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PCSK9 Inhibitors - The hot new approach to lower cholesterol

  • ID: 2254170
  • Report
  • October 2012
  • 43 Pages
  • LifeTech Research
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  • Adnexus
  • Alder Biopharmaceuticals
  • Amgen
  • Idera
  • Merck
  • Pfizer
  • MORE
Several companies are actively pursuing a new strategy to lower cholesterol: the inhibition of the PCSK9 gene/enzyme. This enzyme speeds the degradation of LDL receptors. Thus its inhibition should preserve receptor function and enhance the clearance of LDL-C, thereby lowering plasma levels. Sponsor efforts have focused on three technology platforms as a means to accomplish this—antibodies that target PCSK9, RNA silencing, and antisense oligonucleotides. This report explores the underlying rationale for PCSK9 inhibition and those three technology platforms. Additionally, it looks at the strength of available data, the regulatory paths ahead, and the market opportunities for the two most advanced candidates—Regeneron/Sanofi’s REGN727 and Amgen’s AMG 145.
Note: Product cover images may vary from those shown
2 of 4


  • Adnexus
  • Alder Biopharmaceuticals
  • Amgen
  • Idera
  • Merck
  • Pfizer
  • MORE

1. Lipid metabolism–an overview
2. The role of LDL cholesterol (LDL-C)
3. LDL-C, current therapies, and cardiovascular risk
4. The role of PCSK9 in cardiovascular disease
5. Companies have used three technologies to target PCSK9
- Monoclonal antibody therapy
- Antisense oligonucleotides
- Small interfering RNA (siRNA)


1. Regeneron and Sanofi’s REGN727/SAR236553
- Phase I and I/II trials (Stein EA et al; NEJM 2012)
- Phase II trials
2. Amgen’s AMG 145
3. Pfizer’s RN316 (PF-04950615)
4. Novartis’ LGT209
5. Alnylam’s ALN-PCS02
6. Bristol Myers Squibb/ISIS Pharmaceutical’s BMS-844421/ISIS 394814 and Santaris Pharma A/S’ SPC5001
7. Preclinical programs


1. PCSK9 inhibitors lower LDL-C dramatically—so what are the questions?
2. Which segments of the population would be best served by PCSK9 inhibitors and does that match with the indications that the sponsors are seeking?
3. Can one expect these agents to lower cardiovascular risk even further?
4. PCSK9 inhibition seems safe but, as always, caveats remain
5. Antibody therapeutics are associated with certain risks
6. Antisense and siRNA technologies are newer and untried
7. Are there theoretical concerns related to PCSK9 inhibition itself?
8. The regulatory path forward
- General regulatory considerations
- REGN727 and heterozygous familial hypercholesterolemia
- Amgen’s AMG 145


1. Market overview
- The broad first-line therapy market is huge
- The statin intolerant and adjunct to statin therapy markets are more realistic targets
- The heterozygous familial hypercholesterolemia market
2. Competitive issues
3. Pipeline competitor analysis


Appendix 1. ATP III National Cholesterol Education Program Treatment Guidelines–Adapted
Appendix 2. Treatment Emergent Adverse Events During A 12 Week Study Of REGN727 Therapy In Heterozygous Familial Hypercholesterolemia Patients: N (%)
Appendix 3. PCSK9 Inhibitors In Discovery/Preclinical Development
Appendix 4. Zetia NDA Trials
Appendix 5. Summary Of Mipomersen Trials
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- Regeneron
- Sanofi
- Amgen
- Pfizer
- Novartis
- Alnylam
- Isis Pharmaceuticals
- Bristol Myers Squibb
- Santaris
- Adnexus
- Alder Biopharmaceuticals
- Serometrix
- Shifa
- Idera
- Merck
Note: Product cover images may vary from those shown
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Note: Product cover images may vary from those shown