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RhBMP-2: origin, biology and preclinical safety Gerard E. Riedel, Ph.D. Wyeth-Genetics Institute, Inc. Cambridge, Massachusetts USA.

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Presentation on theme: "RhBMP-2: origin, biology and preclinical safety Gerard E. Riedel, Ph.D. Wyeth-Genetics Institute, Inc. Cambridge, Massachusetts USA."— Presentation transcript:

1 rhBMP-2: origin, biology and preclinical safety Gerard E. Riedel, Ph.D. Wyeth-Genetics Institute, Inc. Cambridge, Massachusetts USA

2 rhBMP-2 = recombinant human bone morphogenetic protein-2

3 Origin of rhBMP-2 The gene for human BMP-2 was isolated This gene was inserted into a chromosome of a mammalian cell This cell line grows in large culture vessels and secretes rhBMP-2 into the media rhBMP-2 is purified, vialed and freeze-dried

4 Properties of rhBMP-2 Member of “growth and differentiation” protein family -Endogenous BMP-2 is active in bone repair and in embryonic development Homodimeric, glycosylated protein that is highly conserved across species Osteoinductive in animals and humans

5 rhBMP-2 induces bone rat ectopic implant assay 14 days post-implantation

6 Mechanism of bone induction Chemotaxis/ proliferation Differentiation of mesenchymal cells Bone induction -trabecular, woven bone -remodels appropriately Increased vascularity

7 Mechanism of rhBMP-2 action Cell biology -Responsive cell types, receptors and signal transduction pathways identified Bone induction biology -Local administration is required

8 Implantation of rhBMP-2 requires a matrix Delivers rhBMP-2 to surgical site Augments rhBMP-2 retention at site Provides a compatible environment for bone induction

9 Matrix = ACS (absorbable collagen sponge) Commercially available in US since Approved PMA (Integra LifeSciences) -Implantable hemostatic agent -Extensive experience of safe use Bovine tendon Type I collagen -Manufacturing process meets/exceeds all US guidance

10 ACS = Helistat®

11 rhBMP-2/ACS preparation ACS rhBMP-2 WFI rhBMP-2 solution

12 rhBMP-2/ACS & LT- CAGE™ device

13 ACS augments rhBMP-2 retention at implantation site Orthotopic model (rabbit ulna) Radiolabelled rhBMP-2 Gamma camera scintigraphy Validated method

14 rhBMP-2 retention with ACS days % initial dose

15 Safety information rhBMP-2/ACS studies -implant safety studies ADME studies rhBMP-2 studies -Tumor biology studies -Systemic toxicity studies -Reproductive toxicity studies

16 rhBMP-2/ACS safety studies Three anatomic sites -craniofacial, long bone, spine Meyer et al Spine 24: Dosing >>> therapeutic range (species-adjusted) Results: no systemic effect -local effects = rhBMP-2 bioactivity

17 Biodistribution studies of rhBMP-2/ACS Two species (rats, rabbits) Two implant sites -ectopic or long-bone (+/- osteotomy) Results: -rhBMP-2 is released slowly from implant site -low systemic availability (rat long-bone model) maximum rhBMP-2 detected = 0.1% of dose

18 rhBMP-2 is slowly released from implantation site

19 ADME studies of rhBMP-2 Pharmacokinetics/biodistribution -rats (adults and juveniles) and NHP -IV administration Results: rhBMP-2 is cleared rapidly from the circulation, primarily through the liver, and rapidly degraded/excreted into urine

20 rhBMP-2 is rapidly cleared from the systemic circulation

21 slow release from implant site + rapid clearance from circulation low rhBMP-2 systemic exposure

22 Tumor biology studies Screening studies -Some tumors express BMP-2, BMP receptors -No evidence that BMP-2 initiates tumors No cytotoxic/mutagenic activity in vitro No evidence of abnormal cell biology in implant toxicity studies Pharmacology studies (in vitro)

23 Effect on tumor growth (in vitro) 51 tumor cell lines tested - 3: growth promotion (in serum-free media) [pancreas (2), prostate] -48: no effect or inhibition 71 primary tumor isolates tested -71: no effect or inhibition Inhibition is not sufficient for therapy

24 Additional tumor studies (FDA consultation) 1. Screen tumor cells for BMP receptor messenger RNA 2. Assess effect on tumor cell growth in vitro (cell culture) 3. Assess effect on tumor cell growth in vivo (xenograft)

25 rhBMP-2 toxicity studies Systemic toxicity of rhBMP-2 -single or repeat IV dosing, two species -exposure > 1000x expected in patients Reproductive toxicity of rhBMP-2 -repeat IV dosing, two species -fertility and teratology -exposure > 1000x expected in patients Results: no systemic effect

26 Additional safety studies Tripartite guideline safety studies -in vivo, in vitro -cytotoxicity, mutagenicity, others General safety studies -in vivo, IV administration -behavior, locomotion, other body functions Results: no effect

27 New studies (FDA consultation) Focus: better understanding of an immune response to rhBMP-2 New clinical assay -measure all human antibody isotypes (current assay measures human IgG) Neutralization assay -ability of antisera to block rhBMP-2 activity

28 Preclinical safety findings No systemic effects -attributed to low systemic exposure -local effects = osteoinduction by rhBMP-2 No toxicity detected Safety assessment supports use of InFUSE™ Bone Graft


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