Topical Application Of Beremagene Geperpavec, An Engineered Herpes Simplex Virus Type I-based Gene Therapy Vector Expressing Type VII Collagen, Is ...
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Topical Application Of Beremagene
Geperpavec, An Engineered Herpes Simplex
Virus Type I-based Gene Therapy Vector
Expressing Type VII Collagen, Is Safe And
Efficacious In A Murine Corneal Wound Model
K. Carroll*, P. Zhang*, M. J. Duermeyer,
N. Reitze, T. Parry, and S. Krishnan
S e p t e m b e r 1 6 th, 2 0 2 1
Krystal Bio |
© Copyright 2021 Krystal Biotech, Inc. All rights reserved.
Beremagene geperpavec (B-VEC) for dystrophic epidermolysis bullosa (DEB)
B-VEC, a non-replicating, engineered herpes simplex virus type I (HSV-1)-based gene therapy vector
• Expresses the human COL7A1 gene, which codes for the COL7 protein
• Formulated for topical application to DEB-associated skin lesions
• Phase I/II clinical trial data showed significant improvement in the healing of DEB-associated skin lesions over
placebo and that repeat doses were well tolerated
• B-VEC is currently in Phase III clinical trials for treatment of DEB skin lesions, including chronic wounds
Anchoring Fibrils
B-VEC (Collagen VII)
Keratinocytes
COL7
Dermoepidermal Blister protein
Junction
COL7
Nucleus transcripts
Fibroblasts
Keratinocyte (or Fibroblast) Cell
Untreated DEB Patient Skin B-VEC-treated Skin
Krystal Bio | 2
© Copyright 2021 Krystal Biotech, Inc. All rights reserved.DEB-associated eye disease and potential ophthalmic use of B-VEC
Eye Disease in Epidermolysis Bullosa (EB) Patients
• EB can result in the development of abrasions, blistering, vascularization, and scarring of the cornea, conjunctiva,
and eyelids
• Eye involvement can occur in most types of EB but is most common in RDEB1
• Current treatments are limited to ophthalmic lubricants and removal of scar tissue2
• Topical B-VEC could be a potential treatment for DEB-associated eye disease
Herpes Stromal Keratitis (HSK)
• Immunopathological condition that can occur after a corneal HSV-1 infection
• Can cause inflammation, irreversible scarring of the cornea, and blindness
• HSK manifests as progressive:
• Opacity
• Neovascularization
• Loss of corneal sensitivity https://www.reviewofcontactlenses.com/artic
le/rccl1117-treating-herpes-simplex-virus
• Mice can be used to study the development of HSK3
1.Fine JD, et al., Eye involvement in inherited epidermolysis bullosa: Experience of the National Epidermolysis Bullosa Registry. American Journal of Ophthalmology, 2004;138(2):254-262.
2.Tong L, et al., The eye in epidermolysis bullosa. British Journal of Ophthalmology, 1999;83:323-326.
3.Yun H, et al., Reversible nerve damage and corneal pathology in murine herpes simplex stromal keratitis. Journal of Virology, 2014;88(14):7870-7880. Krystal Bio | 3
© Copyright 2021 Krystal Biotech, Inc. All rights reserved.Topical B-VEC delivers human COL7A1 to the cornea, but not the underlying
sensory nerves, in a murine corneal wound model
Blinded HSK
Corneal wound Harvest TGs and clinical scoring
Blinded HSK
+ corneas for gene +
clinical scoring
Treatment expression Histology
Days post infection 0 1 10 21
(DPI)
Human COL7A1 Transcripts
5×10 3
Trigeminal Ganglion (TG) Vehicle
hCOL7A1 transcripts/
Ophthalmic Branch (V1) 4×10 3 B-VEC
25ng total RNA
3×10 3
2×10 3
Cornea
1×10 3
Mandibular Branch (V3)
Maxillary Branch (V2)
0
Cornea TG Cornea TG
Tissue
Krystal Bio | 4
© Copyright 2021 Krystal Biotech, Inc. All rights reserved.Topical B-VEC application to the wounded murine cornea does not cause
pathology
Wounded corneas at 21DPI
Unwounded cornea Vehicle B-VEC KOS/Vector
Opacity Vessel Ingrowth Corneal Reflex
✱✱✱✱ ✱✱✱✱ ✱✱✱✱
ns ✱✱
ns ✱✱✱✱ ns ✱✱✱✱
ns ns ns ✱✱
4 5 ns ns ns ✱✱✱✱ ns
6
Vehicle
4 5
Vessel Ingrowth
B-VEC
Corneal Reflex
3
4 KOS/Vector
Opacity
3
2 3
2
2
1
1
1
0 0 0
10 21 10 21 10 21
DPI DPI DPI
Krystal Bio | 5
© Copyright 2021 Krystal Biotech, Inc. All rights reserved. Data analyzed with repeated measures 2-way ANOVAs with Tukey’s post tests. **pRepeated topical B-VEC application to the wounded murine cornea is safe
Corneal wound + Treatment Blinded HSK clinical scoring* Blinded HSK clinical scoring
DPI 0 2 4 10 21
Vehicle 1X X X X
Vehicle 3X X X X X X
B-VEC 1X X X X
B-VEC 2X X X X X
B-VEC 3X X X X X X
KOS/Vector X X X
Opacity Vessel Ingrowth Corneal Reflex
✱✱✱✱
✱✱ ✱
✱✱✱✱
✱✱ ✱
✱✱✱✱
✱✱ ✱
✱✱✱✱
✱✱ ✱
✱ ✱✱✱✱
4 5 ns 6
Vehicle 1X
5 Vehicle 3X
4
Vessel Ingrowth
Corneal Reflex
3
4 B-VEC 1X
Opacity
3
3 B-VEC 2X
2
2 B-VEC 3X
2
1 KOS/Vector
1 1
0 0 0
21 DPI 21 DPI 21 DPI
*10dpi data not shown as B-VEC did not separate from vehicle control at 10 dpi, as shown in previous results Krystal Bio | 6
© Copyright 2021 Krystal Biotech, Inc. All rights reserved. Data analyzed with repeated measures 2-way ANOVAs with Tukey’s post tests. *pSummary
Efficacy • Human COL7A1 was expressed in B-VEC treated corneas, but not the
underlying sensory nerves
Safety • B-VEC treated corneas developed little or no pathology
• B-VEC HSK clinical scores were not statistically different from vehicle
treated corneas in either single and repeat dose experiments
• KOS/Vector treated corneas developed moderate to severe HSK after a
single dose with 190-fold less virus than the B-VEC dose used
Conclusion • B-VEC may be safe for repeated, topical treatment of human DEB corneal
manifestations
Krystal Bio | 7
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