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Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia

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Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia Support for a new therapeutic approach of using a low-dose FGFR tyrosine kinase inhibitor (infigratinib) for achondroplasia Benoit Demuynck,1 Justine Filpo,1 Gary Li,2 Carl Dambkowski,2 Laurence Legeai-Mallet1 1INSERM U1163, Imagine Institute, Paris University, Paris, France; 2QED Therapeutics, Inc., San Francisco, California, USA #5341 Mouse model and drug treatment In-vivo efficacy Figure 6. Effects of infigratinib treatment on the intervertebral disc Figure 9. Survival data Introduction ■ The ACH FgfrY367C/+ mouse model has been described previously.5,6 ■ We observed a statistically significant improvement vs vehicle-treated FgfrY367C/+ ■ Fibroblast Growth Factor Receptor 3 (FGFR3) plays a crucial role in the process ■ Phosphate salt (BGJ398-AZA) of infigratinib was used. Infigratinib phosphate mice in the upper (humerus +7.3%, p<0.01; ulna +11.1%, p<0.001; radius Lumbar vertebrae 100 of endochondral ossification as shown by FGFR3 gain-of-function mutations was formulated as a suspension for subcutaneous administration in DMSO +14.2%, p<0.001) and lower (femur +10.4%, p<0.01; tibia +16.8%, p<0.001) Vehicle limbs with infigratinib at a dose of 0.5 mg/kg, as well as improvement in the Fgfr3+/+ Fgfr3Y367C/+ Fgfr3Y367C/+ that result in common forms of short-stature skeletal dysplasia, such as (1 ml : 2 mg). Infigratinib was given via subcutaneous administration due to + vehicle + vehicle + infigratinib 0.5 mg/kg/day 0.5 mg/kg/day foramen magnum (FM length +11.9%, p<0.001). achondroplasia (ACH). the size and age of the mice, which makes oral gavage impractical. 80 0.2 mg/kg/day Y367C/+ ■ ■ ■ Fgfr mice were treated from Day 1 (Day 0 = birth) to Day 15 with The effect of infigratinib on bone elongation was lower at 0.2 mg/kg (Figure 3), ) 1 mg/kg/3 days ACH is the most common cause of rhizomelic dwarfism, an autosomal % dominant disorder with an incidence between 1 in 10,000 and 1 in 20,000 live infigratinib subcutaneously once daily (daily dose of 0.2 mg/kg or 0.5 mg/ indicating a dose-response relationship. ( 60 1 l births worldwide. kg) or every 3 days (intermittent dosing of 1 mg/kg every 3 days). Animals ■ a To test whether daily treatment was needed, we performed intermittent v were sacrificed on Day 16. Results were compared with those obtained from i ■ injections of infigratinib (1 mg/kg, every 3 days): v 40 In >95% of cases, ACH is caused by an arginine-to-glycine substitution at mutant mice receiving vehicle. r u residue 380 (p.Gly380Arg) in the FGFR3 gene; this is an autosomal dominant – As shown in Figure 3, the gain of growth vs vehicle-treated mice was S Significance p<0.001 gain-of-function mutation that demonstrates 100% penetrance and is de novo In-vivo observations significant for all long bones (humerus +5.0%, p<0.001; ulna +5.6%, p<0.001; 20 2 in 80% of cases. ■ Clinical observations for severity of effect were performed twice a week radius +4.3%, p<0.001; femur +8.7%, p<0.001; tibia +6.4%, p<0.001) and ■ The ACH phenotypes include rhizomelia (shortening of the limbs with proximal (hind limb movement, posture, tail, paws), including assessment for survival. the foramen magnum was increased (FM length +6.3%, p<0.01). Detailed observations were performed at the time of scoring. 0 segments affected disproportionally), large head with frontal bossing, mid-face – In addition to the gain of growth, we observed a modification of the growth 0 10 15 20 25 hypoplasia, and relatively normal trunk, with excessive lumbar lordosis.2 plate structure, displaying a better organization of the hypertrophic zone, X-ray assessments Days ■ Even though they are rare, serious complications are associated with ACH, ■ Lateral X-ray images were taken of all animals by Faxitron MX20 Cabinet X-ray among other improvements (Figures 4 & 5). including cervical spinal cord compression due to a narrowed foramen system (Lincolnshire, IL, USA) following terminal sacrifice. Animals were placed ■ Treatment with infigratinib modified the morphology of the nucleus pulposus Number of mice Number of mice magnum, lumbar nerve root and/or cord compression due to spinal stenosis, on their right side, with the left hind leg more forward than the right, to allow at P1 at P16 3 Figure 3. Overall findings by dose and annulus fibrosus. and severe lower extremity varus deformity. both hind legs to be visible on the X-ray. 0.5 mg/kg/day 12 10 e c ■ i Axial skeleton Appendicular skeleton 0.2 mg/kg/day 12 10 Current management of ACH focuses on the prevention and treatment m Bone length measurement + / 20% FGF23 levels in plasma of its complications as there is no approved therapy that targets the C 1 mg/kg/3 days 14 13 367 *** *** ■ Y Bone length was measured using a caliper (VWRi819-0013, VWR, USA) 3 ■ pathophysiology of the condition. r *** FGF23 levels by ELISA are shown in Figure 7. No statistically significant Vehicle 23 11 gf 16% at necropsy. F Y367C/+ d *** differences in FGF23 were observed in infigratinib-treated Fgfr mice vs e ■ t *** Various therapeutic strategies have been considered, the most advanced a e r 12% *** t untreated wild-type mice (p>0.05). being an analog of C-type Natriuretic Peptide (CNP, vosoritide), which is FGF23 level assessment *** e- l ** c i given as a daily subcutaneous injection and acts by antagonizing the MAP ■ h *** FGF23 levels in plasma collected at the end of in-vivo studies were determined e 8% v ** s ** * *** v kinase pathway. However, both STAT1 and MAPK signaling impact the by ELISA (No. CY-4000) manufactured by Kainos Laboratories. *** *** e *** * * *** s ** * *** a 4% achondroplasia phenotype. e r Figure 7. FGF23 by dose c Phosphorus assessment n i Discussion ■ nt In this study, we evaluated a therapeutic strategy that targets all pathways 0% ■ e Phosphorus levels in plasma collected at the end of in-vivo studies were c Foramen L4-L6 height Skull length Tail length Femur Tibia Humerus Ulna Radius r downstream of FGFR3. e magnum P determined by Phosphate Assy kit (Abcam, ab65622). length 600 ■ In-vitro data demonstrate that infigratinib has superior activity over a CNP ■ We hypothesized that a very low dose of the oral selective FGFR1–3 tyrosine 0.2 mg/kg/day 1 mg/kg/3 days 0.5 mg/kg/day *p<0.05, **p<0.01, ***p<0.001 analog, suggesting that inhibition of multiple key pathways downstream of Statistical analysis kinase inhibitor (TKI) infigratinib (BGJ398) would improve defective bone WT FGFR3 controlling either proliferation and differentiation of the chondrocytes elongation and have greater potency at lower concentrations in an ACH cell line ■ Differences between experimental groups were assessed using ANOVA with leads to better efficacy compared with MAPK inhibition alone. than a CNP analog (e.g., vosoritide). Tukey’s post-hoc test or Mann-Whitney U-test. The significance threshold was 400 Vehicle set at p≤0.05. Figure 4. Infigratinib promotes the formation of the ossification 0.2 mg/kg/day ■ In-vivo data demonstrate that low, as well as intermittent, doses of infigratinib ■ Statistical analyses were performed using GraphPad PRISM (v5.03). center and the number of hypertrophic chondrocytes Figure 1. Infigratinib directly targets the underlying cause of 0.5 mg/kg/day promote growth in this ACH mouse model: 2,4 achondroplasia, FGFR3 overactivity Vehicle 0.2 mg/kg/day 0.5 mg/kg/day 1 mg/kg/3 days 200 Y367C/+ FGF23 (ng/mL) 1 mg/kg/3 days – Low-dose infigratinib treatment of Fgfr mice over 15 days improved the endochondral ossification processes in an ACH mouse model. Mechanism Infigratinib Results • Orally-available, selective, ATP- 0 – Skeletal changes were observed in a dose-dependent manner, based on competitive FGFR-selective In-vitro results FGFR3 NPR2 total dose given over the treatment period. tyrosine kinase inhibitor ■ We observed that in the FGF18-conditioned TAN 4-18-chondrocytes Treatment groups – Selective for FGFR1, 2 & 3 concentrations of 10-6M to 10-10M infigratinib led to statistically significant ■ At the doses of infigratinib examined in these experiments, FGF23 and TK RAS RAF Biochemical activity inhibition of ERK1/2 phosphorylation (p<0.05) compared to untreated cells. of infigratinib phosphate levels did differ from wild-type mice, demonstrating that low-dose (nM IC ) ■ We also observed that vosoritide treatment led to statistically significant MEK cGKII 50 Phosphorus levels in plasma infigratinib can affect dysfunctional FGFR3 signaling in an ACH mouse model Infigratinib STAT1 -4 (FGFR1–3 inhibitor) FGFR1 0.9 inhibition of ERK1/2 phosphorylation at a concentration of 10 M (p<0.05), MAPK p38 -5 ■ Phosphorus levels are shown in Figure 8. No statistically significant differences while having no measurable impact on downstream changes in FGFR1/4, Directly targets the FGFR2 1.4 but not at 10 M (not significant) compared with untreated cells. Y367C/+ gain-of-function in phosphorus levels were observed in infigratinib-treated Fgfr mice vs which is an important signaling pathway regulating phosphate reabsorption in Chondrocyte Chondrocyte 0.9 FGFR3 receptor FGFR3 proliferation hypertrophy untreated FgfrY367C/+ or wild-type mice (p>0.05). renal cells. FGFR4 60 Figure 2. In-vitro findings VEGFR2 180 ■ No apparent toxicity of infigratinib was observed in treatment mice or seen via ■ The secondary ossification center is larger in infigratinib-treated mice vs Y367C/+ TAN 4-18-Chondrocytes (FGFR3-Y373C) control mice. Histological samples demonstrate efficient penetration of the Figure 8. Phosphorus level by dose laboratory measures performed; on the contrary, treatment of Fgfr mice growth plate by infigratinib. with infigratinib improved survival compared with untreated mice.
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