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2 REPORT STATEMENTS

2.1 COMPLIANCE WITH GOOD CLINICAL PRACTICEThis Clinical Study Report is designed to comply with the standards issued by the Interna-tional Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical StudyReports; E6 Good Clinical Practice; and E9 Statistical Principles for Clinical Trials).

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3 SYNOPSISName of Sponsor/Manufacturer:LEO Pharma A/S

Location of study report in Regulatory Dossierfor authorities

Name of Investigational Product/Finished Product, if available:

EinsAlphaVolume:

Name of Active Substance:

Alfacalcidol (1-hydroxyvitamin D3)Page:

Title of study/Protocol Code Number:

A Phase I Pharmacokinetic Study with Repeated Doses of Alfacalcidol in Patients withChronic Renal Failure Undergoing Haemodialysis.International Co-ordinating Investigator:

, MD, , Germany.Centre details:

One centre in Germany.Publication references :

To be decided.Study period details:

First patient was enrolled on 25-Apr-2005Last patient was enrolled on 09-May-2005Last patient completed the study 01-Jun-2005

Phase of development:

Phase I

Objectives/hypothesis, if applicable:

To evaluate the pharmacokinetic profile of alfacalcidol (1-hydroxyvitamin D3) and its mainmetabolite 1.25-dihydroxyvitamin D3 after repeated doses (pulse dose regimen) of alfacalcidol(capsule) in patients with chronic renal failure undergoing haemodialysis.Study methodology:

This was a single centre, prospective, open and repeated dose pharmacokinetic study of LEOPharma alfacalcidol (EinsAlpha) in patients with chronic renal failure undergoing haemodi-alysis. During the trial, dialysis sessions lasting from 3 to 8 hours were performed three times aweek with intervals of 48 or 72 hours. All patients entered a two-week washout period beforethe treatment started. During the treatment phase, patients received a 1.5 g oral dose ofalfacalcidol (6 0.25 g) three times a week for two weeks at the end of their regular dialysissessions (visit days 3 - 8). Blood samples for the pharmacokinetic analysis were obtained overthe 72 hours after the last dose of the two-week treatment phase. During the pharmacokineticphase, patients were housed overnight in the dialysis clinic on visit days 8 and 9 until comple-tion of the 72-hour post dose blood draw.

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Name of Sponsor/Manufacturer:LEO Pharma A/S

Location of study report in Regulatory Dossierfor authorities

Name of Investigational Product/Finished Product, if available:

EinsAlphaVolume:

Name of Active Substance:

Alfacalcidol (1-hydroxyvitamin D3)Page:

Number of patients enrolled:

Fourteen (14) subjects (9 males and 5 females) were enrolled in this study (visit day -1),including two back up patients to account for possible dropouts. Overall the data from twelve(12) subjects (8 males and 4 females), who completed the study, were used for the pharma-cokinetic analysis.Diagnosis and main criteria for patient selection:

Chronic renal failure.Criteria for inclusion: Patients with chronic renal failure undergoing maintenance haemodialysis three times a week.At least 18 years old.Criteria for exclusion: A haemoglobin level below 10 g/dl.Concurrent malignancy or clinically significant liver disease (e.g. ALT, AST, bilirubin morethan twice the upper limit of normal) at qualification.Investigational product:

Finished Product (Brand) Name (if avail-able)/Name investigational product

EinsAlpha

Formulation CapsulesActive Ingredient Name/Concentration Alfacalcidol/0.25 g per capsuleExcipients Sesame oil, -tocopherol, gelatine, glycerol,

potassium sorbate, titanium dioxidePack size(s) 10 10 capsulesManufacturers name LEO PharmaSuppliers name LEO PharmaCertifiers name LEO PharmaLot number/expiry date V7340G/05 2007

Reference product:

None.Duration of treatment:

Washout phase: 2 weeks.Treatment phase: 2 weeks.Pharmacokinetic sampling phase: 3 days.

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Name of Sponsor/Manufacturer:LEO Pharma A/S

Location of study report in Regulatory Dossierfor authorities

Name of Investigational Product/Finished Product, if available:

EinsAlphaVolume:

Name of Active Substance:

Alfacalcidol (1-hydroxyvitamin D3)Page:

Criteria for evaluation on,primary and secondary response criteria

Efficacy :

Primary response criterion: Pharmacokinetic parameters including AUC, Cmax, Tmax and half life (t) of 1-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in serum.

Secondary end point/response criterion: Not applicable.

Safety:

AEs, effects on S-calcium and effects on haematology.Statistical methodology:

As the concentration of alfacalcidol (1(OH) D3) was below the LLOQ (i.e. 50 pg/ml) in allsamples, the PK analysis was only performed on 1.25 (OH)2 D3 (calcitriol), the active metabo-lite of alfacalcidol.Calcitriol AUC 0-t, Cmax, Tmax were calculated for unadjusted and baseline adjusted concentra-tions. In addition, calcitriol AUCinf, AUC 0-t/AUCinf, t and kel were calculated for baselineadjusted concentrations. Descriptive statistics were presented for all pharmacokinetic parame-ters.Summary Conclusions

Efficacy results:

The pharmacokinetics of calcitriol was assessed in 12 patients with chronic renal failure at theend of a two-week treatment with repeated 1.5 g doses of alfacalcidol (EinsAlpha) capsulesadministered three times a week.Mean concentration-time profiles of calcitriol following the last dose of alfacalcidol arepresented below (linear +SD plots).

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Name of Sponsor/Manufacturer:LEO Pharma A/S

Location of study report in Regulatory Dossierfor authorities

Name of Investigational Product/Finished Product, if available:

EinsAlphaVolume:

Name of Active Substance:

Alfacalcidol (1-hydroxyvitamin D3)Page:

below.

AUCa

pgh/mlAUCinfpgh/ml

AUC/AUCinf%

Cmaxpg/ml

Tmaxh

th

Baseline unadjustedcalcitriol

2036(58.5%)

NA NA54.4

(46.8%)9.42

(41.1%)NA

Baseline adjustedcalcitriol

630(49.0%)

967(37.0%)

72.2(21.7%)

34.3(43.4%)

9.42(41.1%)

19.2(29.7%)

aAUC corresponds to AUC 0-t for unadjusted concentrations and AUC 0-48 for baseline adjusted concentrationsNA: not applicable. N = 12

Baseline adjusted calcitriol rate and extent of exposure (Cmax and AUC 0-48) after the last dosewere 34.3 pg/ml and 630 pgh/ml, respectively. Peak concentrations of calcitriol in serumoccurred at approximately 9.5 hours. The elimination t of calcitriol was 19.2 hours in patientswith chronic renal failure. Although this value was markedly higher than that previouslyobserved in healthy subjects, no apparent accumulation of the drug was observed followingrepeated oral administrations of alfacalcidol since predose and pre-treatment concentrationswere similar.Baseline unadjusted results were presented for information purpose only.Safety results:

There were no deaths, but one serious adverse event during this study. This SAE was assessedby the investigator to be not related to study medication. There were no other significant AEsreported in this study.Conclusion:

Following single 1.5 g oral doses of alfacalcidol taken three times a week for two weeks,unadjusted predose concentrations of calcitriol at the end of the last dialysis session (visit day8) were below the endogenous levels expected in healthy subjects.On the other hand, after the last dose of 1.5 g alfacalcidol (EinsAlpha) in patients withchronic renal failure, unadjusted postdose concentrations of calcitriol over 48 hours (visit days8-9) were consistent with the expected endogenous levels of calcitriol in healthy subjects.Baseline adjusted calcitriol rate and extent of exposure (Cmax and AUC(0-48) in patients withchronic renal failure were 34.3 pg/ml and 630 pgh/ml, respectively.The elimination t of calcitriol in patients with chronic renal failure was markedly higher than

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Name of Sponsor/Manufacturer:LEO Pharma A/S

Location of study report in Regulatory Dossierfor authorities

Name of Investigational Product/Finished Product, if available:

EinsAlphaVolume:

Name of Active Substance:

Alfacalcidol (1-hydroxyvitamin D3)Page:

the one previously observed in healthy subjects. The prolonged t of calcitriol in patients withchronic renal failure did not result in significant accumulation of the drug following repeatedoral administrations of alfacalcidol. Alfacalcidol was considered to be safe and well toleratedfollowing 1.5 g oral dose taken 3 times a week for 2 weeks in patients with chronic renalfailure undergoing haemodialysis.

Report date:

28-Feb-2007

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3.1 SCHEDULE/CHART OF STUDY PROCEDURESI II III IV V

Follow-upPhase Quali-fication

Washout Treatment PKsampling

Day -7 - 0 1 - 7 8 14 15 - 21 22 - 28 29 - 31Dialysis sessions * * * * * * * * * * * * * * *Visit no. -1 1 2 3 4 5 6 7 8 9 4 weeksInformed consent *Medical historyand demographic data *Physical examination *Pregnancy test 1) *ECG (12 lead) *Blood pressure/puls *Drug dosing * * * * * *Laboratory tests 2) * * * *6) *PK blood sampling *5) *3)Concomitantmedication * * * * * * * * * *Adverse events4) * * * * * * * * *

Recording

ofseriousadverseevents

(SAEs)

1) For females only: hCG, human chorionic gonadotropin blood test.2) For laboratory tests, please see separate Schedule of Laboratory Tests in section 11.7.4 in the protocol.3) Please see section 11.7.1.1 in this r