TransCon CNP, a Sustained-Release Prodrug of C...
1
TransCon CNP, a Sustained-Release Prodrug of C-Type Natriuretic Peptide, exerts Positive Effects on Bone in Juvenile Cynomolgus Monkeys and in a Mouse Model of Achondroplasia Vibeke Miller Breinholt 1 , Nabil Kaci 3, Caroline Rasmussen 1, , Oliver Keil 2 , Susann Adermann 2 , Ulrich Hersel 2 , Maxence Cornille 3, , Per Holse Mygind 1 , Kennett Sprogøe 1 , and Laurence Legeai-Mallet 3 1 Ascendis Pharma A/S; 2 Ascendis Pharma GmbH, and 3 Imagine Institute, France This study was sponsored by Ascendis Pharma A/S. Conclusion Background An increase in the epiphyses and secondary ossification centers (SOC) was demonstrated by H&E staining. Methods Results Results Methods Percentage Change From Baseline 0 1 2 3 4 5 6 7 8 9 TransCon CNP 10 µg/kg/week TransCon CNP 40 µg/kg/week TransCon CNP 100 µg/kg/week Achondroplasia (ACH), the most common cause of human dwarfism, is caused by a gain-of-function mutation in FGFR3, a key negative regulator of endochondral ossification. Patients with ACH suffer not only from disproportionate limb shortening but also foramen magnum and spinal stenosis caused by premature synchondrosis closure and ossification center fusion. Vosoritide, a mutated CNP analogue in Phase 3 development, has demonstrated efficacy in stimulating growth in patients with ACH. 1,2 TransCon CNP, a once-weekly prodrug of C-Type Natriuretic Peptide (CNP), is being developed for the treatment of ACH. In its prodrug form, CNP is transiently bound to the TransCon carrier via the TransCon linker. Through auto-hydrolysis, fully active, unmodified CNP is released, providing sustained exposure. Bone Growth in Healthy Juvenile Monkeys To determine if once weekly TransCon CNP was efficacious in promoting linear bone growth, TransCon CNP was administered subcutaneously (SC) once weekly to healthy juvenile male cynomolgus monkeys at doses of 0, 10, 40 and 100 µg/kg/week for 6 months. Vosoritide* was administered daily at a dose of 20 µg/kg/day (equivalent to 140 µg/kg/week). A control group received vehicle. Tibial growth was measured radiographically at weeks 4, 8, 12, 22, and 26. Bone Growth in ACH Mice • Body and selected long bones were measured by radiography/µCT and/or with a caliper. • Collagen X and H&E staining were performed on growth plates to assess bone architecture. • The calvaria and occipital bones were assessed by µCT to investigate the effects on ossification. • The foramen magnum was assessed by µCT to investigate the effects on synchondroses. Results Bone Growth in Healthy Juvenile Monkeys In cynomolgus monkeys (n=4/group), once-weekly TransCon CNP afforded dose-proportional increases in tibial overgrowth (week 12). Both weekly TransCon CNP and daily vosoritide stimulated overgrowth of the tibia compared to the control group. TransCon CNP demonstrated only slightly less efficacy than daily vosoritide* at one- third the dose (week 26). Bone Growth in ACH Mice TransCon CNP administration to Fgfr3 Y367C/+ mice from birth to day 15 increased the size of the naso-anal length, femur (blue arrows), and tibia (red arrows). Positive effects on chondrocyte differentiation and organization as well as an increase in the hypertrophic zone was demonstrated by Collagen X staining. TransCon CNP increased calvaria (left) and occipital bones (right) ossification in Fgfr3 Y367C/+ mice. TransCon CNP was shown to counteract premature closure of the anterior intraoccipital synchondroses in Fgfr3 Y367C/+ mice leading to an increased size of the foramen magnum (numbers indicate individual animals). In young healthy cynomolgus monkeys, once-weekly TransCon CNP increased long bone growth in a dose-dependent fashion. In a murine model of ACH, TransCon CNP improved growth plate architecture, and prevented both disease-related craniosynostosis and premature fusion of the synchondrosis of the foramen magnum. These results suggest that TransCon CNP might ameliorate some of the more disabling achondroplasia traits, including spinal stenosis. To determine if TransCon CNP would reverse the phenotype in an ACH disease model, newborn ACH mice harboring the Fgfr3 Y367C/+ mutation (n=9) were administered 5.6 mg CNP/kg/day TransCon CNP for 15 days compared to vehicle and the following studies performed: 1 Wendt et al. J Pharmacol Exp Ther, 2015; 353, 132–149 2 Biomarin 2016, R&D Day * “Vosoritide” refers to a synthesized molecule with the same amino acid sequence prepared by Ascendis Pharma 0 2 4 6 8 10 12 14 16 18 Control TransCon CNP 40 µg/kg/week Vosoritide 20 µg/kg/day (140 µg/kg/week) Vehicle Vehicle TransCon CNP TransCon CNP Percentage Change From Baseline Vehicle TransCon CNP
Transcript of TransCon CNP, a Sustained-Release Prodrug of C...
TransCon CNP, a Sustained-Release Prodrug of C-Type Natriuretic Peptide, exerts Positive Effects on Bone in Juvenile Cynomolgus Monkeys and in a Mouse Model of Achondroplasia
Vibeke Miller Breinholt1, Nabil Kaci3, Caroline Rasmussen1, , Oliver Keil2, Susann Adermann2, Ulrich Hersel2, Maxence Cornille3, , Per Holse Mygind1, Kennett Sprogøe1, and Laurence Legeai-Mallet3
1Ascendis Pharma A/S; 2Ascendis Pharma GmbH, and 3Imagine Institute, FranceThis study was sponsored by Ascendis Pharma A/S.
Conclusion
Background
An increase in the epiphyses and secondary ossification centers (SOC)was demonstrated by H&E staining.
Methods Results Results
MethodsPercentage
Change From Baseline
0123456789
TransConCNP10µg/kg/week
TransConCNP40µg/kg/week
TransConCNP100µg/kg/week
Achondroplasia (ACH), the most common cause of human dwarfism, iscaused by a gain-of-function mutation in FGFR3, a key negativeregulator of endochondral ossification. Patients with ACH suffer not onlyfrom disproportionate limb shortening but also foramen magnum andspinal stenosis caused by premature synchondrosis closure andossification center fusion. Vosoritide, a mutated CNP analogue inPhase 3 development, has demonstrated efficacy in stimulating growthin patients with ACH.1,2
TransCon CNP, a once-weekly prodrug of C-Type Natriuretic Peptide(CNP), is being developed for the treatment of ACH. In its prodrug form,CNP is transiently bound to the TransCon carrier via the TransConlinker. Through auto-hydrolysis, fully active, unmodified CNP isreleased, providing sustained exposure.
Bone Growth in Healthy Juvenile Monkeys
To determine if once weekly TransCon CNP was efficacious inpromoting linear bone growth, TransCon CNP was administeredsubcutaneously (SC) once weekly to healthy juvenile male cynomolgusmonkeys at doses of 0, 10, 40 and 100 µg/kg/week for 6 months.Vosoritide* was administered daily at a dose of 20 µg/kg/day (equivalentto 140 µg/kg/week). A control group received vehicle. Tibial growth wasmeasured radiographically at weeks 4, 8, 12, 22, and 26.
Bone Growth in ACH Mice
• Body and selected long bones were measured by radiography/µCTand/or with a caliper.
• Collagen X and H&E staining were performed on growth plates toassess bone architecture.
• The calvaria and occipital bones were assessed by µCT to investigatethe effects on ossification.
• The foramen magnum was assessed by µCT to investigate the effectson synchondroses.
ResultsBone Growth in Healthy Juvenile Monkeys
In cynomolgus monkeys (n=4/group), once-weekly TransCon CNPafforded dose-proportional increases in tibial overgrowth (week 12).
Both weekly TransCon CNP and daily vosoritide stimulated overgrowthof the tibia compared to the control group. TransCon CNPdemonstrated only slightly less efficacy than daily vosoritide* at one-third the dose (week 26).
Bone Growth in ACH MiceTransCon CNP administration to Fgfr3Y367C/+ mice from birth to day 15increased the size of the naso-anal length, femur (blue arrows), andtibia (red arrows).
Positive effects on chondrocyte differentiation and organization as wellas an increase in the hypertrophic zone was demonstrated by CollagenX staining.
TransCon CNP increased calvaria (left) and occipital bones (right) ossification in Fgfr3Y367C/+ mice.
TransCon CNP was shown to counteract premature closure of the anterior intraoccipital synchondroses in Fgfr3Y367C/+ mice leading to an increased size of the foramen magnum (numbers indicate individual animals).
In young healthy cynomolgus monkeys, once-weekly TransCon CNP increased long bone growth in a dose-dependent fashion.
In a murine model of ACH, TransCon CNP improved growth plate architecture, and prevented both disease-related craniosynostosis and premature fusion of the synchondrosis of the foramen magnum.
These results suggest that TransCon CNP might ameliorate some of the more disabling achondroplasia traits, including spinal stenosis.
To determine if TransCon CNP would reverse the phenotype in an ACHdisease model, newborn ACH mice harboring the Fgfr3Y367C/+ mutation(n=9) were administered 5.6 mg CNP/kg/day TransCon CNP for 15days compared to vehicle and the following studies performed:
1 Wendt et al. J Pharmacol Exp Ther, 2015; 353, 132–1492 Biomarin 2016, R&D Day
* “Vosoritide” refers to a synthesized molecule with the same amino acid sequence prepared by Ascendis Pharma0
2468
1012141618
Control
TransConCNP40µg/kg/week
Vosoritide20µg/kg/day(140 µg/kg/week)
Vehicle VehicleTransCon CNP TransCon CNP
PercentageChange From
Baseline
Vehicle TransCon CNP
