March 16-18, 2019; New Orleans, LA; Day 3 Highlights – Draft

Hello from New Orleans, where ACC 2019 just wrapped up! Below, you’ll find our top four highlights from the last day of the meeting, including lots of positive new DECLARE analyses and total event data from REDUCE-IT, plus coverage of the exhibit hall. Don’t miss our coverage of days 1-2, including the Apple Heart Study and insight on SGLT-2s and heart failure.

Top Four Highlights

1. DECLARE Analysis Indicates Pronounced Benefit with Farxiga in Heart Failure with Reduced Ejection Fraction, But Risk Reduction for Heart Failure Hospitalizations Maintained Across All Participants

Dr. Eri Kato (Kyoto University, Japan) presented a prespecified analysis of the DECLARE trial suggesting that Farxiga’s (dapagliflozin) outcomes benefit on hospitalization for heart failure and CV death may be most pronounced in patients with HFrEF (HF with reduced ejection fraction), though a trend toward benefit was seen in both HF types. In DECLARE participants with HFrEF (n=671), Farxiga gave a significant 38% risk reduction on the composite endpoint of hospitalization for heart failure or CV death (HR=0.62; 95% CI: 0.45-0.86). Significance was barely missed in the much larger cohort of patients (n=16,489) without HFrEF (HR=0.88; 95% CI: 0.76-1.02). As in the overall cohort, the significant result on the composite endpoint of HHF/CV death appeared to be primarily driven by dapagliflozin’s effect on HHF rather than CV death. On the HHF endpoint alone, dapagliflozin delivered a significant benefit in both HFrEF and not HFrEF. Meanwhile, on the CV death endpoint, dapagliflozin achieved superiority only in HFrEF patients, with no trend toward benefit in the not HFrEF cohort (see figure below) – indicating the HFrEF patients may benefit on both HHF and CV death, while HFpEF and no HF patients may only benefit on HHF. Supporting this trend, AZ also broke down data on outcomes by different ejection fraction levels, which strongly indicated a more pronounced benefit at lower EF values (see second figure below). Outcomes of HHF, CV death, and all-cause mortality all strongly trended toward a dapagliflozin treatment benefit in patients with the lowest level of EF, indicating the most progressive forms of HFrEF.

Excitingly, this data represents some of the strongest evidence to date on the link between SGLT-2 inhibition and outcomes effects on the two specific types of heart failure. Broadly speaking, the relationship between ejection fraction and the clinical benefit of SGLT-2 inhibition on cardiovascular outcomes remains unknown, though we find it encouraging that the spectrum of heart failure patients could benefit on HHF. We expect this area to be further scoped out in the coming years, especially with upcoming results from large-scale trials (Dapa-HF, DELIVER, EMPEROR HF-Preserved, and EMPEROR HF-Reduced) exploring this very link.

• Some skepticism emerged during Q&A, with panelists wondering (i) whether the treatment effect was simply driven by helping patients who should have been on a diuretic already and (ii) whether this data suggests dapagliflozin should only be used in HFrEF patients. Of note, nearly 1/3 of HFrEF patients were not on a diuretic at baseline, and it’s possible that dapagliflozin’s benefit came via this function in patients who were not already on a diuretic and needed to be on one (we imagine this analysis could be conducted). In response, Dr. Kato emphasized that the mechanism of dapagliflozin’s effect is likely multifactorial and goes beyond fluid loss or a diuretic effect. She explained that dapagliflozin reduces blood pressure and promotes weight loss (among other potential mechanisms) and that this multifactorial effect, rather than simple fluid loss, is likely responsible for its impact on heart failure. In response to the second point concerning whether dapagliflozin should only be used in HFrEF patients in light of its more pronounced effect in this population, Dr. Kato asserted that dapagliflozin treatment reduced HHF regardless of baseline ejection fraction.

• In a conversation with our team, AZ management (Mr. Rod Wooten, VP of Cardiovascular and Metabolic Disease; Dr. Naeem Kahn, VP of Cardiovascular and Metabolic Disease) highlighted these results as “highly favorable” and confidence-boosting for the ongoing Dapa-HF trial. Representatives emphasized the impact they foresee these results having for busy physicians who will not have to discriminate based on ejection fraction when choosing therapies to prescribe, emphasizing that Farxiga delivered a >20% risk reduction on the HHF endpoint in both groups (HFrEF and not HFrEF). In terms of Dapa-HF, these results are surely promising in hinting at Farxiga’s efficacy specifically in HFrEF patients; as a reminder, the Dapa-HF trial is enrolling nearly 5,000 patients with HFrEF (with or without type 2 diabetes), has a primary endpoint of HHF/CV death/urgent HF visits, and is expected to complete in December 2019. The DELIVER outcomes trial in HFpEF should complete June 2021 and will give a closer look at those with preserved ejection fraction, with or without type 2 diabetes.

• AZ is currently conducting eight mechanistic studies to generate and test hypotheses on how SGLT-2 inhibition may impact heart failure. When asked about current hypotheses regarding SGLT-2 mechanisms in heart failure, AZ reps pointed to several ongoing mechanistic studies as part of its larger DapaCare program. These studies include investigating Farxiga’s effect on kidney function, fluid balance, proteinuria, metabolism, endothelial function, tissue storage, and more. AZ asserted that it’s likely more than one mechanism is driving this benefit, and that the important point is that Farxiga is delivering strong outcomes results, regardless of still-unknown mechanisms.

• For full results, methodology, and discussion on this sub-analysis, see the full paper that was simultaneously published in Circulation.
  

2. Farxiga Gives 16% RRR for Three-Point MACE in Participants with Prior-MI, Driven by 22% RRR in Recurrent MI, According to Prespecified DECLARE Analysis

In AZ’s DECLARE CVOT, Farxiga (dapagliflozin) conferred a 16% relative risk reduction vs. placebo on three-point MACE in participants with a prior MI (HR=0.84, 95% CI: 0.72-0.99), translating to a 2.6% absolute risk reduction (Circulation). In contrast, patients without a prior MI saw no benefit (HR=1.00, 95% CI: 0.88-1.13, ARR=0.0%), per a prespecified analysis presented to a very full room by Dr. Remo Holanda de Mendonca Furtado. From where we stand, this is great news and further supports growing consensus around the notion that SGLT-2s improve MACE (CV death, MI, or stroke) outcomes in higher-risk patients, and heart failure outcomes in both lower and higher risk patients – see Drs. Javed Butler and Subodh Verma at AHA 2018. DECLARE randomized 3,584 participants with a prior MI, fairly evenly split between placebo and dapagliflozin, comprising ~21% of the study’ 17,160 participants; the former had a much higher MACE event rate (17.8% with placebo vs. 15.2% with dapagliflozin) than the latter (7.1% with both placebo and dapagliflozin). Standing in contrast to MACE outcomes, both the prior MI and no MI groups garnered similar degrees of relative benefit on the other co-primary outcome of CV death or hospitalization for heart failure: The prior MI group saw a 19% risk reduction (HR=0.81, 95% CI: 0.65-1.00, ARR 1.9%) and the no MI group a 15% risk reduction (HR=0.85, 95% CI: 0.72-1.00, ARR 0.6%). However, the MI group saw a much greater absolute risk reduction, and we note that both confidence intervals abut unity at 1.00. As a reminder, the whole cohort saw a 17% relative risk reduction on CV death or HHF (HR=0.83, 95% CI: 0.73-0.95).

• Farxiga conferred a 22% relative risk reduction for recurrent MI in those with a prior MI (HR=0.78, ARR 2.5%, p-interaction HR vs. no MI = 0.082, p-int ARR=0.019), strongly driving the benefit seen on three-point MACE. There was a less meaningful difference between the prior MI and no MI groups on CV death (p-int HR=0.56), ischemic stroke (p-int HR=0.55), HHF (p-int HR=0.77), and all-cause death (p-int HR=0.22). Dr. Furtado noted that the 22% RRR in MI compares well to other established, secondary prevention therapies, including intensive lipid-lowering and dual anti-platelet therapy.

• In the DECLARE presentation at AHA 2018, we learned that Farxiga did not significantly reduce risk of three-point MACE in the overall cohort (HR=0.93, 95% CI: 0.84-1.03). This effect was seemingly driven by the trial’s enrollment of an ~60% primary prevention cohort (≥55 years old with multiple risk factors), which saw no benefit on three-point MACE (HR=1.01, 95% CI: 0.86-1.20). However, the smaller secondary prevention cohort (established CVD) trended strongly in favor of MACE benefit (HR=0.90, 95% CI: 0.79-1.02). As such, it seems that honing in even further on those with prior MI – a particularly high-risk subgroup within secondary prevention, to our understanding – enabled detection of a significant MACE benefit. For comparison, the full ASCVD cohorts (not just prior MI) in the CANVAS CVOT for J&J’s Invokana (~66% of participants) and the EMPA-REG OUTCOME CVOT for Lilly/BI’s Jardiance (>99% of participants) did see significant 14% (HR=0.86, 95% CI: 0.74-0.99) and 18% risk reductions (HR=0.82, 95% CI: 0.72-0.95) on three-point MACE, respectively. However, the ~one-third of CANVAS participants without ASCVD did not see benefit on MACE (HR=0.96, 95% CI: 0.74-1.30).

3. REDUCE-IT Post-Hoc Shows Impressive 30% Reduction in Total CV Events with Vascepa; Dr. Bhatt Says Therapy “Likely Cost-Effective”; Dr. Robert Busch on the Emerging Importance of Triglyceride Lowering

Harvard’s Dr. Deepak Bhatt presented an impressive post hoc analysis of the landmark REDUCE-IT trial, indicating that Vascepa treatment was associated with a 30% reduction in total CV events over the length of the trial. As a reminder, initial results from the REDUCE-IT trial – presented at AHA 2018 to much fanfare – demonstrated a 25% relative risk reduction on first cardiovascular events during the trial, but this analysis aimed to tease out Vascepa’s potential effect on potential subsequent events as well. Very impressively, Vascepa treatment was associated with a 32% relative risk reduction (RRR) on second CV events, 31% RRR on third CV events, and 48% RRR on fourth or greater CV events (all p values highly significant). In terms of total CV events, Vascepa treatment drove a 30% RRR (95% CI: 0.62-0.78; p<<0.0001), with 1,076 CV events in the treatment arm of the trial compared to 1,546 events in the placebo arm. Wow! As a reminder, the study’s primary prevention cohort (~30% of participants) was comprised entirely of people with established type 2 diabetes over age 50 with ≥1 CV risk factor, so these results are highly relevant to people with diabetes. Overall, ~58% of REDUCE-IT participants had type 2 diabetes. For a full rundown of this REDUCE-IT analysis, we recommend reading the full paper simultaneously published in JACC.

• Dr. Bhatt asserted that Vascepa is “likely cost-effective given the large reduction in total events” and that ongoing cost-effectiveness analyses will more definitively answer this question. We’ve been pleased with Amarin management’s insistence that Vascepa is a volume rather than pricing opportunity and that its goal is to ensure this treatment is available and affordable to the large population of patients (many of whom have diabetes) who have residual CV risk from triglycerides despite being on statin therapy. On this note, most patients with commercial insurance plans are currently able to access Vascepa at $3/month on average with a copay card. We’re eager to see the results of Amarin’s cost-effectiveness studies for Vascepa, hopefully by the end of 2019. Particularly at a low price, presumably Vascepta is going to be extremely cost effective – we think Dr. Bhatt may be being a bit modest or conservative here!

• On the topic of residual CV risk reduction, we recently spoke to Dr. Robert Busch about the importance of triglyceride lowering for comprehensive risk reduction and how Vascepa can help drive improvements in CV outcomes. He outlined the strides the field had taken over the last 30 years in reducing CV risk via LDL-C and blood pressure lowering, and even now through diabetes drugs proven to lower CV risk. However, he said, triglycerides haven’t gotten as much attention and have traditionally only been treated if very high (>500 mg/dl), more due to the risk of pancreatitis than concern over CV outcomes. In part, this is because previous studies of niacin and fibrates for triglyceride lowering didn’t show any CV benefit – a paradigm that Vascepa flipped on its head, particularly by showing risk reduction in a population with already-low LDL-C (74 mg/dl) and well-treated for CVD. As such, he predicted a paradigm shift toward using triglycerides to identify high-risk patients who have well-controlled LDL-C, as well as the use of Vascepa at lower triglyceride levels (~125-135 mg/dl) than were previously treated. Dr. Busch also emphasized that Vascepa’s effects could be mediated by mechanisms beyond triglyceride lowering, including by lowering LDL-C oxidation, blocking cholesterol deposition more effectively than other omega 3’s, and preventing thrombosis in a way niacin and fibric acid do not. On balance, however, previous lack of success may be attributable to study design. More broadly speaking, Dr. Busch noted that Vascepa’s current indication for use in patients with triglycerides ≥500 mg/dl has allowed managed care organizations to severely limit its use, and a lack of knowledge among pharmacists in particular may mean many patients prescribed Vascepa might end up taking supplement  fish oil, sometimes mistakenly referred to as OTC, instead. Moreover, he said, patients are already taking half a dozen or more prescriptions, and adding countless supplement capsules per day would be an additional burden. However, Dr. Busch was undeniably enthusiastic about the potential of only 4 capsules of Vascepa per day to lower CV risk on individual and population levels.

4. Dr. Bonaca Presents PAD Data from DECLARE: Similar Benefit with No Significantly Increased Risk of Limb Events with Farxiga

Dr. Marc Bonaca presented data on patients with peripheral artery disease (PAD) in DECLARE showing that this subset of very high-risk participants garnered consistent relative and possibly greater absolute benefit with Farxiga compared to those without PAD, with no evidence of significantly increased risk of limb events. Given continually swirling data and opinions around the risk of amputations with SGLT-2s, particularly in high-risk groups like PAD, these data are reassuring; on balance, however, Dr. Bonaca noted that DECLARE and other RCTs have not been designed to evaluate amputations or limb ischemic events. In DECLARE, 1,025 of 6,974 participants with established CVD had PAD, which was defined as current claudication + ankle-brachial index (ABI) <0.90 or history of peripheral revascularization or amputation for ischemia; 10% of PAD patients had a prior amputation, 38% prior revascularization, and 52% claudication only. There was no statistical heterogeneity between those with PAD and those without PAD on three-point MACE (p-interaction=0.42), CV death or hospitalization for heart failure (p-int=0.73), or the composite renal endpoint (p-int=0.84); the most difference was seen between point estimates for three-point MACE (HR=0.92 without, HR=1.05 with PAD), though the confidence intervals for PAD were very wide given the low number of participants. On the flip side, those with PAD saw a 1.4% absolute risk reduction on CVD/HHF and a 2.1% ARR on the renal endpoint, compared to 0.9% and 1.3% in those without PAD respectively.

• Farxiga was not associated with a significantly increased risk of amputations or limb ischemic events in the overall population, nor in those with PAD or in other high-risk subgroups. As presented at AHA, among the full DECLARE cohort there was no significant difference in amputations between Farxiga and placebo (HR=1.09, 95% CI: 0.84-1.40), nor for specific amputation etiologies. Looking at other types of limb events, there was no statistically significant imbalance in any limb ischemia AE (HR=1.07, 95% CI: 0.90-1.26), major adverse limb events (HR=1.12, 95% CI: 0.86-1.46), acute limb ischemia (HR=1.00, 95% CI: 0.59-1.69), critical limb ischemia (HR=1.40, 95% CI: 0.97-2.01), urgent revascularization (HR=0.86, 95% CI: 0.58-1.28), or elective revascularization (HR=1.06, 95% CI: 0.83-1.35). This pattern held when looking at PAD patients specifically: While the HR for amputation skewed strongly against Farxiga at 1.51 (95% CI: 0.94-2.42), the HRs for five of six other limb outcomes actually trended in favor of Farxiga. From where we stand, SGLT-2s should continue to be used with caution and vigilant monitoring in patients at high risk for amputation, and this question remains unanswered. Dr. Bonaca was hesitant to draw conclusions on specific age, renal, A1c, and diabetes duration subgroups given the low number of events.

• From an epidemiological standpoint, patients with PAD in the placebo group were at a dramatically higher risk of cardiac, renal, and limb events compared to those without PAD. In the placebo group, the event rate for MACE events was 15.9% with PAD vs. 9.0% without (HR=1.23, 95% CI: 0.97-1.57); for CV death and HHF, 12.1% vs. 5.4% (HR=1.60, 95% CI: 1.21-2.12); for renal events, 10.9% vs. 5.3% (HR=1.51, 95% CI: 1.13-2.03). Also in the placebo group, those with PAD were at 20.3% risk of any limb event and 5.6% risk of amputation, compared to 2.1% and 1.1% among those without PAD, respectively. Dr. Bonaca explained that infection was the dominant driver of amputation whether or not someone had PAD – infection was the primary etiology for 51% of amputations in PAD and 85% in no PAD. 

Exhibit Hall

Amarin

Following its first appearance in the exhibit hall at a major medical meeting at AHA 2018, Amarin continued this momentum with a similarly-sized and themed booth at ACC 2019. Outside of the booth, however, Amarin also invested heavily in banners throughout the entire exhibit hall leading guests to their booth, and the lanyards handed out to all attendees were inscribed with Vascepa promotions. As expected, REDUCE-IT results were the main focus of the booth, as Amarin touted the “unprecedented reductions in CV events” that Vascepa conveyed in the outcomes trial. Our sense is that cardiologists are growing familiar with Vascepa and REDUCE-IT results, especially as a result of Amarin’s targeted sales focus on this population of physicians – indeed, the therapy was mentioned by speakers during a handful of educational sessions on CV risk lowering that we attended. We imagine that interest in Vascepa will only grow, compounded by its expected label indication for CV risk reduction.

Amgen

Amgen’s booth promoted PCSK9 Repatha with the theme of “lower” – large signs emphasized messaging of lower LDL-C levels, lower cost (related to Amgen’s recent 60% price slash of the PCSK9), lower hassle (highlighting improved access to Repatha, in light of fewer authorization criteria now required), and lower risk (Repatha’s FOURIER CVOT demonstrated significant CV risk reduction with treatment when compared to placebo). Of note, Amgen also just announced a second CVOT for Repatha, to be called VESALIUS-CV. Enrollment in the trial is expected to begin in 2Q19. The study aims to enroll ~13,000 patients and will importantly test Repatha exclusively in a primary prevention cohort. Success in the trial could massively expand the label for Repatha and justify its use in a much broader patient population (the positive FOURIER CVOT, which supported Repatha’s CV indication, only enrolled patients with established CVD, i.e. a secondary prevention population).

AZ

AZ boasted a sizable booth in the center of the exhibit hall with familiar promotional materials for Farxiga as the main focus, in addition to promotion of anticoagulant Brilinta and GLP-1 agonist Bydureon. Visitors to the booth were given the chance to add to a large domino assembly being built in the center of the booth (‘Farxiga’ being spelled out was one part of the display, alongside New Orleans specific imagery) by writing “Who Inspires You” on the piece. It was certainly an impactful ACC 2019 for AZ and Farxiga specifically, with multiple positive new sub-analyses from the DECLARE trial emerging during the meeting. Of note, separate conversations with AZ representatives during ACC revealed that AZ has now officially submitted its sNDA to FDA for Farxiga’s CV indication based on DECLARE data. AZ expressed hope that this label indication will be granted by the end of 2019. When asked specifically about what type of indication they will be pursuing (heart failure risk reduction in primary prevention populations?), AZ simply stated that “we will be seeking an indication for the trial we designed and the population that we studied…in discussions with FDA, we are focusing on the breadth of the trial and the positive primary endpoint.” 

BI

BI hosted one of the more intriguing (and largest) exhibit hall booths at ACC, physically standing out with a two-story tower above the hall with virtual reality headsets that visitors could engage with, offering tours through New Orleans’ famous Bourbon Street, along with our hometown of San Francisco. Facts about Jardiance’s effect on CV outcomes peppered these virtual tours. Moreover, as always, promotional stands prominently featured the 38% relative risk reduction on CV death achieved by Jardiance in the EMPA-REG OUTCOME study – certainly an appealing statistic to the swaths of cardiologists roaming the hall.

Merck/Pfizer

There was no promotion of SGLT-2 inhibitor Steglatro in the exhibit hall or at ACC. Pfizer’s booth was focused on rare disease, while Merck defaulted to the un-manned charging station we often see from them at less diabetes-focused meetings. Neither of these surprised us, as both companies have neglected to focus in any significant way on the Steglatro franchise and the VERTIS-CV outcomes trial has yet to complete.

Sanofi/Regeneron

Sanofi and Regeneron hosted a very large, Praluent-dedicated presence in the middle of the exhibit hall. We spoke with a representative at-length about Praluent access and reimbursement, and she was decidedly positive about improvements the companies’ have achieved in access: By her count, a few years ago every ~eight out of ten prescriptions were rejected, and they’re now up to ~eight to nine out of every ten being approved. She attributed this directly to improvements in the prior authorization process required by PBMs and managed care organizations – now, HCPs simply need to fill out a checklist attestation form rather than document and fax all of the required paperwork. Unfortunately, she said, the lower list price Sanofi/Regeneron offered PBMs in exchange for simplified utilization management criteria was not passed on to patients in the form of lower copays – leading to the recent 60% list price cut (February 2019), heavily advertised throughout the booth. She clarified that this move was largely taken to benefit Part D patients, whose copays are tied directly to list price.

Novo Nordisk

Novo Nordisk brought a medium-sized booth 100% focused on Ozempic, the company’s second-gen GLP-1 agonist. Unlike the company’s once-daily Victoza, Ozempic has yet to receive a CV indication in the US (despite achieving a significant 26% relative risk reduction on three-point MACE in the SUSTAIN-6 CVOT) – reflecting just how strongly Novo Nordisk is shifting its promotional efforts to Ozempic. Company reps emphasized this shift to us and noted that launch and coverage is still progressing smoothly. On Monday, the company sponsored a product theater entitled, “Exploring A1C and Cardiovascular Safety Data in T2D Therapies”; unfortunately, this was closed to media, but it seemed well-attended and was one of two truly diabetes-focused products theaters at ACC (the other focused explicitly on Lilly/BI’s Jardiance).

-- by Ann Carracher, Martin Kurian, and Kelly Close