CRYSVITA 10mg / ml injectible solution medication leaflet

CRYSVITA 10 mg solution for injection

CRYSVITA 20 mg solution for injection

CRYSVITA 30 mg solution for injection

CRYSVITA 10 mg solution for injection in pre-filled syringe

CRYSVITA 20 mg solution for injection in pre-filled syringe

CRYSVITA 30 mg solution for injection in pre-filled syringe

CRYSVITA 10 mg solution for injection

Each vial contains 10 mg of burosumab in 1 ml solution.

CRYSVITA 20 mg solution for injection

Each vial contains 20 mg of burosumab in 1 ml solution.

CRYSVITA 30 mg solution for injection

Each vial contains 30 mg of burosumab in 1 ml solution.

CRYSVITA 10 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 10 mg of burosumab in 0.33 ml solution.

CRYSVITA 20 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 20 mg of burosumab in 0.67 ml solution.

CRYSVITA 30 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 30 mg of burosumab in 1 ml solution.

Burosumab is a recombinant human monoclonal IgG1 antibody for FGF23 and is produced byrecombinant DNA technology using Chinese hamster ovary (CHO) mammalian cell culture.

Each vial contains 45.91 mg sorbitol.

Each 10 mg pre-filled syringe contains 15.30 mg sorbitol.

Each 20 mg pre-filled syringe contains 30.61 mg sorbitol.

Each 30 mg pre-filled syringe contains 45.91 mg sorbitol.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to slightly opalescent, colourless to pale brownish-yellowish solution.

CRYSVITA is indicated for the treatment of X-linked hypophosphataemia, in children and adolescentsaged 1 to 17 years with radiographic evidence of bone disease, and in adults.

CRYSVITA is indicated for the treatment of FGF23-related hypophosphataemia in tumour-inducedosteomalacia associated with phosphaturic mesenchymal tumours that cannot be curatively resected orlocalised in children and adolescents aged 1 to 17 years and in adults.

Treatment should be initiated by a physician experienced in the management of patients with metabolicbone diseases.

Oral phosphate and active vitamin D analogues (e.g. calcitriol) should be discontinued 1 week prior toinitiation of treatment. Vitamin D replacement or supplementation with inactive forms may be started orcontinued as per local guidelines under monitoring of serum calcium and phosphate. At initiation,fasting serum phosphate concentration should be below the reference range for age (see section 4.3).

X-linked hypophosphataemia (XLH)

Dosing in Children and Adolescents with XLH aged 1 to 17 years

The recommended starting dose in children and adolescents aged 1 to 17 years is 0.8 mg/kg of bodyweight given every two weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is90 mg.

After initiation of treatment with burosumab, fasting serum phosphate should be measured every2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter asappropriate. Fasting serum phosphate should also be measured 2 weeks after any dose adjustment.

If fasting serum phosphate is within the reference range for age, the same dose should be maintained.

Dose increase

If fasting serum phosphate is below the reference range for age, the dose may be increased stepwise by0.4 mg/kg up to a maximum dose of 2.0 mg/kg (maximum dose of 90 mg). Fasting serum phosphateshould be measured 2 weeks after dose adjustment. Burosumab should not be adjusted more frequentlythan every 4 weeks.

Dose decrease

If fasting serum phosphate is above the reference range for age, the next dose should be withheld andthe fasting serum phosphate reassessed within 2 weeks. The patient must have fasting serum phosphatebelow the reference range for age to restart burosumab at half of the previous dose, rounding the amountas described above.

Dose Conversion at age 18 years

Children and adolescents aged 1 to 17 years should be treated using the dosing guidance outlined above.

At 18 years of age the patient should convert to the adult dose and dosing regimen as outlined below.

Dosing in Adults with XLH

The recommended starting dose in adults is 1.0 mg/kg of body weight, rounded to the nearest 10 mg upto a maximum dose of 90 mg, given every 4 weeks.

After initiation of treatment with burosumab, fasting serum phosphate should be measured every2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter asappropriate. Fasting serum phosphate should be measured 2 weeks after the previous dose ofburosumab. If serum phosphate is within the normal range, the same dose should be continued.

Dose decrease

If serum phosphate is above the upper limit of normal range, the next dose should be withheld and theserum phosphate level reassessed within 2 weeks. The patient must have serum phosphate below thenormal range before restarting burosumab. Once serum phosphate is below the normal range, treatmentmay be restarted at half the initial starting dose up to a maximum dose of 40 mg every 4 weeks. Serumphosphate should be reassessed 2 weeks after any change in dose.

Tumour-induced osteomalacia (TIO)

The posology in children and adolescents with TIO aged 1 to 17 years has been determined frompharmacokinetic modelling and simulation (see section 5.2)

Dosing in Children with TIO aged 1 to 12 years

The recommended starting dose for children aged 1 to 12 years is 0.4 mg/kg of body weight, givenevery 2 weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 90 mg.

Dose increase

If serum phosphate is below the reference range for age, the dose may be increased in a stepwisemanner. Doses should be increased by an initial increment of 0.6 mg/kg with subsequent increments,depending on patient’s response to treatment, of 0.5 mg/kg (up to a maximum dose of 2.0 mg/kg),rounding the amount as described above, up to a maximum dose of 90 mg, given every 2 weeks. Fastingserum phosphate should be measured 2 weeks after dose adjustment. Burosumab should not be adjustedmore frequently than every 4 weeks.

Dosing in Adolescents with TIO aged 13 to 17 years

The recommended starting dose for adolescents aged 13 to 17 years is 0.3 mg/kg of body weight, givenevery 2 weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 180 mg.

Dose increase

If serum phosphate is below the reference range for age, the dose may be increased in a stepwisemanner. Doses should be increased by an initial increment of 0.3 mg/kg with subsequent increments ofbetween 0.2 mg/kg - 0.5 mg/kg (dose increment dependent on the patient’s serum phosphate responseto treatment), rounding the amount as described above, up to a maximum dose of 2.0 mg/kg (maximumdose 180 mg), given every 2 weeks. Fasting serum phosphate should be measured 2 weeks after doseadjustment. Burosumab should not be adjusted more frequently than every 4 weeks.

Dosing in Children and Adolescents with TIO aged 1 to 17 years

For all paediatric patients, after initiation of treatment with burosumab, fasting serum phosphate shouldbe measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 monthsand thereafter as appropriate. Fasting serum phosphate should also be measured 2 weeks after any doseadjustment. If fasting serum phosphate is within the reference range for age, the same dose should bemaintained.

Dose decrease

If serum phosphate is above the reference range for age, the next dose should be withheld and thefasting serum phosphate level reassessed in 2 weeks. Once serum phosphate is below the referencerange for age, treatment may be restarted at half the previous dose in rounding the amount as describedabove. The fasting serum phosphate level should be assessed 2 weeks after the dose adjustment. If thelevel remains below the reference range for age after the re-started dose, the dose can be furtheradjusted.

Dose Conversion at age 18 years

At 18 years of age the patient should convert to the adult dose and dosing regimen as outlined below.

Dosing in Adults with TIO

The recommended starting dose for adults is 0.3 mg/kg body weight, rounded to the nearest 10 mg,given every 4 weeks.

After initiation of treatment with burosumab, fasting serum phosphate should be measured 2 weeks aftereach dose for the first 3 months of treatment, and thereafter as appropriate. If serum phosphate is withinthe reference range, the same dose should be maintained .

Dose increase

If serum phosphate is below the reference range, the dose may be increased in a stepwise manner. Dosesshould be increased by an initial increment of 0.3 mg/kg, with subsequent increments of between0.2 mg/kg - 0.5 mg/kg (dose dependent on the patient’s response to treatment), up to a maximum doseof 2.0 mg/kg (maximum dose 180 mg), given every 4 weeks. Fasting serum phosphate should bemeasured 2 weeks after dose adjustment.

For patients whose serum phosphate still remains below the reference range, despite providing themaximum dose every 4 weeks, the previous dose may be divided and given every 2 weeks, withincremental increases as required, as outlined above, up to a maximum dose of 2.0 mg/kg every 2 weeks(maximum dose 180 mg).

Dose decrease

If serum phosphate is above the reference range, the next dose should be withheld and the fasting serumphosphate level reassessed in 2 weeks. The patient must have serum phosphate below the referencerange before restarting burosumab. Once serum phosphate is below the reference range, treatment maybe restarted at approximately half the previous dose, administered every 4 weeks. Serum phosphateshould be reassessed 2 weeks after any change in dose.

If the level remains below the reference range after the re-started dose, the dose can be further adjusted.

Dose Interruption in paediatric and adult patients with TIO

If a patient undergoes treatment of the underlying tumour (i.e., surgical excision or radiation therapy)burosumab treatment should be interrupted.

Following completion of the treatment of the underlying tumour, serum phosphate should be reassessedbefore reinitiating treatment with burosumab. Burosumab treatment should be resumed at the patient’soriginal starting dose if serum phosphate level remains below the lower end of the normal referencerange. Follow the recommended dose adjustment outlined above to maintain serum phosphate levelwithin the normal reference range for age.

For all patients with TIO, treatment should be discontinued if the treating physician considers that nomeaningful improvement in biochemical or clinical markers of response are observed, despite themaximum dose being administered.

All Patients

To decrease the risk for ectopic mineralisation, it is recommended that fasting serum phosphate istargeted in the lower end of the normal reference range for age (see section 4.4).

Treatments may be administered 3 days either side of the scheduled treatment date if needed forpractical reasons. If a patient misses a dose, burosumab should be resumed as soon as possible at theprescribed dose.

Burosumab has not been studied in patients with renal impairment. Burosumab must not be given topatients with severe or end stage renal disease (see section 4.3).

X-linked hypophosphataemia (XLH)

The safety and efficacy of burosumab in paediatric patients with XLH aged less than one year have notbeen established in clinical studies.

Tumour-induced osteomalacia (TIO)

The safety and efficacy of burosumab in paediatric patients with TIO have not been established inclinical studies.

Limited data is available in patients over 65 years of age.

For subcutaneous use.

Burosumab should be injected in the upper arm, abdomen, buttock or thigh.

The maximum volume of medicinal product per injection site is 1.5 ml. If more than 1.5 ml is requiredon a given dosing day, the total volume of medicinal product must be split and administered at two ormore different injection sites. Injection sites should be rotated and carefully monitored for signs ofpotential reactions (see section 4.4).

For handling of burosumab before administration, see section 6.6.

For some patients, self/carer-administration with either the vial and/or the pre-filled syringe may besuitable. Once no immediate dose modifications are anticipated, the administration can be performed byan individual who has been trained properly in injection techniques. The first self-administered dose afterdrug initiation or dose change should be conducted under the supervision of a healthcare professional.

Clinical monitoring of the patient, including monitoring of phosphate levels, must continue as requiredand as outlined below. A detailed ‘Instructions for Use’ section intended for the patient is provided atthe end of the Package Leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concurrent administration with oral phosphate, active vitamin D analogues (see section 4.5).

Fasting serum phosphate above the normal range for age due to the risk of hyperphosphatemia (seesection 4.4).

Patients with severe renal impairment or end stage renal disease.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded within the patient’s records.

Ectopic mineralisation

Ectopic mineralisation, as manifested by nephrocalcinosis, has been observed in patients with XLHtreated with oral phosphate and active vitamin D analogues; these medicinal products should be stoppedat least 1 week prior to initiating burosumab treatment (see section 4.2).

Monitoring for signs and symptoms of nephrocalcinosis, e.g. by renal ultrasonography, is recommendedat the start of treatment and every 6 months for the first 12 months of treatment, and annually thereafter.

Monitoring of plasma alkaline phosphatase, calcium, parathyroid hormone (PTH) and creatinine isrecommended every 6 months (every 3 months for children 1 - 2 years) or as indicated.

Monitoring of urine calcium and phosphate is suggested every 3 months.

Hyperphosphataemia

Levels of fasting serum phosphate should be monitored due to the risk of hyperphosphatemia. Todecrease the risk for ectopic mineralisation, it is recommended that fasting serum phosphate is targetedin the lower end of the normal reference range for age. Dose interruption and/or dose reduction may berequired (see section 4.2). Periodic measurement of post prandial serum phosphate is advised.

To prevent hyperphosphataemia, treatment with burosumab should be interrupted in patients withtumour-induced osteomalacia who undergo treatment of the underlying tumour. Burosumab treatmentshould be reinitiated only if the patient’s serum phosphate level remains below the lower end of thenormal reference range (see Section 4.2).

Serum parathyroid hormone

Increases in serum parathyroid hormone have been observed in some XLH patients during treatmentwith burosumab. Periodic measurement of serum parathyroid hormone is advised.

Administration of burosumab may result in local injection site reactions. Administration should beinterrupted in any patient experiencing severe injection site reactions (see section 4.8) and appropriatemedical therapy administered.

Burosumab must be discontinued if serious hypersensitivity reactions occur and appropriate medicaltreatment should be initiated.

CRYSVITA solution for injection in vials

This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml.

CRYSVITA 10 mg solution for injection in pre-filled syringe

This medicine contains 15.30 mg of sorbitol in each pre-filled syringe which is equivalent to45.91 mg/ml.

CRYSVITA 20 mg solution for injection in pre-filled syringe

This medicine contains 30.61 mg of sorbitol in each pre-filled syringe which is equivalent to45.91 mg/ml.

CRYSVITA 30 mg solution for injection in pre-filled syringe

This medicine contains 45.91 mg of sorbitol in each pre-filled syringe which is equivalent to45.91 mg/ml.

Concurrent administration of burosumab with oral phosphate and active vitamin D analogues iscontraindicated as it may cause an increased risk of hyperphosphatemia and hypercalcaemia (see section4.3).

Caution should be exercised when combining burosumab with calcimimetic medicinal products (i.e.agents that mimic the effect of calcium on tissues by activating the calcium receptor). Co-administrationof these medicinal products has not been studied in clinical trials and could potentially exacerbatehypocalcaemia.

There are no or limited amount of data from the use of burosumab in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Burosumab is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether burosumab/metabolites are excreted in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain fromburosumab therapy taking into account the benefit of breast feeding for the child and the benefit oftherapy for the woman.

Studies in animals have shown effects on male reproductive organs (see section 5.3). There are noclinical data available on the effect of burosumab on human fertility. No specific fertility studies inanimals with burosumab were conducted.

Burosumab has a minor influence on the ability to drive and use machines. Dizziness may occurfollowing administration of burosumab.

The most common (> 10%) adverse drug reactions reported in paediatric patients with XLH duringclinical trials based on completed long term studies up to a maximum exposure to burosumab of 214weeks (with variable period of exposure across the safety population) were: cough (55%), injection sitereactions (54%), pyrexia (50%), headache (48%), vomiting (46%), pain in extremity (42%), toothabscess (40%), vitamin D decreased (28%), diarrhoea (27%), nausea (21%), rash (20%), constipation(12%), and dental caries (11%).

The most common (> 10%) adverse drug reactions reported during clinical trials in adult patients with

XLH or adult patients with TIO, based on completed long term studies up to a maximum exposure toburosumab of 300 weeks (with variable period of exposure across the safety population), were: backpain (30%), injection site reaction (29%), headache (28%), tooth infection (28%), vitamin D decrease(28%), muscle spasms (18%), restless legs syndrome (16%), dizziness (16%) and constipation (13%)(see section 4.4 and ‘Description of selected adverse reactions’ below).

Tabulated lists of adverse reactions

The frequencies of adverse reactions are listed in Table 1 (XLH, paediatric patients), and Table 2 (XLHand TIO adult patients).

The adverse reactions are presented by system organ class and frequency categories, defined using thefollowing convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to< 1/100); rare (≥ 1/10 000 to < 1/1000); very rare (< 1/10 000), not known (cannot be estimated fromthe available data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Table 1: Adverse reactions reported in paediatric patients 1 to 17 years of age with XLH, observedfrom clinical trials (N=120) and post-marketing

MedDRA System Organ Class Frequency category Adverse reaction

Infections and infestations Very common Tooth abscess1

Respiratory, thoracic and 2mediastinal disorders Very common Cough

Nervous system disorders Very common Headache

Very common Dizziness3

Nausea

Gastrointestinal disorders Very common Diarrhoea

Dental Caries

Skin and subcutaneous tissuedisorders Very common Rash4

Musculoskeletal and connectivetissue disorders Very common Myalgia

Pain in extremity

General disorders and Very common Injection site reaction5administration site conditions Pyrexia

Investigations Very common Vitamin D decreased6

Not known Blood phosphorus increased71Tooth abscess includes: Tooth abscess, Tooth infection and Toothache2Cough includes: Cough, and Productive cough3Dizziness includes: Dizziness, and Dizziness exertional4Rash includes: Rash, Rash erythematous, Rash generalised, Rash pruritic, Rash maculo-papular, and Rash pustular5Injection site reaction includes: Injection site reaction, Injection site erythema, Injection site pruritus, Injection site swelling,

Injection site pain, Injection site rash, Injection site bruising, Injection site discolouration, Injection site discomfort, Injectionsite haematoma, Injection site haemorrhage, Injection site induration, Injection site macule, and Injection site urticaria6Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased7Blood phosphorus increased includes: Blood phosphorus increased and Hyperphosphataemia

Table 2: Adverse reactions observed from clinical trials in adults (N=203) with XLH (N=176) and

TIO (N=27)

MedDRA System Organ Class Frequency Category Adverse Reaction

Infections and infestations Very common Tooth infection1

Very common Headache2

Nervous system disorders Very common Dizziness

Very common Restless legs syndrome

Gastrointestinal disorders Very common Constipation

Skin and subcutaneous tissue 3disorders Common Rash

Musculoskeletal and connective Very common Back paintissue disorders Very common Muscle spasms

General disorders and 4administration site conditions Very common Injection site reaction

Investigations Very common Vitamin D decreased

Common Blood phosphorus increased61 Tooth infection includes: tooth abscess, tooth infection and toothache2 Headache includes: headache and head discomfort3Rash includes: rash, rash papular and rash erythematous4Injection site reaction includes: Injection site reaction, Injection site erythema, Injection site pruritus, Injection site swelling,

Injection site pain, Injection site rash, Injection site bruising, Injection site discolouration, Injection site discomfort, Injectionsite haematoma, Injection site haemorrhage, Injection site induration, Injection site macule, Injection site urticaria, Injectionsite hypersensitivity and Injection site inflammation5Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased6Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphataemia

Paediatric patients with XLH:

Local reactions (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, andhaematoma) have occurred at the site of injection. In the paediatric studies, approximately 54% of thepatients had an injection site reaction, based on data from clinical studies. The injection site reactionswere generally mild in severity, occurred within 1 day of medicinal product administration, mostlylasted 1 to 3 days, required no treatment, and resolved in almost all instances.

Adult patients with XLH or TIO:

Injection site reactions were generally mild in severity, required no treatment, and resolved in almost allinstances.

In patients with XLH, in the placebo-controlled treatment period of Study UX023-CL303, the frequencyof injection site reactions was 12% in both burosumab and placebo treatment groups (injection sitereaction, erythema, rash, bruising, pain, pruritis and haematoma).

In patients with TIO, the frequency of injection site reactions based on data from completed long termclinical studies was 22% (injection site reaction, injection site pain and injection site swelling).

Paediatric patients with XLH:

Hypersensitivity reactions (e.g.: injection site reactions, rash, urticaria, swelling face, dermatitis, etc)were reported in 39% of paediatric patients, based on data from clinical studies. All reported reactionswere mild or moderate in severity.

Adult patients with XLH or TIO:

Hypersensitivity reactions were mild or moderate in severity.

In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303, the incidence ofpotential hypersensitivity reactions was similar (6%) in the burosumab treated and placebo treatedadults.

In patients with TIO, the frequency of hypersensitivity reactions (rash, drug eruption, andhypersensitivity) based on data from completed long term clinical studies was 30%.

Vitamin D Decreased

Paediatric patients with XLH:

Reduced serum 25 hydroxy-vitamin D has been observed following initiation of burosumab treatment inapproximately 8% of paediatric patients, possibly due to increased conversion to activated 1,25dihydroxy-vitamin D. Supplementation with inactive vitamin D was successful in restoring plasmalevels to normal.

Hyperphosphataemia

Adult patients with XLH or TIO:

In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303 in the burosumabgroup, 9 subjects (13.2%) had high serum phosphate at least once; 5 of these 9 required protocol-specified dose reduction(s). After initiation of burosumab in the open-label Treatment Continuation

Period, 8 subjects (12.1%) in the placebo→burosumab group had high serum phosphate levels. Four ofthese 8 subjects required protocol-specified dose reduction(s). The dose for all patients meeting theprotocol-specified criteria was reduced by 50%. A single patient (1%) required a second dose reductionfor continued hyperphosphataemia.

In patients with TIO, based on data from completed long term clinical studies, 11% of patientsexperienced events of hyperphosphataemia, which were managed with dose reduction.

Restless legs syndrome

Adult patients with XLH or TIO:

In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303 approximately12% of the burosumab treatment group and 8% in the placebo group had a worsening of baselinerestless legs syndrome or new onset restless legs syndrome of mild to moderate severity.

In patients with TIO, based on data from completed long term clinical studies, 11% of patientsexperienced events of restless legs syndrome of mild to moderate severity.

Paediatric patients with XLH:

Overall, the incidence of anti-drug antibodies (ADA) to burosumab in paediatric patients administeredburosumab, based on data from clinical studies was 10%. The incidence of neutralising ADA inpaediatric patients was 3%. No adverse events, loss of efficacy, or changes in the pharmacokineticprofile of burosumab were associated with these findings.

Adult patients with XLH and TIO:

The incidence of patients that tested positive for ADAs to burosumab in adult clinical studies with XLHor TIO, based on data from completed long term clinical studies was 15%. None of these patientsdeveloped neutralising ADA. No adverse events, loss of efficacy, or changes in the pharmacokineticprofile of burosumab were associated with these findings.

Adverse reactions in paediatric patients with TIO

No data are available in paediatric patients with TIO (see section 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

There is no experience with overdose of burosumab. Burosumab has been administered in paediatric

XLH clinical trials without dose limiting toxicity using doses up to 2.0 mg/kg body weight with amaximal dose of 90 mg every two weeks. In adult XLH clinical trials no dose limiting toxicity has beenobserved using doses up to 1.0 mg/kg or a maximal total dose of 128 mg every 4 weeks. In adult TIOclinical trials no dose limiting toxicity has been observed using doses up to 2.0 mg/kg or a maximal totaldose of 184 mg every 4 weeks.

In case of overdose, it is recommended to stop burosumab and to monitor biochemical response.

Pharmacotherapeutic group: Drugs for the treatment of bone diseases, other drugs affecting bonestructure and mineralisation, ATC code: M05BX05.

Burosumab is a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activityof fibroblast growth factor 23 (FGF23). By inhibiting FGF23, burosumab increases tubular reabsorptionof phosphate from the kidney and increases serum concentration of 1,25 dihydroxy-Vitamin D.

Clinical efficacy in paediatric patients with XLH

Study UX023-CL301

In paediatric study UX023-CL301 61 patients aged 1 to 12 years (56% female; 44% male, Age at firstdose, mean (SD): 6.3 (3.31) years) were randomised to burosumab (n=29) or active control (n=32; oralphosphate and active vitamin D). At entry to the study all patients had to have had a minimum of 6months treatment of oral phosphate and active vitamin D. All patients had radiographic evidence ofbone disease due to XLH (Rickets severity score ≥ 2). Burosumab was started at a dose of 0.8 mg/kgevery 2 weeks and increased to 1.2 mg/kg if there was inadequate response, as measured by fastingserum phosphate. Those patients randomised to active control group received multiple daily doses oforal phosphate and active vitamin D.

The primary efficacy endpoint was the change in severity of rickets at Week 40, as assessed by the RGI-

C (Radiographic Global Impression of change) score, compared between the burosumab and activecontrol groups.

The RGI-C is a relative rating scale that compares a patient’s rickets before and after treatment utilisinga 7-point ordinal scale to evaluate change in the same abnormalities rated in the RSS (as describedbelow). Scores range from -3 (indicating severe worsening of rickets) to +3 (indicating complete healingof rickets).

The severity of paediatric rickets was measured using the RSS, a radiographic scoring method based onthe degree of metaphyseal fraying, concavity, and the proportion of the growth plate affected. In the

UX023-CL301 study, the RSS was scored using a predefined scale looking at specific abnormalities inthe wrists and knees.

All patients (n=61) completed the 64 Week randomised Treatment Period. No patients had dosereductions and 8 (28%) of burosumab-treated patients received dose escalations to 1.2 mg/kg. A total of51 patients entered the Treatment Extension Period, 26 patients in the active control→burosumab groupand 25 patients in the burosumab→burosumab group, and were treated with burosumab up to 124

Weeks.

Primary Efficacy Results

Greater healing of rickets at Week 40 was seen with burosumab treatment compared to active controland this effect was maintained at week 64, as shown in Figure 1. These results were sustained to Week88 (n=21).

Figure 1: RGI-C Global Score (Mean ± SE) - Primary Efficacy Endpoint at Week 40 and 64 (Full

Analysis Set)

Secondary Efficacy Results

Key Secondary efficacy endpoint results for Weeks 40 and 64 are presented in Table 3. These resultswere sustained to Week 88 (n=21).

Table 3: Secondary Efficacy Endpoint Results

Endpoint Week Active Control Burosumab Difference

LS Mean (SE) LS Mean (SE) (burosumab -active control)40 +0.22 (0.080) +0.62 (0.153) +0.40 [95% CI:

Lower Limb 0.07, 0.72]

Deformity; assessed p = 0.0162by RGI-C 64 +0.29 (0.119) +1.25 (0.170) +0.97 [95% CI:(GEE model) +0.57, +1.37]p <0.0001

Baseline -2.05 (0.87) -2.32 (1.17)40 a +0.03 (0.031) +0.16 (0.052) +0.12 [95% CI:

0.01, 0.24]

Height; Z-score p = 0.040864 b +0.02 (0.035) +0.17 (0.066) +0.14 [95% CI:0.00, 0.29]p = 0.0490

Baseline 3.19 (1.141) 3.17 (0.975)40 a -0.72 (0.162) -2.08 (0.104) -1.34 [95% CI:

Rickets severity, RSS 1.74, -0.94]total Score p < 0.000164 b -1.01 (0.151) -2.23 (0.117) -1.21 [95% CI:

- 1.59, -0.83]p < 0.0001

Baseline 523 (154) 511 (125)40 a 489 (189) 381 (99) -97 [95% CI:

- 138, -56]

Serum ALP (U/L) p < 0.000164 b 495 (182) 337 (86) -147 [95% CI:

- 192, -102]p < 0.0001

Baseline 450 (106) 385 (86)40 a +4 (14) +47 (16) +43 [95% CI:

Six Minute Walk Test -0.3, 87](m) p = 0.051464 b +29 (17) +75 (13) +46 [95% CI:

2, 89]p = 0.0399a: the change from Baseline to Week 40 from ANCOVA model.b: the change from Baseline to Week 64 from GEE Model.

Serum Phosphate

At each study visit at which serum phosphate was assessed in both groups, changes in serum phosphatefrom Baseline were larger in the burosumab group compared with the active control group (p < 0.0001;

GEE model) (Figure 2).

Figure 2: Serum Phosphate Concentration and Change from Baseline (mg/dL) (Mean ± SE) by

Treatment Group (PD Analysis Set)

Note: Dashed line in figure indicates the lower limit of the normal serum phosphate reference range, 3.2 mg/dL (1.03 mmol/L)

During the Treatment Extension Period (Week 66 to Week 140), prolonger burosumab treatment in bothgroups (burosumab→burosumab (n=25) and active control→burosumab (n=26) the results weresustained.

Study UX023-CL201

In paediatric Study UX023-CL201, 52 paediatric patients aged 5 to 12 years (mean 8.5 years; SD 1.87)with XLH were treated for an initial period of 64 Weeks and dosed either every two weeks (Q2W) orevery four weeks (Q4W). This was followed by two extension periods with dosing Q2W for all patients;the first period up to 96 Weeks (total 160 Weeks) and a further period of up to 56 Weeks for safetyanalysis.

Nearly all patients had radiographic evidence of rickets at baseline and had received prior oralphosphate and vitamin D analogues for a mean (SD) duration of 7 (2.4) years. This conventionaltherapy was discontinued 2-4 weeks prior to burosumab initiation. The burosumab dose was adjusted totarget a fasting serum phosphate concentration of 3.50 to 5.02 mg/dL (1.13 to 1.62 mmol/L). In the first64 Weeks, 26 of 52 patients received burosumab Q4W. Twenty six of 52 patients received burosumab

Q2W at an average dose (min, max) of 0.73 (0.3, 1.5), 0.98 (0.4, 2.0) and 1.04 (0.4, 2.0) mg/kg at weeks16, 40 and 64 respectively, and up to a maximum dose of 2.0 mg/kg.

Burosumab increased serum phosphate concentration and increased TmP/GFR. In the Q2W group,mean (SD) serum phosphate concentration increased from 2.38 (0.405) mg/dL (0.77 (0.131) mmol/L) atbaseline), to 3.3 (0.396) mg/dL (1.07 (0.128) mmol/L) at Week 40 and was maintained to Week 64 at3.35 (0.445) mg/dL (1.08 (0.144) mmol/L). The increased serum phosphate levels were sustained to

Week 160 (n=52).

Alkaline phosphatase activity

Mean (SD) serum total alkaline phosphatase (ALP) activity was 459 (105) U/L at Baseline anddecreased to 369 (76) U/L at Week 64 (-19.6%, p < 0.0001); decreases were similar in the two dosegroups. Overall, decreased serum ALP levels were sustained to Week 160.

Bone-derived serum alkaline phosphatase (BALP) content was 165 (52) μg/L [mean (SD)] at Baselineand 115 (31) μg/L at Week 64 (mean change: -28.5%); decreases were similar in the two dose groups.

Overall, decreased serum BALP levels were sustained to Week 160.

In Study UX023-CL201 the severity of paediatric rickets was measured using the RSS, as describedabove, which was scored using a predefined scale looking at specific abnormalities in the wrists andknees. As a complement to the RSS assessment, the RGI-C rating scale was used. Results aresummarised in Table 4.

Table 4: Rickets Response in Children 5-12 Years Receiving Burosumab in Study UX023-CL201

Duration of

Endpoint Burosumab Effect Size(week) Q2W (N=26) Q4W (N=26)

RSS Total Score

Baseline Mean (SD) 1.92 (1.2) 1.67 (1.0)

LS Mean change (SE) 40 -1.06 (0.100) (p<0.0001) -0.73 (0.100) (p<0.0001)from baseline in totalscorea (reduced RSS scoreindicates improvement in -1.00 (0.1) (p<0.0001) -0.84 (0.1) (p<0.0001)rickets severity)

RGI-C Global Score

LS Mean score (SE)a +1.66 (0.1) (p<0.0001)(positive indicates healing) 40 +1.47 (0.1) (p<0.0001)64 +1.56 (0.1) (p<0.0001) +1.58 (0.1) (p<0.0001)a) The estimates of LS means and p-values are from the generalized estimation equation model accounting forbaseline RSS, visits and regimen and its interaction.

Study UX023-CL205

In paediatric Study UX023-CL205, burosumab was evaluated in 13 XLH patients, aged 1 to4 years (mean 2.9 years; SD 1.1) for a Treatment Period of 64 Weeks. Twelve patients continued toreceive burosumab for an additional 96 Weeks during the Extension Period, for a maximum duration of160 Weeks. All patients had radiographic evidence of rickets at baseline and 12 patients had receivedoral phosphate and vitamin D analogues for a mean (SD) duration of 16.7 (14.4) months. Thisconventional therapy was discontinued 2-6 weeks prior to burosumab initiation. Patients receivedburosumab at a dose of 0.8 mg/kg every two weeks.

Mean (SD) fasting serum phosphate concentration increased from 2.51 (0.284) mg/dL (0.81(0.092) mmol/L) at baseline to 3.47 (0.485) mg/dL (1.12 (0.158) mmol/L) at Week 40 and the increasedlevels were sustained to Week 160.

Serum alkaline phosphatase activity

Mean (SD) serum total alkaline phosphatase activity was 549 (193.8) U/L at baseline and decreased to335 (87.6) U/L at Week 40 (mean change: -36.3%). Decreased serum total alkaline phosphatase activitywas sustained with long-term treatment to Week 160.

Rickets Severity Score (RSS)

Mean total RSS improved from 2.92 (1.367) at baseline to 1.19 (0.522) at Week 40, corresponding to achange from baseline in LS mean (SE) change of -1.73 (0.132) (p <0.0001). The RSS was sustained to

Weeks 64, 112 and 160.

Radiographic Global Impression of Change (RGI-C)

After 40 weeks of treatment with burosumab, the LS mean (SE) RGI-C Global score was +2.21 (0.071)in all 13 patients (p < 0.0001) demonstrating healing of rickets. All 13 patients were considered RGI-Cresponders as defined by RGI-C global score ≥ +2.0. The RGI-C global score was sustained to Weeks64, 112, and 160.

The European Medicines Agency has deferred the obligation to submit the results of studies withburosumab in one or more subsets of the paediatric population in treatment of X-linkedhypophosphataemia. See 4.2 for information on paediatric use.

Clinical efficacy in adults with XLH

Study UX023-CL303

Study UX023-CL303 is a randomised, double-blind, placebo-controlled study in 134 adult XLHpatients. The study comprised of a 24-week placebo-controlled treatment phase followed by a 24-weekopen-label period where all patients received burosumab. Oral phosphate and active vitamin Danalogues were not allowed during the study. Burosumab was administered at a dose of 1 mg/kg every 4weeks. The primary endpoint of this study was normalisation of serum phosphate across the 24-weekdouble-blind period. Key secondary endpoints included worst pain as measured by the Brief Pain

Inventory (BPI) scale and stiffness and physical function as measured by the WOMAC (Western

Ontario and McMaster Universities Osteoarthritis) Index. Exploratory endpoints included fracture andpseudofracture healing, enthesopathy, 6 Minute Walk Test, BPI Pain interference, Brief Fatigue

Inventory (BFI) worst fatigue and BFI global fatigue score.

At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% weremale. 66 patients were randomised to placebo treatment and 68 to burosumab treatment; at baseline,mean (SD) serum phosphate was 0.62 (0.10) mmol/L [1.92 (0.32) mg/dL] and 0.66 (0.1 mmol/L) [2.03(0.30) mg/dL] in the placebo and burosumab groups respectively.

For the primary efficacy endpoint, a greater proportion of patients treated with burosumab achieved amean serum phosphate level above the lower limit of normal (LLN) compared to the placebo groupthrough week 24 (Table 5 and Figure 3).

Table 5: Proportion of Adult Patients Achieving Mean Serum Phosphate Levels Above the LLNat the Midpoint of the Dose Interval in Study UX023-CL303 (Double-Blind Period)

Placebo Burosumab(N = 66) (N = 68)

Achieved Mean Serum Phosphate > LLN Across 7.6% (5/66) 94.1% (64/68)

Midpoints of Dose Intervals Through Week 24 - n (%)95% CI (3.3, 16.5) (85.8, 97.7)p-valuea < 0.0001

The 95% CIs are calculated using the Wilson score method.a P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint andtreatment group, adjusting for randomisation stratifications.

Figure 3: Mean (± SE) Serum Phosphate Peak Concentrations (mg/dL [mmol/L])

Patient reported pain, physical function and stiffness

Change from baseline at Week 24 showed a larger difference for burosumab relative to placebo inpatient reported pain (BPI), physical function (WOMAC Index) and stiffness (WOMAC Index). Themean (SE) difference between treatment groups (burosumab-placebo) reach statistical significance for

WOMAC stiffness at Week 24. Details are shown in Table 6.

Table 6: Patient reported pain, physical function and stiffness score changes from baseline to

Week 24 and analysis of difference at Week 24

Placebo Burosumab

N=66 N=68

BPI worst paina

LS Mean (SE) change from Baseline -0.32 (0.2) -0.79 (0.2)[95% CIs] [-0.76, 0.11] [-1.20, -0.37]

LS Mean (SE) Difference -0.5 (0.28)(Burosumab-Placebo)p-value 0.0919c

WOMAC Index physical functionb

LS Mean (SE) change from Baseline +1.79 (2.7) -3.11 (2.6)[95% CIs] [-3.54, 7.13] [-8.12, 1.89]

LS Mean (SE) Difference -4.9 (2.5)p-value 0.0478c

WOMAC Index stiffnessb

LS Mean (SE) change from Baseline +0.25 (3.1) -7.87 (3.0)[95% CIs] [5.89, 6.39] [-13.82, -1.91]

LS Mean (SE) Difference -8.12 (3.2)(Burosumab-Placebo)p-value 0.0122a BPI worst pain item score ranges from 0 (no pain) to 10 (pain as bad as you can imagine)b WOMAC Index physical function and stiffness domains range from 0 (best health) to 100 (worst health)c Not significant following Hochberg adjustment6 Minute Walk Test

This exercise test was conducted in all patients at Baseline, Week 12, 24, 36 and 48 (LS meandifference in change from baseline, burosumab → placebo; Table 7). Improvements continued throughto Week 48 where distance walked increased from 357 m at baseline to 393 m at Week 48. Patients whocrossed over from placebo to burosumab achieved similar improvements after 24 weeks of treatment.

Table 7: 6 Minute Walk distance (SD) Baseline and Week 24; Least Squares Mean

Difference (SE)6 MWT, m(SD) Placebo Burosumab

Baseline 367 (103) 357 (109)

Week 24 369 (103) 382 (108)

LS Mean difference burosumab-placebo (SE) 20 (7.7)

Radiographic Evaluation of Fractures and Pseudofractures

In Study UX023-CL303, a skeletal survey was conducted at baseline to identify osteomalacia-relatedfractures and pseudofractures. There were 52% (70/134) of patients who had either active fractures(12%, 16/134) or active pseudofractures (47%, 63/134) at baseline. Following burosumab treatmentmore patients showed healing of fractures and pseudofractures compared to the placebo group(Figure 4). During the placebo-controlled treatment period up to week 24, a total of 6 new fractures orpseudofractures appeared in 68 patients receiving burosumab compared to 8 new abnormalities in 66patients receiving placebo. Of the number of new fractures developed prior to week 48 most (10/18)were healed or partially healed at the end of the study.

Figure 4: Percentage of Healed Active Fractures and Pseudofractures in Study UX023-CL303

At Baseline, the mean (SD) total calcaneal enthesopathy burden (sum of superior and inferior calcanealspurs) was 5.64 (3.12) cm in the burosumab group and 5.54 (3.1) cm in the placebo group. At Week 24,the mean (SD) total calcaneal enthesopathy burden was 5.90 (3.56) cm in the burosumab→burosumabgroup and 4.07 (2.38) cm in the placebo→burosumab group.

For the exploratory endpoints of BPI Pain interference, BFI worst fatigue and BFI global fatigue scoreno meaningful difference were observed between treatment arms.

Bone Histomorphometry in Adults

Study UX023-CL304

Study UX023-CL304 is a 48-week, open-label, single-arm study in adult XLH patients to assess theeffects of burosumab on improvement of osteomalacia as determined by histologic andhistomorphometric evaluation of iliac crest bone biopsies. Patients received 1.0 mg/kg burosumab every4 weeks. Oral phosphate and active vitamin D analogues were not allowed during the study.

14 patients were enrolled, and at study entry, the mean age of patients was 40 years (range 25 to 52years) and 43% were male. After 48 weeks of treatment in Study UX023-CL304 paired biopsies wereavailable from 11 patients; healing of osteomalacia was observed in all ten evaluable patients asdemonstrated by decreases in osteoid volume/bone volume (OV/BV) from a mean (SD) score of 26.1%(12.4) at baseline to 11.9% (6.6), Osteoid thickness (O.Th) declined in 11 evaluable patients from amean (SD) of 17.2 (4.1) micrometres to 11.6 (3.1) micrometres.

Clinical Efficacy in adult patients with Tumour-induced osteomalacia

Burosumab has been evaluated in two single-arm open-label studies which enrolled a total of 27 adultpatients with TIO. Oral phosphate and active vitamin D analogues were discontinued between 2-10weeks before burosumab treatment was initiated. Patients received burosumab every 4 weeks at aweight based starting dose of 0.3 mg/kg to achieve a fasting serum phosphate level of 2.5 to 4.0 mg/dL[0.81 to 1.29 mmol/L].

Study UX023T-CL201 enrolled 14 adult patients with a confirmed diagnosis of FGF23-relatedhypophosphataemia induced by an underlying tumour that was not amenable to surgical excision orcould not be located. Eight patients were male and age range for all patients was from 33 years to 68years of age (median 59.5 years). The mean (SD) dose of burosumab was 0.83 (0.41) mg/kg at Week20, 0.87 (0.49) mg/kg at Week 48, 0.77 (0.52) mg/kg at Week 96 and 0.67 (0.54) mg/kg at Week 144.

Study KRN23-002 enrolled 13 adult patients from Japan and South Korea with a confirmed diagnosis of

TIO. Six patients were male and age range for all patients was from 41 years to 73 years of age (median58.0 years). The mean (SD) dose of burosumab was 0.91 (0.59) mg/kg at Week 48, and 0.96(0.70) mg/kg at Week 88.

Serum Phosphate

In both studies, burosumab increased mean serum phosphate levels and these remained stablethroughout the study period, as shown in Figures 5 and 6, respectively.

Figure 5: Study UX023T-CL201 Serum Phosphate Concentration (mg/dL) (Mean ± SD)

Note: Dashed line in figure indicates the lower limit of the serum phosphate reference range, 2.5 mg/dL (0.81 mmol/L)5.04.54.03.53.02.52.01.51.00.5

Before w/d of Baseline/Week 0 14 24 44 96 Week 144oral P/vit D

Mean Serum Phosphate (mg/dL)

Number of Subjects: 8 14 8 14 13 14 14 13 14 14 14 12 14 14 14 12 14 13 13 13 13 12 12 10 12 11 11 11 11

*Before withdrawal of oral phosphate/vitamin D; these values were taken before the enrolment in the study

Serum Phosphate (mg/dL)

Mean(+-SD)

Figure 6: Study KRN23-002 Serum Phosphate Concentration (mg/dL) (Mean ± SD)

Note: Dashed line in figure indicates the lower limit of the serum phosphate reference range, 2.5 mg/dL (0.81 mmol/L)5.04.54.03.53.02.52.01.51.00.5

Before w/d of Baseline/Week 0 14 24 44 Week 88oral P/vit D

Mean Serum Phosphate (mg/dL)

Number of Subjects: 9 13 13 13 12 13 13 13 13 13 12 12 12 12 12 12 12 12 11 12 11 12 11 12 12 11

*Before withdrawal of oral phosphate/vitamin D; these values were taken before the enrolment in the study

In Study UX023T-CL201, the ratio of TmP/GFR increased in these patients from a mean (SD) of 1.12(0.54) mg/dL [0.36 (0.17) mmol/L] at baseline to 2.12 (0.64) mg/dL [0.68 (0.21) mmol/L] at Week 48and remained stable through to Week 144. In Study KRN23-002, the ratio of TmP/GFR, increased froma mean (SD) of 1.15 (0.43) mg/dL [0.46 (0.17) mmol/L] at baseline to 2.30 (0.48) mg/dL [0.92(0.19) mmol/L] at Week 48.

Bone Histomorphometry

In Study UX023T-CL201, 11 patients had paired bone biopsies; changes were assessed after 48 weeksof treatment. Histomorphology parameters are presented below in Table 8 as group mean measurementsat baseline and week 48, followed by the mean of relative changes of individualised measurements.

Table 8: Changes in histomorphology parameters in Study UX023T-CL201

Parameter Group mean (SD) score Percentage change in

Baseline Week 48 group mean values

OV/BV (%) 17.6 (19.5) 12.1 (15.4) -31.3

OS/BS (%) 56.8 (31.0) 56.6 (26.3) -0.004

O.Th (μm) 16.5 (12.0) 11.3 (9.2) -31.5

Radiographic Evaluation99mtechnetium-labelled whole body bone scans and x-ray skeletal surveys were conducted at baselineand post-treatment up to Week 144 to assess the number of fractures and pseudofractures. A reductionin fractures and pseudofractures was observed on both bone scans and x-rays.

Paediatric patients with TIO

There are no clinical trials with burosumab in paediatric patients of any age with TIO. The posology ofburosumab in paediatric TIO patients has been determined from pharmacokinetic modelling andsimulation (see section 5.2).

The European Medicines Agency has waived the obligation to submit the results of studies withburosumab in all subsets of the paediatric population in treatment of Tumour-induced Osteomalacia. See4.2 for information on paediatric use.

Serum Phosphate (mg/dL)

Mean(+-SD)

Burosumab absorption from subcutaneous injection sites to blood circulation is nearly complete.

Following subcutaneous administration, the median time to reach maximum serum concentrations (Tmax)of burosumab is approximately 7-13 days. The peak serum concentration (Cmax) and area under theconcentration-time curve (AUC) of serum burosumab is dose proportional over the dose range of0.1-2.0 mg/kg.

In XLH patients, the observed volume of distribution of burosumab approximates the volume of plasma,suggesting limited extravascular distribution.

Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and isunlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination areexpected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptidesand individual amino acids.

Due to its molecular size, burosumab is not expected to be directly excreted. The clearance ofburosumab is dependent on body weight and estimated to be 0.290 L/day and 0.136 L/day in a typicaladult (70 kg) and paediatric (30 kg) XLH patient, respectively, with corresponding disposition half-life(t1/2) in the serum ranging from approximately 16 to 19 days. Given the t1/2 estimates, the estimated timeto reach the plateau of steady-state exposures is approximately 67 days. Following multiple doseadministration to paediatric subjects, observed serum trough concentrations reach a plateau by 8 weeksafter initiation of treatment.

Burosumab displays time-invariant pharmacokinetics that is linear to dose over the subcutaneous doserange of 0.1 to 2.0 mg/kg.

With the subcutaneous route of administration, in XLH and TIO subjects, a direct PK-PD relationshipbetween serum burosumab concentrations and increases in serum phosphate concentration is observedand well described by an Emax/EC50 model. Serum burosumab and phosphate concentrations, as well as

TmP/GFR, increased and decreased in parallel and reached maximum levels at approximately the sametime point after each dose, supporting a direct PK-PD relationship. The AUC for the change frombaseline in serum phosphate, TmP/GFR and 1,25(OH)2D increased linearly with increasing burosumab

AUC.

Paediatric PK/PD

No significant difference has been observed in paediatric patient pharmacokinetics orpharmacodynamics as compared with PK/PD in the adult population. Burosumab clearance and volumeof distribution are body weight dependent.

Paediatric patients with TIO

The starting dose of burosumab for paediatric patients with TIO is based on Population PK/PDmodeling and simulations which indicate that a starting dose of 0.4 mg/kg every 2 weeks for childrenaged 1- 12 years and 0.3 mg/kg every 2 weeks for adolescents aged 13-17 years is predicted to result ina proportion of paediatric patients with TIO reaching normal serum phosphate levels. These can betitrated up to a maximum of 2.0 mg/kg every 2 weeks (the highest dose simulated).

Population PK analyses using data from paediatric and adult subjects who have XLH and adult subjectswith TIO indicated that age, sex, race, ethnicity, baseline serum albumin, baseline serum alkalinephosphate, baseline serum alanine aminotransferase, and baseline creatinine clearance ≥ 49.9 mL/min,were not significant predictors of burosumab PK. Based on the population PK analysis, the PKcharacteristics of burosumab were similar between XLH and TIO patients.

Post-Prandial Effect on Serum Phosphate and Calcium

The effect of burosumab on serum phosphate and calcium levels after food was investigated in two sub-studies (Study UX023-CL301 and UX023-CL303); 13 paediatric patients (aged > 3 years) and 26 adultpatients (aged 24-65 years). Serum phosphate and calcium were measured at the end of the treatmentinterval in paediatric patients and mid-interval in adults. Blood samples were taken after a period offasting, and again 1-2 hours after a standardised meal.

Burosumab treatment did not cause post-prandial excursions above the age-adjusted upper limits ofnormal in serum phosphate or serum calcium in any paediatric or adult subject in the sub-studies.

Adverse reactions in non-clinical studies with normal animals were observed at exposures whichresulted in serum phosphate concentration greater than normal limits. These effects were consistent withan exaggerated response to the inhibition of normal FGF23 levels resulting in a supraphysiologicincrease in serum phosphate beyond the upper limit of normal.

Studies in rabbits and adult and juvenile cynomolgus monkeys demonstrated dose-dependent elevationsof serum phosphate and 1,25 (OH)2D confirming the pharmacologic actions of burosumab in thesespecies. Ectopic mineralisation of multiple tissues and organs (e.g. kidney, heart, lung, and aorta), andassociated secondary consequences (e.g. nephrocalcinosis) in some cases, due to hyperphosphataemia,was observed in normal animals at doses of burosumab that resulted in serum phosphate concentrationsin animals greater than approximately 8 mg/dL (2.6 mmol/L). In a murine model of XLH, a significantreduction in the incidence of ectopic mineralisation was observed at equivalent levels of serumphosphate, suggesting that the risk of mineralisation is less in the presence of excess FGF23.

Bone effects seen in adult and juvenile monkeys included changes in bone metabolism markers,increases in thickness and density of cortical bone, increased density of total bone and thickening oflong bone. These changes were a consequence of higher than normal serum phosphate levels, whichaccelerated bone turnover and also led to periosteal hyperostosis and a decrease in bone strength in adultanimals, but not in juvenile animals at the doses tested. Burosumab did not promote abnormal bonedevelopment, as no changes in femur length or bone strength were noted in juvenile animals. Bonechanges were consistent with the pharmacology of burosumab and the role of phosphate in bonemineralization, metabolism and turnover.

In repeat-dose toxicology studies of up to 40 weeks duration in cynomolgus monkeys, mineralisation ofthe rete testis/seminiferous tubules was observed in male monkeys; however, no changes were observedin semen analysis. No adverse effects on female reproductive organs were observed in these studies.

In the reproductive and developmental toxicology study performed in pregnant cynomolgus monkeys,moderate mineralisation of the placenta was seen in pregnant animals given 30 mg/kg of burosumab andoccurred in animals with peak serum phosphate concentration greater than approximately 8 mg/dL(2.6 mmol/L). Shortening of the gestation period and associated increased incidence of premature birthswere observed in pregnant monkeys at doses of ≥ 0.3 mg/kg which corresponded to burosumabexposures that are ≥ 0.875- to 1.39-fold anticipated clinical levels. Burosumab was detected in serumfrom fetuses indicating that burosumab was transported across the placenta to the fetus. There was noevidence of teratogenic effects. Ectopic mineralisation was not observed in foetuses or offspring andburosumab did not affect pre- and postnatal growth including survivability of the offspring.

In preclinical studies, ectopic mineralisation has been observed in normal animals, most frequently inthe kidney, given burosumab at doses that resulted in serum phosphate concentrations greater than8 mg/dL (2.6 mmol/L). Neither new or clinically meaningful worsening of nephrocalcinosis nor ectopicmineralisation have been observed in clinical trials of patients with XLH treated with burosumab toachieve normal serum phosphate levels.

L-histidine

D-sorbitol (E 420)

Polysorbate 80

L-methionine

Hydrochloric acid, 10% (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

CRYSVITA solution for injection in pre-filled syringe

Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C when protected fromlight.

From a microbiological point of view, the product should be used immediately. If not used immediately,in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C to 8°C). Do not freeze.

Store in the original package in order to protect from light.

CRYSVITA solution for injection in vials

Clear glass vial with butyl rubber stopper, and aluminium seal.

Pack size of one vial

CRYSVITA solution for injection in pre-filled syringe

Clear type I glass syringe with a staked stainless steel needle. The syringe is closed by a rigidpolypropylene and elastomer needle shield and a fluoropolymer-laminated bromobutyl rubber plungerstopper.

The different strengths of the medicinal product can be identified by a different coloured plunger rod:10 mg (blue), 20 mg (red), and 30 mg (green).

Pack size of one pre-filled syringe.

CRYSVITA solution for injection in vials

Each vial is for single use only.

Do not shake the vial before use.

Burosumab should be administered using aseptic technique and sterile disposable syringes and injectionneedles.

CRYSVITA solution for injection in pre-filled syringe

Before administration, the solution should be inspected visually. The liquid should be clear to slightlyopalescent, colourless to pale brown-yellow. If the solution is cloudy, discoloured or contains particles,the solution should not be used.

After removing the pre-filled syringe from the refrigerator, allow the syringe to reach room temperaturefor 45 minutes before injecting burosumab.

Comprehensive instructions for subcutaneous administration of burosumab in a pre-filled syringe isprovided at the end of the package leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Kyowa Kirin Holdings B.V.

Bloemlaan 22132NP Hoofddorp

The Netherlands+31 (0) 237200822medinfo@kyowakirin.com

EU/1/17/1262/001

EU/1/17/1262/002

EU/1/17/1262/003

EU/1/17/1262/004

EU/1/17/1262/005

EU/1/17/1262/006

Date of first authorisation: 19 February 2018

Date of latest renewal: 21 February 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.