Biopharmaceutical Report II
• Comparable CV effect expected across PCSK9 inhibitor class
• Post-hoc MACE results in previous trials viewed with some restraint
• 50% MACE reduction unlikely, 35% realistic and meaningful for both
Amgen’s (NASDAQ:AMGN) Repatha (evolocumab) and Sanofi (EPA: SAN)/Regeneron Pharmaceuticals’ (NASDAQ:REGN) Praluent (alirocumab) are expected to produce positive cardiovascular (CV) event outcomes in their respective CV outcomes trials (CVOTs), experts agreed. Previous post-hoc major cardiovascular event (MACE) analysis data and low-density lipoprotein-cholesterol (LDL-C) lowering outcomes inspires continued positive signal optimism for the PCSK9 inhibitors. However, experts stressed previous small study sizes and trial design disparities makes signal translation to larger trials difficult to predict and any small differentiator could determine a market winner.
These CVOT results on MACE reduction extent will determine each PCSK9 inhibitor’s costbenefit profile and subsequent competitive value. Repatha and Praluent are approved as an adjunct to maximally tolerated statin therapy in heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic CV disease, with Repatha also being approved for homozygous FH (HoFH). CVOT results aim to expand drug labels into primary prevention of CV events in statin intolerant patients.
Assuming label expansion, analysts predict Repatha and Praluent could achieve respective peak sales of USD 7bn and USD 6.1bn peak sales. Repatha’s Phase III FOURIER 27,564-patient dyslipidemia CVOT (NCT01764633) has primary completion expected in October 2017. Amgen expects topline results in 1Q17. Praluent’s Phase III ODYSSEY Outcomes 18,600-patient acute coronary syndrome (ACS) CVOT (NCT01663402) is due to complete in December 2017. Analysts expect interim efficacy analyses around 2H16-1Q17. Both trials have similar primary endpoints of time to MACE, with Repatha being 60 months long and Praluent 64 months. Amgen declined to comment. Regeneron did not respond to a comment request.
Previous MACE reduction signals creates CVOT hope
Praluent’s previous MACE reduction data in its 78 week ODYSSEY trial (NCT01507831) -- in 2,341 high risk CV patients receiving Praluent or placebo every fortnight -- somewhat encourages CVOT read out optimism, said Dr Robert Rosenson, professor, cardiology, Mount Sinai Hospital, New York. Although the primary endpoint was LDL-C change from baseline to week 24, a post-hoc analysis demonstrated a lower MACE rate with Praluent over placebo at 1.7% versus 3.3% respectively (p=0.02), (Robinson et al. NEJM 2015; 372(16):1489-99).
Further to Praluent’s positive MACE signal, Rosenson and Dr Steven Nissen, chairman, department of cardiovascular medicine, Cleveland Clinic Foundation, Ohio added there is no foreseeable reason why CV outcomes should substantially differ between Praluent and Repatha. Dr Christie Mitchell Ballantyne, director, Atherosclerosis Clinical Research Laboratory, Baylor College of Medicine, Houston, Texas agreed similar PCSK9 inhibitor class effects are expected, however, disparities between the CVOT’s duration, inclusion criteria and dosing regimens may drive some drug class differentiation, which is currently unpredictable
Neither Praluent nor Repatha will likely demonstrate a 50% MACE reduction rate as their CVOTs include heart disease patients with background therapy and therefore PCSK9 inhibitor treatment will unlikely induce such a large incremental benefit, said Rosenson. A 35% MACE reduction is realistic and potentially clinically meaningful, he added. Rosenson also noted patient inclusion disparity between ODYSSEY and ODYSSEY Outcomes creates some uncertainty over MACE results being replicated across trials. ODYSSEY enrolled patients with either HeFH, with or without coronary heart disease (CHD) or CHD risk; or hypercholesterolemia patients with established CHD or CHD risk. Contrastingly, ODYSSEY Outcomes is simply recruiting hospitalized ACS patients in the past year.
Three CVOT results on MACE reduction extent will determine each PCSK9 inhibitor’s costbenefit profile and subsequent competitive value
Overall, post-hoc MACE results encourage a positive CV signal in ODYSSEY Outcomes, however, post-hoc studies are insufficiently powered to definitively demonstrate a therapy’s CV effect, added Ballantyne and Nissen. Although Rosenson maintained CVOT optimism from prior signals, he acknowledged the post-hoc analysis’ limitations, namely its shorter duration (by around 178 weeks), doesn’t guarantee result comparability in a longer, larger study.
Further to past MACE data, PCSK9 inhibitor’s LDL-C lowering mechanism also supports favourable CVOT outcomes for both drugs, experts agreed on the sidelines of the British Cardiovascular Society congress in Manchester this week.
A two stage 511-patient trial (NCT01984424) in uncontrolled LDL-C individuals with a history of statin intolerance evaluated Repatha’s lipid lowering effects in patients receiving subcutaneous evolocumab (Repatha) versus oral ezetimibe (Nissen et al. JAMA 2016;315(15):1580- 90). Mean week 22 and 24 results demonstrated a between group LDL-C difference of -37.8%, favouring evolocumab.
Despite being a surrogate endpoint, a -37.8% LDL-C lowering outcome over commonly prescribed ezetimibe indicates a potentially protective CV effect, however, this is unclear ahead of long-term CVOT read outs, said Ballantyne, Nissen and Rosenson.
CVOT results critical to uptake prospects
Although positive CVOT results are expected, the extent of the potential benefit will drive physician prescription habits, said Ballantyne, Nissen and Rosenson. CVOT results will resolve PCSK9 inhibitors’ currently unknown cost/benefit profile, said Dr Saul Myerson, associate professor, cardiovascular medicine, John Radcliffe Hospital, Oxford, UK. Praluent and Repatha cost around USD 14,000 annually. This news service previously reported PCSK9 inhibitors’ high price makes them reserved for severe patients.
Furthermore, positive CVOT data may sway payer willingness towards permitting the expensive treatments, added Nissen. Payer reluctance is PCSK9 inhibitors’ main uptake barrier as prescriptions require extensive cost justification, whilst patients reluctantly initiate treatment due to potentially large out-of-pocket payments and anticipated prescription hassle, said Ballantyne. Positive CVOT read outs could overcome these issues for both drugs, said Ballantyne.
The realistic expectation of a 35% MACE reduction may boost uptake, however, if a lower rate is demonstrated, treatment benefit may not outweigh its cost, said Rosenson.
Contrastingly, efficacious statins are affordable and have been used clinically for around 50 years in millions of patients, said Dr Pasquale Maffia, honorary senior lecturer, institute of cardiovascular and medical sciences, University of Glasgow, UK. This could dampen PCSK9 inhibitor uptake at its current price -- despite an improved cost-benefit profile -- until longer term data speaks to improved quality of life, said Maffia.
Aside from determining the agents’ CV effects, Amgen and Regeneron’s CVOTs may uncover potential long-term toxicities, potentially influencing uptake, added Ballantyne. Allergic reactions are the most common Praluent/ Repatha-associated adverse events. Praluent and Repatha’s past studies included around 500- 2,000 patients for around six months, whereas CVOTs include many thousands of patients on several years of therapy, he explained. CVOTs therefore include a much longer treatment exposure period and should therefore better determine the therapy’s risk/benefit profile, said Ballantyne.
Amgen has a market cap of USD 117.7bn.
Regeneron has a market cap of USD 39.9bn.
Alexandra is an award-winning healthcare professional journalist. Prior to joining BioPharm Insight, Alex was Editorial Assistant at CIG Healthcare, covering pharmaceutical news for pharmacists and pharmaceutical support staff. She was awarded the annual Johnson & Johnson ‘Best Healthcare Professional Trade Journalist of the Year’ award in 2014 for an article on eczema. Alex graduated from the University of Leeds with a 2.1 Hons in Biology in 2012.