Attachment 1 CMC-PK and Phase 1 Clinical Protocol Summary Valsartan ER Tablets

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Table of Contents
List of Tables and Figures ....................................................................................................3 1.0 Introduction ....................................................................................................................4 2.0 Product Development and Design Rationale ..................................................................4 3.0 Development Stages and Probe Pharmacokinetic Studies ............................................5 3.1 Stage 1 ................................................................................................................5 3.2 Stage 2 ................................................................................................................6 3.3 Pharmacokinetic Study of Valsartan Extended Release Tablets 160 mg ............7 3.4 Observation and Conclusion................................................................................8 4.0 Phase 1 Study ................................................................................................................9 4.1 Study Title............................................................................................................9 4.2 Objectives ............................................................................................................9 4.2.1 Primary Objectives .................................................................................9 4.2.2 Secondary Objectives ............................................................................9 4.3 Study Design .......................................................................................................9 4.4 Study Duration ...................................................................................................10 4.5 Study Site and Location .....................................................................................11 4.6 Planned Sample Size ........................................................................................11 4.7 Dosage Form, Dose and Route of Administration .............................................11

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List of Tables and Figures

Figure 1 ................................................................................................................................7 Semi-Logarithmic Plot of Mean Plasma Valsartan Concentration vs. Time Figure 2 ................................................................................................................................8 Data Normalized Plot of Mean Plasma Valsartan Concentration Test/Reference vs. Time Table 1 .................................................................................................................................8 Summary Statistics of Ln-transformed Pharmacokinetic Parameters

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1.0 Introduction
Angiotensin receptor blockers (ARBs) have proven to be an important treatment in the management of hypertension. Among the ARBs, Diovan has been one of the most frequently prescribed active agent. It is effective and well tolerated both as monotherapy and in combination with diuretics and calcium channel blockers. However, there have been concerns over the duration of action of Diovan, particularly at lower doses, and whether it provides true 24-hour blood pressure (BP) control. In this study we will be comparing a new formulation, Valsartan Extended Release (ER) Tablets, to Diovan Tablets. Valsartan ER utilizes a formulation that achieves the desired pharmacokinetic attributes by combining concepts of solubilisation and gastric retention. The gastric retention is achieved using swelling and floating mechanism. This delivery system results in a slow and continuous release of solubilized drug across the upper gastrointestinal tract, which is perceived to be an absorption site for valsartan. Multiple pharmacokinetic studies have demonstrated that volunteers treated with Valsartan ER have significantly higher plasma levels of drug between 6 and 24 hours compared to Diovan. It is anticipated that these differences in plasma drug levels will result in greater efficacy and a longer duration of action compared to Diovan without compromising the side effect profile. Greater efficacy is likely to result in an increase in the percentage of patients achieving recommended BP control and the prolonged plasma concentrations of the drug will result in better BP control during the important last 4-6 hours of the dosing interval, thus making this a true once-a-day agent. All patients will have 24-hour ambulatory BP monitoring in order to compare the efficacy and duration of action when treated with Diovan and Valsartan ER in a crossover study design. The availability of more effective, true, once-a-day therapy will provide a very important addition to our armamentarium of antihypertensive agents and will be helpful in obtaining better BP control in hypertensive patients. Although EZRA Pharma will pursue Valsartan ER 80mg and 160mg dose strengths, the intended dose for this study will be 160mg. Previous studies with Diovan have shown 160mg is more effective then 80mg. There is no difference, however, in the side effect profile of 80 mg and 160 mg Diovan. Since lower blood pressures seem to be associated with the reduction in cardiovascular disease (CVD), a safe 160mg dose, that is more effective than the 80mg dose would be preferable. The 80mg dose would be more useful for patients with stimulated renin angiotensin systems, such as that which occurs in volume depleted elderly patients.

2.0 Product Developement and Design Rationale Rubicon Research Private Limited (Rubicon), a leading contract product development organization in India had undertaken the development of Valsartan ER Tablets for the Indian domestic market in 2008 to compete against Diovan Tablets of Novartis India Limited (manufactured by Novartis Farmaceutica S.A., Spain). Diovan Tablet is marketed
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in India, Europe and USA in four strengths of 40 mg, 80 mg, 160 mg and 320 mg as immediate release (IR) film coated tablets intended for once-a-day dosing. The ingredients listed for the Diovan Tablets manufactured in Spain for the Indian and European markets and Diovan Tablets manufactured in the USA for the US market (NDA 021283 approved on July 2001) are qualitatively the same. The Diovan Tablets have inherent limitations due to a low, absolute mean bioavailability of approximately 25% (range 10%-35%) and poor solubility of valsartan, coupled with a mean elimination half-life of about 6 hours. There have been concerns regarding the effective duration of action of Diovan, particularly at lower doses, and whether it provides true 24hour blood pressure (BP) control. Furthermore there is a high variability associated with pharmacokinetic parameters. With that knowledge of poor solubility and a specific anatomical window of absorption, believed to be in upper part of small intestine, the development of an extended release dosage form was undertaken at Rubicon in two phases for 80 mg and 160 mg strengths. Stage1: Solubilization of valsartan and study of its impact on bioavailability (bioenhanced valsartan); Stage 2: Incorporation of solubilized valsartan into gastro-retentive (GR) delivery system in the form of a bi-layer tablet. One layer is composed of bio-enhanced valsartan with a functional polymer system and another layer of functional polymers providing the GR attribute via swelling and floating mechanisms.

3. 0 Development Stages and Probe Pharmacokinetic Studies: 3.1 Stage 1 Initially, the goal of improved solubilization of valsartan was achieved by a solid dispersion of valsartan with two solubilizing agents and microcrystalline cellulose (MCC) as absorbent. The obtained semisolid mixture had poor flow properties and was therefore filled into capsules and evaluated by in vitro release studies. Typically due to poor solubility Diovan exhibits low (25-30% release in 120 min) in 0.1N hydrochloric acid; whereas with the bioenhanced valsartan capsule formulation more than 80% drug was released in 30 min. A cross-over pharmacokinetic study (n = 12 volunteers, fasted) was performed on bio-enhanced Valsartan Capsules 80 mg. The study results indicated an approximate 1.6 - 1.7 fold increase in Cmax and AUC for Valsartan capsule f ormulation over Diovan Tablets. Since a 1.6-fold increase in Cmax and AUC was observed with the initial 80 mg Valsartan Capsule formulation, it was possible that a 50 mg Valsartan formulation would be bioequivalent to Diovan tablets 80 mg.
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Further formulation efforts were aimed at the development of tablet formulation rather than a capsule formulation. To maintain a reasonable tablet weight, a portion of MCC was replaced by calcium silicate as the adsorbent. Further development resulted in the inclusion of an acidulant, fumaric acid, to overcome an interaction between valsartan and calcium silicate. This optimized Valsartan Tablet formulation was stable at 40C/75% RH for 1 month. 3.2 Stage 2 Subsequently, it was decided that rather than aiming to reduce the dose to 50 mg, it would be more useful to develop a formulation that would maintain the desired blood levels of the drug (preferably greater than 1.5 times concentration of Diovan at equivalent time points) for 12 18 hours after administration. For maintaining the improved bioavailability of bio-enhanced valsartan over an extended period of time, various extended release approaches were investigated. This led to the development of the gastro-retentive (GR) dosage form of Valsartan Tablet 80 mg, using Generally Recognized as Safe (GRAS) - listed excipients within the IIG ranges. A compatibility study has also been performed with each of the excipients to select excipients that are compatible with Valsartan. A pharmacokinetic study was performed in 32 human volunteers. The formulation exhibited increased AUC values as compared to the reference product, Diovan Tablets. These data indicated that the formulation was retained in the stomach for a prolonged period of time leading to an extended release of the drug that afforded higher plasma drug levels when compared to the reference product. Upon review of the data and comparative plasma profiles, it was concluded that the test formulation provided an extended release of valsartan with improved bioavailability. The formulation was subjected to stability studies and was found to be stable under an accelerated test condition of 40C/75% RH for at least 1 month Based on the same principles of incorporating solubilized valsartan into a GR delivery system, Valsartan Tablet 160 mg dosage strength was developed. The nitial batches were based on maintaining dose proportionality between the 80 mg and 160 mg formulations for the drug layer. The weight of the Gastroretentive layer (GR) was kept similar to that of the 80 mg formulation. The release of the drug from the formulation (160 mg) was found to be slower than the provisionally set finished product specification (FPS). The polymer concentration of the drug layer was therefore optimized to match the release profile with the FPS. The stability of optimized formulation was found to be stable for at least 1month 40 C/75% storage condition. The final 160 mg formulation was evaluated in a pharmacokinetic study. Significantly higher plasma concentrations were observed at the later time points of the plasma profile.

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3.3 Pharmacokinetic Study of Valsartan Extended Release Tablets 160 mg. The statistical summary results and plots for Valsartan ER Tablets160 mg (Fed) and Reference Product Diovan Tablets 160 mg (Fasting) are provided in Figures 1 and 2 and Table 1. The study design was a 2-way crossover using 8+2 volunteers. In order to achieve desired gastric retention the Valsartan ER formulation was administered under fed conditions as fed conditions physiologically delays gastric emptying. As per pack insert Diovan exhibits negative food effect and therefore in order to compare test product against Diovan in best case scenario it was decided t o administer Diovan under fasting conditions and valsartan ER under Fed conditions.

Figure 1: Semi-Logarithmic Plot of Mean Plasma Valsartan Concentration vs. Time

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Figure 2: Data Normalized Plot of Mean Plasma Valsartan Concentration Test/Reference vs. Time

Table 1: Summary statistics of Ln-transformed Pharmacokinetic parameters Test PK Parameters Unit Ref Ratio [%Ref] (1144-011-160) Cmax ng/ml 3227.68 3907.03 82.61 AUC0-t ng*hr/ml 26920.89 25829.66 104.22 AUC0-inf ng*hr/ml 27386.14 26132.99 104.80 Tmax hr 4.88 3.22 151.56

3.4 Observation and Conclusion Data normalized plot has been generated by dividing valsartan concentration for Valsartan ER formulation by plasma concentrations achieved with Diovan at each time point. The graph exhibits that beyond 6-hour time point valsartan ER formulation achieved plasma concentrations that were more than 1.5 fold greater. Further there is corresponding significant increase in AUC during these time points as well. It was also confirmed by the semi-logarithmic plot that Valsartan ER Tablets exhibit higher AUC from 6-24 hours in comparison to Diovan. Currently Rubicon is undertaking further development and scale up efforts for the Valsartan ER Tablets to meet Regulatory requirements. Additional and updated CMC information will be provided in the pre-IND Briefing Document for Agency review before the meeting.
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4.0 Phase 1 Study 4.1 Study Title A prospective, randomized, open label, blinded endpoint, crossover study to c ompare the safety, efficacy, and duration of action of Valsartan ER 160 mg once-daily to Diovan 160 mg once-daily on patients with stage I and stage II hypertension.

4.2 Objectives 4.2.1 Primary Objective Compare the reduction in mean 24 hour systolic BP in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). 4.2.2 Secondary Objectives Compare the reduction in mean daytime systolic and diastolic blood pressure (BP) in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). Compare the reduction in mean nighttime systolic and diastolic BP in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). Compare the mean reduction in systolic and diastolic BP measured during the final 4 hours of the dosing interval in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). Compare the Pharmacokinetic (PK) profile of Valsartan ER 160 mg to Diovan 160 mg. Compare the safety profile of Valsartan ER 160 mg to Diovan 160 mg.

4.3 Study Design In this prospective, randomized, open label, blinded endpoint study, hypertensive patients, either newly diagnosed or treated hypertensive patients, who have been weaned off all antihypertensive medications and who fulfill all inclusion/ exclusion criteria, will enter a 3 week single blind placebo washout period.
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Following the washout period, patients with a mean seated systolic BP o f 150mmHg and 180 mmHg and a mean seated diastolic blood pressure of 110 mmHg will be eligible for the study. Eligible patients will be admitted to the PK unit (within 48 hours of the qualifying office BP). Following an 8 hour fast, patients will be attached to an ambulatory BP monitor and will be monitored for a period of at least 24 hours in the PK unit to establish a baseline BP. Patients with a mean daytime SBP (8am-4pm) of 130 mmHg and 180 mmHg and a mean daytime DBP of 110 mmHg will be randomized to either Valsartan ER 160 mg, PO, oncedaily in the morning or to Diovan 160 mg, PO, once-daily in the morning. Patients randomized to Diovan 160 mg will be instructed to take their medication approximately 1 hour before their breakfast. Patients randomized to Valsartan ER 160 mg will be instructed to take their medication once daily about 15 minutes after completing their breakfast Patients will then be given their first dose of the study medication in the PK unit. Medication will be dispensed to the patients and they will be discharged from the PK unit and told to return to the clinic in 1 week for a BP check and a compliance assessment. At the clinic visit, patients will have drug dispensed and told to return to into the PK unit for PK period 2 in 2 weeks. Following an 8-hour fast in the PK unit, patients will be dosed with their current medication at approximately 8am. Patients randomized to Diovan 160mg will be dosed in the fasting state and patients randomized to Valsartan ER 160 mg will be dosed 15 minutes after a full breakfast once daily. An Ambulatory BP monitor will be attached to the patient for 24 hours (BPs will be measured at 20 minute intervals) and PK measurements (0, , 1,1 , 2, 3, 4, 5, 6, 7, 8, 12, 16, 24 hours) will be performed. Following at least 24 hours of BP monitoring the ABPM will be removed. Following removal of the ABPM patients will be discharged from the PK unit. Patients will enter a 1-week single blind placebo washout period. After, the 1-week washout period patients will return for a clinic visit. Patients who were treated on Valsartan ER 160 mg will be crossed over to receive Diovan 160 mg and those who were treated on Diovan 160 mg will be crossed over to receive Valsartan ER 160 mg. Patients will be dosed in the clinic. Those on Diovan 160 mg will be dosed in the fasting state, and those on Valsartan ER 160 mg will be does after a full breakfast. Patients will be seen after 1 week in the clinic for a BP check and a compliance check. Patients will have drug dispensed and be instructed to return to the PK unit after a further 2 weeks for PK period 3. Following an 8-hour fast, patients will be attached to an ABPM unit and will be dosed with study medication at about 8 am. (Diovan 160mg patients in the fasting state and Valsartan ER 160mg patients 15 minutes after a full breakfast) 24- hour BP measurements will be obtained and PK measurements will be performed as in PK period 2. After completion of the 24 hour BP monitoring, patients will exit the study and be treated at the discretion of the Principal Investigator (PI).

4.4 Study Duration The maximum duration of subject participation is approximately 10 weeks. The Screening period is 3 weeks and on each treatment regimen the period is 3 weeks with a 1-week washout between treatment periods.
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4.5 Study Site and Location One US investigative site. 4.6 Planned Sample Size Approximately 30 subjects will enter active treatment. Males and Females 18 -75 years old will be enrolled in the Study.

4.7 Dosage Form, Dose and Route of Administration All doses of this study medication will be taken orally as tablets once daily in the morning. Patients being treated with Divan 160 mg will be dosed 1 hour before breakfast. Patients being treated with Valsartan ER 160 mg will be dosed 15 minutes after breakfast.

EZRA:SS: Feb 28 2013

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