved, multiple organizations involved (contractors, subcontractors, etc) making communication challenging NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 14

15 Challenge for Today s Workshop Focus Point #1:How can we specifically learn from the current crop of manufactured proteins or those being manufactured and use these shared learning efficiencies to help guide the next set of collaborations? Especially when we know that without an Industry partner this will be difficult Focus Point #2: What learned efficiencies can be harnessed to prevent repeat mistakes for others? Reduce Siloing effect Focus Point #3: Can any of these learning efficiencies be translated into pathways for acceleration NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 15

16 Proposed Approaches for Acceleration 16

17 Proposed Approaches for Acceleration HIV Vaccine Aggregated Learning Efficiencies Analytics Cores Industry Consultants with Appropriate SME Preferred Providers (CMOs) Phase-Appropriate Product Development Technical Approaches Transient Transfection 17

18 Acceleration of HIV Env Manufacturing VRP is now funding efforts to manage product development challenges The aim of is to provide support for Env manufacturing for investigational testing by: Developing a pool of experienced, preferred vendors to take advantage of lessons learned Analytic and Process Development Cores Employing phase-appropriate product development strategies does NOT need to be on a Product Development Path! Need Quality and Reproducability Investigating novel technologies that may accelerate product development for early phase clinical trials Transient Transfection Generic Downstream Purification approaches NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 18

19 Workshop Goals and Expected Outcomes 19

20 Questions for Workshop What are the major obstacles currently observed in HIV Env Manufacturing? How can we extract as much as possible from learning efficiencies to avoid repeating the same mistakes What technical approaches can be used to accelerate? Have we explored all possibilities to accelerate discussion needed Maximum input at an early stage so as to get buy in on paths forward NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 20

21 Acknowledgments Vaccine Translational Research Branch: Jane Halpern, Candra Tomlinson, Jack Hill, Ronelle Lucas, Vijaya Rangavajhula, Joellyn Bowser, Jeff Pullen, Chris Butler, Vijay Mehra, Tina Tong, Becky Sheets DAIDS Senior Management: Mary Marovich, Kevin Ryan, Carl Dieffenbach ABL: Tom VanCott, Jim Richardson, Deb Deane, Gerry Kovacs Global HIV Vaccine Enterprise for co-sponsoring NIAID/DAIDS/VRP/VTRB CONFIDENTIAL 21