FDA approves Amgen’s PCSK9 inhibitor Repatha (evolocumab) for prevention of heart attack, stroke, and coronary revascularization – December 5, 2017

Executive Highlights

  • The FDA just approved a new CV indication for Amgen’s PCSK9 inhibitor Repatha (evolocumab) for the prevention of heart attack, stroke, and coronary revascularization in people with established CV disease. This news came right on time with Amgen management’s expectation of a regulatory decision by December 2.
  • Management has previously shared that Amgen is prepared to begin promoting Repatha’s cardioprotective effects to both patients and HCPs “in a matter of weeks” following this label update. We’re eager to see what rollout of the new label will entail, and our fingers are crossed that it will improve the product’s value proposition in payers’ eyes.

Right on schedule with Amgen’s expected timeline of a decision by December 2, the FDA approved a new CV indication for the company’s PCSK9 inhibitor Repatha (evolocumab) for the prevention of heart attack, stroke, and coronary revascularization in people with established CV disease. Repatha is the first PCSK9 inhibitor to receive such an indication (the ODYSSEY Outcomes CVOT for Sanofi/Regeneron’s Praluent is expected to report data in 1Q18). This label update reflects positive data from the FOURIER trial, in which Repatha reduced risk for the composite primary endpoint (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization) by 15% (p<0.0001 vs. placebo) and for the key secondary endpoint of three-point MACE (CV death, non-fatal MI, or non-fatal stroke) by 20% (p<0.00001). Thanks to priority review from FDA, this regulatory decision was announced just six months after Amgen submitted a Supplemental Biologics License Application (sBLA) in June 2017. The company also filed for a similar Repatha indication with the EMA in June 2017, and a decision on the EU label is expected between April-June 2018, assuming a standard 10-12 month review cycle.

In the company’s 3Q17 update, management shared that Amgen is prepared to begin promoting Repatha’s cardioprotective effects to both patients and HCPs “in a matter of weeks” following approval. We’re eager to see what rollout of the new label will entail, and to see how the new indication influences prescription habits. Most importantly, we expect to see that it will improve Repatha’s value proposition in payers’ eyes – it if does not, this should prompt a major outcry from advocates. Indeed, access remains a major hurdle for both PCSK9 inhibitors on the market, which are currently very pricey products. Negotiating with payers to improve Repatha reimbursement is a much-discussed “top priority” for Amgen, and we expect the company to go all-in leveraging this new CV indication, since it shows the drug’s benefit on concrete, costly outcomes. Perhaps determining cost-savings from LDL-lowering alone is more of an estimate, but now the Repatha label shows heart attacks, strokes, and expensive hospitalizations avoided, and this should absolutely be compelling to payers.

  • Though Repatha is not a diabetes therapy, we see this label update as very good news for people with diabetes, given the high burden of CV disease in this population. A pre-specified sub-analysis of people with diabetes within the FOURIER trial was presented at EASD: Repatha was associated with a 17% relative risk reduction for the primary composite endpoint (HR=0.83, 95% CI: 0.75-0.93, p<0.0008), and with an 18% relative risk reduction for the secondary outcome of three-point MACE (HR=0.82, 95% CI: 0.72-0.93, p<0.0021). This is comparable to the 13% relative risk reduction (HR=0.87, 95% CI: 0.79-0.96, p=0.0052) for the primary endpoint and the 22% relative risk reduction (HR=0.78, 95% CI:0.69-0.89, p=0.0002) for three-point MACE in FOURIER participants without diabetes at baseline. Importantly, this significant reduction in CV risk occurred against the backdrop of overall higher risk for MACE events in people with diabetes. At baseline, diabetes patients had 26% higher relative risk for the primary endpoint (HR=1.26, 95% CI:1.13-1.40, p<0.0001) – a 17% three-year risk of an event vs. 13% for people without diabetes. People with diabetes also had a 40% higher relative risk for three-point MACE (HR=1.40, 95% CI: 1.23-1.60, p<0.0001) – a 12% three-year risk of an event vs. 8% for their counterparts without diabetes. This residual CV risk conferred by a diabetes diagnosis underscores the particular importance of cardioprotective therapies for this patient population, and even more so for individuals with comorbid diabetes/hyperlipidemia. At AHA 2017, Toronto’s Dr. Michael Farkouh laid out a compelling case for using PCSK9 inhibitors in diabetes management: These highly-effectively lipid-lowering – and now cardioprotective – therapies should be prescribed to people in the highest stratum of CV risk, and without a doubt, that includes diabetes patients. We’ll be keen to see if Repatha prescriptions increase for people with diabetes, and if Repatha and/or Praluent are incorporated into future iterations of diabetes treatment algorithms.
  • Results from the ODYSSEY Outcomes CVOT of Sanofi’s Praluent (alirocumab) are expected in 1Q18. Positive data could suggest a CV class effect for PCSK9 inhibitors and could provide a push for better reimbursement of the class. While we can only speculate, our sense is that most cardiologists treat Repatha and Praluent as essentially interchangeable in clinical practice (please let us know if you have insight to the contrary!), and given the remarkable lipid-lowering efficacy that both drugs showed in phase 3 trials, we wouldn’t be surprised to have a second positive CVOT for the class come 1Q18 (that said, we know any clinical trialist would warn us not to draw conclusions before seeing the real data, and we do agree). Although a finding of CV efficacy could pose competition for Repatha, Amgen management has asserted that similar results on Praluent as seen in FOURIER will “reinforce the value of the PCSK9 inhibitor class.” We agree that having two positive CVOTs can only grow volume for the class, and can only make a more compelling case for these agents in the eyes of payers and guideline-writing committees. We also look forward to the ODYSSEY Outcomes readout for more insight into how PCSK9 inhibitors impact risk for CV death, as this CVOT has longer median follow-up time vs. FOURIER. As we’ve gathered from thought leaders, FOURIER was a shorter trial (median follow-up 26 months), which may be the reason that evolocumab didn’t show significant risk reduction for CV death (HR=1.05, 95% CI=0.88-1.25), with only 251 deaths in the treatment arm and 240 in the placebo arm.
  • Repatha has been a growing source of excitement in the cardiology community, and new FOURIER sub-analyses continue to shed light on the agent’s compelling clinical benefits. Just a few weeks ago at AHA 2017, Dr. Sabina Murphy presented a post-hoc analysis showing that Repatha reduced risk for total CV events in FOURIER, including recurring events in addition to first events. Evolocumab reduced risk for these recurrent events by 26% (risk ratio=0.74, 95% CI: 0.65-0.85), and for total events (first + recurrent) by 18% (risk ratio=0.82, 95% CI: 0.75-0.90, p<0.001). Dr. Murphy emphasized that both time to first event analysis and total event analysis offer valuable insight: “When we look at first event, we’re really testing the hypothesis of the trial – does this work? When you look at total events, you’re looking at overall clinical burden of this therapy – how will this ultimately affect the patient? These are two complementary questions, and we think it’s helpful to answer both of them when you’re evaluating new therapies.” Another sub-analysis at AHA 2017 demonstrated that Repatha reduced risk for major adverse CV events in patients with lower-extremity peripheral artery disease (PAD). This cardioprotection was achieved through aggressive lipid-lowering with evolocumab, which also significantly reduced risk for major adverse limb events (MALE; acute limb ischemia, major amputation, or urgent revascularization).


-- by Abigail Dove, Payal Marathe, and Kelly Close