Treatment methods for skeletal dysplasia

Abstract

Described herein are methods for treating skeletal dysplasia (such as hypochondroplasia or achondroplasia) in a subject in need thereof. These methods generally involve administering to the subject an effective amount of infigratinib or a pharmaceutically acceptable salt thereof. Also provided herein are mini-tablets comprising infigratinib monophosphate and a pharmaceutically acceptable excipient for use in treating skeletal dysplasia (such as hypochondroplasia or achondroplasia) in a subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 488,709, filed March 6, 2023, and U.S. Provisional Patent Application No. 63 / 508,789, filed June 16, 2023, the contents of each of which are incorporated by reference herein in their entirety. [Background technology]

[0002] Skeletal dysplasias can affect bone development, cartilage growth, and neurological function. Certain skeletal dysplasias, including achondroplasia (ACH) and hypochondroplasia (HCH), are forms of dwarfism. ACH is the most common nonfatal skeletal dysplasia, occurring in 1:15,000 to 1:30,000 individuals (Horton WA, Hall JG, Hecht JT., Achondroplasia. Lancet, 2007, 370, 162-72; Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, et al., US. Am. J. Med. Genet. A., 2008, 146A(18), 2385-2389). Patients with ACH are short, growing to an average height of approximately 4 feet (125 cm), and prone to significant comorbidities such as sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, obesity, and, in some cases, foramen magnum stenosis, which requires emergency surgery. HCH is similar to ACH, but the physical signs are milder. However, patients with HCH may be affected by more severe neurological challenges, including mild to moderate intellectual disability and learning disabilities.

[0003] ACH is characterized by defects in endochondral ossification due to gain-of-function mutations in the fibroblast growth factor receptor (FGFR) 3 gene. Ninety-nine percent of these mutations are G380R mutations (Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, et al., Am. J. Hu. Genet., 56, 368-373, 1995), which maintain the receptor in a constitutively active state, inhibiting chondrocyte proliferation and differentiation in the growth plate and suppressing linear bone growth (Unger S, Bonafe L, Gouze D., Curr. Osteoporos. Rep., 2017, 15, 53-60). The primary phenotype of ACH is disproportionate short stature with radicular limb shortening (proximal limb shortening).

[0004] Approximately 80% of cases are due to de novo mutations (Ornitz DM, Legeai-Mallet L., Dev. Dyn., 2017, 246, 291-309). Diagnosis is usually made at birth, but may be suspected based on late fetal ultrasound.

[0005] In North America, Europe, and Australia, there are no approved therapeutic interventions for ACH (achondroplasia) or HCH (hypodachondroplasia), and no widely accepted consensus regarding treatment exists (Unger). Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating the complications of ACH (FDA Background Document. Joint Meeting of the Pediatric Advisory Committee and the Endocrine and Metabolic Drugs Advisory Committee. May 11, 2018. See: https: / / www.fda.gov / downloads / AdvisoryCommittees / ; Unger).

[0006] No clear growth benefit has been demonstrated after recombinant human growth hormone (r-hGH) treatment. Although an increase in growth velocity (height increased from -5.0 standard deviations to -4.0 standard deviations over a 5-year period) has been observed, no clear benefit has been established with long-term treatment (Miccoli M, Bertelloni S, Massart F., Horm. Res. Paediatr., 2016, 86, 27-34). It is not generally recommended as a treatment for ACH (Horton; FDA).

[0007] Limb lengthening procedures can result in a 15-30 cm increase in height (approximately 20% increase in bone segment length), but they are associated with postoperative pain, frequent need for reoperation, and a high complication rate (Horton). Furthermore, these procedures may disrupt growth plate development, and the cosmetic effect of longer legs and shorter arms may not be suitable for some patients (FDA). Currently, clinicians considering limb lengthening procedures typically require a psychological evaluation and ensure that the child is old enough to consent to surgery (Wright MJ, Irving MD., Arch. Dis. Child., 2012, 97(2), 129-134). Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there remains an unmet need in the development of novel therapeutic strategies to treat children with skeletal dysplasias such as achondroplasia and hypochondroplasia. [Means for solving the problem]

[0009] The present disclosure provides methods of treating skeletal dysplasias, such as achondroplasia (ACH) and hypochondroplasia (HCH), using an FGFR inhibitor, namely infigratinib.

[0010] In one embodiment, the disclosure provides a method of treating skeletal dysplasia in a subject in need thereof, the method comprising administering to the subject about 0.250 milligrams per kilogram (mg / kg) of infigratinib or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the present disclosure provides a method of treating skeletal dysplasia in a subject in need thereof, comprising administering to the subject about 2.5 mg to about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the skeletal dysplasia is achondroplasia or hypochondroplasia. In some embodiments, the skeletal dysplasia is achondroplasia. In some embodiments, the skeletal dysplasia is hypochondroplasia.

[0013] In one embodiment, infigratinib or a pharmaceutically acceptable salt thereof is administered orally to the subject. In one embodiment, infigratinib or a pharmaceutically acceptable salt thereof is administered daily to the subject.

[0014] In certain embodiments, the subject has an FGFR3 mutation. In certain embodiments, the FGFR3 mutation is a G380R mutation. In certain embodiments, the FGFR3 mutation is an N540K mutation. In certain embodiments, the FGFR3 mutation is a G380R mutation or an N540K mutation.

[0015] In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered as mini-tablets, each mini-tablet containing about 0.1 mg or about 1 mg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, infigratinib is contained in the mini-tablets as infigratinib monophosphate.

[0016] In one embodiment, the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate. In certain embodiments, infigratinib monophosphate exists as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak at 15.0°±0.2° (2θ).

[0017] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in height velocity compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in absolute height velocity.

[0018] In one embodiment, during or after treatment, the subject has a mean change from baseline in annual height velocity (AHV) of at least about 2.0 centimeters per year (cm / year).

[0019] In one embodiment, during or after treatment, the subject's AHV shows a change from baseline of between about 1.0 cm / year and about 14 cm / year.

[0020] In one embodiment, during or after treatment, the subject has an AHV of about 1.0 cm / year, about 1.1 cm / year, about 1.2 cm / year, about 1.3 cm / year, about 1.4 cm / year, about 1.5 cm / year, about 1.6 cm / year, about 1.7 cm / year, about 1.8 cm / year, about 1.9 cm / year, about 2.0 cm / year, about 2.1 cm / year, about 2.2 cm / year, about 2.3 cm / year, about 2.4 cm / year, about 2.5 cm / year, about 2.6 cm / year, about 2.7 cm / year, about 2.8 cm / year, about 2.9 cm / year, about 3.0 cm / year, about 3.1 cm / year, about 3.2 cm / year, about 3.3 cm / year, about 3.4 cm / year, about 3.5 cm / year, about 3.6 cm / year, about 3.7 cm / year, about 3.8 cm / year, about 3.9 cm / year, about 4.0 cm / year, about 4.1 cm / year, about 4.2 cm / year, about 4.3 cm / year, about 4.4 cm / year, about 4.5 cm / year, about 4.6 cm / year, about 4.7 cm / year, about 4.8 cm / year, about 4.9 cm / year, about 5.0 cm / year, about 5.1 cm / year, about 5.2 cm / year, about 5.3 cm / year, about 5.4 cm / year, about 5.5 cm / year, about 5.6 cm / year, about 5.7 cm / year, about 5.8 cm / year, about 5.9 cm / year, about 6.0 cm / year, about 6.1 cm / year, about 6.2 cm / year, about 6.3 cm / year, about 6.4 cm / year, about 6.5 cm / year, about 6.6 cm / year, about 6.7 cm / year, about 6.8 cm / year, about 6.9 cm / year, about 7.0 cm / year, about 7.1 cm / year, about 7.2 cm / year, about 7.3 cm / year, about 7.4 cm / year, about 7.5 cm / year, about 7.6 cm / year, about 7.7 cm / year, about 7.8 cm / year, about 7.9 cm / year, about 8.0 cm / year, about 8.1 cm / year, about 8.2 cm / year, about 8.3 cm / year, about 8.4 cm / year, about 8.5 cm / year, about 8.6 cm / year, about 8.7 cm / year, about 8.8 cm / year, about 8.9 cm / year, about 9.0 cm / year, about 9.1 cm / year, about 9.2 cm / year, about 9.3 cm / year, about 9.4 cm / year, about 9.5 cm / year, about 9.6 cm / year, about 9.7 cm / year, about 9.8 cm / year, about 9.9 cm / year, about 10.0 cm / year, about 10.1 cm / year, about 10.2 cm / year, about 10.3 cm / year, about 10.4 cm / year, about 10.5 cm / year, about 10.6 cm / year, about 10.7 cm / year, about 10.8 cm / year, about 10.9 cm / year, about 11.0 cm / year, about 11.1 cm / year, about 11.2 cm / year, about 11.3 cm / year, about 11.4 cm / year, about 11.5cm / year, approximately 11.6cm / year, approximately 11.7cm / year, approximately 11.8cm / year, approximately 11.9cm / year, approximately 12.0cm / year, approximately 12.1cm / year, approximately 12.2cm / year, approximately 12.3cm / year, approximately 12.4cm / year, approximately 12.5cm / year, approximately 12.6cm / year, approximately 12.7cm / year, approximately 12.8cm / year, approximately 12.9cm / year, approximately 13.0cm / year, approximately 13.1cm / year, approximately 13.2cm / year, approximately 13.3cm / year, approximately 13.4cm / year, approximately 13.5cm / year, approximately 13.6cm / year, approximately 13.7cm / year, approximately 13.8cm / year, approximately 13.9cm / year or approximately 14.0cm / year.

[0021] In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.0 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.1 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.2 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.3 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.4 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.5 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.6 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.7 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.8 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 2.9 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.0 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.1 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.2 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.3 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.4 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.5 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.6 cm / year.In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.7 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.8 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 3.9 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.0 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.1 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.2 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.3 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.4 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.5 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.6 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.7 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.8 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 4.9 cm / year. In one embodiment, during or after treatment, subjects experience a mean change from baseline in AHV of about 5.0 cm / year.

[0022] In one embodiment, during or after treatment, the subject has an absolute AHV of at least about 2.0 centimeters per year (cm / yr). In one embodiment, during or after treatment, the subject has an absolute AHV of at least about 4.0 cm / yr. In one embodiment, during or after treatment, the subject has an absolute AHV of at least about 7.0 cm / yr.

[0023] In one embodiment, during or after treatment, the subject has an absolute AHV of between about 1.0 cm / year and about 14 cm / year.

[0024] In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 3.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 4.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.1 cm / year.In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 5.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 6.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.3 cm / year.In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 7.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 8.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.5 cm / year.In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 9.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.7 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 10.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.0 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.1 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.2 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.3 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.4 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.5 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.6 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.7 cm / year.In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.8 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 11.9 cm / year. In one embodiment, during or after treatment, the subject has an absolute AHV of about 12.0 cm / year.

[0025] In one embodiment, the subject experiences no treatment-related adverse events during or after treatment. In one embodiment, the subject experiences no serious adverse events during or after treatment. In one embodiment, the subject experiences no serious treatment-related adverse events during or after treatment.

[0026] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase over baseline in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

[0027] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in body weight compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute decrease in body weight.

[0028] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits a proportional increase in head circumference compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute proportional increase in head circumference.

[0029] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits normalization of body proportion measurement ratios compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits absolute normalization of body proportion measurement ratios. In certain embodiments, the body proportion measurement ratios are selected from the group consisting of upper body to lower body segment ratio, upper arm to forearm ratio, thigh to calf length ratio, arm span to height ratio, head circumference to height ratio, and combinations thereof.

[0030] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in a bone metabolism biomarker selected from the group consisting of type X collagen degradation fragments, collagen X markers, and combinations thereof, compared to baseline.

[0031] In one embodiment, during or after treatment, the subject experiences a mean change from baseline in collagen X markers of at least about 5%. In one embodiment, during or after treatment, the subject experiences a mean change from baseline in collagen X markers of at least about 5.0%. In one embodiment, the subject experiences a mean change from baseline in collagen X markers ranging from about 10.0% to about 40.0%.

[0032] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in exercise capacity compared to baseline.

[0033] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits a reduced number of episodes of otitis media compared to baseline.

[0034] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in the number and / or severity of sleep apnea episodes compared to baseline.

[0035] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits improved quality of life as assessed using the Pediatric Quality of Life Scale.

[0036] In certain embodiments, the subject is 12 years of age or younger. In certain embodiments, the subject is 3 to 11 years of age. In certain embodiments, the subject is under 8 years of age. In certain embodiments, the subject is 8 years of age or older.

[0037] In one embodiment, the subject is a pediatric subject (e.g., a subject under the age of 18). In one embodiment, the subject is under the age of 18.

[0038] In another aspect, mini-tablets for oral administration of about 1 mg of infigratinib are provided, which generally contain an amount of infigratinib monophosphate necessary to administer about 1 mg of infigratinib, and a pharmaceutically acceptable excipient.

[0039] In another aspect, mini-tablets for oral administration of about 0.1 mg of infigratinib are provided, which generally comprise an amount of infigratinib monophosphate necessary to administer about 0.1 mg of infigratinib, and a pharmaceutically acceptable excipient.

[0040] In certain embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of mannitol, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, croscarmellose sodium, and combinations thereof.

[0041] In another aspect, mini-tablets for oral administration are provided, the mini-tablets comprising about 1% to about 20% by weight of infigratinib monophosphate and about 30% to about 95% by weight of a filler.

[0042] In certain embodiments, the filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, and combinations thereof. In certain embodiments, the filler comprises microcrystalline cellulose and mannitol.

[0043] In certain embodiments, the mini-tablets further comprise about 5% to about 10% by weight of a binder, hi certain embodiments, the binder is selected from the group consisting of sugar, gelatin, natural gum, sorbitol, maltodextrin, alginate, alginate derivatives, polyvinylpyrrolidone, cellulose, cellulose derivatives, and combinations thereof.

[0044] In certain embodiments, the mini-tablets further comprise about 5% to about 10% by weight of a disintegrant, hi certain embodiments, the disintegrant is selected from the group consisting of starch, starch derivatives, clay, cross-linked cellulose, cross-linked cellulose derivatives, cross-linked polyvinylpyrrolidone, and combinations thereof.

[0045] In another aspect, mini-tablets for oral administration are provided, comprising about 1% to about 20% by weight of infigratinib monophosphate, about 30% to about 60% by weight of mannitol, and about 30% to about 45% by weight of microcrystalline cellulose.

[0046] In certain embodiments, the mini-tablets comprise about 10% to about 20% by weight of infigratinib monophosphate, hi certain embodiments, the mini-tablets comprise about 1% to about 5% by weight of infigratinib monophosphate.

[0047] In certain embodiments, the mini-tablets comprise about 30% to about 45% by weight of mannitol, in certain embodiments, about 45% to about 60% by weight of mannitol, in certain embodiments, about 35% to about 40% by weight of microcrystalline cellulose.

[0048] In another aspect, mini-tablets for oral administration are provided, comprising about 10% to about 20% by weight of infigratinib monophosphate, about 30% to about 45% by weight of mannitol, and about 30% to about 40% by weight of microcrystalline cellulose.

[0049] In another aspect, mini-tablets for oral administration are provided, comprising about 1% to about 5% by weight of infigratinib monophosphate, about 45% to about 60% by weight of mannitol, and about 30% to about 40% by weight of microcrystalline cellulose.

[0050] In certain embodiments, the mini-tablets further comprise about 5% to about 10% by weight of polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 5% to about 10% by weight of cross-linked polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 2% to about 6% by weight of croscarmellose sodium.

[0051] In another aspect, mini-tablets for oral administration are provided, the mini-tablets comprising about 1.2 mg of infigratinib monophosphate, about 3 mg to about 4 mg of mannitol, and about 2 mg to about 4.4 mg of microcrystalline cellulose.

[0052] In certain embodiments, the mini-tablets further comprise about 0.6 mg to about 0.8 mg of polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 0.5 mg to about 0.7 mg of cross-linked polyvinylpyrrolidone.

[0053] In another aspect, mini-tablets for oral administration are provided, the mini-tablets comprising about 0.12 mg of infigratinib monophosphate, about 3 mg to about 4 mg of mannitol, and about 2 mg to about 3 mg of microcrystalline cellulose.

[0054] In certain embodiments, the mini-tablets further comprise about 0.4 mg to about 0.6 mg of polyvinylpyrrolidone, about 0.3 mg to about 0.5 mg of cross-linked polyvinylpyrrolidone, or about 0.2 mg to about 0.4 mg of croscarmellose sodium. [Brief explanation of the drawings]

[0055] [Figure 1] FIG. 1 shows an overview of the clinical trials described in Examples 4 and 5.

[0056] [Figure 2] FIG. 2 shows the demographics of patients receiving infigratinib at 0.25 milligrams per kilogram (mg / kg) per day in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0057] [Figure 3] FIG. 3 summarizes preliminary results for patients receiving infigratinib at 0.25 mg / kg per day in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0058] [Figure 4] FIG. 4 shows that infigratinib demonstrated a significant dose-dependent increase in annual height velocity (AHV) compared to baseline in patients receiving 0.25 mg / kg of infigratinib per day in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0059] [Figure 5] FIG. 5 shows the mean increase in annual height velocity (AHV) in patients receiving up to 0.25 mg / kg daily of infigratinib.

[0060] [Figure 6]FIG. 6 shows individual level data for patients receiving 0.25 mg / kg infigratinib daily in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0061] [Figure 7] FIG. 7 shows that in Cohort 5 of the clinical trial described in Examples 4 and 5, patients receiving infigratinib at 0.25 mg / kg per day had a median AHV of over 7 cm / year.

[0062] [Figure 8] FIG. 8 shows the consistency of AHV observed over time in the clinical trials described in Examples 4 and 5.

[0063] [Figure 9] FIG. 9 shows the percent increase in collagen X marker levels observed in patients participating in the clinical trials described in Examples 4 and 5.

[0064] [Figure 10] FIG. 10 shows an updated summary of the clinical trials described in FIG. 1 and Examples 4 and 5.

[0065] [Figure 11] FIG. 11 shows a table summarizing the most frequently reported adverse events (AEs) observed during the course of the studies described in Examples 4 and 5.

[0066] [Figure 12] Figure 12 is an updated version of Figure 4 and shows that infigratinib demonstrated a significant dose-dependent increase in annual height velocity compared to baseline in patients receiving 0.25 mg / kg infigratinib daily in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0067] [Figure 13]Figure 13 is an updated version of Figure 5 and shows the mean increase in annual height velocity (AHV) in patients receiving infigratinib up to 0.25 mg / kg daily.

[0068] [Figure 14] FIG. 14 shows the change in height Z-score and body proportions for ACH patients in cohorts 1-5 of the study described in Example 4 and Example 5 after 6 months of treatment with infigratinib compared to baseline.

[0069] [Figure 15] FIG. 15 is an updated version of FIG. 9 and shows the increase in collagen X marker levels (%) observed in patients participating in the clinical trials described in Examples 4 and 5. DETAILED DESCRIPTION OF THE INVENTION

[0070] As outlined herein, the present disclosure provides methods for treating skeletal dysplasia (such as hypochondroplasia or achondroplasia) in a subject (e.g., a pediatric patient) in need thereof. These methods generally involve administering to the subject an effective amount of infigratinib or a pharmaceutically acceptable salt thereof (e.g., 0.01 milligrams per kilogram (mg / kg) to about 0.51 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof). The present disclosure also provides mini-tablets for administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof to a subject. The mini-tablets described herein generally comprise infigratinib monophosphate and one or more pharmaceutically acceptable excipients (e.g., a filler, binder, disintegrant, and / or lubricant).

[0071] definition To facilitate understanding of the present invention, several terms and expressions are defined below.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.The abbreviations used herein have their conventional meanings in the chemical and biological fields.The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence well known in the chemical field.

[0073] Throughout this specification, where compositions and kits are described as having, comprising, or including particular components, or where processes and methods are described as having, comprising, or including particular steps, it is further assumed that there are compositions and kits of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0074] In this application, when an element or component is included and / or selected from a list of described elements or components, it should be understood that the element or component may be any one of the described elements or components, or may be selected from a group consisting of two or more of the described elements or components.

[0075] Furthermore, it should be understood that elements and / or features of the compositions or methods described herein, whether expressly or implicitly, can be combined in various ways without departing from the spirit and scope of the invention. For example, when a particular compound is referenced, unless otherwise understood from the context, that compound can be used in various embodiments of the compositions and / or methods of the invention. In other words, although embodiments are described and illustrated in this application in a manner that allows for clear and concise application writing and illustration, it is intended and should be understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention. For example, it will be understood that all features described and illustrated herein are applicable to all aspects of the invention described and illustrated herein.

[0076] As used herein, the articles "a" and "an" are used, unless the context indicates otherwise, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0077] As used herein, the term "and / or" means either "and" or "or" unless stated otherwise.

[0078] The phrase "at least one," unless otherwise understood from context and usage, should be understood to include each listed subject matter individually as well as various combinations of two or more listed objects. The phrase "and / or" in connection with more than two listed objects should be understood to have the same meaning unless otherwise understood from context.

[0079] The use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," and their grammatical equivalents, unless the context specifically dictates otherwise, should be understood to be generally open-ended and not limiting, e.g., meaning not to exclude additional, unrecited elements or steps.

[0080] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0081] In various places herein, variables or parameters are disclosed as groups or ranges. This description is specifically intended to include all individual subcombinations of the members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0082] Any examples or use of exemplary language such as "for example," "including," etc. herein are intended merely to better describe the invention and do not constitute limitations on the scope of the invention unless recited in the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0083] In general, compositions specifying percentages are by weight unless otherwise specified. Additionally, if a variable is not accompanied by a definition, the preceding definition of that variable controls.

[0084] As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent and an inert or active excipient, making the composition or formulation particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0085] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the U.S. federal or state government, or a corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, and approved for use in animals, and particularly humans.

[0086] As used herein, "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds of the present invention (e.g., infigratinib), which are compatible with pharmaceutical administration.

[0087] As is well known to those skilled in the art, "salts" of compounds can be derived from inorganic or organic acids and inorganic or organic bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, can be used to prepare salts useful as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0088] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases of formula NW4 + (Where W is C 1-4Examples of compounds include, but are not limited to, compounds in which the aryl group is an alkyl group.

[0089] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include those in which the anion of a compound of the invention is Na + , K. + , Ca 2+ , NH4 + and NW4 + (Where W is C 1-4 and the like, in combination with a suitable cation such as a methyl group, which may be an alkyl group.

[0090] For therapeutic applications, salts of the compounds of the invention (e.g., infigratinib) will be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0091] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solutions such as phosphate-buffered saline, emulsions (e.g., oil / water or water / oil emulsions), Ringer's lactate, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, coloring agents, and the like. Such preparations can be sterilized and, if necessary, mixed with auxiliary substances that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring agents, and / or aromatic substances. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publ. Co., Easton, PA (1975).

[0092] The term "AUC" refers to the area under the time / plasma concentration curve following administration of a pharmaceutical composition. AUC 0-∞ is the area under the plasma concentration versus time curve from time 0 to infinity, and AUC 0-t denotes the area under the plasma concentration versus time curve from time 0 to time t. Note that AUC values ​​can be determined by those skilled in the art using well-known methods.

[0093] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "subject" and "patient" are used interchangeably herein. In certain embodiments, the subject is a pediatric patient.

[0094] "C max " refers to the maximum concentration of a therapeutic agent (e.g., infigratinib) in the blood (e.g., plasma) after administration of a pharmaceutical composition.

[0095] "t max " refers to the C after administration of a pharmaceutical composition containing a therapeutic agent (e.g., infigratinib). max This refers to the time in hours it takes for this to be reached.

[0096] As used herein, "solid dosage form" means a pharmaceutical dose(s) in solid form, including, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.

[0097] As used herein, "administration" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, subcutaneous administration, or implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. Routes of administration include any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracerebral administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Concomitant administration" refers to administration of a composition described herein simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, agents for treating neurodegenerative diseases). Infigratinib or a pharmaceutically acceptable salt thereof can be administered alone or in combination (e.g., with other therapeutic agents) to a patient. Co-administration includes simultaneous or sequential administration of the compound alone or in combination with one or more additional agents (e.g., one or more additional therapeutic agents). Thus, if necessary, the compound can be combined with other active substances (e.g., to reduce metabolic degradation).

[0098] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0099] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" refer to actions taken while a subject is afflicted with a particular disease, disorder, or condition, which have the effect of reducing the severity of the disease, disorder, or condition or slowing or inhibiting its progression (e.g., "therapeutic treatment"). Treatment refers to any indication of success in ameliorating a disease, disorder, or condition, including the following objective or subjective parameters: symptom relief, remission, reduction in symptoms or making the disease, disorder, or condition more tolerable for the patient, slowing the rate of degeneration or decline, reducing physical disability in the final degenerative stage, and / or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Treatment may also be prophylactic in nature, i.e., including preventing the disease, disorder, or condition, preventing the onset of one or more symptoms of the disease, disorder, or condition, and / or preventing the disease, disorder, or condition from worsening. Preventing a disease, disorder, or condition can include complete protection from the disease and / or preventing the progression of the disease (e.g., progression of the disease, disorder, or condition to a later stage). For example, preventing a disease may not mean completely eliminating all effects associated with the disease at any level, but instead preventing the state of the disease, disorder, or condition from reaching a clinically significant or detectable level.

[0100] In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response (e.g., treatment of a skeletal dysplasia, such as hypochondroplasia or achondroplasia). As one skilled in the art will appreciate, the effective amount of a compound herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease of the treated subject, and the age, weight, health and condition of the subject.

[0101] Infigratinib Infigratinib, represented by formula (I), is a selective, ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, also known as 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethyl-1-piperazin-1-yl)phenylamino]-pyrimidinyl-4-yl}-1-methylurea. Infigratinib selectively inhibits the kinase activity of FGFR1, FGFR2, and FGFR3. TIFF2026507903000002.tif32125

[0102] Methods for the chemical synthesis of infigratinib (including Example 1 described herein), multiple crystalline and amorphous forms of infigratinib (including the anhydrous crystalline monophosphate salt described herein), and methods for making said forms (including Example 2 described herein) are described in U.S. Pat. No. 9,067,896, which is incorporated herein by reference in its entirety.

[0103] In one aspect, provided herein is infigratinib or a pharmaceutically acceptable salt thereof for the treatment of a skeletal dysplasia (such as hypochondroplasia or achondroplasia) in a subject in need thereof.

[0104] In certain embodiments, the present disclosure provides a pharmaceutically acceptable salt of infigratinib for the treatment of skeletal dysplasia (such as hypochondroplasia or achondroplasia) in a subject in need thereof. In one embodiment, the pharmaceutically acceptable salt of infigratinib is a monophosphate. The monophosphate of infigratinib is also referred to as BGJ398, infigratinib phosphate, and infigratinib monophosphate.

[0105] In one embodiment, infigratinib monophosphate exists as anhydrous crystalline monophosphate. In one embodiment, the anhydrous crystalline monophosphate exhibits an X-ray powder diffraction (XRPD) pattern with a characteristic peak at about 15.0° or 15.0°±0.2° 2θ. In one embodiment, the XRPD pattern of the anhydrous crystalline monophosphate further comprises one or more characteristic peaks selected from peaks at about 13.7°±0.2°, about 16.8°±0.2°, about 21.3°±0.2°, and about 22.4°±0.2° 2θ. In one embodiment, the XRPD pattern of the anhydrous crystalline monophosphate further comprises one or more characteristic peaks selected from peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2° 2θ. In one embodiment, the anhydrous crystalline monophosphate has an XRPD pattern comprising at least three characteristic peaks selected from peaks at about 13.7°, about 15°, about 16.8°, about 21.3°, and about 22.4° in 2θ. In one embodiment, the XRPD pattern of the anhydrous crystalline monophosphate comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 characteristic peaks selected from peaks at about 9.2°, about 9.6°, about 13.7°, about 15°, about 16.8°, about 18.7°, about 20.0°, about 21.3°, about 22.4°, about 22.9°, and about 27.2° in 2θ.

[0106] Pharmaceutical Composition In one aspect, the present invention provides a pharmaceutical composition comprising infigratinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the treatment of a skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject in need thereof.

[0107] In various embodiments, the present invention provides pharmaceutical compositions comprising infigratinib and a pharmaceutically acceptable excipient for the treatment of skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject in need thereof.

[0108] In various embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of infigratinib and a pharmaceutically acceptable excipient, for use in a patient in need of treatment for a skeletal dysplasia, such as hypochondroplasia or achondroplasia. In certain embodiments, the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate.

[0109] In various embodiments, the present invention provides a pharmaceutical composition comprising infigratinib monophosphate and a pharmaceutically acceptable excipient in a subject in need of treatment for a skeletal dysplasia (e.g., hypochondroplasia or achondroplasia).

[0110] In certain embodiments, the pharmaceutical composition is a mini-tablet. In certain embodiments, the mini-tablet is for oral administration.

[0111] In various embodiments, the present invention provides mini-tablets for oral administration of infigratinib to a subject, comprising infigratinib monophosphate and a pharmaceutically acceptable excipient. In certain embodiments, the mini-tablets orally administer about 0.1 milligrams (mg) of infigratinib to a subject. In certain embodiments, the mini-tablets orally administer about 1 mg of infigratinib to a subject.

[0112] In various embodiments, the present invention provides mini-tablets for oral administration of about 0.1 mg of infigratinib to a subject, comprising infigratinib monophosphate and a pharmaceutically acceptable excipient.

[0113] In various embodiments, the present invention provides mini-tablets for oral administration of about 1 mg of infigratinib to a subject, comprising infigratinib monophosphate and a pharmaceutically acceptable excipient.

[0114] In certain embodiments, the mini-tablets contain an amount of infigratinib monophosphate sufficient to administer about 0.1 mg of infigratinib to a subject. In certain embodiments, the amount of infigratinib monophosphate required to administer 0.1 mg of infigratinib to a subject is about 0.12 mg of infigratinib monophosphate. In certain embodiments, the mini-tablets contain an amount of infigratinib monophosphate sufficient to administer about 1 mg of infigratinib to a subject. In certain embodiments, the amount of infigratinib monophosphate required to administer 1 mg of infigratinib to a subject is about 1.2 mg of infigratinib monophosphate.

[0115] In certain embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of mannitol, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, croscarmellose sodium, and combinations thereof.

[0116] In various embodiments, provided herein are mini-tablets for oral administration comprising about 1% w / w to about 20% w / w of infigratinib monophosphate and about 30% w / w to about 95% w / w of a filler.

[0117] In certain embodiments, the mini-tablets comprise from about 1% w / w to about 20% w / w, from about 2% w / w to about 20% w / w, from about 3% w / w to about 20% w / w, from about 4% w / w to about 20% w / w, from about 5% w / w to about 20% w / w, from about 6% w / w to about 20% w / w, from about 7% w / w to about 20% w / w, from about 8% w / w to about 20% w / w, from about 9% w / w to about 20% w / w, from about 10% w / w to about 20% w / w, from about 11% w / w to about 20% w / w, from about 12% w / w to about 20% w / w, from about 13% w / w to about 20% w / w, from about 14% w / w to about 20% w / w, 15% w / w to about 20% w / w, about 16% w / w to about 20% w / w, about 17% w / w to about 20% w / w, about 18% w / w to about 20% w / w, about 19% w / w to about 20% w / w, about 1% w / w to about 19% w / w, about 1% w / w to about 18% w / w, about 1% w / w to about 17% w / w, about 1% w / w to about 16% w / w, about 1% w / w to about 15% w / w, about 1% w / w to about 14% w / w, about 1% w / w to about 13% w / w, about 1% w / w to about 12% w / w, about 1% w / w to about 11% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 9% w / w, about 1% w / w to about 8% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 6% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 19% w / w, about 2% w / w to about 18% w / w, about 2% w / w to about 17% w / w, about 2% w / w to about 16% w / w, about 2% w / w to about 15% w / w, about 2% w / w to about 14% w / w, about 2% w / w to about 13% w / w, about 2% w / w to about 12 ... % w / w to about 11% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 9% w / w, about 2% w / w to about 8% w / w, about 2% w / w to about 7% w / w, about 2% w / w to about 6% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 19% w / w, about 3% w / w to about 18% w / w, about 3% w / w to about 17% w / w, about 3% w / w to about 16% w / w, about 3% w / w to about 15% w / w, about 3% w / w to about 14% w / w, about 3% w / w to about 13% w / w,About 3% w / w to about 12% w / w, about 3% w / w to about 11% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 9% w / w, about 3% w / w to about 8% w / w, about 3% w / w to about 7% w / w, about 3% w / w to about 6% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 19% w / w, about 4% w / w to about 18% w / w, about 4% w / w to about 17% w / w, about 4% w / w to about 16% w / w, about 4% w / w to about 15% w / w, about 4% w / w to about 14% w / w, about 4% w / w to about 13% w / w / w, about 4% w / w to about 12% w / w, about 4% w / w to about 11% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 9% w / w, about 4% w / w to about 8% w / w, about 4% w / w to about 7% w / w, about 4% w / w to about 6% w / w, about 4% w / w to about 5% w / w, about 5% w / w to about 19% w / w, about 5% w / w to about 18% w / w, about 5% w / w to about 17% w / w, about 5% w / w to about 16% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 14% w / w, about 5% w / w to about 13% w / w, about 5% w / w to about 12% w / w, about 5% w / w to about 11% w / w, about 5% w / w to about 10% w / w, about 5% w / w to about 9% w / w, about 5% w / w to about 8% w / w, about 5% w / w to about 7% w / w, about 5% w / w to about 6% w / w, about 6% w / w to about 19% w / w, about 6% w / w to about 18% w / w, about 6% w / w to about 17% w / w, about 6% w / w to about 16% w / w, about 6% w / w to about 15% w / w, about 6% w / w to about 14% w / w, about 6% w / w to about 13% w / w, about 6% w / w to about 12% w / w, about 6% w / w to about 11% w / w, about 6% w / w / w to about 10% w / w, about 6% w / w to about 9% w / w, about 6% w / w to about 8% w / w, about 6% w / w to about 7% w / w, about 7% w / w to about 19% w / w, about 7% w / w to about 18% w / w, about 7% w / w to about 17% w / w, about 7% w / w to about 16% w / w, about 7% w / w to about 15% w / w, about 7% w / w to about 14% w / w, about 7% w / w to about 13% w / w, about 7% w / w to about 12% w / w, about 7% w / w to about 11% w / w, about 7% w / w to about 10% w / w, about 7% w / w to about 9% w / w, about 7% w / w to about 8% w / w,about 8% w / w to about 19% w / w, about 8% w / w to about 18% w / w, about 8% w / w to about 17% w / w, about 8% w / w to about 16% w / w, about 8% w / w to about 15% w / w, about 8% w / w to about 14% w / w, about 8% w / w to about 13% w / w, about 8% w / w to about 12% w / w, about 8% w / w to about 11% w / w, about 8% w / w to about 10% w / w, about 8% w / w to about 9% w / w, about 9% w / w to about 19% w / w, about 9% w / w to about 18% w / w, about 9% w / w to about 17% w / w, about 9% w / w to about 16% w / w, about 9% w / w to about 15% w / w % w / w, about 9% w / w to about 14% w / w, about 9% w / w to about 13% w / w, about 9% w / w to about 12% w / w, about 9% w / w to about 11% w / w, about 9% w / w to about 10% w / w, about 10% w / w to about 19% w / w, about 10% w / w to about 18% w / w, about 10% w / w to about 17% w / w, about 10% w / w to about 16% w / w, about 10% w / w to about 15% w / w, about 10% w / w to about 14% w / w, about 10% w / w to about 13% w / w, about 10% w / w to about 12% w / w, about 10% w / w to about 11% w / w, about 11% w / w to about 19 % w / w, about 11% w / w to about 18% w / w, about 11% w / w to about 17% w / w, about 11% w / w to about 16% w / w, about 11% w / w to about 15% w / w, about 11% w / w to about 14% w / w, about 11% w / w to about 13% w / w, about 11% w / w to about 12% w / w, about 12% w / w to about 19% w / w, about 12% w / w to about 18% w / w, about 12% w / w to about 17% w / w, about 12% w / w to about 16% w / w, about 12% w / w to about 15% w / w, about 12% w / w to about 14% w / w, about 12% w / w to about 13% w / w, about 13% w / w from about 19% w / w, from about 13% w / w to about 18% w / w, from about 13% w / w to about 17% w / w, from about 13% w / w to about 16% w / w, from about 13% w / w to about 15% w / w, from about 13% w / w to about 14% w / w, from about 14% w / w to about 19% w / w, from about 14% w / w to about 18% w / w, from about 14% w / w to about 17% w / w, from about 14% w / w to about 16% w / w, from about 14% w / w to about 15% w / w, from about 15% w / w to about 19% w / w, from about 15% w / w to about 18% w / w, from about 15% w / w to about 17% w / w, from about 15% w / w to about 16% w / w,The mini-tablets contain about 16% to about 19% w / w, about 16% to about 18% w / w, about 16% to about 17% w / w, about 17% to about 19% w / w, about 17% to about 18% w / w, or about 18% to about 19% w / w of infigratinib monophosphate. In certain embodiments, the mini-tablets contain about 1% to about 5% w / w of infigratinib monophosphate. In certain embodiments, the mini-tablets contain about 10% to about 20% w / w of infigratinib monophosphate.

[0118] In certain embodiments, the mini-tablets comprise about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w or about 20% w / w of infigratinib monophosphate.

[0119] In certain embodiments, the mini-tablets are from about 30% w / w to about 95% w / w, from about 35% w / w to about 95% w / w, from about 40% w / w to about 95% w / w, from about 45% w / w to about 95% w / w, from about 50% w / w to about 95% w / w, from about 55% w / w to about 95% w / w, from about 60% w / w to about 95% w / w, from about 65% w / w to about 95% w / w, from about 70% w / w to about 95% w / w, from about 75% w / w to about 95% w / w, from about 80% w / w to about 95% w / w, from about 85% w / w to about 95% w / w, from about 90% w / w to about 95% w / w, ... about 90% w / w, about 30% w / w to about 85% w / w, about 30% w / w to about 80% w / w, about 30% w / w to about 75% w / w, about 30% w / w to about 70% w / w, about 30% w / w to about 65% w / w, about 30% w / w to about 60% w / w, about 30% w / w to about 55% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 45% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 35% w / w to about 90% w / w, about 35% w / w to about 85% w / w, about 35% w / w to about 80% w / w, About 35% w / w to about 75% w / w, about 35% w / w to about 70% w / w, about 35% w / w to about 65% w / w, about 35% w / w to about 60% w / w, about 35% w / w to about 55% w / w, about 35% w / w to about 50% w / w, about 35% w / w to about 45% w / w, about 35% w / w to about 40% w / w, about 40% w / w to about 90% w / w, about 40% w / w to about 85% w / w, about 40% w / w to about 80% w / w, about 40% w / w to about 75% w / w, about 40% w / w to about 70% w / w, about 40% w / w to about 65% w / w, about 40 ...45% w / w to about 40% w / w, about 40% w / w to about 90% w / w, about 40% w / from about 60% w / w, from about 40% w / w to about 55% w / w, from about 40% w / w to about 50% w / w, from about 40% w / w to about 45% w / w, from about 45% w / w to about 90% w / w, from about 45% w / w to about 85% w / w, from about 45% w / w to about 80% w / w, from about 45% w / w to about 75% w / w, from about 45% w / w to about 70% w / w, from about 45% w / w to about 65% w / w, from about 45% w / w to about 60% w / w, from about 45% w / w to about 55% w / w, from about 45% w / w to about 50% w / w, from about 50% w / w to about 90% w / w, from about 50% w / w to about 85% w / w,About 50% w / w to about 80% w / w, about 50% w / w to about 75% w / w, about 50% w / w to about 70% w / w, about 50% w / w to about 65% w / w, about 50% w / w to about 60% w / w, about 50% w / w to about 55% w / w, about 55% w / w to about 90% w / w, about 55% w / w to about 85% w / w, about 55% w / w to about 80% w / w, about 55% w / w to about 75% w / w, about 55% w / w to about 70% w / w, about 55% w / w to about 65% w / w, about 55% w / w to about 60% w / w, about 60% w / w to about 90% w / w, about 60% w / w to about 85% w / w, about 60% w / w to about 80% w / w, about 60% w / w to about 75% w / w, about 60% w / w to about 70% w / w, about 60% w / w to about 65% w / w, about 65% w / w to about 90% w / w, about 65% w / w to about 85% w / w, about 65% w / w to about 80% w / w, about 65% w / w to about 75% w / w, about 65% w / w to about 70% w / w, about 70% w / w to about 90% w / w, about 70% w / w to about 85% w / w about 70% w / w to about 80% w / w, about 70% w / w to about 75% w / w, about 75% w / w to about 90% w / w, about 75% w / w to about 85% w / w, about 75% w / w to about 80% w / w, about 80% w / w to about 90% w / w, about 80% w / w to about 85% w / w, or about 80% w / w to about 90% w / w of filler.

[0120] In certain embodiments, the mini-tablets comprise about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w or about 95% w / w of filler.

[0121] In certain embodiments, the filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, and combinations thereof.

[0122] In certain embodiments, the filler comprises microcrystalline cellulose and mannitol.

[0123] In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w, about 6% w / w to about 10% w / w, about 7% w / w to about 10% w / w, about 8% w / w to about 10% w / w, about 9% w / w to about 10% w / w, about 5% w / w to about 9% w / w, about 5% w / w to about 8% w / w, about 5% w / w to about 7% w / w, about 5% w / w to about 6% w / w, about 6% w / w to about 9% w / w, about 6% w / w to about 8% w / w, about 6% w / w to about 7% w / w, about 7% w / w to about 9% w / w, about 7% w / w to about 8% w / w, or about 8% w / w to about 9% w / w of a binder.

[0124] In certain embodiments, the mini-tablets further comprise about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w or about 10% w / w of a binder.

[0125] In certain embodiments, the binder is selected from the group consisting of sugars (e.g., glucose, sucrose), gelatin, natural gums (e.g., acacia, tragacanth), sorbitol, maltodextrin, alginates (e.g., sodium alginate, alginate derivatives, polyvinylpyrrolidone), cellulose (e.g., microcrystalline cellulose), cellulose derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), and combinations thereof.

[0126] In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w, about 6% w / w to about 10% w / w, about 7% w / w to about 10% w / w, about 8% w / w to about 10% w / w, about 9% w / w to about 10% w / w, about 5% w / w to about 9% w / w, about 5% w / w to about 8% w / w, about 5% w / w to about 7% w / w, about 5% w / w to about 6% w / w, about 6% w / w to about 9% w / w, about 6% w / w to about 8% w / w, about 6% w / w to about 7% w / w, about 7% w / w to about 9% w / w, about 7% w / w to about 8% w / w, or about 8% w / w to about 9% w / w of a disintegrant. In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w of a disintegrant.

[0127] In certain embodiments, the mini-tablets further comprise about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w or about 10% w / w of a disintegrant.

[0128] In certain embodiments, the disintegrant is selected from the group consisting of starch (e.g., potato starch, corn starch, and maize starch), starch derivatives (e.g., low-substituted carboxymethyl starch, pregelatinized starch), clays (e.g., Veegum HV and bentonite), cross-linked cellulose, cross-linked cellulose derivatives (e.g., cross-linked forms of sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone, and combinations thereof.

[0129] In various embodiments, provided herein are mini-tablets for oral administration comprising the following ingredients: about 1% w / w to about 20% w / w of infigratinib monophosphate; about 30% w / w to about 60% w / w mannitol, and about 30% w / w to about 45% w / w microcrystalline cellulose.

[0130] In certain embodiments, the mini-tablets are from about 30% w / w to 60% w / w, from about 35% w / w to about 60% w / w, from about 40% w / w to about 60% w / w, from about 45% w / w to about 60% w / w, from about 50% w / w to about 60% w / w, from about 55% w / w to about 60% w / w, from about 30% w / w to about 55% w / w, from about 30% w / w to about 50% w / w, from about 30% w / w to about 45% w / w, from about 30% w / w to about 40% w / w, from about 30% w / w to about 55% w / w, In certain embodiments, the mini-tablets comprise from about 30% w / w to about 45% w / w mannitol. In certain embodiments, the mini-tablets comprise from about 45% w / w to about 60% w / w mannitol.

[0131] In certain embodiments, the mini-tablets comprise about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w or about 60% w / w of mannitol.

[0132] In certain embodiments, the mini-tablets comprise about 30% to about 45% w / w, about 35% to about 45% w / w, about 40% to about 45% w / w, about 30% to about 40% w / w, about 30% to about 35% w / w, or about 35% to about 40% w / w of microcrystalline cellulose. In certain embodiments, the mini-tablets comprise about 35% to about 40% w / w of microcrystalline cellulose.

[0133] In various embodiments, provided herein are mini-tablets for oral administration comprising the following ingredients: about 10% w / w to about 20% w / w of infigratinib monophosphate; about 30% w / w to about 45% w / w mannitol, and About 30% w / w to about 40% w / w microcrystalline cellulose.

[0134] In various embodiments, provided herein are mini-tablets for oral administration comprising the following ingredients: about 1% w / w to about 5% w / w of infigratinib monophosphate; about 45% w / w to about 60% w / w mannitol, and About 30% w / w to about 40% w / w microcrystalline cellulose.

[0135] In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w, about 6% w / w to about 10% w / w, about 8% w / w to about 10% w / w, about 9% w / w to about 10% w / w, about 5% w / w to about 9% w / w, about 5% w / w to about 8% w / w, about 5% w / w to about 7% w / w, about 5% w / w to about 6% w / w, about 6% w / w to about 9% w / w, about 6% w / w to about 8% w / w, about 6% w / w to about 7% w / w, about 7% w / w to about 9% w / w, about 7% w / w to about 8% w / w, or about 8% w / w to about 9% w / w of polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w polyvinylpyrrolidone.

[0136] In certain embodiments, the mini-tablets further comprise about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w or about 10% w / w of polyvinylpyrrolidone.

[0137] In certain embodiments, the mini-tablets further comprise from about 5% w / w to about 10% w / w, from about 6% w / w to about 10% w / w, from about 7% w / w to about 10% w / w, from about 8% w / w to about 10% w / w, from about 9% w / w to about 10% w / w, from about 5% w / w to about 9% w / w, from about 5% w / w to about 8% w / w, from about 5% w / w to about 7% w / w, from about 5% w / w to about 6% w / w, from about 6% w / w to about 9% w / w, from about 6% w / w to about 8% w / w, from about 6% w / w to about 7% w / w, from about 7% w / w to about 9% w / w, from about 7% w / w to about 8% w / w, from about 8% w / w to about 9% w / w of cross-linked polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 5% w / w to about 10% w / w of cross-linked polyvinylpyrrolidone.

[0138] In certain embodiments, the mini-tablets further comprise about 2% to about 6% w / w, about 3% to about 6% w / w, about 4% to about 6% w / w, about 5% to about 6% w / w, about 2% to about 5% w / w, about 2% to about 4% w / w, about 2% to about 3% w / w, about 3% to about 5% w / w, about 3% to about 4% w / w, or about 4% to about 5% w / w of croscarmellose sodium. In certain embodiments, the mini-tablets further comprise about 2% to about 6% w / w of croscarmellose sodium.

[0139] In certain embodiments, the mini-tablets further comprise a lubricant at about 0.25% to about 1% w / w, about 0.5% to about 1% w / w, about 0.75% to about 1% w / w, about 0.25% to about 0.75% w / w, about 0.25% to about 0.5% w / w, or about 0.5% to about 0.75% w / w of a lubricant. In certain embodiments, the mini-tablets further comprise about 0.5% to about 0.75% w / w of a lubricant.

[0140] In certain embodiments, the mini-tablets further comprise about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / w, about 0.45% w / w, about 0.5% w / w, about 0.55% w / w, about 0.6% w / w, about 0.65% w / w, about 0.7% w / w, about 0.75% w / w, about 0.8% w / w, about 0.85% w / w, about 0.9% w / w, about 0.95% w / w, or about 1% w / w of a lubricant. In certain embodiments, the mini-tablets further comprise about 0.5% w / w of a lubricant. In certain embodiments, the mini-tablets further comprise about 0.75% w / w of a lubricant. In certain embodiments, the mini-tablets further comprise about 1% w / w of a lubricant.

[0141] In certain embodiments, the lubricant is magnesium stearate.

[0142] In certain embodiments, the mini-tablets further comprise a colorant.

[0143] In various embodiments, provided herein are mini-tablets for oral administration comprising the following ingredients: approximately 1.2 mg of infigratinib monophosphate, about 3 mg to about 4 mg of mannitol and Approximately 2 mg to approximately 4.4 mg of microcrystalline cellulose.

[0144] In various embodiments, provided herein are mini-tablets for oral administration comprising the following ingredients: approximately 0.12 mg of infigratinib monophosphate, about 3 mg to about 4 mg of mannitol and About 2 mg to about 3 mg of microcrystalline cellulose.

[0145] In certain embodiments, the mini-tablets contain about 3 mg to about 4 mg, about 3.2 mg to about 4 mg, about 3.4 mg to about 4 mg, about 3.6 mg to about 4 mg, about 3.8 mg to about 4 mg, about 3 mg to about 3.8 mg, about 3 mg to about 3.6 mg, about 3 mg to about 3.4 mg, about 3 mg to about 3.2 mg, about 3.2 mg to about 3.8 mg, about 3.2 mg to about 3.6 mg, about 3.2 mg to about 3.4 mg, about 3.4 mg to about 3.8 mg, about 3.4 mg to about 3.6 mg, or about 3.6 mg to about 3.8 mg of mannitol.

[0146] In certain embodiments, the mini-tablets contain about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg or about 4 mg of mannitol.

[0147] In certain embodiments, the mini-tablets are from about 2 mg to about 4.4 mg, from about 2.2 mg to about 4.4 mg, from about 2.4 mg to about 4.4 mg, from about 2.6 mg to about 4.4 mg, from about 2.8 mg to about 4.4 mg, from about 3 mg to about 4.4 mg, from about 3.2 mg to about 4.4 mg, from about 3.4 mg to about 4.4 mg, from about 3.6 mg to about 4.4 mg, from about 3.8 mg to about 4.4 mg, from about 4 mg to about 4.4 mg, from about 4.2 mg to about 4.4 mg, from about 2 mg to about 4.2 mg, from about 2 mg to about 4 mg, from about 2 mg to about 3.8 mg, from about 2 mg to about 3.6 mg, from about 2 mg to about 3.8 mg. 4mg, about 2mg to about 3.2mg, about 2mg to about 3mg, about 2mg to about 2.8mg, about 2mg to about 2.6mg, about 2mg to about 2.4mg, about 2mg to about 2.2mg, about 2.2mg to about 4.2mg, about 2.2mg to about 4mg, about 2.2mg to about 3.8mg, about 2.2mg to about 3.6mg, about 2.2mg to about 3.4mg, about 2.2mg to about 3.2mg, about 2.2mg to about 3mg, about 2.2mg to about 2.8mg, about 2.2mg to about 2.6mg, about 2.2mg to about 2.4mg, about 2.4mg to about 4.2mg, about 2.4mg to about 4 mg, about 2.4 mg to about 3.8 mg, about 2.4 mg to about 3.6 mg, about 2.4 mg to about 3.4 mg, about 2.4 mg to about 3.2 mg, about 2.4 mg to about 3 mg, about 2.4 mg to about 2.8 mg, about 2.4 mg to about 2.6 mg, about 2.6 mg to about 4.2 mg, about 2.6 mg to about 4 mg, about 2.6 mg to about 3.8 mg, about 2.6 mg to about 3.6 mg, about 2.6 mg to about 3.4 mg, about 2.6 mg to about 3.2 mg, about 2.6 mg to about 3 mg, about 2.6 mg to about 2.8 mg, about 2.8 mg to about 4.2 mg, about 2.8 mg to about 4 mg, About 2.8mg to about 3.8mg, about 2.8mg to about 3.6mg, about 2.8mg to about 3.4mg, about 2.8mg to about 3.2mg, about 2.8mg to about 3.0mg, about 3mg to about 4.2mg, about 3mg to about 4mg, about 3mg to about 3.8mg, about 3mg to about 3.6mg, about 3mg to about 3.4mg, about 3mg to about 3.2mg, about 3.2mg to about 4.2mg, about 3.2mg to about 4mg, about 3.2mg to about 3.8mg, about 3.2mg to about 3.6mg, about 3.2mg to about 3.4mg, about 3.4mg to about 4.2mg, about 3.4mg to about 3.8 mg, about 3.4 mg to about 3.6 mg, about 3.6 mg to about 4.2 mg, about 3.6 mg to about 4 mg, about 3.6 mg to about 3.8 mg, about 3.8 mg to about 4.2 mg, about 3.8 mg to about 4 mg, or about 4 mg to about 4.2 mg of microcrystalline cellulose.

[0148] In certain embodiments, the mini-tablets contain about 2 mg, about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg, about 4 mg, about 4.2 mg or about 4.4 mg of microcrystalline cellulose.

[0149] In certain embodiments, the mini-tablets further comprise about 0.4 mg to about 0.6 mg, about 0.45 mg to about 0.6 mg, about 0.5 mg to about 0.6 mg, about 0.55 mg to about 0.6 mg, about 0.4 mg to about 0.55 mg, about 0.4 mg to about 0.5 mg, about 0.4 mg to about 0.45 mg, about 0.45 mg to about 0.55 mg, about 0.45 mg to about 0.5 mg, or about 0.5 mg to about 0.55 mg of polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 0.4 mg to about 0.6 mg of polyvinylpyrrolidone.

[0150] In certain embodiments, the mini-tablets further comprise about 0.4 mg, about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, about 0.5 mg, about 0.52 mg, about 0.54 mg, about 0.56 mg, about 0.58 mg, or about 0.6 mg of polyvinylpyrrolidone.

[0151] In certain embodiments, the mini-tablets further comprise about 0.3 mg to about 0.5 mg, about 0.35 mg to about 0.5 mg, about 0.4 mg to about 0.5 mg, about 0.45 mg to about 0.5 mg, about 0.3 mg to about 0.45 mg, about 0.3 mg to about 0.4 mg, about 0.3 mg to about 0.35 mg, about 0.35 mg to about 0.45 mg, about 0.35 mg to about 0.4 mg, or about 0.4 mg to about 0.45 mg of cross-linked polyvinylpyrrolidone. In certain embodiments, the mini-tablets further comprise about 0.3 mg to about 0.5 mg of cross-linked polyvinylpyrrolidone.

[0152] In certain embodiments, the mini-tablets further comprise about 0.3 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, or about 0.5 mg of cross-linked polyvinylpyrrolidone.

[0153] In certain embodiments, the mini-tablets further comprise about 0.2 mg to about 0.4 mg, about 0.25 mg to about 0.4 mg, about 0.3 mg to about 0.4 mg, about 0.35 mg to about 0.4 mg, about 0.2 mg to about 0.35 mg, about 0.2 mg to about 0.3 mg, about 0.2 mg to about 0.25 mg, about 0.25 mg to about 0.35 mg, about 0.25 mg to about 0.3 mg, or about 0.3 mg to about 0.35 mg of croscarmellose sodium. In certain embodiments, the mini-tablets further comprise about 0.2 mg to about 0.4 mg of croscarmellose sodium.

[0154] In certain embodiments, the mini-tablets further comprise about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.3 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, or about 0.4 mg of croscarmellose sodium.

[0155] In certain embodiments, the mini-tablets comprise from about 0.03 mg to about 0.09 mg, from about 0.04 mg to about 0.09 mg, from about 0.05 mg to about 0.09 mg, from about 0.06 mg to about 0.09 mg, from about 0.07 mg to about 0.09 mg, from about 0.08 mg to about 0.09 mg, from about 0.03 mg to about 0.08 mg, from about 0.03 mg to about 0.07 mg, from about 0.03 mg to about 0.06 mg, from about 0.03 mg to about 0.05 mg, from about 0.03 mg to about 0.08 mg, Further comprising about 0.04 mg, about 0.04 mg to about 0.08 mg, about 0.04 mg to about 0.07 mg, about 0.04 mg to about 0.06 mg, about 0.04 mg to about 0.05 mg, about 0.05 mg to about 0.08 mg, about 0.05 mg to about 0.07 mg, about 0.05 mg to about 0.06 mg, about 0.06 mg to about 0.08 mg, about 0.06 mg to about 0.07 mg, or about 0.07 mg to about 0.08 mg of magnesium stearate.

[0156] In certain embodiments, the mini-tablets further comprise about 0.03 mg, about 0.035 mg, about 0.04 mg, about 0.045 mg, about 0.05 mg, about 0.055 mg, about 0.06 mg, about 0.065 mg, about 0.07 mg, about 0.075 mg, about 0.08 mg, about 0.085 mg, about 0.09 mg, about 0.095 mg, or about 0.1 mg of magnesium stearate. In certain embodiments, the mini-tablets further comprise about 0.035 mg of magnesium stearate. In certain embodiments, the mini-tablets further comprise about 0.055 mg of magnesium stearate. In certain embodiments, the mini-tablets further comprise about 0.07 mg of magnesium stearate. In certain embodiments, the mini-tablets further comprise about 0.085 mg of magnesium stearate.

[0157] In certain embodiments, infigratinib monophosphate exists as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak at 15.0°±0.2° 2θ.

[0158] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and an ordinarily skilled veterinary pharmacologist can design and / or perform such modifications using routine experimentation. General considerations regarding the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0159] Methods of Use and Treatment Skeletal dysplasias that affect bone development and other functions include, for example, achondroplasia and Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia and is characterized by defective endochondral ossification due to gain-of-function mutations in the fibroblast growth factor receptor (FGFR) 3 gene.

[0160] In one aspect, the present invention provides methods for treating skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject (e.g., a pediatric patient) in need thereof. These methods generally involve administering to the subject an effective amount of infigratinib or a pharmaceutically acceptable salt thereof.

[0161] In various embodiments, provided herein are methods for treating skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject (e.g., a pediatric patient) in need thereof, the methods comprising orally administering to the subject about 0.01 mg / kg to about 0.51 mg / kg (e.g., about 0.250 mg / kg) of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0162] In certain embodiments, the method provides a subject (e.g., a pediatric patient) with a dose of from about 0.01 mg / kg to about 0.51 mg / kg, from about 0.05 mg / kg to about 0.51 mg / kg, from about 0.1 mg / kg to about 0.51 mg / kg, from about 0.15 mg / kg to about 0.51 mg / kg, from about 0.2 mg / kg to about 0.51 mg / kg, from about 0.25 mg / kg to about 0.51 mg / kg, from about 0.3 mg / kg to about 0.51 mg / kg, from about 0.35 mg / kg to about 0.51 mg / kg, from about 0.4 mg / kg to about 0.51 mg / kg, or from about 0.45 mg / kg to about 0. 51 mg / kg, about 0.01 mg / kg to about 0.45 mg / kg, about 0.01 mg / kg to about 0.4 mg / kg, about 0.01 mg / kg to about 0.35 mg / kg, about 0.01 mg / kg to about 0.3 mg / kg, about 0.01 mg / kg to about 0.25 mg / kg, about 0.01 mg / kg to about 0.2 mg / kg, about 0.01 mg / kg to about 0.15 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.01 mg / kg to about 0.05 mg / kg, about 0.05 mg / kg to about 0.45 mg / kg, about 0.05 mg / kg to about 0 0.4mg / kg, about 0.05mg / kg to about 0.35mg / kg, about 0.05mg / kg to about 0.3mg / kg, about 0.05mg / kg to about 0.25mg / kg, about 0.05mg / kg to about 0.2mg / kg, about 0.05mg / kg to about 0.15mg / kg, about 0.05mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 0.45mg / kg, about 0.1mg / kg to about 0.4mg / kg, about 0.1mg / kg to about 0.35mg / kg, about 0.1mg / kg to about 0.3mg / kg, about 0.1mg / kg to about 0.25mg / kg kg, about 0.1mg / kg to about 0.2mg / kg, about 0.1mg / kg to about 0.15mg / kg, about 0.15mg / kg to about 0.45mg / kg, about 0.15mg / kg to about 0.4mg / kg, about 0.15mg / kg to about 0.35mg / kg, about 0.15mg / kg to about 0.3mg / kg, about 0.15mg / kg to about 0.25mg / kg, about 0.15mg / kg to about 0.2mg / kg, about 0.2mg / kg to about 0.45mg / kg, about 0.2mg / kg to about 0.4mg / kg, about 0.2mg / kg to about 0.35mg / kg, about 0.The method comprises administering infigratinib or a pharmaceutically acceptable salt thereof in an amount of 2 mg / kg to about 0.3 mg / kg, about 0.2 mg / kg to about 0.25 mg / kg, about 0.25 mg / kg to about 0.45 mg / kg, about 0.25 mg / kg to about 0.4 mg / kg, about 0.25 mg / kg to about 0.35 mg / kg, about 0.25 mg / kg to about 0.3 mg / kg, about 0.3 mg / kg to about 0.45 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.3 mg / kg to about 0.35 mg / kg, about 0.35 mg / kg to about 0.45 mg / kg, about 0.35 mg / kg to about 0.4 mg / kg, or about 0.4 mg / kg to about 0.45 mg / kg. In certain embodiments, the method comprises administering to the pediatric patient about 0.01 mg / kg to about 0.15 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering to the pediatric patient about 0.01 mg / kg to about 0.3 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof.

[0163] In certain embodiments, the method provides a subject (e.g., a pediatric patient) with a dose of about 0.01 mg / kg to about 0.15 mg / kg, about 0.015 mg / kg to about 0.15 mg / kg, about 0.02 mg / kg to about 0.15 mg / kg, about 0.025 mg / kg to about 0.15 mg / kg, about 0.03 mg / kg to about 0.15 mg / kg, about 0.05 mg / kg to about 0.15 mg / kg, about 0.07 mg / kg to about 0.15 mg / kg, about 0.09 mg / kg to about 0.15 mg / kg, about 0.11 mg / kg to about 0.15 mg / kg, about 0.13 mg / kg to about 0.15 mg / kg, about 0.01 mg / kg to about 0.13 mg / kg, about 0.01 mg / kg to about 0.11 mg / kg, about 0.01 mg / kg to about 0.09 mg / kg, about 0.01 mg / kg to about 0.07 mg / kg, about 0.01 mg / kg to about 0.05 mg / kg, about 0.01 mg / kg to about 0.03 mg / kg, about 0.01 mg / kg to about 0.025 mg / kg, about 0.01 mg / kg to about 0.02 mg / kg, about 0.01 mg / kg to about 0.015 mg / kg, about 0.015 mg / kg to about 0.13 mg / kg, about 0. 0.015mg / kg to about 0.11mg / kg, about 0.015mg / kg to about 0.09mg / kg, about 0.015mg / kg to about 0.07mg / kg, about 0.015mg / kg to about 0.05mg / kg, about 0.015mg / kg to about 0.03mg / kg, about 0.015mg / kg to about 0.025mg / kg, about 0.015mg / kg to about 0.02mg / kg, about 0.02mg / kg to about 0.13mg / kg, about 0.02mg / kg to about 0.11mg / kg, about 0.02mg / kg to about 0.09mg / kg, about 0.02 ... .07mg / kg, about 0.02mg / kg to about 0.05mg / kg, about 0.02mg / kg to about 0.03mg / kg, about 0.02mg / kg to about 0.025mg / kg, about 0.025mg / kg to about 0.13mg / kg, about 0.025mg / kg to about 0.11mg / kg, about 0.025mg / kg to about 0.09mg / kg, about 0.025mg / kg to about 0.07mg / kg, about 0.025mg / kg to about 0.05mg / kg, about 0.025mg / kg to about 0.03mg / kg, about 0.03mg / kg to about 0.13mg / kg, about 0.0.03mg / kg to about 0.11mg / kg, about 0.03mg / kg to about 0.09mg / kg, about 0.03mg / kg to about 0.07mg / kg, about 0.03mg / kg to about 0.05mg / kg, about 0.05mg / kg to about 0.13mg / kg, about 0.05mg / kg to about 0.11mg / kg, about 0.05mg / kg to about 0.09mg / kg, about 0.05mg / kg to about 0.07mg / kg In certain embodiments, the method comprises administering to the pediatric patient about 0.015 mg / kg to about 0.13 mg / kg, about 0.07 mg / kg to about 0.13 mg / kg, about 0.07 mg / kg to about 0.11 mg / kg, about 0.07 mg / kg to about 0.09 mg / kg, about 0.09 mg / kg to about 0.13 mg / kg, about 0.09 mg / kg to about 0.11 mg / kg, or about 0.11 mg / kg to about 0.13 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, the methods comprise administering to a subject (e.g., a pediatric patient) about 0.004 mg / kg, about 0.008 mg / kg, about 0.016 mg / kg, about 0.032 mg / kg, about 0.064 mg / kg, about 0.128 mg / kg, about 0.250 mg / kg, about 0.256 mg / kg, or about 0.51 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof.

[0165] In various embodiments, provided herein are methods for treating achondroplasia or hypochondroplasia in a subject in need thereof, the methods comprising orally administering to the subject about 0.250 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0166] In various embodiments, provided herein are methods of treating a subject (e.g., a pediatric patient) suffering from a skeletal dysplasia, such as hypochondroplasia or achondroplasia, comprising orally administering to the subject about 0.1 mg to about 25 mg of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0167] In one embodiment, a method of treating a skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject in need thereof comprises orally administering to the subject about 0.1 mg to about 8 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0168] In certain embodiments, the method provides a method for administering a medicament comprising administering to a patient a dose of about 0.1 mg to about 25 mg, about 0.1 mg to about 24 mg, about 0.1 mg to about 23 mg, about 0.1 mg to about 22 mg, about 0.1 mg to about 21 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 19 mg, about 0.1 mg to about 18 mg, about 0.1 mg to about 17 mg, about 0.1 mg to about 16 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 14 mg, about 0.1 mg to about 13 mg, about 0.1 mg to about 12 mg, about 0.1 mg to about 1 1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 9 mg, about 1 mg to about 25 mg, about 1 mg to about 24 mg, about 1 mg to about 23 mg, about 1 mg to about 22 mg, about 1 mg to about 21 mg, about 1 mg to about 20 mg, about 1 mg to about 19 mg, about 1 mg to about 18 mg, about 1 mg to about 17 mg, about 1 mg to about 16 mg, about 1 mg to about 15 mg, about 1 mg to about 14 mg, about 1 mg to about 13 mg, about 1 mg to about 12 mg, about 1 mg to about 11 mg, about 1 mg to about 10 mg g, about 1 mg to about 9 mg, about 2 mg to about 25 mg, about 2 mg to about 24 mg, about 2 mg to about 23 mg, about 2 mg to about 22 mg, about 2 mg to about 21 mg, about 2 mg to about 20 mg, about 2 mg to about 19 mg, about 2 mg to about 18 mg, about 2 mg to about 17 mg, about 2 mg to about 16 mg, about 2 mg to about 15 mg, about 2 mg to about 14 mg, about 2 mg to about 13 mg, about 2 mg to about 12 mg, about 2 mg to about 11 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2.5 mg g to about 25 mg, about 2.5 mg to about 24 mg, about 2.5 mg to about 23 mg, about 2.5 mg to about 22 mg, about 2.5 mg to about 21 mg, about 2.5 mg to about 20 mg, about 2.5 mg to about 19 mg, about 2.5 mg to about 18 mg, about 2.5 mg to about 17 mg, about 2.5 mg to about 16 mg, about 2.5 mg to about 15 mg, about 2.5 mg to about 14 mg, about 2.5 mg to about 13 mg, about 2.5 mg to about 12 mg, about 2.5 mg to about 11 mg, about 2.5 mg to about 10 mg, about 2.5 mg to about 15 mg.5mg to about 9mg, about 3mg to about 25mg, about 3mg to about 24mg, about 3mg to about 23mg, about 3mg to about 22mg, about 3mg to about 21mg, about 3mg to about 20mg, about 3mg to about 19mg, about 3mg to about 18mg, about 3mg to about 17mg, about 3mg to about 16mg, about 3mg to about 15mg, about 3mg to about 14mg, about 3mg to about 13mg, about 3mg to about 12mg, about 3mg to about 11mg, about 3mg to about 10mg, about 3mg to about 9mg, about 3.5mg to about 25 mg, about 3.5 mg to about 24 mg, about 3.5 mg to about 23 mg, about 3.5 mg to about 22 mg, about 3.5 mg to about 21 mg, about 3.5 mg to about 20 mg, about 3.5 mg to about 19 mg, about 3.5 mg to about 18 mg, about 3.5 mg to about 17 mg, about 3.5 mg to about 16 mg, about 3.5 mg to about 15 mg, about 3.5 mg to about 14 mg, about 3.5 mg to about 13 mg, about 3.5 mg to about 12 mg, about 3.5 mg to about 11 mg, about 3.5 mg to about 10 mg, about 3.5mg to about 9mg, about 5mg to about 25mg, about 5mg to about 24mg, about 5mg to about 23mg, about 5mg to about 22mg, about 5mg to about 21mg, about 5mg to about 20mg, about 5mg to about 19mg, about 5mg to about 18mg, about 5mg to about 17mg, about 5mg to about 16mg, about 5mg to about 15mg, about 5mg to about 14mg, about 5mg to about 13mg, about 5mg to about 12mg, about 5mg to about 11mg, about 5mg to about 10mg, about 5mg to about 9mg, about 7mg to about 25mg, about 7mg to about 24mg, about 7mg to about 23mg , about 7mg to about 22mg, about 7mg to about 21mg, about 7mg to about 20mg, about 7mg to about 19mg, about 7mg to about 18mg, about 7mg to about 17mg, about 7mg to about 16mg, about 7mg to about 15mg, about 7mg to about 14mg, about 7mg to about 13mg, about 7mg to about 12mg, about 7mg to about 11mg, about 7mg to about 10mg, about 7mg to about 9mg, about 10mg to about 25mg, about 10mg to about 24mg, about 10mg to about 23mg, about 10mg to about 22mg, about 10mg to about 21mg, about 10mg to about 20 ...5mg, about 10mg to about 24mg, about 10mg to about 23mg, about 10mg to about 22mg, about 10mg to about mg to about 19 mg, about 10 mg to about 18 mg, about 10 mg to about 17 mg, about 10 mg to about 16 mg, about 10 mg to about 15 mg, about 10 mg to about 14 mg, about 10 mg to about 13 mg, about 10 mg to about 12 mg, about 10 mg to about 11 mg, about 0.1 mg to about 8 mg, about 0.2 mg to about 8 mg, about 0.3 mg to about 8 mg, about 0.4 mg to about 8 mg, about 0.5 mg to about 8 mg, about 1 mg to about 8 mg, about 1.5 mg to about 8 mg, about 2 mg to about 8 mg, about 2.5 mg to about 8 mg, about 3 mg to about 8 mg, about 3.5 mg to about 8 mg g, about 4 mg to about 8 mg, about 4.5 mg to about 8 mg, about 5 mg to about 8 mg, about 5.5 mg to about 8 mg, about 6 mg to about 8 mg, about 6.5 mg to about 8 mg, about 7 mg to about 8 mg, about 7.5 mg to about 8 mg, about 0.1 mg to about 7.5 mg, about 0.1 mg to about 7 mg, about 0.1 mg to about 6.5 mg, about 0.1 mg to about 6 mg, about 0.1 mg to about 5.5 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 4.5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 3.5 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2.5mg, about 0.1mg to about 2mg, about 0.1mg to about 1.5mg, about 0.1mg to about 1mg, about 0.1mg to about 0.5mg, about 0.1mg to about 0.4mg, about 0.1mg to about 0.3mg, about 0.1mg to about 0.2mg, about 0.2mg to about 7.5mg, about 0.2mg to about 7mg, about 0.2mg to about 6.5mg, about 0.2mg to about 6mg, about 0.2mg to about 5.5mg, about 0.2mg to about 5mg, about 0.2mg to about 4.5mg, about 0.2mg to about 4mg, about 0.2mg to about 3.5mg, about 0.2mg to about 3mg, about 0. 2mg to about 2.5mg, about 0.2mg to about 2mg, about 0.2mg to about 1.5mg, about 0.2mg to about 1mg, about 0.2mg to about 0.5mg, about 0.2mg to about 0.4mg, about 0.2mg to about 0.3mg, about 0.3mg to about 7.5mg, about 0.3mg to about 7mg, about 0.3mg to about 6.5mg, about 0.3mg to about 6mg, about 0.3mg to about 5.5mg, about 0.3mg to about 5mg, about 0.3mg to about 4.5mg, about 0.3mg to about 4mg, about 0.3mg to about 3.5mg, about 0.3mg to about 3mg, about 0.3mg to about 2. 5mg, about 0.3mg to about 2mg, about 0.3mg to about 1.5mg, about 0.3mg to about 1mg, about 0.3mg to about 0.5mg, about 0.3mg to about 0.4mg, about 0.4mg to about 7.5mg, about 0.4mg to about 7mg, about 0.4mg to about 6.5mg, about 0.4mg to about 6mg, about 0.4mg to about 5.5mg, about 0.4mg to about 5mg, about 0.4mg to about 4.5mg, about 0.4mg to about 4mg, about 0.4mg to about 3.5mg, about 0.4mg to about 3mg, about 0.4mg to about 2.5mg, about 0.4mg to about 2mg, about 0.4mg to About 1.5 mg, about 0.4 mg to about 1 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1 mg, about 1.5 mg to about 7.5 mg, about 1.5 mg to about 7 mg, about 1.5 mg to about 6.5 mg, about 1.5 mg to about 6 mg, about 1.5 mg to about 5.5 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 4.5 mg, about 1.5 mg to about 4 mg, about 1.5 mg to about 3.5 mg, about 1.5 mg to about 3 mg, about 1.5 mg to about 2.5 mg, about 1.5 mg to about 2 mg, about 2 mg to about 7.5 mg, about 2 mg to about 7 mg, about 2 mg to about 6.5 mg, about 2 mg to about 6 mg, about 2 mg to about 5.5 mg, about 2 mg to about 5 mg, about 2 mg to about 4.5 mg, about 2 mg to about 4 mg, About 2mg to about 3.5mg, about 2mg to about 3mg, about 2mg to about 2.5mg, about 2.5mg to about 7.5mg, about 2.5mg to about 7mg, about 2.5mg to about 6.5mg, about 2.5mg to about 6mg, about 2.5mg to about 5.5mg, about 2.5mg to about 5mg, about 2.5mg to about 4.5mg, about 2.5mg to about 4mg, about 2.5mg to about 3.5mg, about 2.5mg to about 3mg, about 3mg to about 7.5mg, about 3mg to about 7mg, about 3mg to about 6.5mg, about 3mg to about 6mg, about 3mg to about 5.5mg, about 3mg to about 5 mg, about 3mg to about 4.5mg, about 3mg to about 4mg, about 3mg to about 3.5mg, about 3.5mg to about 7.5mg, about 3.5mg to about 7mg, about 3.5mg to about 6.5mg, about 3.5mg to about 6mg, about 3.5mg to about 5.5mg, about 3.5mg to about 5mg, about 3.5mg to about 4.5mg, about 3.5mg to about 4mg, about 4mg to about 7.5mg, about 4mg to about 7mg, about 4mg to about 6.5mg, about 4mg to about 6mg, about 4mg to about 5.5mg, about 4mg to about 5mg, about 4mg to about 4.5mg, about 4.5mg to about 7.5mg, about 4.5mg to about 7mg, about 4.5mg to about 6.5mg, about 4.5mg to about 6mg, about 4.5mg to about 5.5mg, about 4.5mg to about 5mg, about 5mg to about 7.5mg, about 5mg to about 7mg, about 5mg to about 6.5mg, about 5mg to about 6mg, about 5mg to about 5.5mg, about 5.5mg to about 7mg, about 5.5mg to about 7mg, about 5.5mg to about 6.5mg, about 5.5mg to about 6mg, about 6mg to about 7.5mg, about 6mg to about 7mg, about 6mg to about 6.5mg, about 6.5mg to about 7.5mg, about 6.The method comprises administering 5 mg to about 7 mg, about 7 mg to about 7.5 mg, or about 7 mg to about 7.5 mg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering about 0.1 mg to about 7 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0169] In certain embodiments, the methods comprise administering about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, or about 8 mg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering about 2.5 mg, about 3.5 mg, about 5 mg, about 7 mg, about 10 mg, about 14 mg, or about 20 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the amount of infigratinib or a pharmaceutically acceptable salt thereof administered to a subject (e.g., a pediatric patient) is determined based on the subject's body weight. In some embodiments, the amount of infigratinib or a pharmaceutically acceptable salt thereof administered to a subject is determined according to Table 1. [Table 1] TIFF2026507903000004.tif108156

[0171] In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0172] In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject once, twice, three times, four times, or five times daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject once daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject twice daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject three times daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject four times daily. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject five times daily.

[0173] In various embodiments, provided herein are methods of treating achondroplasia or hypochondroplasia in a subject in need thereof, the methods comprising orally administering to the subject about 2.5 to about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0174] In certain embodiments, the method provides a subject with an oral dose of about 2.5 mg to about 20.0 mg, about 3.0 mg to about 20.0 mg, about 3.5 mg to about 20.0 mg, about 4.0 mg to about 20.0 mg, about 5.0 mg to about 20.0 mg, about 6.0 mg to about 20.0 mg, about 7.0 mg to about 20.0 mg, about 8.0 mg to about 20.0 mg, about 10.0 mg to about 20.0 mg, about 12.0 mg to about 20.0 mg, about 14.0 mg to about 20.0 mg, about 16.0 mg to about 20.0 mg, about 18.0 mg to about 20.0 mg, about 2.5 mg to about 18.0 mg g, about 2.5 mg to about 16.0 mg, about 2.5 mg to about 14.0 mg, about 2.5 mg to about 12.0 mg, about 2.5 mg to about 10.0 mg, about 2.5 mg to about 8.0 mg, about 2.5 mg to about 7.0 mg, about 2.5 mg to about 6.0 mg, about 2.5 mg to about 5.0 mg, about 2.5 mg to about 4.0 mg, about 2.5 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 18.0 mg, about 3.0 mg to about 16.0 mg, about 3.0 mg to about 14.0 mg, about 3.0 mg to about 12.0 mg, about 3.0 mg to about 10.0 mg g, about 3.0mg to about 8.0mg, about 3.0mg to about 7.0mg, about 3.0mg to about 6.0mg, about 3.0mg to about 5.0mg, about 3.0mg to about 4.0mg, about 3.0mg to about 3.5mg, about 3.5mg to about 18.0mg, about 3.5mg to about 16.0mg, about 3.5mg to about 14.0mg, about 3.5mg to about 12.0mg, about 3.5mg to about 10.0mg, about 3.5mg to about 8.0mg, about 3.5mg to about 7.0mg, about 3.5mg to about 6.0mg, about 3.5mg to about 5.0mg, about 3.5mg to about 4.0mg, about 4.0 mg to about 18.0 mg, about 4.0 mg to about 16.0 mg, about 4.0 mg to about 14.0 mg, about 4.0 mg to about 12.0 mg, about 4.0 mg to about 10.0 mg, about 4.0 mg to about 8.0 mg, about 4.0 mg to about 7.0 mg, about 4.0 mg to about 6.0 mg, about 4.0 mg to about 5.0 mg, about 5.0 mg to about 18.0 mg, about 5.0 mg to about 16.0 mg, about 5.0 mg to about 14.0 mg, about 5.0 mg to about 12.0 mg, about 5.0 mg to about 10.0 mg, about 5.0 mg to about 8.0 mg, about 5.0 mg to about 7.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 18.0 mg, about 6.0 mg to about 16.0 mg, about 6.0 mg to about 14.0 mg, about 6.0 mg to about 12.0 mg, about 6.0 mg to about 10.0 mg, about 6.0 mg to about 8.0 mg, about 6.0 mg to about 7.0 mg, about 7.0 mg to about 18.0 mg, about 7.0 mg to about 16.0 mg, about 7.0 mg to about 14.0 mg, about 7.0 mg to about 12.0 mg, about 7.0 mg to about 10.0 mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to about 18.0 mg, about 8.0 mg to about 16.0 mg, about 8.0 mg The present invention relates to a method for treating infigratinib or a pharmaceutically acceptable salt thereof, the method comprising daily oral administration of about 10 mg to about 14.0 mg, about 8.0 mg to about 12.0 mg, about 8.0 mg to about 10.0 mg, about 10.0 mg to about 18.0 mg, about 10.0 mg to about 16.0 mg, about 10.0 mg to about 14.0 mg, about 10.0 mg to about 12.0 mg, about 12.0 mg to about 18.0 mg, about 12.0 mg to about 16.0 mg, about 12.0 mg to about 14.0 mg, about 14.0 mg to about 18.0 mg, about 14.0 mg to about 16.0 mg, or about 16.0 mg to about 18.0 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0175] In various embodiments, provided herein are methods for treating achondroplasia or hypochondroplasia in a subject in need thereof, the methods comprising orally administering to the subject about 2.5 mg, about 3.5 mg, about 5.0 mg, about 7.0 mg, about 10.0 mg, about 14.0 mg, or about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0176] In certain embodiments, the method comprises orally administering to a subject about 2.5 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to a subject about 3.5 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to a subject about 5.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to a subject about 7.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to a subject about 10.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to a subject about 14.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the method comprises orally administering to the subject about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily.

[0177] In certain embodiments, about 2.5 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 3.5 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 5.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 7.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 10.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 14.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily. In certain embodiments, about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to a subject daily.

[0178] In certain embodiments, the subject weighs less than about 12 kg. In certain embodiments, the subject weighs about 6 kg to about 12 kg. In certain embodiments, the subject weighs about 8 kg to about 12 kg. In certain embodiments, the subject weighs about 10 kg to about 12 kg. In certain embodiments, the subject weighs about 12 kg to about 15 kg. In certain embodiments, the subject weighs about 16 kg to about 22 kg. In certain embodiments, the subject weighs about 23 kg to about 31 kg. In certain embodiments, the subject weighs about 32 kg to about 43 kg. In certain embodiments, the subject weighs about 44 kg to about 70 kg. In certain embodiments, the subject weighs at least about 70 kg.

[0179] In certain embodiments, the subject (e.g., a pediatric patient) has an FGFR3 mutation. In certain embodiments, the FGFR3 mutation is selected from the group consisting of G380R, N540K, N328I, I538V, N540S, K650N, and K650G. In certain embodiments, the FGFR3 mutation is selected from the group consisting of N540K, N328I, I538V, N540S, K650N, and K650G. In certain embodiments, the FGFR3 mutation is a G380R mutation. In certain embodiments, the FGFR3 mutation is an N540K mutation. In certain embodiments, the FGFR3 mutation is a G380R mutation or an N540K mutation.

[0180] In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered in the form of mini-tablets. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered in the form of mini-tablets as described herein. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered as mini-tablets, each mini-tablet containing about 0.1 mg or about 1 mg of infigratinib or a pharmaceutically acceptable salt thereof. In certain embodiments, infigratinib or a pharmaceutically acceptable salt thereof is administered as mini-tablets, each mini-tablet containing 0.1 mg or 1 mg of infigratinib or a pharmaceutically acceptable salt thereof.

[0181] In certain embodiments, infigratinib is present in the mini-tablets as infigratinib monophosphate.

[0182] In some embodiments, the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate. In certain embodiments, infigratinib monophosphate exists as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an X-ray powder diffraction (XRPD) peak (2θ) of 15.0°±0.2°.

[0183] In certain embodiments, after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits an increase in height velocity compared to baseline. In certain embodiments, after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase in height velocity compared to baseline.

[0184] In certain embodiments, during or after treatment, the subject's mean change from baseline in annual height velocity (AHV) is at least about 2.0 centimeters per year (cm / year), at least about 2.1 cm / year, at least about 2.2 cm / year, at least about 2.3 cm / year, at least about 2.4 cm / year, at least about 2.5 cm / year, at least about 2.6 cm / year, at least about 2.7 cm / year, at least about 2.8 cm / year, at least about 2.9 cm / year, at least about 3.0 cm / year, at least about 3.1 cm / year, at least about 3.2 cm / year, at least about 3.3 cm / year, at least about 3.4 cm / year, at least about 3.5 cm / year, at least about 3.6 cm / year, at least about 3.7 cm / year, at least about 3.8 cm / year, at least about 3.9 cm / year, or at least about 4.0 cm / year. In certain embodiments, the subject's mean change from baseline in AHV during or after treatment is at least about 2.0 centimeters per year (cm / year).

[0185] In one embodiment, during or after treatment, a subject's change from baseline in AHV is from about 1.0 cm / year to about 14 cm / year, from about 1.0 cm / year to about 13.0 cm / year, from about 1.0 cm / year to about 12.0 cm / year, from about 1.0 cm / year to about 11.0 cm / year, from about 1.0 cm / year to about 10.0 cm / year, from about 1.0 cm / year to about 9.0 cm / year, from about 1.0 cm / year to about 8.0 cm / year, from about 1.0 cm / year to about 7.0 cm / year, from about 1.0 cm / year to about 6.0 cm / year, from about 1.0 cm / year to about 5.0 cm / year, and from about 1.0 cm / year to about 4.5 cm / year. m / year, from about 1.0cm / year to about 4.0cm / year, from about 1.0cm / year to about 3.5cm / year, from about 1.0cm / year to about 3.0cm / year, from about 1.0cm / year to about 2.5cm / year, from about 1.0cm / year to about 2.0cm / year, from about 1.0cm / year to about 1.5cm / year, from about 1.5cm / year to about 14.0cm / year, from about 1.5cm / year to about 13.0cm / year, from about 1.5cm / year to about 12.0cm / year, from about 1.5cm / year to about 11.0cm / year, from about 1.5cm / year to about 10.0cm / year, from about 1.5cm / year to about 9.0cm / year, from about 1.5cm / year to about 8.0cm / year, from about 1.5cm / year to about 7.0cm / year, from about 1.5cm / year to about 6.0cm / year, from about 1.5cm / year to about 5.0cm / year, from about 1.5cm / year to about 4.5cm / year, from about 1.5cm / year to about 4.0cm / year, from about 1.5cm / year to about 3.5cm / year, from about 1.5cm / year to about 3.0cm / year, from about 1.5cm / year to about 2.5cm / year, from about 1.5cm / year to about 2.0cm / year, from about 2.0cm / year to about 14cm / year, from about 2.0cm / year to about 13.0cm / year, from about 2.0cm / year to about 12.0cm / year, from about 2.0cm / year to about 1 1.0cm / year, from about 2.0cm / year to about 10.0cm / year, from about 2.0cm / year to about 9.0cm / year, from about 2.0cm / year to about 8.0cm / year, from about 2.0cm / year to about 7.0cm / year, from about 2.0cm / year to about 6.0cm / year, from about 2.0cm / year to about 5.0cm / year, from about 2.0cm / year to about 4.5cm / year, from about 2.0cm / year to about 4.0cm / year, from about 2.0cm / year to about 3.5cm / year, from about 2.0cm / year to about 3.0cm / year, from about 2.0cm / year to about 2.5cm / year, from about 2.5cm / year to about 14cm / year, from about 2.5cm / year to about 13cm / year.0cm / year, from about 2.5cm / year to about 12.0cm / year, from about 2.5cm / year to about 11.0cm / year, from about 2.5cm / year to about 10.0cm / year, from about 2.5cm / year to about 9.0cm / year, from about 2.5cm / year to about 8.0cm / year, from about 2.5cm / year to about 7.0cm / year, from about 2.5cm / year to about 6.0cm / year, from about 2.5cm / year to about 5.0cm / year, from about 2.5cm / year to about 4.5cm / year, from about 2.5cm / year to about 4.0cm / year, from about 2.5cm / year to about 3.5cm / year, from about 2.5cm / year to about 3.0cm / year, from about 3.0cm / year to about 14cm / year, from about 3.0cm / year to about 13.0cm / year, from about 3.0cm / year to about 12.0cm / year, from about 3.0cm / year to about 11.0cm / year, from about 3.0cm / year to about 10.0cm / year, from about 3.0cm / year to about 9.0cm / year, from about 3.0cm / year to about 8.0cm / year, from about 3.0cm / year to about 7.0cm / year, from about 3.0cm / year to about 6.0cm / year, from about 3.0cm / year to about 5.0cm / year, from about 3.0cm / year to about 4.5cm / year, from about 3.0cm / year to about 4.0cm / year, from about 3.0cm / year to about 3.5cm / year, or From about 14cm / year, from about 3.5cm / year to about 13.0cm / year, from about 3.5cm / year to about 12.0cm / year, from about 3.5cm / year to about 11.0cm / year, from about 3.5cm / year to about 10.0cm / year, from about 3.5cm / year to about 9.0cm / year, from about 3.5cm / year to about 8.0cm / year, from about 3.5cm / year to about 7.0cm / year, from about 3.5cm / year to about 6.0cm / year, from about 3.5cm / year to about 5.0cm / year, from about 3.5cm / year to about 4.5cm / year, from about 3.5cm / year to about 4.0cm / year, from about 4.0cm / year to about 14cm / year, from about 4.0cm / year From about 2000 to about 13.0cm / year, from about 4.0cm / year to about 12.0cm / year, from about 4.0cm / year to about 11.0cm / year, from about 4.0cm / year to about 10.0cm / year, from about 4.0cm / year to about 9.0cm / year, from about 4.0cm / year to about 8.0cm / year, from about 4.0cm / year to about 7.0cm / year, from about 4.0cm / year to about 6.0cm / year, from about 4.0cm / year to about 5.0cm / year, from about 4.0cm / year to about 4.5cm / year, from about 4.5cm / year to about 14cm / year, from about 4.5cm / year to about 13.0cm / year, from about 4.5cm / year to about 12.0cm / year, about 4.From 5cm / year to about 11.0cm / year, from about 4.5cm / year to about 10.0cm / year, from about 4.5cm / year to about 9.0cm / year, from about 4.5cm / year to about 8.0cm / year, from about 4.5cm / year to about 7.0cm / year, from about 4.5cm / year to about 6.0cm / year, from about 4.5cm / year to about 5.0cm / year, from about 5.0cm / year to about 14cm / year, from about 5.0cm / year to about 13.0cm / year, from about 5.0cm / year to about 12.0cm / year, from about 5.0cm / year to about 11.0cm / year, from about 5.0cm / year to about 10.0cm / year, from about 5.0cm / year to about 9.0cm / year, from about 5.0cm / year to about 8.0cm / year, from about 5.0cm / year to about 7.0cm / year or from about 5.0cm / year to about 6.0cm / year. In one embodiment, during or after treatment, a subject's change from baseline in AHV is between about 1.0 cm / year and about 14 cm / year.

[0186] In certain embodiments, during or after treatment, the change in AHV from baseline for the subject is about 1.0 cm / year, about 1.1 cm / year, about 1.2 cm / year, about 1.3 cm / year, about 1.4 cm / year, about 1.5 cm / year, about 1.6 cm / year, about 1.7 cm / year, about 1.8 cm / year, about 1.9 cm / year, about 2.0 cm / year, about 2.1 cm / year, about 2.2 cm / year, about 2.3 cm / year, about 2.4 cm / year, about 2.5 cm / year, about 2.6 cm / year, about 2.7 cm / year, about 2.8 cm / year, about 2.9 cm / year, about 3.0 cm / year, about 3.1 cm / year, about 3.2 cm / year, about 3.3 cm / year, about 3.4 cm / year, about 3.5 cm / year, about 3.6 cm / year, about 3.7 cm / year, about 3.8 cm / year, about 3.9 cm / year, about 4.0 cm / year, about 4.1 cm / year, about 4.2 cm / year, about 4.3 cm / year, about 4.4 cm / year, about 4.5 cm / year, about 4.6 cm / year, about 4.7 cm / year, about 4.8 cm / year, about 4.9 cm / year, about 5.0 cm / year, about 5.1 cm / year, about 5.2 cm / year, about 5.3 cm / year, about 5.4 cm / year, about 5.5 cm / year, about 5.6 cm / year, about 5.7 cm / year, about 5.8 cm / year, about 5.9 cm / year, about 6.0 cm / year, about 6.1 cm / year, about 6.2 cm / year, about 6.3 cm / year, about 6.4 cm / year, about 6.5 cm / year, about 6.6 cm / year, about 6.7 cm / year, about 6.8 cm / year, about 6.9 cm / year, about 7.0 cm / year, about 7.1 cm / year, about 7.2 cm / year, about 7.3 cm / year, about 7.4 cm / year, about 7.5 cm / year, about 7.6 cm / year, about 7.7 cm / year, about 7.8 cm / year, about 7.9 cm / year, about 8.0 cm / year, about 8.1 cm / year, about 8.2 cm / year, about 8.3 cm / year, about 8.4 cm / year, about 8.5 cm / year, about 8.6 cm / year, about 8.7 cm / year, about 8.8 cm / year, about 8.9 cm / year, about 9.0 cm / year, about 9.1 cm / year, about 9.2 cm / year, about 9.3 cm / year, about 9.4 cm / year, about 9.5 cm / year, about 9.6 cm / year, about 9.7 cm / year, about 9.8 cm / year, about 9.9 cm / year, about 10.0 cm / year, about 10.1 cm / year, about 10.2 cm / year, about 10.3 cm / year, about 10.4 cm / year, about 10.5 cm / year, about 10.6 cm / year, about 10.7 cm / year, about 10.8 cm / year, about 10.9 cm / year, about 11.0 cm / year, about 11.1 cm / year, about 11.2 cm / year, about 11.3 cm / year, about 11.4cm / year, 11.5cm / year, 11.6cm / year, 11.7cm / year, 11.8cm / year, 11.9cm / year, 12.0cm / year, 12.1cm / year, 12.2cm / year, 12.3cm / year, 12.4cm / year, 12.5cm / year, 12.6cm / year, 12.7cm / year, 12.8cm / year, 12.9cm / year, 13.0cm / year, 13.1cm / year, 13.2cm / year, 13.3cm / year, 13.4cm / year, 13.5cm / year, 13.6cm / year, 13.7cm / year, 13.8cm / year, 13.9cm / year, or 14.0cm / year.

[0187] In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.0 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.1 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.2 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.3 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.4 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.5 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.6 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.7 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.8 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 2.9 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.0 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.1 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.2 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.3 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.4 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.5 cm / year. In one embodiment, the mean change from baseline in AHV in subjects during or after treatment is about 3.6 cm / year. In one embodiment, the mean change from baseline in AHV in subjects during or after treatment is about 3.7 cm / year.In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.8 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 3.9 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.0 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.1 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.2 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.3 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.4 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.5 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.6 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.7 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.8 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 4.9 cm / year. In one embodiment, the mean change in AHV from baseline in subjects during or after treatment is about 5.0 cm / year.

[0188] In certain embodiments, during or after treatment, the subject's absolute AHV is at least about 2.0 cm / year, at least about 2.1 cm / year, at least about 2.2 cm / year, at least about 2.3 cm / year, at least about 2.4 cm / year, at least about 2.5 cm / year, at least about 2.6 cm / year, at least about 2.7 cm / year, at least about 2.8 cm / year, at least about 2.9 cm / year, at least about 3.0 cm / year, at least about 3.1 cm / year, at least about 3.2 cm / year, at least about 3.3 cm / year, at least about 3.4 cm / year, at least about 3.5cm / year, at least about 3.6cm / year, at least about 3.7cm / year, at least about 3.8cm / year, at least about 3.9cm / year, at least about 4.0cm / year, at least about 4.1cm / year, at least about 4.2cm / year, at least about 4.3cm / year, at least about 4.4cm / year, at least about 4.5cm / year, at least about 4.6cm / year, at least about 4.7cm / year, at least about 4.8cm / year, at least about 4.9cm / year, at least about 5.0cm / year, at least about 5.1cm / year, at least about 5.2cm / year, at least about at least about 5.3cm / year, at least about 5.4cm / year, at least about 5.5cm / year, at least about 5.6cm / year, at least about 5.7cm / year, at least about 5.8cm / year, at least about 5.9cm / year, at least about 6.0cm / year, at least about 6.1cm / year, at least about 6.2cm / year, at least about 6.3cm / year, at least about 6.4cm / year, at least about 6.5cm / year, at least about 6.6cm / year, at least about 6.7cm / year, at least about 6.8cm / year, at least about 6.9cm / year, at least about 7.0cm / year years, at least about 7.1cm / year, at least about 7.2cm / year, at least about 7.3cm / year, at least about 7.4cm / year, at least about 7.5cm / year, at least about 7.6cm / year, at least about 7.7cm / year, at least about 7.8cm / year, at least about 7.9cm / year, at least about 8.0cm / year, at least about 8.1cm / year, at least about 8.2cm / year, at least about 8.3cm / year, at least about 8.4cm / year, at least about 8.5cm / year, at least about 8.6cm / year, at least about 8.7cm / year, at least about 8.8cm / year, at least about 8.9cm / year, at least about 9.0cm / year, at least about 9.1cm / year, at least about 9.2cm / year, at least about 9.3cm / year, at least about 9.4cm / year, at least about 9.5cm / year, at least about 9.6cm / year, at least about 9.7cm / year, at least about 9.8cm / year, at least about 9.9cm / year, at least about 10.0cm / year, at least about 10.1cm / year, about 10.2cm / year, at least about 10.3cm / year, at least about 10.4cm / year, at least about 10.5cm / year, at least about 10.6cm / year, at least about 10.7cm / year, at least about 10.8cm / year, at least about 10.9cm / year, at least about 11.0cm / year, at least about 11.1cm / year, at least about 11.2cm / year, at least about 11.3cm / year, at least about 11.4cm / year, at least about 11.5cm / year, at least about 11.6cm / year, at least about 11.7cm / year, at least about 11.8cm / year, at least about 11.9cm / year, at least about 12.0cm / year, at least about 12.1cm / year, at least about 12.2cm / year, at least about 12.3cm / year, at least about 12.4cm / year, at least about 12.5cm / year, at least about 12.6cm / year, at least about 12.7cm / year, about 12.8cm / year, at least about 12.9cm / year, at least about 13.0cm / year, at least about 13.1cm / year, at least about 13.2cm / year, at least about 13.3cm / year, at least about 13.4cm / year, at least about 13.5cm / year, at least about 13.6cm / year, at least about 13.7cm / year, at least about 13.8cm / year, at least about 13.9cm / year or at least about 14.0cm / year. In certain embodiments, during or after treatment, the subject's absolute AHV is at least about 4.0 cm / year, at least about 4.1 cm / year, at least about 4.2 cm / year, at least about 4.3 cm / year, at least about 4.4 cm / year, at least about 4.5 cm / year, at least about 4.6 cm / year, at least about 4.7 cm / year, at least about 4.8 cm / year, at least about 4.9 cm / year, at least about 5.0 cm / year, at least about 5.1 cm / year, at least about 5.2 cm / year, at least about 5.3 cm / year, at least about 5.4 cm / year, at least about 5.5 cm / year, at least about 5.6 cm / year, at least about 5.7 cm / year, at least about 5.8 cm / year, at least about 5.9 cm / year, at least about 6.0 cm / year, at least about 6.1 cm / year, at least about 6.2 cm / year, at least about 6.3 cm / year, at least about 6.4 cm / year, at least about 6.5 cm / year, at least about 6.6 cm / year, at least about 6.7 cm / year, at least about 6.8 cm / year, at least about 6.9 cm / year, at least about 7.0 cm / year, at least about 7.1 cm / year, at least about 7.2 cm / year, at least about 7.3 cm / year, at least about 7.4 cm / year, at least about 7.5 cm / year, at least about 7.6 cm / year, at least about 7.7 cm / year, at least about 7.8 cm / year, at least about 7.9 cm / year, at least about 8.0 cm / year, at least about 8.1 cm / year, at least about 8.2 cm / year, at least about 8.3 cm / year, at least about 8.4 cm / 3cm / year, at least about 5.4cm / year, at least about 5.5cm / year, at least about 5.6cm / year, at least about 5.7cm / year, at least about 5.8cm / year, at least about 5.9cm / year, at least about 6.0cm / year, at least about 6.1cm / year, at least about 6.2cm / year, at least about 6.3cm / year, at least about 6.4cm / year, at least about 6.5cm / year, at least about 6.6cm / year, at least about 6.7cm / year, at least about 6.8cm / year, at least about 6.9cm / year, at least about 7.0cm / year, at least about 7.1cm / year, at least about 7.2cm / year, at least about 7.3cm / year, at least about 7.4cm / year, at least about 7.5cm / year, at least about 7.6cm / year, at least about 7.7cm / year, at least about 7.8cm / year, at least about 7.9cm / year, at least about 8.0cm / year, at least about 8.1cm / year, at least about 8.2cm / year, at least about 8.3cm / year, at least about 8.4cm / year, at least about 8.5cm / year, at least about 8.6cm / year, at least about 8.7cm / year, at least about 8.8cm / year years, at least about 8.9cm / year, at least about 9.0cm / year, at least about 9.1cm / year, at least about 9.2cm / year, at least about 9.3cm / year, at least about 9.4cm / year, at least about 9.5cm / year, at least about 9.6cm / year, at least about 9.7cm / year, at least about 9.8cm / year, at least about 9.9cm / year, at least about 10.0cm / year, at least about 10.1cm / year, at least about 10.2cm / year, at least about 10.3cm / year, at least about 10.4cm / year, at least about 10.5cm / year, at least about 10.6cm / year, at least about 10.7cm / year, at least about 10.8cm / year, at least about 10.9cm / year, at least about 11.0cm / year, at least about 11.1cm / year, at least about 11.2cm / year, at least about 11.3cm / year, at least about 11.4cm / year, at least about 11.5cm / year, at least about 11.6cm / year, at least about 11.7cm / year, at least about 11.8cm / year, at least about 11.9cm / year, at least about 12.0cm / year, at least about 12.1cm / year, at least about 12.2 cm / year, at least about 12.3 cm / year, at least about 12.4 cm / year, at least about 12.5 cm / year, at least about 12.6 cm / year, at least about 12.7 cm / year, at least about 12.8 cm / year, at least about 12.9 cm / year, at least about 13.0 cm / year, at least about 13.1 cm / year, at least about 13.2 cm / year, at least about 13.3 cm / year, at least about 13.4 cm / year, at least about 13.5 cm / year, at least about 13.6 cm / year, at least about 13.7 cm / year, at least about 13.8 cm / year, at least about 13.9 cm / year or at least about 14.0 cm / year. In certain embodiments, during or after treatment, the subject's absolute AHV is at least about 7.0 cm / year, at least about 7.1 cm / year, at least about 7.2 cm / year, at least about 7.3 cm / year, at least about 7.4 cm / year, at least about 7.5 cm / year, at least about 7.6 cm / year, at least about 7.7 cm / year, at least about 7.8 cm / year, at least about 7.9 cm / year, at least about 8.0 cm / year, at least about 8.1 cm / year, at least about 8.2 cm / year, at least about 8.3 cm / year, at least about 8.4 cm / year, at least about 8.5 cm / year, at least about 8.6 cm / year, at least about 8.7 cm / year, at least about 8.8 cm / year, at least about 8.9 cm / year, at least about 9.0 cm / year, at least about 9.1 cm / year, at least about 9.2 cm / year, at least about 9.3 cm / year, at least about 9.4 cm / year, at least about 9.5 cm / year, at least about 9.6 cm / year, at least about 9.7 cm / year, at least about 9.8 cm / year, at least about 9.9 cm / year, at least about 10 cm / year, at least about 10 cm / year, at least about 11 cm / year, at least about 12 cm / year, at least about 13 cm / year, at least about 14 cm / year, at least about 15 cm / year, at least about 16 cm / year, at least about 17 cm / year, at least about 18 cm / year, at least about 19 cm / year, at least about 20 cm / year, at least about 21 cm / year, at least about 22 cm / year, at least about 23 cm / year, at least about 24 cm / year, at least about Also about 9.3cm / year, at least about 9.4cm / year, at least about 9.5cm / year, at least about 9.6cm / year, at least about 9.7cm / year, at least about 9.8cm / year, at least about 9.9cm / year, at least about 10.0cm / year, at least about 10.1cm / year, at least about 10.2cm / year, at least about 10.3cm / year, at least about 10.4cm / year, at least about 10.5cm / year, at least about 10.6cm / year, at least about 10.7cm / year, at least about 10.8cm / year, at least about 10.9cm / year, at least about 11.0cm / year, at least about 11.1cm / year, at least about 11.2cm / year, at least about 11.3cm / year, at least about 11.4cm / year, at least about 11.5cm / year, at least about 11.6cm / year, at least about 11.7cm / year, at least about 11.8cm / year, at least about 11.9cm / year, at least about 12.0cm / year, at least about 12.1cm / year, at least about 12.2cm / year, at least about 12.3cm / year, at least about 12.4cm / year, at least about 12.5cm / year, at least about 12.6cm / year, at least about 12.7cm / year, at least about 12.8cm / year, at least about 12.9cm / year, at least about 13.0cm / year, at least about 13.1cm / year, at least about 13.2cm / year, at least about 13.3cm / year, at least about 13.4cm / year, at least about 13.5cm / year, at least about 13.6cm / year, at least about 13.7cm / year, at least about 13.8cm / year, at least about 13.9cm / year, or at least about 14.0cm / year.

[0189] In one embodiment, during or after treatment, the subject's absolute AHV increases from about 1.0cm / year to about 14cm / year, from about 1.0cm / year to about 13.0cm / year, from about 1.0cm / year to about 12.0cm / year, from about 1.0cm / year to about 11.0cm / year, from about 1.0cm / year to about 10.0cm / year, from about 1.0cm / year to about 9.0cm / year, from about 1.0cm / year to about 8.0cm / year, from about 1.0cm / year to about 7.0cm / year, from about 1.0cm / year to about 6.0cm / year, from about 1.0cm / year to about 5.0cm / year, from about 1.0cm / year to about 4.5cm / year, and from about 1.0cm / year to about 5.0cm / year. From about m / year to about 4.0 cm / year, from about 1.0 cm / year to about 3.5 cm / year, from about 1.0 cm / year to about 3.0 cm / year, from about 1.0 cm / year to about 2.5 cm / year, from about 1.0 cm / year to about 2.0 cm / year, from about 1.0 cm / year to about 1.5 cm / year, from about 1.5 cm / year to about 14.0 cm / year, from about 1.5 cm / year to about 13.0 cm / year, from about 1.5 cm / year to about 12.0 cm / year, from about 1.5 cm / year to about 11.0 cm / year, from about 1.5 cm / year to about 10.0 cm / year, from about 1.5 cm / year to about 9.0 cm / year, from about 1.5 cm / year to about 8.0 cm / year, From 0.5cm / year to about 7.0cm / year, from about 1.5cm / year to about 6.0cm / year, from about 1.5cm / year to about 5.0cm / year, from about 1.5cm / year to about 4.5cm / year, from about 1.5cm / year to about 4.0cm / year, from about 1.5cm / year to about 3.5cm / year, from about 1.5cm / year to about 3.0cm / year, from about 1.5cm / year to about 2.5cm / year, from about 1.5cm / year to about 2.0cm / year, from about 2.0cm / year to about 14cm / year, from about 2.0cm / year to about 13.0cm / year, from about 2.0cm / year to about 12.0cm / year, from about 2.0cm / year to about 11.0cm / year, From 0.0cm / year to about 10.0cm / year, from about 2.0cm / year to about 9.0cm / year, from about 2.0cm / year to about 8.0cm / year, from about 2.0cm / year to about 7.0cm / year, from about 2.0cm / year to about 6.0cm / year, from about 2.0cm / year to about 5.0cm / year, from about 2.0cm / year to about 4.5cm / year, from about 2.0cm / year to about 4.0cm / year, from about 2.0cm / year to about 3.5cm / year, from about 2.0cm / year to about 3.0cm / year, from about 2.0cm / year to about 2.5cm / year, from about 2.5cm / year to about 14cm / year, from about 2.5cm / year to about 13.0cm / year, about 2.From 5cm / year to approximately 12.0cm / year, from approximately 2.5cm / year to approximately 11.0cm / year, from approximately 2.5cm / year to approximately 10.0cm / year, from approximately 2.5cm / year to approximately 9.0cm / year, from approximately 2.5cm / year to approximately 8.0cm / year, from approximately 2.5cm / year to approximately 7.0cm / year, from approximately 2.5cm / year to approximately 6.0cm / year, from approximately 2.5cm / year to approximately 5.0cm / year, from approximately 2.5cm / year to approximately 4.5cm / year, from approximately 2.5cm / year to approximately 4.0cm / year, from approximately 2.5cm / year to approximately 3.5cm / year, from approximately 2.5cm / year to approximately 3.0cm / year, from approximately 3.0cm / year to approximately 14cm / year, From 0.0cm / year to approximately 13.0cm / year, from approximately 3.0cm / year to approximately 12.0cm / year, from approximately 3.0cm / year to approximately 11.0cm / year, from approximately 3.0cm / year to approximately 10.0cm / year, from approximately 3.0cm / year to approximately 9.0cm / year, from approximately 3.0cm / year to approximately 8.0cm / year, from approximately 3.0cm / year to approximately 7.0cm / year, from approximately 3.0cm / year to approximately 6.0cm / year, from approximately 3.0cm / year to approximately 5.0cm / year, from approximately 3.0cm / year to approximately 4.5cm / year, from approximately 3.0cm / year to approximately 4.0cm / year, from approximately 3.0cm / year to approximately 3.5cm / year, from approximately 3.5cm / year to approximately 14cm / year, From about 3.5cm / year to about 13.0cm / year, from about 3.5cm / year to about 12.0cm / year, from about 3.5cm / year to about 11.0cm / year, from about 3.5cm / year to about 10.0cm / year, from about 3.5cm / year to about 9.0cm / year, from about 3.5cm / year to about 8.0cm / year, from about 3.5cm / year to about 7.0cm / year, from about 3.5cm / year to about 6.0cm / year, from about 3.5cm / year to about 5.0cm / year, from about 3.5cm / year to about 4.5cm / year, from about 3.5cm / year to about 4.0cm / year, from about 4.0cm / year to about 14cm / year, from about 4.0cm / year to about 13.0cm / year, from about 4.0cm / year to about 12.0cm / year, from about 4.0cm / year to about 11.0cm / year, from about 4.0cm / year to about 10.0cm / year, from about 4.0cm / year to about 9.0cm / year, from about 4.0cm / year to about 8.0cm / year, from about 4.0cm / year to about 7.0cm / year, from about 4.0cm / year to about 6.0cm / year, from about 4.0cm / year to about 5.0cm / year, from about 4.0cm / year to about 4.5cm / year, from about 4.5cm / year to about 14cm / year, from about 4.5cm / year to about 13.0cm / year, from about 4.5cm / year to about 12.0cm / year, from about 4.5cm / year to about 11.0cm / year, from about 4.5cm / year to about 10.0cm / year, from about 4.5cm / year to about 9.0cm / year, from about 4.5cm / year to about 8.0cm / year, from about 4.5cm / year to about 7.0cm / year, from about 4.5cm / year to about 6.0cm / year, from about 4.5cm / year to about 5.0cm / year, from about 5.0cm / year to about 14cm / year, from about 5.0cm / year to about 13.0cm / year, from about 5.0cm / year to about 12.0cm / year, from about 5.0cm / year to about 11.0cm / year, from about 5.0cm / year to about 10.0cm / year, from about 5.0cm / year to about 9.0cm / year, from about 5.0cm / year to about 8.0cm / year, from about 5.0cm / year to about 7.0cm / year or from about 5.0cm / year to about 6.0cm / year. In one embodiment, during or after treatment, the subject's absolute AHV is from about 1.0 cm / year to about 14 cm / year.

[0190] In some embodiments, during or after treatment, the subject's absolute AHV is about 3.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 3.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 4.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.3 cm / year.In some embodiments, during or after treatment, the subject's absolute AHV is about 5.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 5.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 6.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.7 cm / year.In some embodiments, during or after treatment, the subject's absolute AHV is about 7.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 7.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 8.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 9.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.1 cm / year.In some embodiments, during or after treatment, the subject's absolute AHV is about 10.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 10.9 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.0 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.1 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.2 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.3 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.4 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.5 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.6 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.7 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.8 cm / year. In some embodiments, during or after treatment, the subject's absolute AHV is about 11.9 cm / year. In one embodiment, during or after treatment, the subject's absolute AHV is about 12.0 cm / year.

[0191] In some embodiments, the subject experiences no treatment-related adverse events during or after treatment. In some embodiments, the subject experiences no serious adverse events during or after treatment. In some embodiments, the subject experiences no serious treatment-related adverse events during or after treatment.

[0192] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits an increase compared to baseline in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or 100% increase compared to baseline in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

[0193] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an absolute increase of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or 100% in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

[0194] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject's (e.g., pediatric patient's) body weight is reduced compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient's body weight is reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% compared to baseline.

[0195] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) experiences an absolute weight loss. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient experiences an absolute weight loss of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0196] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., pediatric patient) shows a proportional increase in head circumference compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient shows an absolute proportional increase in head circumference. For example, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the body may become proportional to the head. In contrast, if not treated with infigratinib or a pharmaceutically acceptable salt thereof, the patient may exhibit macrocephaly.

[0197] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, subjects (e.g., pediatric patients) show normalization of body proportion measurement ratios compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, pediatric patients show absolute normalization of body proportion measurement ratios. For example, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, limbs may show more balanced growth compared to the trunk. In contrast, without treatment with infigratinib or a pharmaceutically acceptable salt thereof, patients may have limbs that are disproportionately shorter than the trunk.

[0198] In certain embodiments, the body proportion measurement ratio is selected from the group consisting of upper body to lower body segment ratio, upper arm to forearm ratio, thigh to leg length ratio, arm span to height ratio, head circumference to height ratio, and combinations thereof.

[0199] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., pediatric patient) exhibits an increase in a biomarker of bone metabolism selected from the group consisting of type X collagen degradation fragments, collagen X markers, and combinations thereof, compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase in a biomarker of bone metabolism selected from the group consisting of type X collagen degradation fragments, collagen X markers, and combinations thereof, compared to baseline.

[0200] In some embodiments, the subject's mean change from baseline in collagen X markers during or after treatment is at least about 5%. In some embodiments, the subject's mean change from baseline in collagen X markers during or after treatment is at least about 5.0%, for example, at least about 10.0%, about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, about 33.0%, about 34.0%, about 35.0%, about 36.0%, about 37.0%, about 38.0%, about 39.0%, about 40.0% or more. In one embodiment, the subject has a mean change from baseline in collagen X markers of about 10.0% to about 40.0%, e.g., about 10.0% to about 35.0%, about 10.0% to about 30.0%, about 10.0% to about 25.0%, about 10.0% to about 20.0%, about 10.0% to about 15.0%, about 15.0% to about 40.0%, about 15.0% to about 35.0%, about 15.0% to about 30.0%, about 15.0% to about 25.0%, about 15.0% to about 20.0%, about 20.0% to about 40.0%, about 20.0% to about 35.0%, about 20.0% to about 30.0%, about 20.0% to about 25.0%, about 25.0% to about 40.0%, about 25.0% to about 35.0%, or about 25.0% to about 30.0%.

[0201] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits an increase in exercise capacity compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase in exercise capacity compared to baseline.

[0202] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits a reduction in the number of episodes of otitis media compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient experiences a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% reduction in the number of episodes of otitis media compared to baseline.

[0203] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., a pediatric patient) exhibits a reduction in the number and / or severity of sleep apnea episodes compared to baseline. In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% reduction in the number and / or severity of sleep apnea episodes compared to baseline.

[0204] In certain embodiments, after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject (e.g., pediatric patient) exhibits improved quality of life, wherein the quality of life is assessed using a pediatric quality of life scale.

[0205] In certain embodiments, the subject (e.g., pediatric patient) is 2 or younger, 3 or younger, 4 or younger, 5 or younger, 6 or younger, 7 or younger, 8 or younger, 9 or younger, 10 or younger, 11 or younger, 12 or younger, 13 or younger, 14 or younger, 15 or younger, 16 or younger, 17 or younger, 18 or younger, 19 or younger, 20 or younger, or 21 or younger. In certain embodiments, the subject (e.g., pediatric patient) is 12 or younger.

[0206] In certain embodiments, the subject (e.g., pediatric patient) is between 2 and 21 years old, 3 and 21 years old, 4 and 21 years old, 5 and 21 years old, 6 and 21 years old, 7 and 21 years old, 8 and 21 years old, 9 and 21 years old, 10 and 21 years old, 11 and 21 years old, 12 and 21 years old, 13 and 21 years old, 14 and 21 years old, 15 and 21 years old, 16 and 21 years old, 17 and 21 years old, 18 and 21 years old, 19 and 21 years old, 20 and 21 years old, 2 and 20 years old, 2 and 19 years old, 2 and 18 years old, 2 and 17 years old, 2 and 16 years old, 2 and 15 years old, 2 and 14 years old, 2 and 13 years old, 2 and 12 years old, 2 and 11 years old, 2 and 10 years old, 2 and 9 years old, Ages, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 20, 4 to 19, 4 to 18, 4 to 17, 4 to 16, 4 to 15, 4 to 14, 4 to 13, 4 to 12, 4 to 11, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6 Ages, 4 to 5 years, 5 to 20 years, 5 to 19 years, 5 to 18 years, 5 to 17 years, 5 to 16 years, 5 to 15 years, 5 to 14 years, 5 to 13 years, 5 to 12 years, 5 to 11 years, 5 to 10 years, 5 to 9 years, 5 to 8 years, 5 to 7 years, 5 to 6 years, 6 to 20 years, 6 to 19 years, 6 to 18 years, 6 to 17 years, 6 to 16 years, 6 to 15 years, 6 to 14 years, 6 to 13 years, 6 to 12 years, 6 to 11 years, 6 to 10 years, 6 to 9 years, 6 to 8 years, 6 to 7 years, 7 to 20 years, 7 to 19 years, 7 to 18 years, 7 to 17 years, 7 to 16 years, 7 to 15 years, 7 to 1 years 4 years old, 7 to 13 years old, 7 to 12 years old, 7 to 11 years old, 7 to 10 years old, 7 to 9 years old, 7 to 8 years old, 8 to 20 years old, 8 to 19 years old, 8 to 18 years old, 8 to 17 years old, 8 to 16 years old, 8 to 15 years old, 8 to 14 years old, 8 to 13 years old, 8 to 12 years old, 8 to 11 years old, 8 to 10 years old, 8 to 9 years old, 9 to 20 years old, 9 to 19 years old, 9 to 18 years old, 9 to 17 years old, 9 to 16 years old, 9 to 15 years old, 9 to 14 years old, 9 to 13 years old, 9 to 12 years old, 9 to 11 years old, 9 to 10 years old, 10 to 20 years old, 10 to 19 years old, 10 to 18 years old, 10 to 17 years old, 10 to 16 years old, 10 to 15 years old,10 to 14 years old, 10 to 13 years old, 10 to 12 years old, 10 to 11 years old, 11 to 20 years old, 11 to 19 years old, 11 to 18 years old, 11 to 17 years old, 11 to 16 years old, 11 to 15 years old, 11 to 14 years old, 11 to 13 years old, 11 to 12 years old, 12 to 20 years old, 12 to 19 years old, 12 to 18 years old, 12 to 17 years old, 12 to 16 years old, 12 to 15 years old, 12 to 14 years old, 12 to 13 years old, 13 to 20 years old, 13 to 19 years old, 13 to 18 years old, 13 to 17 years old 13 to 16 years old, 13 to 15 years old, 13 to 14 years old, 14 to 20 years old, 14 to 19 years old, 14 to 18 years old, 14 to 17 years old, 14 to 16 years old, 14 to 15 years old, 15 to 20 years old, 15 to 19 years old, 15 to 18 years old, 15 to 17 years old, 15 to 16 years old, 16 to 20 years old, 16 to 19 years old, 16 to 18 years old, 16 to 17 years old, 17 to 20 years old, 17 to 19 years old, 17 to 18 years old, 18 to 20 years old, 18 to 19 years old, or 19 to 20 years old. In certain embodiments, the subject (e.g., pediatric patient) is 3 to 11 years old. In certain embodiments, the subject (e.g., pediatric patient) is 12 to 17 years old. In certain embodiments, the subject (e.g., pediatric patient) is 5 to 8 years old. In certain embodiments, the subject (e.g., a pediatric patient) is between 8 and 11 years of age.

[0207] In certain embodiments, the pediatric patient is under 3 years old, under 4 years old, under 5 years old, under 6 years old, under 7 years old, under 8 years old, under 9 years old, under 10 years old, under 11 years old, under 12 years old, under 13 years old, under 14 years old, under 15 years old, under 16 years old, under 17 years old, under 18 years old, under 19 years old, under 20 years old, or under 21 years old. In certain embodiments, the pediatric patient is under 8 years old. In certain embodiments, the pediatric patient is under 5 years old. In certain embodiments, the pediatric patient is under 12 years old.

[0208] In certain embodiments, the pediatric patient is 2 years of age or older, 3 years of age or older, 4 years of age or older, 5 years of age or older, 6 years of age or older, 7 years of age or older, 8 years of age or older, 9 years of age or older, 10 years of age or older, 11 years of age or older, 12 years of age or older, 13 years of age or older, 14 years of age or older, 15 years of age or older, 16 years of age or older, 17 years of age or older, 18 years of age or older, 19 years of age or older, or 20 years of age or older. In certain embodiments, the pediatric patient is 8 years of age or older.

[0209] In some embodiments, the subject is a pediatric subject (e.g., a subject under 18 years of age). In some embodiments, the subject is under 18 years of age, e.g., under 12 years of age, under 10 years of age, under 8 years of age, under 6 years of age, or under 5 years of age. In some embodiments, the subject is between 2 and 18 years of age, 2 and 16 years of age, 2 and 12 years of age, 2 and 11 years of age, 2 and 8 years of age, 2 and 5 years of age, 3 and 18 years of age, 3 and 16 years of age, 3 and 12 years of age, 3 and 11 years of age, 3 and 8 years of age, 3 and 5 years of age, 5 and 18 years of age, 5 and 16 years of age, 5 and 12 years of age, 5 and 11 years of age, 5 and 8 years of age, 8 and 18 years of age, 8 and 16 years of age, 8 and 12 years of age, 8 and 11 years of age, 11 and 18 years of age, 11 and 16 years of age, or 5 and 8 years of age.

[0210] In certain embodiments, a subject may be treated by the methods described herein until they present with open epiphyses and / or open growth plates.

[0211] In certain embodiments, the methods provided herein further comprise administering to the patient an effective amount of a second therapeutic agent. Details regarding the treatment of skeletal dysplasias, such as achondroplasia and hypochondroplasia, are described in International Patent Application No. PCT / US2021 / 064033, filed December 17, 2021, which is incorporated herein by reference in its entirety.

[0212] Enumerated Embodiments 1. A method for treating achondroplasia or hypochondroplasia in a pediatric patient in need thereof, comprising orally administering to the pediatric patient from about 0.01 mg / kg to about 0.51 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof daily. 2. The method of embodiment 1 comprising administering to the pediatric patient about 0.01 mg / kg to about 0.3 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof. 3. The method of embodiment 1 comprising administering to the pediatric patient about 0.01 mg / kg to about 0.15 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof. 4. The method of embodiment 1 comprising administering to the pediatric patient about 0.015 mg / kg to about 0.13 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof. 5. The method of embodiment 1 comprising administering to the pediatric patient about 0.016 mg / kg, about 0.032 mg / kg, about 0.064 mg / kg, about 0.128 mg / kg, about 0.25 mg / kg, about 0.256 mg / kg, or about 0.51 mg / kg of infigratinib or a pharmaceutically acceptable salt thereof. 6. A method of treating a pediatric patient suffering from achondroplasia or hypochondroplasia, comprising orally administering to the patient from about 0.1 mg to about 8 mg of infigratinib or a pharmaceutically acceptable salt thereof daily. 7. The method of embodiment 6, comprising administering to the pediatric patient about 1 mg to about 7 mg of infigratinib or a pharmaceutically acceptable salt thereof. 8. The method of any one of embodiments 1-7, wherein the pediatric patient has an FGFR3 mutation. 9. The method of embodiment 8, wherein the FGFR3 mutation is a G380R mutation or a N540K mutation. 10. The method of any one of embodiments 1-9, wherein infigratinib or a pharmaceutically acceptable salt thereof is administered as mini-tablets containing 0.1 mg or about 1 mg of infigratinib or a pharmaceutically acceptable salt thereof. 11. The method of embodiment 10, wherein infigratinib is present in the mini-tablets as infigratinib monophosphate. 12. The method of embodiment 11, wherein infigratinib monophosphate is present as an anhydrous crystalline form. 13. The mini-tablets of embodiment 12, wherein the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak at 15.0°±0.2° 2θ. 14. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the height of the pediatric patient exhibits an increase in height velocity compared to baseline. 15. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase in absolute height velocity. 16. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase compared to baseline in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. 17. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. 18. The method of any one of embodiments 1 to 13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient experiences a decrease in body weight compared to baseline. 19. The method according to any one of embodiments 1 to 13, wherein the pediatric patient experiences absolute weight loss after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof. 20. The method of any one of embodiments 1 to 13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient experiences a proportional increase in head circumference compared to baseline. 21. The method of any one of embodiments 1-13, wherein the pediatric patient shows an absolute proportional increase in head circumference after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof. 22. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient's body proportion measurement ratios show normalization compared to baseline. 23. The method of any one of embodiments 1-13, wherein the pediatric patient's body proportion measurement ratios show absolute normalization after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof. 24. The method of embodiment 22 or 23, wherein the body proportion measurement ratio is selected from the group consisting of upper body to lower body segment ratio, upper arm to forearm ratio, thigh to leg length ratio, arm span to height ratio, head circumference to height ratio, and combinations thereof. 25. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase compared to baseline in a biomarker of bone metabolism selected from the group consisting of type X collagen degradation fragments, collagen X markers, and combinations thereof. 26. The method of any one of embodiments 1-13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase in exercise capacity compared to baseline. 27. The method of any one of embodiments 1 to 13, wherein the number of episodes of otitis media in the pediatric patient is reduced compared to baseline after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof. 28. The method of any one of embodiments 1 to 13, wherein after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, the number and / or severity of sleep apnea episodes in the pediatric patient is reduced compared to baseline. 29. The method of any one of embodiments 1-13, wherein the pediatric patient has an improved quality of life after daily administration of a dose of infigratinib or a pharmaceutically acceptable salt thereof, wherein the quality of life is assessed using a Pediatric Quality of Life Scale. 30. The method of any one of embodiments 1-29, wherein the pediatric patient is 12 years of age or younger. 31. The method of any one of embodiments 1-30, wherein the pediatric patient is aged 3-11 years. 30. The method of any one of embodiments 1-30, wherein the pediatric patient is under 8 years of age. 32. The method of any one of embodiments 1-29, wherein the pediatric patient is 8 years of age or older. 33. Mini-tablets for oral administration of 1 mg of infigratinib, comprising infigratinib monophosphate in an amount sufficient to administer 1 mg of infigratinib and pharmaceutically acceptable excipients. 34. A mini-tablet for oral administration of 0.1 mg of infigratinib, comprising infigratinib monophosphate in an amount to administer 0.1 mg of infigratinib and pharmaceutically acceptable excipients. 35. The mini-tablet of embodiment 33 or 34, wherein the pharmaceutically acceptable excipient is selected from the group consisting of mannitol, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, croscarmellose sodium, and combinations thereof. 36. Mini-tablets for oral administration, comprising about 1% w / w to about 20% w / w of infigratinib monophosphate and about 30% w / w to about 95% w / w of a filler. 37. The mini-tablet according to embodiment 38, wherein the filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, and combinations thereof. 38. The mini-tablet according to embodiment 36 or 37, wherein the filler comprises microcrystalline cellulose and mannitol. 39. The mini-tablet according to any one of embodiments 36-38, further comprising about 5% w / w to about 10% w / w of a binder. 40. The mini-tablet according to embodiment 39, wherein the binder is selected from the group consisting of sugars, gelatin, natural gums, sorbitol, maltodextrin, alginates, alginate derivatives, polyvinylpyrrolidone, cellulose, cellulose derivatives and combinations thereof. 41. The mini-tablet according to any one of embodiments 36 to 40, further comprising about 5% w / w to about 10% w / w of a disintegrant. 42. The mini-tablet according to embodiment 41, wherein the disintegrant is selected from the group consisting of starch, starch derivatives, clays, cross-linked cellulose, cross-linked cellulose derivatives, cross-linked polyvinylpyrrolidone and combinations thereof. 43. Mini-tablets for oral administration, comprising: about 1% w / w to about 20% w / w of infigratinib monophosphate; about 30% w / w to about 60% w / w mannitol, and A mini-tablet comprising about 30% w / w to about 45% w / w microcrystalline cellulose. 44. The minita tablet according to embodiment 43, comprising about 10% w / w to about 20% w / w of infigratinib monophosphate. 45. The mini-tablets according to embodiment 43, comprising about 1% w / w to about 5% w / w of infigratinib monophosphate. 46. ​​The mini-tablets according to embodiment 43, comprising about 30% w / w to about 45% w / w of mannitol. 47. The mini-tablets according to embodiment 43, comprising about 45% w / w to about 60% w / w of mannitol. 48. The mini-tablet according to any one of embodiments 43 to 47, comprising about 35% w / w to about 40% w / w of microcrystalline cellulose. 49. Mini-tablets for oral administration, comprising: about 10% w / w to about 20% w / w of infigratinib monophosphate; about 30% w / w to about 45% w / w mannitol, and A mini-tablet comprising about 30% w / w to about 40% w / w microcrystalline cellulose. 50. Mini-tablets for oral administration, comprising: about 1% w / w to about 5% w / w of infigratinib monophosphate; about 45% w / w to about 60% w / w mannitol, and A mini-tablet comprising about 30% w / w to about 40% w / w microcrystalline cellulose. 51. The mini-tablets according to embodiment 49 or 50, further comprising about 5% w / w to about 10% w / w of polyvinylpyrrolidone. 52. The mini-tablets according to any one of embodiments 49-51, further comprising about 5% w / w to about 10% w / w of cross-linked polyvinylpyrrolidone. 53. The mini-tablets of any one of embodiments 49-52, further comprising about 2% w / w to about 6% w / w of croscarmellose sodium. 54. Mini-tablets for oral administration, comprising: approximately 1.2 mg of infigratinib monophosphate, about 3 mg to about 4 mg of mannitol and Mini-tablets containing about 2 mg to about 4.4 mg of microcrystalline cellulose. 55. The mini-tablet of embodiment 54, further comprising about 0.6 mg to about 0.8 mg of polyvinylpyrrolidone. 56. The mini-tablet of embodiment 54, further comprising about 0.5 mg to about 0.7 mg of cross-linked polyvinylpyrrolidone. 57. Mini-tablets for oral administration, Approximately 0.12 mg of infigratinib monophosphate, Mannitol about 3 mg to about 4 mg and Mini-tablets containing approximately 2 mg to 3 mg of microcrystalline cellulose. 58. The mini-tablet of embodiment 57, further comprising about 0.4 mg to about 0.6 mg of polyvinylpyrrolidone. 59. The mini-tablets according to embodiment 57 or 58, further comprising about 0.3 mg to about 0.5 mg of cross-linked polyvinylpyrrolidone. 60. The mini-tablets of any one of embodiments 54-59, further comprising about 0.2 mg to about 0.4 mg of croscarmellose sodium. 61. The mini-tablet according to any one of embodiments 33-60, wherein infigratinib monophosphate is present as an anhydrous crystalline form. 62. The mini-tablet according to embodiment 61, wherein the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak at 15.0°±0.2° 2θ. [Example]

[0213] In order to provide a better understanding of the disclosure set forth herein, the following examples are set forth: The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods described herein, and are not to be construed as limiting the scope thereof.

[0214] Example 1: Synthesis of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-4-(4-ethyl-piperazin-1-yl)-phenylamino-pyrimidin-4-yl}-1-methylurea (infigratinib) Step A: Synthesis of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methylpyrimidine-4,6-diamine A mixture of 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol), (6-chloro-pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 equiv.) and 4N HCl in dioxane (15 mL) is heated in a sealed tube at 150 °C for 5 h. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate solution. The aqueous layer is separated and extracted with DCM. The organic phase is washed with saturated brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7), followed by trituration with diethyl ether to give the title compound as a white solid. ESI-MS: 313.2 [MH] + ;t R =1.10 min (gradient J); TLC: R f = 0.21 (DCM / MeOH, 93:7)

[0215] Step B: Synthesis of 4-(4-ethylpiperazin-1-yl)-aniline A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney nickel (2 g) in methanol (120 mL) is stirred under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture is filtered through a pad of Celite and concentrated to give 5.3 g of the title compound as a purple solid. ESI-MS: 206.1 [MH] + ; TLC: R f = 0.15 (DCM / MeOH + 1% NH3 aqueous solution, 9:1).

[0216] Step C: Synthesis of 1-ethyl-4-(4-nitro-phenyl)-piperazine A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv.) is heated at 80 °C for 15 h. After cooling to room temperature, the reaction mixture is diluted with water and DCM / MeOH (9:1). The aqueous layer is separated and extracted with DCM / MeOH (9:1). The organic phase is washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1% NH3 aqueous solution, 9:1) to give 6.2 g of the title compound as a yellow solid. ESI-MS: 236.0 [MH] + ;t R = 2.35 min (purity: 100%, gradient J); TLC: R f = 0.50 (DCM / MeOH + 1% NH3 aqueous solution, 9:1).

[0217] Step D: Synthesis of (6-chloro-pyrimidin-4-yl)-methyl-amine This material was prepared by modifying a literature procedure (J. Appl. Chem. 1955, 5, 358). To a suspension of commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 equiv.) in isopropanol (60 mL), a 33% solution of methylamine in ethanol (40.1 mL, 328.9 mmol, 2.5 equiv.) was added at a rate such that the internal temperature did not exceed 50°C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. Water (50 mL) was then added, and the resulting suspension was cooled to 5°C in an ice bath. The precipitated product was filtered off and washed with cold isopropanol / water 2:1 (45 mL) and water. The collected material was dried under vacuum at 45°C overnight to give the title compound as a colorless powder. t R = 3.57 min (purity: >99%, gradient A), ESI-MS: 144.3 / 146.2 [MH] + .

[0218] vinegar Step E: Synthesis of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-4-(4-ethyl-piperazin-1-yl)-phenylamino-pyrimidin-4-yl}-1-methylurea The title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl isocyanate (1.25 equiv.) to a toluene solution of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 equiv.) and stirring the reaction mixture at reflux for 1.5 h. The crude product was purified by silica gel column chromatography (DCM / MeOH + 1% NH3 in water, 95:5) to give the title compound as a white solid. ESI-MS: 560.0 / 561.9 [MH] + ;t R = 3.54 min (purity: 100%, gradient J); TLC: R f = 0.28 (DCM / MeOH + 1% aqueous NH3, 95:5). Analysis: C 26 H 31 N7O3Cl2, calculated, 55.72%; H, 5.57%; N, 17.49%; O, 8.56%; C1, 12.65%. Found, 55.96%: H, 5.84%: N, 17.17%; O, 8.46%; C1, 12.57%.

[0219] Example 2: Synthesis of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-4-(4-ethyl-piperazin-1-yl)-phenylamino-pyrimidin-4-yl}-1-methylurea (BGJ398) monophosphate salt form A A round-bottom flask was charged with 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-4-(4-ethylpiperazin-1-yl)phenylamino-pyrimidin-4-yl)-1-methylurea (134 g, 240 mmol) and isopropanol (IPA) (2000 mL). The suspension was stirred and heated to 50 °C, and a solution of phosphoric acid (73.5 g, 750 mmol) in water (2000 mL) was added portionwise. The mixture was stirred at 60 °C for 30 minutes and then filtered through a polypropylene pad. The pad was washed with warm IPA / water (1:1, 200 mL), and the filtrates were combined. To this clear solution was added IPA (6000 mL), and the mixture was stirred under reflux for 20 minutes, then slowly cooled to room temperature (25 °C), and stirred for 24 hours. The white salt product was collected by filtration, washed with IPA (2 x 500 mL), and dried in an oven at 60 °C under reduced pressure for 2 days to give the anhydrous crystalline monophosphate salt (110 g), 70% yield, with a purity of >98% by HPLC. Analysis: C 26 H 34 N7O7Cl2P, calculated, 47.42%; H, 5.20%; N, 14.89%; O, 17.01%; Cl, ​​10.77%; P, 4.70%. Found, 47.40%; H, 5.11%; N, 14.71%; O, 17.18%; Cl, ​​10.73%; P, 4.87%.

[0220] Example 3: Infigratinib Monophosphate Minitablets in 0.1 mg and 1 mg Doses The following examples outline the manufacturing process for all exemplified doses.

[0221] The amounts of the corresponding components are shown in the formulas in Examples 3.1, 3.2, 3.3 and 3.4 below.

[0222] Mini-tablet manufacturing The manufacturing process for 0.1 mg and 1.0 mg infigratinib minitablets (described in Example 3.1 (Table 2) and Example 3.3 (Table 4), respectively) consists of wet granulation, blending, and compression molding, in one example with a batch size of 5000 g. The manufacturing process is as follows: Add povidone to the purified water dispensed into a container and mix until the povidone dissolves and forms a binding solution. Pass the granulated mannitol, microcrystalline cellulose, and crospovidone through a #30 mesh screen. Divide the mannitol and microcrystalline cellulose into four and three doses, respectively. Add mannitol (part 1) and microcrystalline cellulose (part 1) to a high shear granulator and mix for 5 minutes at 100 rpm. Pass the milled infigratinib phosphate (BGJ398API) and mannitol (portion 2) through a #60 mesh screen for infigratinib 0.1 mg minitablets or a #50 mesh screen for infigratinib 1.0 mg minitablets. Add the above sieved API, mannitol (part 2) and MCC (part 2) to the high shear granulator and mix for 5 minutes with the impeller speed at 100 rpm. Add mannitol (part 3) to the high shear granulator and mix for 5 minutes with the impeller at 100 rpm. Add the remaining mannitol, microcrystalline cellulose, and intragranular crospovidone to the high shear granulator and mix for 5 minutes with the impeller at 150 rpm. Turn on the high shear granulator, set the impeller speed to 150 rpm, and spray the binder solution over about 1 minute. Once the addition of the binder solution is complete, set the impeller speed to 150 rpm and mix the wet mass for 30 seconds. · Further, the impeller speed is set to 150 rpm and the chopper speed to 1500 rpm and the wet mass is mixed for 30 seconds. A fluidized bed dryer of appropriate size, with an inlet air temperature of approximately 60°C and an air volume of approximately 250 m 3 / h to dry the wet granules until the LOD is NMT 2%. The dried granules are milled in a Quadro Comil equipped with a 2A032R screen at a speed of approximately 1500 rpm. Pass the extragranular crospovidone through a #30 mesh screen and FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake through a #80 mesh screen (FD&C Blue #1 for infigratinib 1.0 mg minitablets only). Place the milled granules, extragranular crospovidone, and FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake (FD&C Blue #1 for infigratinib 1.0 mg minitablets only) into an appropriate-sized bin blender and blend at 26 rpm for 5 minutes. · Add magnesium stearate sieved through a #40 mesh screen to the blender and mix for 5 minutes at 26 rpm and discharge as the final blend. · Compress the final blend into mini tablets in a suitable press using a 2.2 mm round tablet press. The manufacturing process for 0.1 mg infigratinib minitablets according to the formulation of Example 3.1 (Table 3) consists of dry blending and compression in an example batch size of 5000 g according to the following procedure. The milled API is passed through a #50 mesh screen and the sieved API is dispensed into double polyethylene bag-lined containers. The mannitol, microcrystalline cellulose, and croscarmellose sodium are passed through a #30 mesh screen. The sieved mannitol is divided into three portions and the microcrystalline cellulose into two portions. · Add mannitol (part 1) to the bag containing the sieved milled API and mix manually for 1 minute. Transfer the above mixture to a suitable size V-blender and blend for 10 minutes. Add sieved microcrystalline cellulose (part 1) to the blender and blend for 10 minutes. Drain the mixture and pass it through a #30 mesh screen and return it to the blender. Add sieved mannitol (part 2) to the blender and blend for 10 minutes. · Drain mixture and pass through a #30 mesh screen back into the blender. Add sieved microcrystalline cellulose (part 2) to the blender and blend for 10 minutes. Discard the mixture from the blender and pass it through a #30 mesh sieve, then put it back into the blender. Add the sieved croscarmellose sodium to the blender and blend for 10 minutes. Pass the magnesium stearate through a #40 mesh screen and place in a blender. Blend at 21 rpm for 3 minutes and discharge into the final blend. · Compress the final mixture into mini tablets using a 2 mm round tablet press. The manufacturing process for 1.0 mg infigratinib minitablets of the formulation described in Example 3.4 (Table 5), for example in a 5000 g batch size, consists of dry granulation, blending and compression, and is carried out as follows: The milled API is passed through a #50 mesh screen and the sieved API is dispensed into double polyethylene bag-lined containers. The intragranular portions of mannitol, microcrystalline cellulose, and croscarmellose sodium are passed through a #30 mesh screen, and FD&C Blue #1 / Brilliant Blue FCF Aluminum are passed through a #50 mesh screen and transferred to appropriately labeled plastic bag containers. Place the mannitol, milled API, FD&C Blue #1 / Brilliant Blue FCF Aluminum, microcrystalline cellulose, and intragranular portion of croscarmellose sodium into an appropriate size V-blender and blend at 21 rpm for 10 minutes. Drain the mixture and pass it through a #30 mesh screen into an LDPE bagged container. Place the sieved mixture into a blender and blend for 5 minutes at 21 rpm. Pass the magnesium stearate through a #40 mesh screen and collect in a stainless steel pan. Add the sieved magnesium stearate to the blender and blend for 3 minutes at 21 rpm. The mixture is granulated in a roller compactor to obtain a continuous flow of brittle ribbons. The crushed granules are collected in a tared double PE bag-lined container. The extra-glanular portion of the microcrystalline cellulose and croscarmellose sodium is passed through a #30 mesh screen. Place half of the dry granules, extragranular microcrystalline cellulose, extragranular croscarmellose sodium, and the remaining dry granules into a suitable V-blender and blend for 7 minutes at 21 rpm. · Pass the extragranular magnesium stearate through a #40 mesh screen, add to the V-blender, mix at 21 rpm for 5 minutes, and discharge as the final blend. · Compress the final blend into mini tablets using a 2mm round tablet press. [Table 2] [Table 3] [Table 4] [Table 5]

[0223] Example 4: Study of Oral Infigratinib Monophosphate (BGJ398) in Pediatric Patients with Achondroplasia the purpose Dose escalation: Main purpose Identifying a dose of oral infigratinib for children with achondroplasia (ACH) for further study based on safety and efficacy evaluations

[0224] Dose expansion: Main purpose : Provide preliminary evidence of the efficacy of oral infigratinib for the treatment of ACH, as assessed by change from baseline in height velocity in children with ACH.

[0225] Dose escalation and expansion: Secondary Objectives :To evaluate the safety and tolerability of oral infigratinib in children with ACH, to evaluate the changes from baseline in anthropometric measurements after oral infigratinib administration, and to evaluate the pharmacokinetic and pharmacodynamic (PK / PD) profile of infigratinib in children with ACH after oral infigratinib administration. exploratory purpose:Evaluation of changes in disease burden in ACH

[0226] methodology The safety, tolerability, and efficacy of infigratinib, a fibroblast growth factor receptor (FGFR) 1-3-selective tyrosine kinase inhibitor, were evaluated in children aged 3 to 11 years with ACH who received the drug for at least 6 months. The study included dose escalation and expansion with extended treatment duration.

[0227] Dose escalation and treatment extension (total 18 months of treatment and follow-up) Eligible subjects aged 3 to 11 years were enrolled in dose-escalation cohorts of approximately 10. The proportion of subjects under 8 years of age and over 8 years of age was roughly equal between cohorts.

[0228] Up to four cohorts were planned. Each cohort began after the Data Review Committee (DRC) determined the previous dose was safe based on prespecified criteria (see "Cohort Dose Escalation" and "Cohort Dose De-escalation" below). In the United States, subjects began enrolling in Cohorts 3 and 4 (i.e., no US subjects were enrolled in Cohorts 1 and 2).

[0229] Subjects in each cohort received treatment and follow-up at their assigned dose for 6 months. After the 6-month study visit, subjects continued treatment for an additional 12 months (extension treatment period). To avoid long-term treatment at a potentially ineffective or less effective dose, subjects in cohorts 1 and 2 had their dose escalated to the next dose level at the 6-month and 12-month study visits (up to two dose escalations were permitted) if no safety concerns were identified and annual height velocity did not increase by 25% or more from baseline (not applicable in the United States). The 12-month dose escalation occurred if the dose identified for further study had not been determined by the time a subject reached 12 months of treatment. Subjects in all cohorts may have had their dose adjusted to the dose identified for further study at this time. The dose identified for further study was selected based on a thorough review of efficacy and safety findings from dose escalation after all subjects had potentially completed 6 months of infigratinib treatment.

[0230] Dose expansion (total 12 months of treatment): To support and confirm the dose / administration regimen identified for further testing, 20 subjects were enrolled in a dose-expansion study and received infigratinib treatment at the identified dose for 12 months.

[0231] All subjects: After completing study activities, all subjects may have had the opportunity to enroll in an open-label, long-term extension study (conducted under a separate protocol) to evaluate the safety and efficacy of long-term infigratinib treatment in children with ACH.

[0232] Determination of starting dose and other cohort doses Starting dose: The starting dose for this Phase 2 study was determined based on the no-observed-adverse-effect level (NOAEL) in juvenile toxicity studies using rats, with a 10-fold safety margin. In the United States, the study began with cohort 3. This dose also took into account the estimated pharmacologically effective dose based on studies using a mouse model resembling achondroplasia.

[0233] Other dose cohorts: Dose-escalation cohorts were initiated after the Data Review Committee (DRC) confirmed the safety of the previous cohorts. Each dose was twice the previous dose. In the United States, the dose in Cohort 4 was twice the dose administered in Cohort 3. Dose cohort de-escalation was performed based on pre-specified criteria for safety reasons (see "Cohort Dose Escalation" and "Cohort Dose De-escalation" below).

[0234] Number of subjects A total of approximately 60 subjects were enrolled: 40 in the dose-escalation extension and 20 in the dose-expansion treatment.

[0235] Diagnosis and main inclusion criteria Inclusion Criteria: 1. Signed informed consent by subject, parent or legal representative (LAR) and signed informed ascent by subject (if applicable). 2. Age must be between 3 and 11 years old at the time of screening. 3. The diagnosis of ACH must be clinically documented and confirmed by genetic testing. 4. Have undergone growth assessment in the PROPEL study (protocol QBGJ398-001) for at least 6 months prior to study entry. 5. Able to walk and stand without assistance. 6. For girls aged 10 years and older, a negative pregnancy test. 7. If sexually active, willing to use effective contraception while taking study drug and for 3 months after the last dose of study drug. 8. Subject and parent or legal representative (LAR) are willing and able to comply with study visits and procedures. 9. Ability to take oral medications. 10. Willing to discontinue consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomelo, starfruit, Seville orange, or products containing the juice of these fruits, and have not consumed any of these within 7 days prior to the first dose of study medication.

[0236] Exclusion criteria: 1. Hypochondroplasia or short stature other than ACH (e.g., trisomy 21, pseudoachondroplasia, psychosocial short stature). 2. For females, they have had their first period. 3. Height for age and sex less than -2 or more than +2 standard deviations based on the ACH Child Growth Reference Tables (Horton 1978). 4. Annual height growth velocity is 1.5 cm / year or less for a period of 6 months or more prior to screening. 5. Any significant comorbid disease or condition that, in the judgment of the investigator and / or sponsor, may interfere with the evaluation of the efficacy or safety of infigratinib, including but not limited to: Heart or vascular disease History of myocardial infarction, left ventricular hypertrophy, flat T waves (especially in inferior leads), or significant electrocardiographic abnormalities such as non-trivial nonspecific ST-T wave changes, QRS >90 ms, QT interval corrected using Fridericia's formula (QTcF) >440 ms, PR interval >170 ms, or complete right or left bundle branch block. ·Hyperthyroidism Dysthyroidism or recently diagnosed hypothyroidism without stable treatment for at least 3 months Diabetes mellitus (HbA1c > 9%) or requiring insulin therapy Adrenal insufficiency ·Autoimmune inflammatory diseases ·Inflammatory bowel disease Severe sleep apnea requiring surgery or new use of a continuous positive airway pressure (CPAP) device (based on a screening sleep study) 6. Significant abnormalities on screening tests, including but not limited to: Hemoglobin less than 10.0 g / dL b. Total bilirubin level exceeds 1.5 times the upper limit of normal c. AST / SGOT or ALT / SGPT levels exceeding twice the upper limit of normal d. Measured or calculated creatinine clearance less than 60 mL / min 7. Current evidence of corneal or retinal disorder / keratopathy (including but not limited to bullous / band keratopathy, corneal abrasion, inflammation / ulcer, keratoconjunctivitis, etc.) confirmed by ophthalmologic examination. 8. History and / or current findings of extensive ectopic tissue calcification. 9. History of malignant tumor. 10. Currently using medications known to prolong the QT / QTc interval (within 7 days or 5 half-lives prior to the screening visit, whichever is longer) or are being treated with drugs known to be strong inducers or inhibitors of CYP3A4 and drugs that increase serum phosphorus and / or calcium concentrations. Subjects cannot be receiving medications that alter gastrointestinal pH, such as vitamin D analogs, antacids, H2 receptor antagonists (e.g., ranitidine), proton pump inhibitors (e.g., omeprazole), or enzyme-inducing antiepileptic drugs, such as carbamazepine, phenytoin, phenobarbital, or primidone. 11. Current evidence of endocrine abnormalities of calcium / phosphorus homeostasis: a. Inorganic phosphorus is outside the normal range. b. Serum total calcium (corrected value) is outside the normal range. 12. Allergy to any component of the study drug. 13. Treatment with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids within the past 6 months, or long-term treatment for more than 3 months at any time. 14. Receipt of targeted therapy with C-type natriuretic peptide (CNP) analogues, fibroblast growth factor (FGF) ligand traps, or FGFR inhibition at any time point. 15. Within 6 months of the screening visit, have received supraphysiological doses of glucocorticoid therapy (i.e., 15 mg / m 2 Regular long-term treatment (≥3 weeks) with hydrocortisone or equivalent (>1 / day) or anti-inflammatory doses of glucocorticoids for ≥3 weeks (continuous use of low-dose inhaled corticosteroids for asthma is permitted). 16. Treatment with any other investigational drug or investigational medical device intended to treat ACH or short stature. 17. History of limb lengthening or guided growth surgery. 18. Have had a fracture within 6 months of screening (due to potential effects on bone biomarkers and bone morphology).

[0237] Test product, dosage and administration method Four dose cohorts were used. Cohort 1: 0.016 mg / kg Cohort 2: 0.032 mg / kg Cohort 3: 0.064 mg / kg Cohort 4: 0.128 mg / kg

[0238] In countries outside the United States, infigratinib is administered orally, with the starting dose (Cohort 1) at 0.016 mg / kg QD, which corresponds to one-tenth of the preclinical no-toxicity dose. In the United States, the trial began with Cohort 3 (0.064 mg / kg), which corresponds to an estimated pharmacologically effective dose based on studies using a mouse model resembling achondroplasia.

[0239] Evaluation items Dose escalation: Primary endpoint Treatment-emergent adverse events (TEAEs) leading to dose reduction or discontinuation. Change from baseline in height velocity (annualized, cm / year). (Baseline is defined as the annualized height velocity from a minimum 6-month observation period in the PROPEL trial.)

[0240] Dose expansion: Primary endpoint Change in height growth velocity from baseline (annualized, cm / year).

[0241] Dose escalation and expansion: secondary endpoints Safety assessment by incidence, type, severity and causality of adverse events (AEs), serious adverse events (SAEs), clinical laboratory results (urinalysis, biochemistry, hematology), vital signs, physical examination (including ophthalmological and dental evaluation), electrocardiogram, and clinically significant changes in diagnostic imaging. Absolute height velocity (annualized cm / year), expressed as a numerical value and a Z-score for non-ACH tables. Changes from baseline in anthropometric measurements, including absolute values ​​(expressed as absolute values ​​and Z-scores relative to ACH and non-ACH standardized pediatric growth charts) and body habitus. Anthropometric measurements include, but are not limited to, standing height, sitting height, weight, head circumference, upper and lower arm lengths, thigh length, knee height, and arm span. Body proportion measurements include, but are not limited to, upper body to lower body segment ratio, upper arm to forearm ratio, thigh to leg length ratio, arm span to height ratio, and head circumference to height ratio. PK parameters (e.g. C max and t max ) Changes in PD parameters (biomarkers of bone metabolism, e.g., type X collagen degradation fragments, collagen X marker [CXM]).

[0242] Dose Escalation and Dose Expansion: Exploratory endpoints Changes in disease-specific complications, such as changes in mobility (assessed by range of motion of elbows, hips, and knees), changes in annual number of episodes of otitis media, changes in number and / or severity of sleep apnea episodes, and changes in quality of life (QoL) according to PedsQL (Generic Core Scale Short Form, child and parent reported). Baseline range of motion and PedsQL were consistent with values ​​obtained at the baseline visit. The baseline incidence of otitis media was the number of episodes recorded during the PROPEL trial (events / year). Baseline sleep apnea was consistent with a polysomnogram performed at screening (to rule out severe sleep apnea).

[0243] Data Review Committee (DRC); Cohort Dose Escalation; Cohort Dose De-escalation; Individual Subject Dose Reduction / Discontinuation Data Review Committee (DRC) The study utilized a Data Review Committee (DRC) to monitor subject safety and key efficacy data and provide recommendations to the sponsor regarding dose escalation, de-escalation, and / or dose cohort expansion. Dose escalation and deescalation of the cohorts was determined by the DRC based on a Bayesian optimal interval (BOIN) design (Liu 2015) with a target toxicity rate of 25%.

[0244] Cohort dose escalation Each cohort was initiated after the safety of the previous dose cohort (electrocardiogram, vital signs, physical examination, TEAE assessment, and laboratory tests) was reviewed and confirmed by the DRC. During dose escalation, the initiation of a new dose escalation cohort was determined by the DRC based on safety data from approximately 10 subjects in each cohort who completed at least 4 weeks of treatment and safety assessments. After at least 4 weeks of treatment, the next dose cohort was initiated if ≤1 in 10 subjects met the dose reduction / discontinuation criteria (see "Individual Subject Dose Reduction / Discontinuation" below) and no other safety concerns were identified by the DRC.

[0245] Cohort Dose Tapering The need for cohort dose reduction was determined by the DRC based on safety assessments and the incidence of TEAEs leading to dose reduction / discontinuation in individual subjects (see below). If 3 or more subjects in a cohort met the dose reduction / discontinuation criteria after 3 subjects had been treated, enrollment in that cohort and / or the higher-dose cohort (if applicable) was paused and a DRC was convened. The DRC determined whether the dose of the current or higher-dose cohort should be reduced (i.e., subjects in the current cohort continue treatment at the next lower dose for efficacy evaluation), whether treatment could continue at the same dose, and / or whether cohort expansion was necessary to continue safety evaluation of that dose level.

[0246] Dose reduction / discontinuation in individual subjects The DRC monitored subject safety and, taking into account the number of subjects meeting dose reduction / discontinuation criteria, determined whether cohort-level dose escalation or cohort-level dose decrement was necessary, but dose modifications in individual subjects were managed by the investigator. The following events were considered adverse events requiring dose reduction / discontinuation in individual subjects: 1. Phosphorus > 4.5 mg / dL (or the age-adjusted upper limit of normal for the reported laboratory value) (confirmed by repeat testing). 2. Calcium level >10.7 mg / dL (or the age-adjusted upper limit of normal for the reported laboratory value) (confirmed by repeat testing). 3. Treatment-related adverse events of grade 2 or greater as assessed by the investigator. 4. Grade 1 or greater corneal toxicity. Subjects who experienced at least one of the above adverse events had their dose modified as follows: In individual subjects, treatment will be suspended until one of the following conditions is met: · Phosphorus and / or calcium levels return to normal. - Reduction in the severity of treatment-related adverse events of Grade 2 or higher to < Grade 2. Abnormal eye findings disappear. Resume administration at the next lower dose level. If the adverse event leading to treatment discontinuation did not resolve within 4 weeks with appropriate supportive care, the subject discontinued treatment.

[0247] Subject discontinuation / withdrawal from study or study drug Early withdrawal from the study or study drug occurred for any of the following reasons: Subject (or guardian / LAR) requests withdrawal or withdraws consent. The adverse event leading to treatment discontinuation did not resolve within 4 weeks despite appropriate supportive care. The investigator determines that discontinuation of the study drug or the study is in the subject's best interest, including (but not limited to) worsening of growth imbalance, development or worsening of tibial bowing, development of infigratinib-related bone and growth plate fractures, or deterioration of elbow range of motion. Subjects were at or nearing final height as defined by pubertal Tanner stage 4 or greater and a growth velocity of 1.5 cm / year or less (Marshall 1969; Marshall 1970). Subjects' height growth velocity was less than 1.5 cm / year for at least 6 months. The subject developed a clinically significant condition that could interfere with the evaluation of efficacy or safety or required treatment with prohibited medications such as vitamin D analogues, antacids, H2 receptor antagonists (e.g., ranitidine), drugs that alter gastrointestinal pH such as proton pump inhibitors (e.g., omeprazole), or enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin, phenobarbital, or primidone (see Section 8.3 [Main Protocol]). The female subject became pregnant. · Protocol deviations (at the sponsor's discretion). · Cancellation of the trial by the sponsor. Lost to follow-up.

[0248] statistical methods Sample size Dose escalation and deescalation rules were implemented based on a BOIN design with a target toxicity rate of 25%. The interval boundaries in Table 11 (main protocol) were selected based on a maximum toxicity rate of 15% for subtherapeutic doses and a minimum toxicity rate of 35% for over-toxic doses. Furthermore, based on observational data, if there was a 95% or greater probability that the incidence of TEAEs leading to dose reduction or discontinuation would exceed 25%, the current dose cohort was excluded from the study. If the first dose level was excluded, the study was terminated or a lower dose was evaluated according to the DRC's recommendations. Dose selection for dose expansion was based on evaluation of approximately 10 subjects per cohort. If the true adverse event rate was 25%, there would be 94.4% confidence that at least one adverse event would be observed in 10 subjects per cohort. Furthermore, assuming a normal distribution of height velocity change from baseline with a standard deviation of 2 cm / year, there was a 62.5% probability that the 95% confidence interval (CI) for height velocity would be at most 1.5 cm / year. In the dose-expansion study, approximately 20 subjects were enrolled at each selected dose level. An increase in annual height velocity of 0.5 cm / year or less was considered clinically insignificant and was used as the null hypothesis. Assuming a 2 cm / year increase in height velocity after initiating infigratinib treatment with a standard deviation of 2 cm / year, 20 subjects would provide approximately 88.9% power to demonstrate that infigratinib treatment increases height velocity by more than 0.5 cm / year at a one-sided significance level of 0.025.

[0249] Dose escalation For dose escalation, separate analyses were performed for each treatment cohort based on the initial dose and total dose. A continuous analysis was performed to support the DRC review. The doses considered for dose escalation were selected based on a thorough review of safety and efficacy data, after considering the likelihood that all subjects would complete 6 months of infigratinib treatment.

[0250] Dose expansion Subjects enrolled in the dose-expansion study were analyzed for both safety and efficacy. These data were used to infer changes from baseline in height velocity. Extension analyses could have been performed, and the final analysis of the dose-expansion study was performed after all subjects had had an opportunity to complete 12 months of treatment in the dose-expansion study.

[0251] statistical analysis All safety analyses were performed using the safety analysis population, which was defined as subjects who received at least one dose of study drug. Analyses of growth parameter endpoints were performed in subjects who underwent at least one baseline and post-baseline growth parameter assessment. Baseline and demographic variables were summarized. A safety summary included adverse events (AEs) recorded for 30 days from the last dose. All TEAEs were summarized and tabulated. TEAEs leading to dose reductions or discontinuation were summarized. Laboratory changes, disease-specific comorbidities, and surgical procedures were summarized. For subjects enrolled in dose escalation, baseline and post-baseline changes in weight, height, head circumference, and body shape, as well as change from baseline in annual height velocity and changes in these parameters, were summarized based on the first 6-month assessment. For assessments performed after 6 months, summaries were provided every 6 months based on the initial dose. For subjects enrolled in the dose-expansion study, change in annual height velocity from baseline was tested using a one-sample t-test to assess whether the increase was greater than 0.5 cm / year. Descriptive statistics, including 95% confidence intervals, for baseline and post-baseline weight, height, head circumference, and body shape, as well as height velocity parameters, and the change from baseline in these parameters were presented. Descriptive statistics were also provided to examine the association between biomarkers and height velocity. Assessment of disease-specific complications was summarized by visit.

[0252] Example 5: Study of Oral Infigratinib Monophosphate (BGJ398) in Pediatric Patients with Achondroplasia: Updated Study Protocol and Results Updated Testing Protocol The study described in Example 4 is a phase 2, open-label study designed to provide preliminary evidence of the safety and efficacy of oral infigratinib in children with achondroplasia and to identify doses of infigratinib that should be investigated in future phase 3 trials.

[0253] The study consisted of three parts. -Dose escalation phase with extended treatment duration; PK substudy: Five dose-escalation cohorts (doses from 0.016 to 0.25 mg / kg / day) Treat at the assigned dose for 6 months, then continue treatment for an additional 12 months (extension). Dose escalation (M6 and M12) was permitted for children enrolled in cohorts 1 and 2 if height velocity did not increase by more than 25% compared to baseline and no safety concerns were identified. -Dose expansion phase: During the confirmatory phase, additional children were enrolled and treated with infigratinib for 12 months at the doses selected in the dose-escalation phase.

[0254] Children aged 3 to less than 11 years with a confirmed molecular diagnosis of achondroplasia and who completed at least 6 months of observation in the PROPEL trial (NCT04035811, https: / / clinicaltrials.gov / ct2 / show / NCT04035811?term=NCT04035811&draw=2&rank=1) were enrolled. The PROPEL trial is incorporated herein by reference in its entirety.

[0255] 1 and 10 show an overview of the clinical studies described in Examples 4 and 5.

[0256] Subject breakdown and demographics breakdown: -Early cancellation: 4 · Consent withdrawal: 3 cases (due to personal circumstances that prevented compliance with the study activities). One subject required a procedure that interfered with efficacy and safety assessments. -Number of completed tests: 39

[0257] Demographics: -Female: 42 people (58.3%), Male: 30 people (41.7%) -Age (at time of consent): Mean 7.5±2.2 years Age range: 3.1 to 11.5 years Under 8 years old: 37 (51.4%) Ages 3 to 5: 12 (16.7%) 8 years old and above: 35 people (48.6%) -Ethnicity: ·White: 44 people (61.1%) Black or African American: 4 (5.6%) Asian: 6 (8.3%) Multiple: 2 people (2.8%) Other: 3 (4.2%), Unreported: 13 (18.1%)

[0258] FIG. 2 shows the demographics of patients receiving 0.25 milligrams per kilogram (mg / kg) of infigratinib per day in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0259] result Safety - Adverse Events (AE) Overview Treatment with infigratinib was well tolerated.

[0260] There were no serious adverse events (SAEs), and no AEs requiring treatment discontinuation were observed.

[0261] Seventy-one of 72 children (98.6%) experienced at least one TEAE. TEAE severity was grade 1 (58.3%) and grade 2 (34.7%), and most were unrelated to the study drug. Four children (two from cohort 2 and two from cohort 3) experienced a grade 3 TEAE that was assessed as unrelated to the study drug. These TEAEs corresponded to expected complications in children with ACH (cholesteatoma, hydrocephalus, severe sleep apnea, and worsening adenoid hypertrophy).

[0262] In the highest dose group (cohort 5-0.25 mg / kg / day), no serious adverse events (SAEs) or adverse events requiring treatment discontinuation were observed. Most TEAEs were grade 1 in severity and were not assessed for relationship to study drug. There were no grade 3 TEAEs. There were no ocular adverse events. There were no cases of hyperphosphatemia. Acceleration of bone age and deterioration of body mass index were not observed.

[0263] A summary of the most frequently reported adverse events is shown in Figure 11.

[0264] result 3-9 and 12-15 show the results of tests carried out according to Examples 4 and 5.

[0265] FIG. 3 summarizes preliminary results for patients receiving infigratinib 0.25 mg / kg once daily in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0266] FIG. 4 shows that infigratinib demonstrated a significant dose-responsive increase in annual height velocity compared to baseline in patients receiving infigratinib 0.25 mg / kg once daily in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0267] FIG. 5 shows the mean increase in annual height velocity (AHV) in patients receiving infigratinib up to 0.25 mg / kg daily.

[0268] FIG. 6 shows individual-level data for patients in Cohort 5 of the clinical trial described in Examples 4 and 5 who received infigratinib at 0.25 mg / kg once daily.

[0269] FIG. 7 shows that in Cohort 5 of the clinical trial described in Examples 4 and 5, patients receiving infigratinib 0.25 mg / kg once daily had a median AHV of over 7 cm / year.

[0270] FIG. 8 shows the consistency of AHV over time observed in the clinical trials described in Examples 4 and 5.

[0271] FIG. 9 shows the percent increase in collagen X marker levels observed in patients participating in the clinical trials described in Examples 4 and 5.

[0272] FIG. 12 is an updated version of FIG. 4 and shows that infigratinib demonstrated a significant dose-responsive increase in annual height velocity compared to baseline in patients receiving 0.25 mg / kg / day of infigratinib in Cohort 5 of the clinical trial described in Examples 4 and 5.

[0273] Figure 13 is an updated version of Figure 5 and shows the mean increase in annual height velocity (AHV) in patients receiving up to 0.25 mg / kg / day of infigratinib.

[0274] FIG. 14 shows the change in height Z-score and body habitus after 6 months of treatment with infigratinib in patients with ACH in cohorts 1-5 compared to baseline (study described in Examples 4 and 5).

[0275] FIG. 15 is an updated version of FIG. 9 showing the percent increase in collagen X marker levels observed in patients participating in the clinical trial described in Examples 4 and 5.

[0276] summary Treatment with oral infigratinib was well tolerated, with no serious adverse events (SAEs) or TEAEs leading to treatment discontinuation.

[0277] At the Cohort 5 dose level (0.25 mg / kg / day), no hyperphosphatemia, ocular adverse events (retinal or corneal disorders), accelerated bone age progression, or worsening body size ratio were observed (data suggest that the Cohort 5 dose level may have a favorable effect on upper / lower body segment ratio).

[0278] Infigratinib treatment at the dose level in cohort 5 resulted in a significant and robust increase in AHV compared with BL, showing a change of +3.38 cm / year.

[0279] This increase in growth was expressed as an increase of +0.29 standard deviations in Z-scores compared to the ACH growth chart and +0.25 standard deviations in Z-scores compared to the mean height growth chart.

[0280] The linear growth changes are supported by increases in CXM, supporting a true biological effect.

[0281] Incorporation by Reference This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification will control. Furthermore, certain embodiments of the present disclosure that fall within the prior art may be expressly excluded from one or more claims. Such embodiments may be excluded even if not explicitly set forth herein, as they are deemed to be known to those of ordinary skill in the art. Certain embodiments of the present disclosure may be excluded from any claim for any reason, regardless of whether they fall within the prior art.

[0282] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A method for treating achondroplasia or hypochondroplasia in a subject in need thereof, comprising orally administering to the subject about 0.250 milligrams per kilogram (mg / kg) of infigratinib or a pharmaceutically acceptable salt thereof daily.

2. 1. A method for treating achondroplasia or hypochondroplasia in a subject in need thereof, comprising orally administering to the subject about 2.5 milligrams (mg) to about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof daily.

3. 3. The method of claim 2, wherein about 2.5 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

4. 4. The method of claim 3, wherein the subject weighs less than about 12 kilograms (kg).

5. 3. The method of claim 2, wherein about 3.5 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

6. 6. The method of claim 5, wherein the subject weighs between about 12 kg and about 15 kg.

7. 3. The method of claim 2, wherein about 5.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

8. 8. The method of claim 7, wherein the subject weighs between about 16 kg and about 22 kg.

9. 3. The method of claim 2, wherein about 7.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

10. 10. The method of claim 9, wherein the subject weighs between about 23 kg and about 31 kg.

11. 3. The method of claim 2, wherein about 10.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

12. 12. The method of claim 11, wherein the subject weighs between about 32 kg and about 43 kg.

13. 3. The method of claim 2, wherein about 14.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

14. 14. The method of claim 13, wherein the subject weighs between about 44 kg and about 70 kg.

15. 3. The method of claim 2, wherein about 20.0 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the subject daily.

16. 16. The method of claim 15, wherein the subject weighs at least about 70 kg.

17. The method according to any one of claims 1 to 16, wherein the subject has achondroplasia.

18. The method according to any one of claims 1 to 17, wherein the subject has hypochondroplasia.

19. The method according to any one of claims 1 to 18, wherein the subject has an FGFR3 mutation.

20. The method according to claim 19, wherein the FGFR3 mutation is a G380R mutation or an N540K mutation.

21. 21. The method of any one of claims 1 to 20, wherein infigratinib or a pharmaceutically acceptable salt thereof is administered as mini-tablets, each mini-tablet containing about 0.1 mg or about 1 mg of infigratinib or a pharmaceutically acceptable salt thereof.

22. The method according to any one of claims 1 to 21, wherein the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate.

23. 23. The method of claim 22, wherein infigratinib monophosphate is present as an anhydrous crystalline form.

24. 24. The method of claim 23, wherein the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak at 15.0°±0.2° (2θ).

25. 25. The method of any one of claims 1 to 24, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in height growth velocity compared to baseline.

26. 26. The method of any one of claims 1 to 25, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in absolute height growth velocity.

27. 27. The method of any one of claims 1-26, wherein the subject's mean change from baseline in annual height velocity (AHV) during or after treatment is at least about 2.0 centimeters per year (cm / year).

28. 27. The method of any one of claims 1-26, wherein the subject's change from baseline in AHV during or after treatment is from about 1.0 cm / year to about 14 cm / year.

29. 29. The method of claim 28, wherein the subject's change from baseline in AHV during or after treatment is from about 2.5 cm / year to about 4.5 cm / year.

30. The changes in the AHV of the person being treated are approximately 1.0 cm / year, 1.1 cm / year, 1.2 cm / year, 1.3 cm / year, 1.4 cm / year, 1.5 cm / year, 1.6 cm / year, 1.7 cm / year, 1.8 cm / year, and 1.9 cm / year. Approximately 2.0 cm / year, approximately 2.1 cm / year, approximately 2.2 cm / year, approximately 2.3 cm / year, approximately 2.4 cm / year, approximately 2.5 cm / year, approximately 2.6 cm / year, approximately 2.7 cm / year, approximately 2.8 cm / year, approximately 2.9 cm / year, approximately 3.0 cm / year, approximately 3.1 cm / year, approximately 3.2 cm / year, approximately 3.3 cm / year Approximately 3.4 cm / year, approximately 3.5 cm / year, approximately 3.6 cm / year, approximately 3.7 cm / year, approximately 3.8 cm / year, approximately 3.9 cm / year, approximately 4.0 cm / year, approximately 4.1 cm / year, approximately 4.2 cm / year, approximately 4.3 cm / year, approximately 4.4 cm / year, approximately 4.5 cm / year, approximately 4.6 cm / year, approximately 4.7 cm / year. m / year, approximately 4.8 cm / year, approximately 4.9 cm / year, approximately 5.0 cm / year, approximately 5.1 cm / year, approximately 5.2 cm / year, approximately 5.3 cm / year, approximately 5.4 cm / year, approximately 5.5 cm / year, approximately 5.6 cm / year, approximately 5.7 cm / year, approximately 5.8 cm / year, approximately 5.9 cm / year, approximately 6.0 cm / year, approximately 6.1 cm / year cm / year, approximately 6.2 cm / year, approximately 6.3 cm / year, approximately 6.4 cm / year, approximately 6.5 cm / year, approximately 6.6 cm / year, approximately 6.7 cm / year, approximately 6.8 cm / year, approximately 6.9 cm / year, approximately 7.0 cm / year, approximately 7.1 cm / year, approximately 7.2 cm / year, approximately 7.3 cm / year, approximately 7.4 cm / year, approximately 7 5 cm / year, approximately 7.6 cm / year, approximately 7.7 cm / year, approximately 7.8 cm / year, approximately 7.9 cm / year, approximately 8.0 cm / year, approximately 8.1 cm / year, approximately 8.2 cm / year, approximately 8.3 cm / year, approximately 8.4 cm / year, approximately 8.5 cm / year, approximately 8.6 cm / year, approximately 8.7 cm / year, approximately 8.8 cm / year, Approximately 8.9 cm / year, approximately 9.0 cm / year, approximately 9.1 cm / year, approximately 9.2 cm / year, approximately 9.3 cm / year, approximately 9.4 cm / year, approximately 9.5 cm / year, approximately 9.6 cm / year, approximately 9.7 cm / year, approximately 9.8 cm / year, approximately 9.9 cm / year, approximately 10.0 cm / year, approximately 10.1 cm / year, approximately 10.2 cm / year. cm / year, approximately 10.3 cm / year, approximately 10.4 cm / year, approximately 10.5 cm / year, approximately 10.6 cm / year, approximately 10.7 cm / year, approximately 10.8 cm / year, approximately 10.9 cm / year, approximately 11.0 cm / year, approximately 11.1 cm / year, approximately 11.2 cm / year, approximately 11.3 cm / year, approximately 11.4 cm / year,27. The method of any one of claims 1 to 26, wherein the growth rate is about 11.5 cm / year, about 11.6 cm / year, about 11.7 cm / year, about 11.8 cm / year, about 11.9 cm / year, about 12.0 cm / year, about 12.1 cm / year, about 12.2 cm / year, about 12.3 cm / year, about 12.4 cm / year, about 12.5 cm / year, about 12.6 cm / year, about 12.7 cm / year, about 12.8 cm / year, about 12.9 cm / year, about 13.0 cm / year, about 13.1 cm / year, about 13.2 cm / year, about 13.3 cm / year, about 13.4 cm / year, about 13.5 cm / year, about 13.6 cm / year, about 13.7 cm / year, about 13.8 cm / year, about 13.9 cm / year, or about 14.0 cm / year. ,

31. 31. The method of claim 30, wherein the subject's change from baseline in AHV during or after treatment is about 3.0 cm / year.

32. 31. The method of claim 30, wherein the subject's change from baseline in AHV during or after treatment is about 4.0 cm / year.

33. 27. The method of any one of claims 1-26, wherein the subject has an absolute AHV of at least about 2.0 centimeters per year (cm / yr) during or after treatment.

34. 34. The method of claim 33, wherein the subject has an absolute AHV of at least about 7.0 cm / year during or after treatment.

35. 27. The method of any one of claims 1 to 26, wherein the subject has an absolute AHV of about 1.0 cm / year to about 14 cm / year during or after treatment.

36. 36. The method of any one of claims 1 to 35, wherein the subject experiences no treatment-related adverse events during or after treatment.

37. 37. The method of claim 36, wherein the subject experiences no serious adverse events during or after treatment.

38. 38. The method of any one of claims 1 to 37, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an increase over baseline in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

39. 39. The method of any one of claims 1 to 38, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

40. 40. The method of any one of claims 1 to 39, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in body weight compared to baseline.

41. 41. The method of any one of claims 1 to 40, wherein the subject exhibits an absolute loss in body weight after daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

42. 42. The method of any one of claims 1 to 41, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject's head circumference increases proportionally compared to baseline.

43. 43. The method of any one of claims 1 to 42, wherein the subject experiences a proportional increase in head circumference in absolute terms following daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

44. 44. The method of any one of claims 1 to 43, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the subject's body proportion measurement ratios are normalized compared to baseline.

45. 45. The method of any one of claims 1 to 44, wherein the subject's body proportion measurement ratios are absolutely normalized after daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

46. 46. ​​The method of claim 44 or 45, wherein the body proportion measurement ratio is selected from the group consisting of upper body to lower body segment ratio, upper arm to forearm ratio, thigh to leg length ratio, arm span to height ratio, head circumference to height ratio, and combinations thereof.

47. 47. The method of any one of claims 1 to 46, wherein after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase compared to baseline in a biomarker of bone metabolism selected from the group consisting of type X collagen degradation fragments, collagen X markers, and combinations thereof.

48. 48. The method of any one of claims 1 to 47, wherein the subject's mean change from baseline in collagen X markers during or after treatment is at least about 5%.

49. 49. The method of any one of claims 1 to 48, wherein the mean change from baseline in the collagen X marker in the subject is about 10.0% to about 40.0%.

50. 50. The method of any one of claims 1 to 49, wherein the subject's exercise capacity increases compared to baseline after daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

51. 51. The method of any one of claims 1 to 50, wherein the number of episodes of otitis media in the subject is reduced compared to baseline after daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

52. 52. The method of any one of claims 1 to 51, wherein the number and / or severity of sleep apnea episodes in the pediatric patient is reduced compared to baseline after daily administration of infigratinib or a pharmaceutically acceptable salt thereof.

53. 53. The method of any one of claims 1 to 52, wherein the pediatric patient exhibits improved quality of life after daily administration of infigratinib or a pharmaceutically acceptable salt thereof, wherein the quality of life is assessed using a Pediatric Quality of Life Scale.

54. 54. The method of any one of claims 1 to 53, wherein the subject is under 18 years of age.

55. 55. The method of claim 54, wherein the subject is between 12 and 17 years old.

56. 55. The method of claim 54, wherein the subject is between 3 and 11 years old.

57. 55. The method of claim 54, wherein the subject is between 5 and 8 years old.

58. 55. The method of claim 54, wherein the subject is 8 to 11 years old.

59. 55. The method of claim 54, wherein the subject is less than 5 years old.

60. 55. The method of claim 54, wherein the subject is under 12 years of age.

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