ACC 2018 (American College of Cardiology)

March 10-12, 2018; Orlando, FL; Day #1 Highlights – Draft

Executive Highlights

  • The indisputable highlight from day #1 of ACC 2018 was late-breaking data from ODYSSEY Outcomes. Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab) showed a 15% risk reduction vs. placebo (p=0.0003) for the primary CV endpoint (CHD death, non-fatal MI, stroke, hospitalization for unstable angina). The study drug also showed a 15% relative risk reduction for all-cause death (p=0.026), but this finding can only be considered observational due to the CVOT’s hierarchical testing structure. According to an interaction analysis, participants with baseline LDL ≥100 mg/dl (~one-third of the 18,924 enrolled) drove the positive results on both these endpoints; this “highest-risk” subgroup experienced a 24% relative risk reduction for the primary MACE outcome (HR=0.76, 95% CI: 0.65-0.87) and a 29% relative risk reduction for all-cause mortality (HR=0.71, 95% CI: 0.56-0.90). This trend wasn’t seen in FOURIER for Amgen’s PCSK9 inhibitor Repatha (evolocumab). We include much more detail on the results below, alongside in-depth commentary. We’re very hopeful that ODYSSEY Outcomes will translate into better reimbursement for PCSK9 inhibitors across the board, especially since this second positive CVOT points to a cardioprotective class effect, though we’ve gathered that many thought leaders are keen on the idea of risk stratification, or targeting PCSK9 inhibitors to the patients with highest LDL for the greatest cost-savings.
  • Other day #1 highlights include Toronto’s Dr. Lawrence Leiter on diabetes CVOT design, Emory’s Dr. Peter Wilson on the need to individualize CV risk assessments in people with diabetes, and NYU’s Dr. James Underberg on the urgency of treating LDL in the context of diabetes care. Dr. Leiter described current CVOTs, with a high-risk population at baseline and relatively short duration, as “crash tests” in safety. He advocated for CVOTs that start treatment in patients earlier in the course of disease development and follow them for a longer time – this would of course be expensive, so Dr. Leiter spoke to the importance of coming up with less expensive alternatives to traditional RCTs. We also would look for different investors – sure, CVOTs with younger patients are expensive, but nothing like what society is spending on CV disease generally or what could be saved. Dr. Leiter also highlighted the fact that we have come a long way in that we are now being asked “which” of our evidence-based therapies should be used in patients with diabetes/CV disease. The key message is that the presence of CV disease should be a priority consideration for the choice of antihyperglycemic agents and that cardiologists must get involved in prescribing these evidence-based therapies. Notably, Dr. Wilson added important nuance to the common conception that diabetes confers equivalent risk for MI as having a prior MI (but no diabetes). Ultimately, he argued that this view is too simplistic. We loved Dr. Underberg’s emphasis on people with diabetes as a group facing particularly high CV risk, in need of effective CV risk mitigation strategies. Dr. Underberg spoke to a major theme of ACC overall: To move the needle on CV morbidity/mortality, patients with cardiometabolic dysfunction need more multidisciplinary medical care from coordinated teams of specialists.
  • ACC 2018 offered no shortage of content on PCSK9 inhibitors (even beyond ODYSSEY Outcomes). A day #1 poster session featured new findings that (i) utilization management criteria from payers are likely not getting PCSK9 inhibitors to the right patients, and that (ii) an outcomes-based reimbursement strategy for PCSK9 inhibitors would not be cost-effective across the board, again reminding us of the need for risk stratification.
  • Exhibit hall: Novo Nordisk joined this year’s lineup of diabetes companies at ACC 2018, highlighting its GLP-1 agonist business – Victoza’s CV indication as well as recently-launched Ozempic. J&J promoted SGLT-2 inhibitor Invokana in one corner of its large booth, while Sanofi promoted Praluent as well as next-gen basal insulin Toujeo and fixed-ratio combination Soliqua – we were particularly glad to see the latter as it is a very easy product to prescribe and take. We also include coverage of Amgen (all about Repatha), AZ (Bydureon BCise available for demo, Dr. Jim McDermott on DECLARE for SGLT-2 Farxiga), and Merck (sadly, a scarce/unmanned booth).

We spent the weekend at ACC 2018 in sunny Orlando, Florida, and this report includes our top six highlights from the day #1 agenda on Saturday. Up first, we have results from ODYSSEY Outcomes, the CVOT for Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab), followed by some compelling commentary on diabetes and CV disease, plus new data on both the science and insurance coverage of PCSK9 inhibitors.

We also enclose exhibit hall coverage in this report. Notably, diabetes companies are showing up in greater numbers, and with greater presence, at every subsequent cardiology conference. For context, check out our exhibit hall coverage from AHA 2017, ESC 2017, and ACC 2017.

Check back later this week for ACC days #2-3 highlights – we promise exciting CVD-REAL 2 results, new data on J&J’s SGLT-2 Invokana (canagliflozin) in heart failure, and an intriguing (and extremely well-attended) dinner session on comprehensive diabetes care (!) featuring Drs. Mikhail Kosiborod and Robert Eckel.

Top Six Highlights

1. ODYSSEY Outcomes: Sanofi/Regeneron’s PCSK9 Praluent (Alirocumab) Shows Significant 15% Reduction in Primary MACE Endpoint, All-Cause Death; Virtually All Benefit Appears in Group with Highest Baseline LDL (≥100 mg/dl) – What Are the Implications for Reimbursement?

Dr. Philippe Steg presented the very first ODYSSEY Outcomes (n=18,924) results on Sanofi/Regeneron’s Praluent (alirocumab), revealing that treatment with the PCSK9 inhibitor led to significant 15% relative risk reductions on a primary composite MACE endpoint and on an observational endpoint of all-cause death. In the CVOT (median follow-up time 2.8 years), alirocumab gave a 15% risk reduction (HR=0.85, 95% CI: 0.78-0.93, p=0.0003 vs. placebo) on the composite primary outcome of coronary heart disease-related death, non-fatal MI, non-fatal stroke, or unstable angina requiring hospitalization, which translated to a 1.6% absolute risk reduction at four years. In the FOURIER trial, which read out at last year’s ACC meeting, Amgen’s PCSK9 inhibitor Repatha (evolocumab) gave a similar 15% relative risk reduction (p<0.0001) for the primary endpoint (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization). The alirocumab group experienced 903 MACE events in total (occurring in 9.5% of participants) vs. 1,052 MACE events in the placebo group (11.1% of participants). The positive primary endpoint result was driven by significant decreases in non-fatal MI (HR=0.86, 95% CI: 0.77-0.96, p=0.006), ischemic stroke (HR=0.73, 95% CI: 0.57-0.93, p=0.01), and unstable angina (HR=0.61, 95% CI: 0.41-0.92, p=0.02), but not CHD death (HR=0.92, 95% CI: 0.76-1.11, p=0.38) with Praluent vs. placebo. Moreover, there was a 15% relative risk reduction for all-cause death in the trial (HR=0.85, 95% CI: 0.73-0.98, p=0.026), though this finding is considered observational because of the hierarchical testing structure. Numerically, there were 334 deaths in the alirocumab arm vs. 392 in the placebo arm. Dr. Steg seemed particularly enthused by the all-cause mortality results, and he opened his presentation by noting that neither high-intensity statins (compared to moderate intensity) nor ezetimibe on top of a statin affect mortality, despite reducing LDL levels. FOURIER actually trended in the wrong direction on all-cause death (HR=1.04, p=0.54), favoring placebo over Repatha, but this result was far from statistically significant. Dr. Steg referred to the p-value for all-cause death in ODYSSEY Outcomes as “nominal,” and we’ve heard hallway chatter that Sanofi/Regeneron will try to “massage” the mortality data in positioning this CVOT to guideline-writing committees, payers, and regulators. We’re very positive on these results overall, and we hope healthcare stakeholders view ODYSSEY Outcomes through the same lens. We have our fingers crossed that payers, in particular, appreciate cardioprotection as a class effect of PCSK9s now that FOURIER and ODYSSEY Outcomes have both reported; leading up to ACC, Amgen management was optimistic that a second positive CVOT would be good news for the class overall in terms of reimbursement prospects. Sanofi plans to file with FDA for Praluent’s CV indication in 3Q18.

  • Additional secondary endpoints were also tested hierarchically in ODYSSEY Outcomes. Dr. Steg reported a 12% drop in coronary heart disease events (CHD death, non-fatal MI, unstable angina requiring hospitalization, ischemia-driven coronary revascularization) with alirocumab vs. placebo (HR=0.88, 95% CI: 0.81-0.95, p=0.001). Risk for major CHD events, including CHD death or non-fatal MI, fell by 12% with alirocumab (HR=0.88, 95% CI: 0.80-0.96, p=0.006), while risk for CV events (CV death, non-fatal CHD event, non-fatal stroke) fell by 13% (HR=0.87, 95% CI: 0.81-0.94, p=0.0003). The triple endpoint of all-cause death, non-fatal MI, and non-fatal stroke showed a 14% risk reduction with alirocumab vs. placebo (HR=0.86, 95% CI: 0.79-0.93, p=0.0003). Neither CHD death (HR=0.92, 95% CI: 0.76-1.11, p=0.38) nor CV death (HR=0.88, 95% CI: 0.74-1.05, p=0.15) were significantly reduced, though this data trended in the right direction, favoring alirocumab over placebo. Risk for ischemia-driven coronary revascularization was reduced by 12% with alirocumab vs. placebo (HR=0.88, 95% CI: 0.79-0.97, p=0.009), while risk for congestive heart failure requiring hospitalization was not impacted (HR=0.98, 95% CI: 0.79-1.20, p=0.84); both of these analyses were pre-specified.
  • An interaction analysis showed that the ~one-third of patients with the highest LDL levels at baseline drove positive CV results in ODYSSEY Outcomes. Importantly, the magnitude of benefit in these patients is much higher (i.e. there’s more room for improvement when starting at higher LDL), which has implications for clinical practice, access, and reimbursement. Primary endpoint efficacy in pre-specified subgroups showed no interaction with age, sex, region, or time from event to randomization; however, there was a borderline significant interaction (p=0.09) with baseline LDL. Participants with LDL <80 mg/dl (n=7,164) or between 80-100 mg/dl (n=6,128) at baseline did not experience significant reductions in the primary composite endpoint with alirocumab vs. placebo (HR=0.86, 95% CI: 0.74-1.01 and HR=0.96, 95% CI: 0.82-1.14, respectively). Note that the 95% confidence interval spans unity, or 1.00, for both subgroups, indicating a non-significant result. On the other hand, participants with baseline LDL ≥100 mg/dl (n=5,629) experienced an impressive 24% risk reduction for the primary composite endpoint (HR=0.76, 95% CI: 0.65-0.87), although no subgroup was powered to show superiority alone, hence the wider confidence intervals. An analogous pattern was seen for all-cause death, where the subgroup with highest baseline LDL experienced a significant 29% relative risk reduction (HR=0.71, 95% CI: 0.56-0.90) and the overall interaction had a p-value of 0.12. During Q&A, Dr. Steg emphasized that this interaction was indeed borderline. He underscored that the trial was positive overall, with all baseline LDL subgroups trending toward benefit with alirocumab. The heterogeneity is somewhat disappointing – it would have been a tremendous victory if Praluent demonstrated cardioprotection regardless of a patient’s starting LDL, because this could have positioned PCSK9 therapy as broadly applicable and beneficial (Repatha conferred similar risk reduction for the primary CV endpoint across all baseline LDL subgroups in FOURIER). That said, we don’t want to undercut the importance of ODYSSEY Outcomes results, which do highlight cardioprotection as a class effect of PCSK9 inhibitors, showing a significant impact on hard outcomes with effective lipid-lowering. Dr. Steg concluded that these data support the long-term safety/efficacy of alirocumab, and that patients with high (≥100 mg/dl) LDL may benefit the most from Praluent.
    • We expect ODYSSEY Outcomes to have big implications for PCSK9 inhibitor reimbursement. In our view, the combination of FOURIER and ODYSSEY Outcomes absolutely points to a cardioprotective class effect. The borderline significant interactions in ODYSSEY related to baseline LDL could lead payers to reserve PCSK9 inhibitor coverage for only the highest-risk patients – but this isn’t necessarily bad news. Considering the abysmal state of reimbursement right now, Sanofi/Regeneron and Amgen have to start somewhere in improving coverage for their products, and risk stratification is a useful strategy to get the ball rolling and convince payers of the potential cost-savings. We can’t ignore that Praluent and Repatha are expensive drugs, and widespread use would levy a substantial cost on the healthcare system; Dr. Naveed Sattar elaborated on this point at ADA 2016. Eventually, we do hope to see PCSK9 inhibitors reimbursed for everyone who could benefit from a more efficacious lipid-lowering agent, but it will likely be a slow-and-steady climb to “ideal” coverage. Notably, given that diabetes also confers residual CV risk (on top of dyslipidemia), many type 2s may fall into the category of “highest-risk.” We’ve certainly heard thought leaders advocate for more consideration of PCSK9 inhibitor therapy in diabetes care. Look out for much more on the topics of patient selection and cost in the rest of our ACC coverage.
    • Very notably, ICER (Institute for Clinical and Economic Review) immediately issued a Preliminary New Evidence Update after Dr. Steg’s ACC presentation – this is terrific news for Sanofi/Regeneron. ICER will continue to refine its cost-effectiveness analysis on Praluent, and a final New Evidence Update is promised by May 3, 2018. In ICER’s interpretation, ODYSSEY Outcomes does confirm a mortality benefit with alirocumab treatment. Per the comment on page 7, ICER will not extend a more favorable cost-effectiveness calculation to Amgen’s Repatha (evolocumab).
  • As in FOURIER, both the MACE and all-cause mortality curves started to diverge around one year. Both CVOTs showed a similar 15% risk reduction on their primary endpoint, although some expected a greater magnitude of benefit in ODYSSEY Outcomes due to the longer duration of follow-up. In presenting FOURIER at ACC 2017, Dr. Marc Sabatine asserted that it takes time for LDL-lowering to translate to clinical benefit. Median follow-up time in FOURIER was 26 months, compared to 34 months in ODYSSEY Outcomes. Dr. Steg highlighted this as a key difference between the studies. He also addressed population differences: FOURIER enrolled stable patients with atherosclerosis in contrast to ODYSSEY Outcomes’ recent ACS (acute coronary syndrome) population; Dr. Steg characterized background statin therapy as truly maximal in ODYSSEY (and perhaps less so in FOURIER). One panelist inquired during Q&A, should we have expected an even greater risk reduction with a sicker population and longer follow-up, rather than these results which are nearly identical to FOURIER? This remains an open question, although Dr. Steg did advance a couple hypotheses. First, a large fraction of early events in ACS are thrombosis-related rather than plaque-related, he explained, and it’s uncertain how a PCSK9 inhibitor would affect thrombosis. Second, maximizing statin therapy may hamper further LDL-lowering, hiding some of the impact of alirocumab vs. a placebo group also on high statin doses.
    • Following the ODYSSEY Outcomes presentation, we’ve heard the divergence of Kaplan-Meier curves characterized as slightly earlier in FOURIER. That said, during a Sunday session, Dr. Jennifer Robinson was quick to fight the suggestion that evolocumab and alirocumab are inherently different molecules. Rather, she attributed the divergence timing to differences in study population and trial design.
  • ODYSSEY Outcomes provides excellent long-term data showing the durability of Praluent’s lipid-lowering effect. Average LDL was lowest in the alirocumab group at four months, when mean LDL was 38 mg/dl for participants on treatment vs. 93 mg/dl in the placebo group (treatment difference of 56 mg/dl, 63% lower). Over 48 months, mean LDL level drifted upward to 53 mg/dl with alirocumab, but this was still 48 mg/dl (or 55%) lower than the 101 mg/dl seen in the placebo group. During Q&A, Dr. Steg attributed most of this upward drift to participants stopping or de-intensifying background statin therapy.
  • Study design: ODYSSEY Outcomes enrolled 18,924 patients who had experienced acute coronary syndrome (acute MI or unstable angina) in the past 1-12 months. All participants also had elevated levels of LDL cholesterol despite being on high-intensity statin therapy (or, they had documented statin intolerance). After a run-in period of 2-16 weeks on high-intensity/maximum-tolerated atorvastatin or rosuvastatin, participants who still met one of three high-lipid criteria were randomized to alirocumab 75 mg twice-monthly (n=9,462) or matched placebo (n=9,462). The study used a treat-to-target design, meaning HCPs were instructed to aim for a target LDL of 25-50 mg/dl in all patients. To maximize the number of participants reaching target range, investigators blindly titrated up or down, but also blindly switched to placebo if two consecutive LDL readings were below 15 mg/dl. A striking 7.7% of participants (730 individuals) were blindly switched to placebo – to our understanding, this could have partially muted the effect seen in the intention-to-treat analysis, although it also signals impressive lipid-lowering efficacy with Praluent (since so many people were experiencing consecutive readings <15 mg/dl). Median follow-up was 2.8 years in ODYSSEY Outcomes (compared to 2.2 years in FOURIER). Treatment was prematurely discontinued in 14.2% of alirocumab participants and in 15.8% of placebo participants. Only 23 people (~0.1%) were lost to follow-up. Dr. Steg also alluded to the possibility of artifacts related to titration, which may have caused patients to receive slightly varying doses of alirocumab.
  • Baseline characteristics: Average age in both arms was 58, and 25% of participants were female. Diabetes was present in 29% of participants at baseline, 24% were current smokers, 65% had hypertension, and 19% had prior MI. We’re extremely eager for subgroup analysis focused on the patients with baseline diabetes, and we imagine these are coming soon from Sanofi/Regeneron (Sanofi management shared on the company’s 4Q17 earnings call that ODYSSEY Outcomes data was coming in the nick of time for ACC 2018, so it’s understandable that post-hocs won’t be ready until subsequent scientific meetings). Median time from acute coronary syndrome (ACS) to randomization was 2.6 months; of those ACS events, 49% were non-ST-elevated MI (NSTEMI), 35% were ST-elevated MI (STEMI), and 17% were unstable angina. Median LDL at baseline was 87 mg/dl, and 93% of patients met lipid criteria based on LDL cholesterol alone. At baseline, 89% of participants were on high-dose atorvastatin/rosuvastatin, and another 9% were on low to moderate doses; only 1% were on no lipid-lowering therapy. Drawing a contrast to FOURIER, Dr. Steg emphasized that this was truly a maximally-treated population in terms of statin therapy.
  • Safety: There was no overall imbalance in treatment-emergent adverse events, including worsening diabetes or complications and new-onset diabetes. There were more local injection site reactions with alirocumab (3.8%) vs. placebo (2.1%), but this was expected, and we’re quite impressed by how safe/tolerable the PCSK9 inhibitor class has turned out.

2. Dr. Lawrence Leiter Considers Potential for Long-Duration Outcomes Trials in Low-Risk Populations to Demonstrate Greater Efficacy; Commentary on SGLT-2 Mechanisms of CV Benefit, Amputation Risk, Heart Failure Benefit

Toronto’s Dr. Lawrence Leiter shared his thoughts on diabetes CVOT design, commenting that current trials are limited in their short duration and high-risk populations. As he put it, these “crash tests” for safety may not be the best way to demonstrate CV efficacy. Dr. Leiter noted that when early CVOTs (ELIXA for Sanofi’s GLP-1 lixisenatide and the DPP-4 studies like SAVOR-TIMI, EXAMINE, and TECOS) all showed neutrality, experts thought the populations being investigated were too late in the course of disease; thought leaders suggested that trials instead enroll lower-risk patients for a longer study duration. As we understand it, the main incentive in selecting an enriched, higher-risk population is that “sicker” participants have a higher CV event rate, allowing for shorter trials (and these outcomes studies are already a major investment of time and resources). Indeed, >80% of participants in LEADER and SUSTAIN 6 had baseline CV disease, and those trials demonstrated CV superiority of Novo Nordisk’s GLP-1 agonists liraglutide (Victoza) and semaglutide (Ozempic). In contrast, only 73% of patients in EXSCEL for AZ’s GLP-1 Bydureon (exenatide once-weekly) had baseline CV disease, and that study just missed the threshold for CV superiority. Moreover, only 31% of people in REWIND for Lilly’s GLP-1 Trulicity (dulaglutide) have baseline CV disease, which is one reason that Novo Nordisk CSO Dr. Mads Thomsen doesn’t believe this CVOT will show significant CV superiority (REWIND is expected to complete in July 2018). For SGLT-2 inhibitors, all of EMPA-REG OUTCOME and 66% of CANVAS participants had baseline CV disease, while DECLARE (the CVOT for AZ’s Farxiga, likely reading out in 2H18) has enrolled only ~41% of participants with baseline CV disease. Could a much longer study show a greater magnitude of benefit if the intervention is started in the early stages of disease? REWIND and DECLARE should help shed some light on this issue, with their larger primary prevention cohorts, but these trials are a fairly mild change compared to their predecessors. We often think about the potential for SGLT-2s and GLP-1s in diabetes prevention, and we’d be over the moon if a long outcomes trial investigated CV/renal effects with treatment beginning in prediabetes. We imagine SGLT-2s and GLP-1s may offer different advantages/disadvantages when started earlier in the course of hyperglycemia development, based on their distinct mechanisms of action. There is growing consensus that GLP-1 agonists exert their CV benefit via atherosclerotic effects, in which case a patient would need to have pre-existing plaques to experience appreciable CV risk reduction. Of course, there’s also the chance that a treatment prevents plaques from forming in the first place. Meanwhile, a post-hoc analysis of CANVAS presented at AHA 2017 found significant heart failure benefit with canagliflozin (J&J’s SGLT-2 inhibitor Invokana) in both the primary and secondary prevention cohorts, so perhaps SGLT-2s reduce risk for heart failure independent of CV or diabetes status – we’ll have a much more definitive answer on this in a couple years, now that AZ and Lilly/BI are investigating their SGLT-2 inhibitors in people with chronic heart failure, with or without diabetes (and we anticipate a subgroup of these studies will have prediabetes, allowing for interesting subgroup analyses). Dr. Leiter also highlighted the fact that we have come a long way in that we are now being asked “which” of our evidence-based therapies should be used in patients with diabetes/CV disease. The key message is that the presence of CV disease should be a priority consideration for the choice of antihyperglycemic agents and that cardiologists must get involved in prescribing these evidence-based therapies.

  • When asked if metformin should remain first-line therapy in type 2 diabetes, Dr. Leiter again characterized modern CVOT design as restrictive, an obstacle to change. He pointed out that most guidelines recommend adding drugs to background metformin because most clinical trial participants were on metformin at baseline. For guidelines to change, an advanced therapy would have to go head-to-head against metformin. Dr. Leiter suggested that there is significant interest for these trials within the medical community, but he also underscored that they will have to be done much less expensively than a standard CVOT – for example, by utilizing data sources like EMRs. If anyone has ideas on how to get pharma to focus on low-risk populations, , or on how to perform less expensive RCTs utilizing EMRs that are still compelling and convincing to all parties (including FDA and guideline-writers), we’d love to hear them.
  • Dr. Leiter also commented on SGLT-2 inhibitor CVOTs and mechanisms of cardioprotection. He cited a recent post-hoc analysis of EMPA-REG OUTCOME (presented by Dr. David Fitchett at AHA 2017) demonstrating that hematocrit and hemoglobin were each associated with >50% mediation of heart failure benefit, while A1c and fasting plasma glucose showed 20%-30% mediating effect. According to Dr. Leiter, glucose-lowering takes a long time to exert an impact on CV risk, and the early separation of the Kaplan-Meier curves in this trial (and in CANVAS) are more likely to indicate a volume effect – but there is still significant discussion happening on this front. Combined with the fact that these trials were designed for glycemic equipoise, we can be almost certain that CV health isn’t being improved primarily through glycemic benefit. We’ve noticed that cardiologists are especially enthused by SGLT-2 inhibitors, which was reflected in an audience polling question: 63% of audience members increased their use of SGLT-2 inhibitors in clinical practice following CVOT readouts, compared to only 42% for GLP-1 agonists.
    • As for the amputation signal seen in CANVAS, Dr. Leiter explained that he would be cautious about prescribing canagliflozin to patients with peripheral arterial disease (PAD). He reviewed the overall two-fold increase in amputation risk observed in CANVAS, but also a 7-8-fold increase in those with PAD and a 20-fold increase in those with prior amputation. Pushing the question even further, Dr. Leiter asked whether you should ever use any SGLT-2 inhibitor in patients with PAD, noting EMA’s (conservative) class-wide warning for increased amputation risk (FDA has added a lower limb amputation warning only to the Invokana label, but not to other SGLT-2 products). While we’ve heard strong support in favor of a cardioprotective class effect for SGLT-2 inhibitors, the judge and jury are still out on class effects for amputation – another reason we’re looking forward to DECLARE results.
    • SGLT-2 inhibitors are particularly intriguing because of their demonstrated heart failure benefit in EMPA-REG and CANVAS alike (not to mention CVD-REAL). There have been suggestions that this class may exert a heart failure benefit regardless of patients’ baseline heart failure status (i.e. primary as well as secondary prevention), but Dr. Leiter pointed out that in both EMPA-REG and CANVAS, heart failure status was determined by the investigator simply checking a box, without a more formal assessment of cardiac function. After the impressive hospitalization for heart failure findings in EMPA-REG and CANVAS, AZ’s DECLARE trial for Farxiga (dapagliflozin) was modified to include collect assessments of cardiac function, e.g. a cardiac echo, if already preformed prior, so we’ll have a more precise picture of baseline cardiac function.

3. An Argument Against Type 2 Diabetes as a CV Risk Equivalent from Dr. Peter Wilson; Advocates for More Consideration of Individual Risk Factors

In a very well-attended session on diabetes risk management, Emory’s Dr. Peter Wilson argued against the commonly-used heuristic that diabetes confers equivalent CV risk as a prior MI in someone without diabetes; instead, he illustrated the importance of considering both individual risk and atherosclerotic CV disease heterogeneity. Dr. Wilson traced the commonly-cited assertion back to a 1998 Finnish population-based study, published in NEJM, which found equivalent MI risk among 1,373 people without diabetes and 1,059 people with diabetes. While he acknowledged that people with diabetes are often affected by CV disease (~two-thirds of people with diabetes will experience comorbid CV disease), he described the heuristic as too simplistic overall, since relative risk for CV events is also impacted by cholesterol, tobacco use, renal function, age, and blood pressure in addition to diabetes status. Moreover, it’s not just atherosclerotic events that HCPs must consider in treating diabetes: Intermittent claudication (pain in the legs caused by obstruction of arteries) and heart failure are at least as important. Dr. Wilson reviewed data showing a general doubling or tripling of CV risk with type 2 diabetes, but he ultimately emphasized that data on the magnitude of risk are mixed. In fact, in a 2009 meta-analysis, the 1998 Finnish study was the only one to support the conception of diabetes as a risk equivalent to prior MI. This meta-analysis (n=45,108) found that patients with diabetes and no prior MI actually have a 43% lower risk of overall coronary heart disease-related events vs. people with no diabetes and a previous MI. Ultimately, there’s no arguing that people with diabetes experience devastatingly higher rates of MI, stroke, and renal disease than the general population, but Dr. Wilson cautioned against blanket assumptions; he emphasized the importance of a range of factors when it comes to an individual’s CV risk and how that should be treated. Although he didn’t explicitly mention precision medicine, we felt this talk was a compelling argument for why we need better tools to personalize treatment plans that reduce cardiometabolic risk. As one example, BI and Geisinger have teamed up to develop a risk-prediction model for CV death, kidney failure, and heart failure in type 2, which could eventually become a decision-support tool for providers. Indeed, when session chair Dr. Mikhail Kosiborod (who very much agreed with Dr. Wilson’s argument) asked what providers should be using right now to identify people with diabetes who do have equivalent CV risk, Dr. Wilson acknowledged the lack of tools, data, and guidelines.

4. Posters Tackle PCSK9 Coverage and Reimbursement, Pointing to Arbitrary Utilization Management Criteria and Currently Low Cost-Effectiveness

In a poster session on the latest in dyslipidemia care, PCSK9 inhibitors were heavily featured. Within these posters, we noticed a theme of research focused on access, reimbursement, and cost-effectiveness. Below, we highlight two particularly notable studies:

  • Payers create utilization management (UM) criteria to ensure that the patients most in-need have access to advanced (expensive) therapies. However, this analysis showed that current criteria for PCSK9 products are not actually associated with increased risk of CV events. Researchers used a drug formulary database to identify four common UM criteria for PCSK9 inhibitors: (i) statin use, (ii) high-intensity statins, (iii) duration of statin use, and (iv) duration of ezetimibe use. Patients were considered to be participants (n=5,276) if they had at least one LDL reading in the past year ≥70 mg/dl; all participants were commercially-insured and had atherosclerotic CV disease (51% female, mean age 56). A multivariate analysis evaluated whether UM criteria were associated with more or less risk of CV events in the year following an LDL reading of at least 70 mg/dl. After controlling for demographic characteristics and baseline comorbidities, no association with CV events was found for (i) current vs. prior statin use (95% CI: 0.77-1.48), (ii) number of high-intensity statins used, compared to one statin (95% CI: 0.63-1.10 for zero statins, 0.91-3.64 for two+ statins), (iii) duration of statin use, compared to <60 days (95% CI: 0.98-3.15 for 60-90 days, 0.61-1.72 for 90-180 days, and 0.37-1.01 for >180 days), or (iv) duration of ezetimibe use, compared to 1-180 days (95% CI: 0.29-1.01 for no ezetimibe, 0.47-2.22 for >180 days). Since all of these 95% confidence intervals cross unity, the implication is that none of these criteria were significantly associated with CV risk, which is arguably how payers should determine candidates first in line for PCSK9 inhibitor coverage. The poster noted that some selection bias may have influenced results for ezetimibe and multiple statin usage, as patients with high CV risk are more likely to meet those criteria. The authors emphasized that <half of prior authorizations for PCSK9 inhibitors are approved based on these criteria – our sense is that this number has improved as providers have learned to work the system (according to a 2016 survey, only 36% of PCSK9 prior authorizations were approved), but payers are nevertheless using these potentially irrelevant UM criteria to make coverage decisions. We certainly agree with the authors that ample data and provider expertise exist and should be used to create a more accurate and data-driven algorithm for assessing CV risk and determining who could benefit most from treatment with a PCSK9 inhibitor.
  • Another poster concluded that an outcomes-based reimbursement model for Amgen’s Repatha (evolocumab), in which the company would offer refunds to payers and/or patients who “failed” therapy, would not meaningfully change the cost-effectiveness of PCSK9 inhibitors. Researchers calculated four hypothetical incremental cost-effectiveness ratios (ICERs) using FOURIER data, assuming full reimbursement to payers/patients if evolocumab (i) did not reduce LDL cholesterol to one of three thresholds or (ii) in the case of a CV event. In this cost-utility analysis, the ICER was synonymous with the QALY, or cost per quality-adjusted life year. Naturally, the literature-derived ICER for evolocumab was much higher than that of atorvastatin, at $274,000/QALY vs. $20,300/QALY. In the case of compensation based on a CV event, the ICER for evolocumab fell to $246,000/QALY. With thresholds of LDL >70 mg/dl, >40 mg/dl, and >25 mg/dl evolocumab’s ICER value dropped to $239,000/QALY, $184,000/QALY, and $115,000/QALY, respectively. Thus, even with an outcomes-based contract of sorts, it’s difficult to make Repatha as appealing to payers as atorvastatin. Indeed, we’ve heard quite a few presenters remark that PCSK9 inhibitors are simply not an effective population-level solution for hyperlipidemia at their current price. We’re noticing more mentions of risk stratification as cardiologists try to determine which of their patients would benefit most from PCSK9 inhibitor therapy. How can risk stratification be most effectively incorporated into treatment algorithms? While we’re glad manufacturers are working on expanding access broadly from their end, we acknowledge that (at least for now) targeting of PCSK9s to the patients most in-need is probably the only way to move the needle on reimbursement. That being said, Sanofi/Regeneron have announced plans to lower net price for payers willing to lower access barriers, in line with a new cost-effectiveness analysis from the Institute for Clinical and Economic Review (also ICER) including ODYSSEY Outcomes results (above) – we’ll keep a close eye on how this impacts access in the coming months and years.

5. Dr. James Underberg Highlights Lack of Success in Treating Hyperlipidemia; Calls for More Aggressive Treatment of LDL in People with Diabetes

In an Amgen-sponsored session, NYU’s Dr. James Underberg made a strong case for the urgency of LDL-lowering in patients with diabetes, while also highlighting the factors that make meeting LDL targets difficult. He presented lipids as one of the more modifiable CV risk factors, compared to type 2 diabetes (hyperglycemia), smoking, obesity, and blood pressure. In characterizing groups with the highest CV risk, Dr. Underberg placed specific emphasis on people with atherosclerotic CV disease and comorbid diabetes, naming a target LDL level of <70 mg/dl for these patients in line with the 2017 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia. This echoes commentary we’ve heard from other thought leaders as well – diabetes and dyslipidemia are both independent risk factors for CV morbidity/mortality, and when the two exist together, CV risk reduction strategies become especially urgent. Unfortunately, Dr. Underberg showed how hyperlipidemia is undertreated worldwide: Although statins are relatively inexpensive (~$10/month in the US), ~70% of people globally are not reaching LDL goal <70 mg/dl. Dr. Underberg cited limited exposure to statins in some populations and difficulty maintaining adherence, but also genetic dispositions (including but not limited to familial hypercholesterolemia). He also mentioned lack of responsiveness to statins that makes lipid control difficult even on high-dose statins – this is where PCSK9 inhibitors come in. We appreciated Dr. Underberg’s emphasis on patients with diabetes as a particularly high-risk group. We imagine that more can be done to mitigate CV risk in patients with diabetes – and that some risk factors, like hyperlipidemia, might even sit in the shadow of A1c. Dr. Underberg spoke to a major theme of ACC: To move the needle on CV morbidity/mortality, patients with cardiometabolic dysfunction need more multidisciplinary medical care from coordinated teams of specialists.

6. Lp(a) Levels Could Predict Who Responds Best to PCSK9 Inhibitor Repatha, According to New Post-Hoc Analysis of GLAGOV

Dr. Daniel Scherer (South Australian Health and Medical Research Institute, Adelaide, Australia) presented a poster showing that higher Lipoprotein(a), or Lp(a), levels could help identify patients likely to achieve a greater degree of atheroma volume regression with evolocumab (Amgen’s Repatha). Dr. Scherer’s analysis was a post-hoc of GLAGOV (n=970), an Amgen-sponsored study looking at change in percent and total atheroma volume with evolocumab vs. placebo as add-on to statin therapy. Dr. Scherer stratified patients according to baseline Lp(a), a cholesterol and fat transporter and risk factor for CV disease. His group found that 71% of those with above-median Lp(a) experienced percent atheroma volume (PAV) regression vs. only 59% of those below-median (p=0.01 for comparison). PAV reduction from baseline was 1.2% in the high Lp(a) group vs. 0.8% in the low Lp(a) group. Total atheroma volume (TAV) reduction was 7.7 mm3 vs. 5.3 mm3 in the above-median Lp(a) and below-median Lp(a) groups, respectively. Median Lp(a) was 11.8 mg/dl. No p-values were reported for a between-groups comparison of PAV or TAV regression. We were particularly compelled by Dr. Scherer’s analysis showing that baseline Lp(a) >11.8 mg/dl was associated with increased plaque regression with evolocumab (p=0.04 vs. placebo); however, this became marginally non-significant (p=0.09) when adjusting for baseline plaque burden. In GLAGOV participants with Lp(a) <11.8 mg/dl at baseline, a similar degree of regression was seen with evolocumab vs. placebo (p=0.35). We think these findings are most interesting in light of ODYSSEY Outcomes data showing that people with higher baseline LDL (≥100 mg/dl) experienced seemingly all of the CV benefit (see highlight no. 1 above). In GLAGOV, too, higher Lp(a) drove benefit on PAV. Certainly, more analyses of how baseline lipid status affects response to PCSK9 inhibitors are needed to help determine who the “best responders” might be. Dr. Scherer suggested that Lp(a) may indicate a more “modifiable” form of atherosclerosis, but it seems just as likely to us that patients with higher Lp(a) are high-risk overall, making the benefit on a CV biomarker more visible (this seems to be partially realized in the drop in statistical significance when adjusting for baseline plaque burden). Interestingly, patients with an above-median baseline Lp(a) level experienced lower risk for new-onset diabetes (16% vs. 26%, p=0.02) and hypertension (75% vs. 87%, p=0.001), and also had lower baseline CRP levels (1.3 vs. 1.8 mg/l, p=0.02) but slightly higher on-treatment LDL levels (33.9 vs. 32.6 mg/dl, p=0.02). Ultimately, we’re not sure that the marginal differences in some of these measurements are clinically-meaningful, but we’re looking forward to future analyses aimed at predicting PCSK9 inhibitor response.

Exhibit Hall

Amgen

Amgen hosted one of the largest and most well-staffed booths in the ACC Exhibit Hall, promoting Repatha (evolocumab) and the PCSK9 inhibitor’s new indication for prevention of heart attack, stroke, and coronary revascularization in people with established CV disease. The sprawling space was dedicated almost entirely to Repatha and featured informational panels on both the drug and the importance of LDL-lowering more generally. The booth itself was very open, including a charging area for attendees to power up their electronics, where a large screen played a Repatha commercial on loop. A robust medical affairs corner offered information on CV disease states. The main area included take-home resources on best practices for gaining access to Repatha, including a co-pay card for monthly payments as low as $5 – navigating the payer landscape was a theme in common with Sanofi/Regeneron’s booth, though it was more heavily featured in the Amgen booth, as far as we could tell. Overall, Repatha might have been the most highly-advertised drug in Orlando (alongside a nice effort from Sanofi/Regeneron for Praluent).

AstraZeneca

AZ’s large, central booth was brightly-illuminated. White couches were surrounded mainly by advertisements for CV drug Brillinta, but a diabetes display also promoted SGLT-2 inhibitor Farxiga (dapagliflozin) and the new Bydureon (exenatide) BCise autoinjector, which was also available for demo. AZ has been a bit quiet about BCise launch since its approval last October, though the company originally planned to make the product in US pharmacies in 1Q18. We’re hopeful that the autoinjector (more patient friendly than the single-dose reconstitution kits or dual chamber Bydureon pen) can help further grow the Bydureon franchise. We also got to hear from AZ’s Dr. Jim McDermott (VP of US Medical Affairs for Diabetes) about DECLARE, the CVOT for Farxiga on track to report this year. Dr. McDermott expressed particular optimism about the impressive size of the trial (n=17,276, including a remarkable primary prevention cohort at ~60%), which could lead to very robust findings on Farxiga’s CV effects. We imagine the large sample size will help drive event rate, despite the lower-risk population overall relative to EMPA-REG (0% primary prevention) or CANVAS (34% primary prevention). Dr. McDermott also highlighted that DECLARE has a co-primary endpoint of CV death or hospitalization for heart failure, distinguishing it from EMPA-REG and CANVAS (where heart failure was only a secondary, exploratory endpoint). Could this support a heart failure indication prior to the read out of Dapa-HF, a dedicated study investigating dapagliflozin in chronic heart failure?

J&J (Janssen)

Although Janssen’s booth was dedicated almost entirely to blood thinner Xarelto, a small but mighty back corner highlighted the Invokana (canagliflozin) franchise. This reflects the strong and growing interest of cardiologists in SGLT-2 inhibitors. While J&J’s sNDA for a CV indication for Invokana, submitted October 2017, is still under review at FDA (a decision is expected late 3Q18 or early 4Q18), our sense is that many thought leaders have already accepted a CV benefit associated with canagliflozin. On-site reps didn’t have anything to share on where the sNDA might stand at FDA or Janssen, but we imagine they’re confident: FDA has already shown its openness to putting CV indications on diabetes drug labels with SGLT-2 inhibitor Jardiance (Lilly/BI’s empagliflozin) and GLP-1 agonist Victoza (Novo Nordisk’s liraglutide), and Invokana gave nearly identical results to Jardiance on three-point MACE. The one caveat is the signal for lower limb amputations in CANVAS (which was absent from EMPA-REG, at least the way the data was collected), although in our view, this shouldn’t interfere with FDA recognizing the tremendous CV benefit of the drug and granting the label change. A boxed warning for amputations is already on the Invokana label.

Lilly/BI

Lilly/BI’s mid-sized booth was easily recognized by the characteristic deep teal/yellow color scheme we’ve come to associate with SGLT-2 Jardiance (empagliflozin). We also noticed ads scattered about the convention center. The booth promoted Jardiance as the only SGLT-2 inhibitor with a CV indication on its label, and EMPA-REG OUTCOME data on display was targeted to cardiologists (highlighting all the reasons that CV specialists should care about – and prescribe – a diabetes therapy). Lilly/BI broke into the cardiology conference circuit following the December 2016 FDA approval of Jardiance’s CV indication; since then, we’ve noticed increasing enthusiasm for SGLT-2 inhibitors within the cardiology community.

Merck

We were disappointed to see that Merck’s booth was an unmanned charging station, though we understand that launch of SGLT-2 inhibitor Steglatro (ertugliflozin), Steglujan (ertugliflozin/sitagliptin), and Segluromet (ertugliflozin/metformin) is progressing and that Merck/Pfizer aren’t ready to promote their new SGLT-2 franchise to cardiologists since VERTIS CV is ongoing (expected to complete October 2019). Still, we see this as somewhat of a missed opportunity, since the cardiology field has shown distinct interest in the SGLT-2 class, and since the field as a whole is making an effort to get cardiologists more involved in diabetes care.

Merck/Pfizer’s pricing strategy could be the key to Steglatro’s success. At our local CVS in San Francisco, standalone Steglatro is listed at $319 for a 30-day supply (at both the 5 mg and 15 mg doses), which corresponds to a list price of ~$10.63/day. Merck/Pfizer previously announced a list price of $8.94/day, but we understand that price can differ across pharmacies. The average price for other standalone SGLT-2 inhibitors (Lilly/BI’s Jardiance, AZ’s Farxiga, and J&J’s Invokana) is $17/day – significantly higher than $8.94/day or even $10.63/day, which could make Steglatro an attractive option for payers and patients. A 30-day supply of fixed-dose SGLT-2/DPP-4 Steglujan costs $620 at our local CVS, which translates to ~$20.67/day. Merck/Pfizer previously announced a list price of $17.45/day, but nevertheless, Steglujan is cheaper than its competitors – Lilly/BI’s Glyxambi (empagliflozin/linagliptin) costs ~$22/day while AZ’s Qtern (dapagliflozin/saxagliptin) costs $24/day.

Novo Nordisk

A small but notable booth from Novo Nordisk was framed by two informational panels, promoting second-gen GLP-1 agonist Ozempic (semaglutide) – recently launched in the US – and GLP-1 agonist Victoza’s (liraglutide) CV indication in equal turn. Reps predominantly spoke about Victoza and the 13% risk reduction for three-point MACE seen in LEADER (p=0.01 for superiority vs. placebo), which is understandable, as only Victoza has a CV indication (Novo Nordisk will initiate the SOUL CVOT in mid-2018 toward a CV indication for Ozempic). No on-the-ground reps were able to comment on the relative interest they were seeing from cardiology attendees in Victoza vs. Ozempic, or in GLP-1 agonists as a class. Our overall sense from the meeting was that many cardiologists are still reluctant to incorporate GLP-1 agonists into their clinical practice, largely due to a lack of familiarity with injectable therapies on the part of the provider – indeed, Dr. Lawrence Leiter asserted on Saturday that providers are much more reluctant than patients to initiate injectable therapy. We do think this is changing – with PCSK9s as well as GLP-1s demonstrating highly-significant and clinically-meaningful cardioprotection – but we’d like to see this change faster.

Sanofi/Regeneron

With a major focus on Praluent (alirocumab), Sanofi/Regeneron’s booth embodied the emphasis on PCSK9 inhibitors that we saw throughout the meeting. Lots of content on Praluent was also fitting, considering that ODYSSEY Outcomes CVOT results were a key conference highlight (read our coverage above). Beyond this, however, we were excited to see that diabetes reps were on-site to promote next-gen basal insulin Toujeo (glargine U300) and Soliqua (insulin glargine/lixisenatide fixed-ratio combination), in line with the greater presence of diabetes companies and therapies overall at this year’s ACC. A large wall of the exhibit was dedicated to MyPraluent, a free program for patients that offers seven days/week live nurse support, injection reminders via text message, and other practical, educational resources. We’re glad to see this digital health effort from Sanofi/Regeneron to support adherence and patient success on Praluent, which we think could boost real-world outcomes – to this end, we wonder how many MyPraluent users there are. Observational data on display showed that, at the end of 12 months, ~25% more patients refilled their prescription when enrolled in MyPraluent (42% of patients vs. 34% without MyPraluent). We were also intrigued to learn that Praluent leads the PCSK9 inhibitor class in lives covered (meaning more lives covered vs. Amgen’s Repatha). That said, Praluent lags slightly behind Repatha in volume/sales, despite this greater commercial opportunity. In 2017, Praluent revenue totaled ~$194 million compared to ~$319 million for Repatha. As of 4Q17, Amgen held 61% of the market by value vs. Sanofi/Regeneron’s 39%.

 

-- by Ann Carracher, Megan Clyne, Payal Marathe, and Kelly Close