Sample Pages. PCSK9 and Other. Novel Hypercholesterolemia Drugs Market, Copyright 2014 Roots Analysis Private Limited Page 1

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1 Sample Pages PCSK9 and Other Novel Hypercholesterolemia Drugs Market, Copyright 2014 Roots Analysis Private Limited Page 1

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3 4.1. SCOPE AND OBSERVATIONS Statins and other cholesterol lowering drugs are prescribed to patients with several different indications. To define the scope of this study, we have covered the following indications to build our pipeline: Hypercholesterolemia, including familial forms Hyperlipidemia Dyslipidemia Atherosclerosis Report Page 31 It is important to note that omega-3 fatty acids are not a part of our analysis. The pipeline for the above indications has mainly been collated through extensive search on clinicaltrials.gov and other secondary sources. Most of our analysis presented in this chapter is based on the marketed and under development novel cholesterol lowering drugs; these drugs are highlighted in Table 4.1 below. Table 4.1 Pipeline of Novel Cholesterol Lowering Drugs, 2014 Molecule Kynamro (Mipomersen) Juxtapid (Lomitapide) Lipaglyn (Saroglitazar) Alirocumab (REGN727/ SAR236553) Type of Molecule Biologic (ASO) Synthetic Company ISIS Pharmaceuticals/ Genzyme Aegerion Pharmaceuticals Indication HoFH HoFH Synthetic Zydus Cadila Diabetic dyslipidemia Biologic (Human mab) Phase of Development Marketed (FDA approved) Marketed (FDA & EMA approved III (Japan) Market (India) Route of Delivery SC Class ApoB ASO MTTP inhibitor MTTP inhibitor PPAR alpha gamma agonist Regeneron/Sanofi Hypercholesterolemia III SC PCSK9 inhibitor Bococizumab (RN316/ PF ) Biologic (Humanized mab) Pfizer Hyperlipidemia HoFH III SC PCSK9 inhibitor Evolocumab (AMG145) Biologic (Human mab) Amgen Dyslipidemia, Hypercholesterolemia Filed (US and EU) SC PCSK9 inhibitor Anacetrapib (MK-0859) Synthetic Merck & Co. Hypercholesterolemia HoFH Dyslipidemia Atherosclerosis III CETP inhibitor K-877 Synthetic Kowa Dyslipidemia Evacetrapib (LY ) RG7652 / MPSK3169A Continued on Page 32 Synthetic Eli Lilly Dyslipidemia III (Japan) II (EU & US) II (Japan, completed) PPAR-alpha agonist CETP inhibitor Biologic (mab) Roche Hypercholesterolemia IIa SC PCSK9 inhibitor Molecules highlighted in Orange are currently commercially available SC: Subcutaneous; IV: Intravenous Copyright 2014 Roots Analysis Private Limited Page 3

4 4.4. MARKET ATTRACTING BOTH LARGE AND SMALL PHARMA COMPANIES The market for developing novel cholesterol lowering drugs has gained attention of a number of multinational pharmaceutical companies including Amgen, Sanofi, Pfizer, GSK, Eli Lilly, Roche, Johnson & Johnson and more. Of these, Amgen will likely have the first mover advantage, with its PCSK9 inhibitor Evolocumab being the farthest in development. Pfizer is active in this therapeutic area with its PCSK9 inhibitor, Bococizumab. More recently, Pfizer had another synthetic oral drug PF in Phase I clinical trial; however, the program was discontinued from development. Eli Lilly, which is competing in the PCSK9 and CETP inhibitor market, has its molecules in Phase II clinical trials at present. Roche, although entered the competition late, has three clinical stage molecules, with its PCSK9 antibody RG7652 being the farthest in development. Report Page 35 Several smaller biopharmaceutical companies are also looking to gain a share of this attractive market. Overall, there are 27 companies developing 29 molecules in clinical trials (Figure 4.1). The number of molecules in Figure 4.1 below is more than 29 owing to the co-development of some molecules by multiple companies, in which case the molecule has been counted separately for each developer FIVE NOVEL DRUGS IN LATE STAGE DEVELOPMENT In addition to the three marketed drugs mentioned above, one drug, evolocumab, has been filed with the FDA and EMA for approval and four more drugs are being evaluated in Phase III clinical trials (Figure 4.2). Three of these five late stage drugs are PCSK9 inhibitors, all of which are being developed by large multinational pharmaceutical companies. The first PCSK9 inhibitor, anticipated to reach the market in 2015, is Amgen s Evolocumab. Figure 4.2 Pipeline Analysis: Distribution by Phase of Development 7, 24% 3, 10% 1, 4% 4, 14% Market Filed III II I 14, 48% Source: Roots Analysis Copyright 2014 Roots Analysis Private Limited Page 4

5 5.4. MIPOMERSEN AND LOMITAPIDE: ROOTS ANALYSIS PERSPECTIVE Familial hypercholesterolemia is an autosomal dominant disorder characterized by gene dosage effect. The defect can be in both the alleles of same gene, giving rise to HoFH (Homozygous Familial Hypercholesterolemia) or can be in one allele, forming HeFH (Heterozygous Familial Hypercholesterolemia). The mutations in FH can vary: Loss-of-function mutation in LDL receptor gene which is more common, Mutation in gene encoding ApoB, Gain-of-function mutation in PCSK9 gene or Very rare loss-of-function mutation in LDLRAP1 resulting in autosomal recessive form of FH Report Page 65 In HoFH patients, the prevalence of which is 1 in million, the plasma LDL is elevated around 6-10 fold from birth. Statins, the standard care to lower LDLC levels, work by increasing LDLR to decrease LDLC from the blood; therefore, they work to some extent in HeFH patients but fail to work in HoFH and severe or compound HeFH patients. Figure 5.2 MTTP Inhibitor and apob Gene Silencer: Drivers and Restraints Only drugs approved for HoFH Better efficacy than statins in HoFH patients Mipomersen is most advanced oligonucleotide drug capable of systemic delivery Expansion in markets other than the US Under review for additional indications including HeFH In contrast to PCSK9 inhibitors, efficacious even in patients with no LDLR activity Liver toxicity concerns in both the drugs Injection-site reactions in mipomersen can lead to discontinuation Available only through REMS program High price Targeting a small fraction of population of HoFH patients Mipomersen rejected by EMA last year Evolocumab (a PCSK9 inhibitor), showed good results in phase III HoFH trials and could be a credible threat Source: Roots Analysis Mipomersen and Lomitapide are the only therapies approved by FDA recently for treating HoFH. The mechanism of both the molecules is to eventually target apob100, an essential component of LDL. Since they work through mechanism other than LDLR increase, the HoFH patients who are Copyright 2014 Roots Analysis Private Limited Page 5

6 6.5. BOCOCIZUMAB (RN-316/PF ) OVERVIEW Bococizumab, under development by Pfizer, is one of the three PCSK9 inhibitors that are currently being evaluated in Phase III clinical trials. The company acquired the humanized monoclonal antibody from its original developers Rinat Neuroscience, after its acquisition in We believe the drug will be launched in Pfizer has ambitious plans for the Phase III studies by enrolling more than 22,000 patients, almost same number as the competitors Regeneron-Sanofi and Amgen. The exclusive feature of bococizumab s Phase III trials is the inclusion of two expensive cardiovascular outcome studies which investigate the drug s capability to reduce the occurrence of Report Page 88 cardiovascular events, such as heart attack and stroke, as compared to the current standard. The completed studies for the drug are detailed in Table Table 6.12 Bococizumab: Phase I and Phase II Completed Studies Phase Clinicaltrials.gov identifier Sponsor Patients Study Duration Location I NCT Pfizer Healthy N=48 A Study To Access The Safety And Tolerability Of RN316 When Administered To Healthy Adult Subjects Nov May 2010 US I NCT Pfizer Hypercholesterolemia, dyslipidemia, N=68 Safety And Tolerability Of Multiple Doses Of RN316 In Subjects With Hypercholesterolemia Feb Oct 2011 US I NCT Pfizer Hypercholesterolemia, dyslipidemia, N=25 Pharmacokinetic And Pharmacodynamic Study Of A Single-Dose Of RN316 In Combination With Atrovastatin Jul Apr 2011 US II NCT Pfizer Hypercholesterolemia, dyslipidemia, N=93 II NCT Pfizer Hypercholesterolemia, dyslipidemia, N=46 A Multiple Dose Study of RN316 in Subjects on High Doses of Statins A Multiple Dose Study Of RN316 In Subjects On Maximum Doses Of Statins Jul 2011 Jul 2012 Jun Jun study locations in US and Canada 29 study locations in US and Canada II NCT Pfizer Hypercholesterolemia, dyslipidemia, N=356 Monthly And Twice Monthly Jul May Subcutaneous Dosing Of 2013 RN316 In Hypercholesterolemia Subjects On A Statin 73 study locations in US Source: Table 6.13 provides additional details of a recent Phase II trial studied in 356 patients (NCT ). The results were positive, showing significant reduction in LDLC across all doses; the reduction in 2-weekly dosing regimen was 34.3% with 50 mg, 45.1% for 100 mg and 53.4% for 150 mg, and for the monthly dosing regimen was 27.6% for 200 mg and 44.9% for 300 mg. Copyright 2014 Roots Analysis Private Limited Page 6

7 18,000 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2, % 120% 100% 80% 60% 40% 20% 0% 8.3. OVERALL MARKET FORECAST Figure 8.1 profiles the base scenario of the overall PCSK9 and other novel cholesterol lowering drugs market for the period This market is based on the sum of the sales forecast of the individual pipeline drugs. As briefly outlined in the earlier section, sales forecast for each drug is based on the probable trends such as expected market penetration and adoption, expected price of the drug, uniqueness of the drug and the patient population to which the drugs cater to. Report Page 107 Figure 8.1 Overall PCSK9 and Other Novel Cholesterol Lowering Drugs Market Forecast: Base Scenario (USD Million) Overall Sales (USD Million) Annual Growth Rate (%) 2014E 2015E 2016E 2017E 2018E 2019E 2020E 2021E 2022E 2023E 2024E Source: Roots Analysis The market is still in its infancy. In 2014, we estimate the market to be worth around USD million driven primarily by the sales of Juxtapid. With the expected launch of Evolocumab and Alirocumab in near future, the market is expected to witness a step change and grow to USD million by Post this, aided by the launch of Bococizumab and Anacetrapib in 2017, we have forecasted the growth to continue sharply for a few years. As the market matures, a vivid dip in the annual growth rate shall be witnessed in the forthcoming years ( ). However, it is important to mention that the growth could receive a boost if other molecules (not currently in Phase III and, as such, not considered for this forecasting exercise) continue to progress through the clinical trials and get marketed. The peak sales of USD billion, in our base scenario, are expected to be hit in In the optimistic scenario, we predict the market to reach USD billion and USD billion in the year 2019 and 2024 respectively. On the other hand, in the conservative scenario, the forecast Copyright 2014 Roots Analysis Private Limited Page 7

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