Bococizumab Product Analysis

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Ref Code: DMKC0144967 Publication Date: 29/06/2016 Author: Louisa Joseph bococizumab Product Analysis DMKC0144967 | Published on 29/06/2016

Reference: DMKC0144967 First published: 29/06/2016

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TABLE OF CONTENTS

4 PRODUCT PROFILES 4 bococizumab : Dyslipidemia

LIST OF FIGURES

12 Figure 1: Bococizumab for dyslipidemia – SWOT analysis 13 Figure 2: Datamonitor Healthcare’s drug assessment summary of bococizumab for dyslipidemia 13 Figure 3: Datamonitor Healthcare’s drug assessment summary of bococizumab for dyslipidemia

LIST OF TABLES

4 Table 1: Bococizumab drug profile 6 Table 2: Bococizumab Phase III data in dyslipidemia 8 Table 3: Bococizumab Phase III trials in dyslipidemia 11 Table 4: Bococizumab efficacy in adults with high cholesterol on statin therapy

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PRODUCT PROFILES

bococizumab : Dyslipidemia

PRODUCT PROFILE

Analyst Outlook Bococizumab (Pfizer) will likely be the third proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to enter the dyslipidemia market. This third-to-market status may hinder bococizumab’s uptake as it will have to compete with Repatha (evolocumab; Amgen/Astellas) and Praluent (alirocumab; Sanofi/Regeneron) at launch. Additionally, cardiovascular (CV) outcomes data for both Repatha and Praluent are expected to be released before bococizumab, further decreasing the drug’s competitive potential within the PCSK9 inhibitor space. However, the broad patient base in Pfizer’s CV outcomes trial (CVOT) program may help demonstrate value to payers if bococizumab can demonstrate a reduction in CV risk in patients receiving a high-dose statin with uncontrolled low- density lipoprotein cholesterol (LDL-C) levels. Pfizer also intends to explore a once-monthly formulation of bococizumab that will utilize Halozyme’s Enhanze technology.

Drug Overview Bococizumab is an antidyslipidemic humanized antibody that inhibits PCSK9. PCSK9 is a protease involved in the intracellular and extracellular regulation of LDL receptor (LDLR) expression. It binds to the LDLR at the epidermal growth factor-like repeat A domain, targeting the receptor for lysosomal degradation within the hepatocytes. PCSK9 is also known to increase the production of apolipoprotein B-containing lipoproteins. Bococizumab inhibits the degradation of LDLR by preventing circulating PCSK9 from binding. This allows the receptors to be recycled to the surface of hepatocytes, leading to an increase in LDL-C clearance (Hooper and Burnett, 2013; Wierzbicki et al., 2012).

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Table 1: Bococizumab drug profile

Molecule bococizumab

Phase of development Phase III

Mechanism of action PCSK9 inhibitor

Originator Pfizer

Marketing company Pfizer

Targeted indication Hypercholesterolemia

Formulation 150mg subcutaneous injection

Pricing strategy Estimated to cost around $14,100 based on Repatha’s US price

Dosing frequency Once every two weeks

Estimated approval date Q3 2017 (US), Q4 2017 (5EU), Q3 2020 (Japan)

Alternative names RN316, PF-4950615, PF-04950615

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); PCSK9 = proprotein convertase subtilisin/kexin type 9

Source: Biomedtracker; Pharmaprojects

DEVELOPMENT OVERVIEW

Phase III trial program is underway, including two large-scale CVOTs Pfizer’s ongoing Phase III program is investigating the safety and efficacy of 150mg injections of bococizumab, administered once every two weeks. The program consists of two large CVOTs (SPIRE-1 and SPIRE-2), as well as multiple LDL-C-lowering studies in more than 22,000 patients. The SPIRE-1 study will assess whether lowering LDL-C beneath currently recommended levels results in further reductions in CV events in patients with LDL-C levels of 70–100mg/dL. The SPIRE-2 study will assess the efficacy and safety of bococizumab in high-risk patients with LDL-C levels of 100mg/dL or above, who have not been able to reach LDL-C goals with statin therapy, or are statin intolerant. The results of these two studies are expected in 2018 (ClinicalTrials.gov identifiers: NCT01975376, NCT01975389).

The table below summarizes the design of the Phase III studies.

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Table 2: Bococizumab Phase III data in dyslipidemia

Trial Sample size Target patients Study design Dosing tested and Results Reference duration

SPIRE-SI (NCT02135029) 150 Hyperlipidemia patients Randomized, double-blind, Duration: 24 weeks Week 24: ClinicalTrials.gov (Phase III) intolerant to statins placebo-controlled, parallel-group Arm 1: 150mg SC Percentage decrease of LDL-C from baseline compared bococizumab (Q2W) to placebo = 39.8%

Arm 2: SC placebo (Q2W) Percentage increase of HDL-C from baseline compared to placebo = 138.1% ;

Week 76:

Percentage decrease of LDL-C from baseline compared to placebo = 36.2%

Percentage increase of HDL-C from baseline compared to placebo = 138.8%

CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol

Source: see above

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Table 3: Bococizumab Phase III trials in dyslipidemia

Trial Sample size Target patients Study design Treatment arms Primary endpoints Start date/primary completion date

SPIRE-1 (NCT01975376) 12,000 High-risk patients with Randomized, double- Duration: 3–4 years Time from randomization September 2013/April (Phase III) LDL-C ≥70mg/dL and blind, placebo-controlled, to first occurrence of CV 2018 <100mg/dL; or non-HDL- parallel-group Arm 1: 150mg SC event, up to month 60 C >100mg/dL and bococizumab (Q2W) <130mg/dL

Arm 2: SC placebo (Q2W)

SPIRE-2 (NCT01975389) 6,300 High-risk patients with Randomized, double- Duration: 3–4 years Time from randomization September 2013/January (Phase III) LDL-C ≥100mg/dL or non- blind, placebo-controlled, to first occurrence of CV 2018 HDL-C ≥130mg/dL parallel-group Arm 1: 150mg SC event, up to month 60 bococizumab (Q2W)

Arm 2: SC placebo (Q2W)

SPIRE-HR (NCT01968954) 600 Patients with primary Randomized, double- Duration: 18 months Percentage change from October 2013/April 2016* (Phase III) hyperlipidemia or mixed blind, placebo-controlled, baseline in LDL-C at week dyslipidemia at risk of CV parallel-group Arm 1: 150mg SC 12 events bococizumab (Q2W)

Arm 2: SC placebo (Q2W)

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Table 3: Bococizumab Phase III trials in dyslipidemia

Trial Sample size Target patients Study design Treatment arms Primary endpoints Start date/primary completion date

SPIRE-LDL 1,600 Patients with primary Randomized, double- Duration: 18 months Percentage change from October 2013/July 2016 (NCT01968967) (Phase III) hyperlipidemia or mixed blind, placebo-controlled, baseline in LDL-C at week dyslipidemia at risk of CV parallel-group Arm 1: 150mg SC 12 events bococizumab (Q2W)

Arm 2: SC placebo (Q2W)

SPIRE-HF (NCT01968980) 300 HeFH patients Randomized, double- Duration: 12 months Percentage change from October 2013/April 2016* (Phase III) blind, placebo-controlled, baseline in LDL-C at week parallel-group Arm 1: 150mg SC 12 bococizumab (Q2W)

Arm 2: SC placebo (Q2W)

SPIRE-SI (NCT02135029) 150 Hyperlipidemia patients Randomized, double- Duration: 24 weeks Percentage change from May 2014/November (Phase III) intolerant to statins blind, placebo-controlled, baseline in LDL-C at week 2015* parallel-group Arm 1: 150mg SC 12 bococizumab (Q2W)

Arm 2: SC placebo (Q2W)

*Complete study results will be presented at an upcoming scientific congress.

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Table 3: Bococizumab Phase III trials in dyslipidemia

Trial Sample size Target patients Study design Treatment arms Primary endpoints Start date/primary completion date

CV = cardiovascular; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; Q2W = every two weeks; SC = subcutaneous

Source: ClinicalTrials.gov

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Bococizumab demonstrated significant LDL-C reductions in a Phase IIb trial Data from a 24-week Phase IIb trial for bococizumab were presented at the American College of Cardiology 2014 Scientific Sessions, showing that bococizumab plus statin therapy significantly reduced LDL-C levels compared to statin therapy alone in adults with high cholesterol (Ballantyne et al., 2014).

Patients were treated with either twice-monthly (50mg, 100mg, or 150mg) or once-monthly (200mg or 300mg) bococizumab or placebo. The dose of bococizumab was reduced if LDL-C levels reached 25mg/dL or lower. Maximum LDL-C reduction was seen with the 150mg dose given once every two weeks and the 300mg dose given once monthly. Pfizer reported that the frequency of severe treatment-related adverse events was similar across placebo and all treatment groups (Ballantyne et al., 2014).

Results from the study are summarized in the table below.

Table 4: Bococizumab efficacy in adults with high cholesterol on statin therapy

50mg bococizumab 100mg 150mg 200mg 300mg Q14d (n=50) bococizumab Q14d bococizumab Q14d bococizumab Q28d bococizumab Q28d (n=51) (n=49) (n=50) (n=51)

Mean placebo-adjusted -34.3 -45.1 -53.4 -27.6 -44.9 change from baseline in LDL-C at week 12 (mg/dL)

Mean predicted placebo- -36.3 -60.6 -72.1 -40.3 -55.7 adjusted change in LDL-C from baseline at week 12 assuming no dose reduction (mg/dL)

Participants with dose 0 16 35 44 39

reduction (%)

Participants with severe 0 0 2 0 0

treatment-related AEs (%)

AE = adverse event; LDL-C = low-density lipoprotein cholesterol; Q14d = twice monthly; Q28d = once monthly

Source: Ballantyne et al., 2014

Datamonitor Healthcare 11 Pharma intelligence | bococizumab Product Analysis DMKC0144967 | Published on 29/06/2016

SWOT ANALYSIS

Figure 1: Bococizumab for dyslipidemia – SWOT analysis

Source: Datamonitor Healthcare

Datamonitor Healthcare 12 Pharma intelligence | bococizumab Product Analysis DMKC0144967 | Published on 29/06/2016

CLINICAL AND COMMERCIAL ATTRACTIVENESS The figure below depicts Datamonitor Healthcare’s drug assessment summary for bococizumab in dyslipidemia.

Figure 2: Datamonitor Healthcare’s drug assessment summary of bococizumab for dyslipidemia

Source: Datamonitor Healthcare

The figure below provides a breakdown of how Datamonitor Healthcare scored bococizumab’s clinical and commercial attractiveness. The weighting given to each attribute is also shown.

Datamonitor Healthcare 13 Pharma intelligence | bococizumab Product Analysis DMKC0144967 | Published on 29/06/2016

Figure 3: Datamonitor Healthcare’s drug assessment summary of bococizumab for dyslipidemia

Source: Datamonitor Healthcare

Third-to-market status may hinder bococizumab’s uptake in high-risk population Bococizumab’s third-to-market status may hinder the drug’s uptake in the high-risk dyslipidemia population as it will have to compete with Praluent and Repatha at launch. Following the approvals of Praluent and Repatha in Q3 2015, bococizumab will likely be the third PCSK9 inhibitor to enter the dyslipidemia market. Given that bococizumab is not expected to be approved until Q3 2017, Praluent and Repatha will have a considerable window of time in which to gain a hold on the high-risk dyslipidemia market prior to its approval (Biomedtracker, 2016). Bococizumab’s third-to-market status may therefore put the drug at a competitive disadvantage, as high-risk patients may already be treated with Praluent or Repatha by the time bococizumab launches.

The initial uptake of Praluent and Repatha in the high-risk dyslipidemia population has been limited by the drugs’ high annual costs and lack of outcomes data, and both have struggled to penetrate the dyslipidemia market since their launches in 2015 due to strict reimbursement protocols. At around $14,000 per patient per year (before negotiated discounts) and without the availability of outcomes data, regulators and payers have put severe restrictions on the availability of the two drugs, limiting their use to the most high-risk dyslipidemia patients. This may prove advantageous for bococizumab, as fewer patients may already be receiving PCSK9 inhibitor treatment by the time the drug launches.

Repatha and Praluent are expected to release CV outcomes data before bococizumab Bococizumab is expected to release its CV outcomes data at a later date than Repatha and Praluent,

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further decreasing the drug’s competitive potential in the PCSK9 inhibitor space. Repatha is likely to be the first PCSK9 inhibitor to complete its CVOT, with topline results of the FOURIER trial expected by Q1 2017 (Biomedtracker, 2016). Praluent’s CVOT is lagging behind Repatha’s but interim data are due to be released in H2 2016, with full results of the trial expected by late 2017 (Biomedtracker, 2016). Bococizumab will likely release its outcomes data after both Praluent and Repatha, with results of the SPIRE-1 and SPIRE-2 CVOTs expected in H1 2018 and H2 2017, respectively (ClinicalTrials.gov identifiers: NCT01975376, NCT01975389). This may hinder bococizumab’s uptake in the dyslipidemia market, as positive CV outcomes data are expected to be one of the most important factors in determining the market successes of the PCSK9 inhibitors. Demonstrating a reduction in CV risk through these large-scale CVOTs will be required to reduce reimbursement barriers and increase uptake of the drugs in their approved indications for high-risk patients. Additionally, significant positive results will help to convince regulators and physicians of their clinical benefits in the wider, more commercially lucrative dyslipidemia population.

Broad patient population of bococizumab’s CVOT may provide a competitive advantage over Praluent and Repatha Pfizer’s clinical outcomes program is thought to cover the broadest range of dyslipidemia patients, including high-risk primary- and secondary-prevention patients (Pfizer press release, 2014). Demonstrating safety and efficacy in a wider range of patient populations may provide bococizumab with a competitive advantage over Repatha and Praluent, increasing physician confidence and driving uptake of the drug. The SPIRE-1 trial is investigating whether reducing LDL-C to levels well below those currently recommended will further decrease the rate of cardiac events in patients with LDL-C levels of 70–100mg/dL (ClinicalTrials.gov identifier: NCT01975376). As many physicians have expressed concerns about driving LDL-C down to severely low levels, positive outcomes data from the SPIRE-1 trial may help inspire confidence in bococizumab and boost the drug’s uptake.

The SPIRE-2 trial has been designed to investigate the efficacy and safety of bococizumab in patients with LDL-C levels 100mg/dL or above in spite of high-statin therapy, or in patients who are intolerant to statins (ClinicalTrials.gov identifier: NCT01975389). Positive results from the SPIRE-2 trial could help justify bococizumab’s addition to drug formularies and ensure reimbursement, as these high-risk, uncontrolled patients remain a significant economic burden to the healthcare system (Pfizer conference call transcript, 2013).

A once-monthly formulation of bococizumab is to be developed Pfizer has announced plans to develop a once-monthly formulation of bococizumab to become available after the drug gains approval (Pfizer conference call transcript, 2013). As the three PCSK9 inhibitors have shown comparable safety and efficacy profiles throughout clinical trials, their different dosing regimens may be their main distinguishing features. Therefore, this more convenient once- monthly dosing option could make bococizumab more competitive in the PCSK9 inhibitor market. The development of bococizumab’s once-monthly dosing formulation will involve Halozyme, as Pfizer has an exclusive license to use Halozyme’s Enhanze technology (Halozyme press release, 2012). Enhanze is a proprietary delivery platform that uses a recombinant enzyme to degrade a structural component of the skin, providing improved subcutaneous delivery of injectable biologics (Halozyme website, 2016).

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Bibliography Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang E, Plowchalk D, Sweeney K, Kaila N, Vincent J, Bays H (2014) Efficacy and Safety of Bococizumab (RN316/PF-04950615), a Monoclonal Antibody against Proprotein Convertase Subtilisin/Kexin Type 9 in Statin-Treated Hypercholesterolemic Subjects: Results from a Randomized, Placebo-Controlled, Dose-Ranging Study (NCT: 01592240). Journal of the American College of Cardiology, 63(12-S) 25784512.

Halozyme press release (2012) Halozyme Therapeutics And Pfizer Enter Into A Collaboration To Develop And Commercialize Subcutaneous Biologics Using Recombinant Human Hyaluronidase. Available from: http://www.halozyme.com/Investors/News-Releases/News-Release- Details/2012/Halozyme-Therapeutics-And-Pfizer-Enter-Into-A-Collaboration-To-Develop-And- Commercialize-Subcutaneous-Biologics-Using-Recombi/default.aspx [Accessed 20 May 2016].

Halozyme website (2016) Available from: www.halozyme.com/Technology/Technology/default.aspx [Accessed 20 May 2016].

Hooper AJ, Burnett JR (2013) Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opinion on Biological Therapy, 13(3), 429–35 10.1517/14712598.2012.748743.

Pfizer conference call transcript (2013) Edited Transcript Q3 2013 Pfizer Earnings Conference Call. Available from: http://www.pfizer.com/system/files/presentation/PFE-Transcript-2013-10- 29T14_00.pdf [Accessed 20 May 2016].

Pfizer press release (2014) Available from: http://press.pfizer.com/press-release/bococizumab-rn316- significantly-reduced-ldl-cholesterol-statin-treated-adults-high-cho [Accessed 20 July 2015].

Wierzbicki AS, Hardman TC, Viljoen A (2012) Inhibition of pre-protein convertase subtilisin kexin 9 (PCSK-9) as a treatment for hyperlipidaemia. Expert Opinion on Investigational Drugs, 21(5), 667–76 10.1517/13543784.2012.679340.

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