The European Society of Cardiology (ESC) Congress 2018 was held in Munich, Germany, from August 25–29, 2018.

The highlight of this year's conference was groundbreaking data from Vyndaqel (tafamidis; PFE) showing a substantial mortality benefit in transthyretin amyloid cardiomyopathy. The study included both the wild type and hereditary forms of the disease. In addition, while the omega-3 fatty acid product Omacor/Lovaza (omega-3-acid ethyl esters; GSK, MYL, BASFY) not surprisingly failed to show a cardiovascular (CV) benefit in the primary prevention trial ASCEND, in landmark results released after the conference, Amarin's Vascepa, which consists solely of EPA (eicosapentaenoic acid) and was tested at a higher dose, showed an encouraging reduction in major adverse cardiovascular events (MACE) in patients starting with higher triglycerides. In anticoagulation, Xarelto (rivaroxaban; JNJ, BAYRY) had mixed results in medically ill patients when started at discharge, though JNJ still plans to explore a submission to the US Food and Drug Administration (FDA), and failed to show a benefit in patients with heart failure (HF) and coronary arterial disease (CAD).

On the device front, ABT's MitraClip's failed to show a benefit in mitral regurgitation (MR) secondary to heart failure in the MITRA-FR study at the ESC, but the follow-on trial COAPT, presented soon afterwards at TCT 2018, was more positive, allowing ABT to plan a regulatory submission.

We highlight these and other presentations below.

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Heart Failure

• In groundbreaking results, Vyndaqel's ATTR-ACT found a ~30% reduction in the risks for both all-cause mortality and CV hospitalizations in patients with transthyretin amyloid cardiomyopathy.
  • On subgroup analysis, the benefit on mortality appeared to be larger for patients with NYHA heart failure class I/II than class III, and in the class III patients, tafamidis actually had significantly more CV hospitalizations, though the latter was suggested to be due to patients living longer. Hence, it is somewhat unclear if regulators may restrict an indication to those with less advanced disease, or just include verbiage about the difference.
  • The mortality benefit was seen whether patients had a wild type or hereditary form of the disease. While it was only statistically significant for those with wild type disease, that should not be a regulatory issue, given the lower number of hereditary patients.
    • The hereditary patients also did not have much benefit on CV hospitalizations, but that was possibly because they present with more advanced disease, with overlap with the NYHA class III category.
  • The discussant noted a poster at the conference that found ATTR amyloid deposits in a fairly large minority of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) patients on scintigraphy and felt there was now an indication to screen most patients with non- ischemic, unexplained HF for the condition.
  • We await decisions from competitors with stronger gene silencing drugs on whether they will pursue a cardiomyopathy indication with a cardiovascular outcomes trial (CVOT) against Vyndaqel.
    • Ionis is still modeling options, but says an initial analysis indicates it is feasible.
    • While speculative, it remains to be seen that there are no other safety concerns with gene silencers. For example, ALNY's Onpattro (patisiran), recently approved for ATTR patients with polyneuropathy, had some cases of heart block, which the FDA review said could be particularly concerning if the drug were indicated for cardiomyopathy (a different formulation is being developed for that indication). The review hypothesized about remodeling or inflammation in the heart as possible contributing factors.

Anticoagulation

• Mixed results were seen in Xarelto's Phase III MARINER trial for thromboprophylaxis after hospitalization for medical illness. Xarelto failed to meet its primary endpoint (venous thromboembolism [VTE] and VTE-related death), though exploratory analyses of the secondary endpoint symptomatic VTE (with or without all-cause mortality added in), appeared more favorable.
  • While JNJ still hopes to be able to file in the US, the mixed efficacy results combined with a numerical increase in major bleeding raise doubts about approval for the indication and subsequent use, if approved. Still, name recognition could help the drug.
• Xarelto had even more negative findings in the COMMANDER HF study of patients with HF, CAD, and a recent episode of heart failure decompensation, with absolutely no benefit on the primary composite outcome (mortality, myocardial infarction [MI], or stroke) or the secondary outcome of CV death or rehospitalization for worsening of HF.
  • Nevertheless, given the unique setting, it does not necessarily impact the FDA's ongoing review of the COMPASS trial in patients with coronary or peripheral arterial disease (the EC already granted supplemental approval in Europe based on that trial).

Dyslipidemia

• While details from bempedoic acid's (ESPR) CLEAR Harmony long-term safety trial were presented, there was little new information. However, new data from a combination study with ezetimibe in high CV risk patients, released by the company during the conference, showed mixed results, with only a modest benefit on low-density lipoprotein cholesterol (LDL-C) beyond ezetimibe itself in those on statins, but closer to an additive effect in statin intolerant patients.
  • Given the modest effects, questions linger whether the drug will be approved in the US without first having CVOT results, though PCSK9 CVOTs have bolstered the LDL-C hypothesis, at least for some mechanisms. It will be important to see summary data on fatal adverse events, since there was a slight imbalance in CLEAR Harmony top-line data (not included in the conference presentation), though events were deemed unrelated to the drug.
  • CLEAR Harmony did find a significantly lower rate of new onset or worsening diabetes as an adverse event, but given the statistical multiplicity, it is unclear if it was real or not, and the rate of gout was higher with the drug.
• Omacor/Lovaza failed to show a CV benefit in ASCEND, a primary prevention trial in diabetics, though this was not surprising given the failure of a number of other trials testing the EPA / DHA (docosahexaenoic acid) products around that dose level.
  • In contrast, in landmark results released after the conference, Amarin's Vascepa, which consists solely of EPA and was tested at a higher dose that has a stronger impact on triglycerides, showed a 25% reduction in MACE in patients starting with higher triglycerides. Barring any surprises in the details, the data should expand the drug's label to include those with triglyceride levels of 150-499mg/dL, along with a cardiovascular indication. We discuss contrasts between the trials and potential reimbursement issues.

Obesity

• In a high-risk population of overweight or obese patients, Belviq (lorcaserin; Eisai, ARNA) facilitated sustained, but quite modest weight loss (-1.9kg versus placebo at 40 months), and as might be expected, only showed similar rates of MACE, rather than a CV benefit.
  • More information is needed on the upper bound for the relative risk of valvulopathy and discussions with the FDA. Per the trial design paper, the data were to be pooled to rule out a risk over 1.5, but it is possible that may be exceeded.
  • A lower rate of new-onset diabetes in those with pre-diabetes was positive, but the difference was not large enough to overcome other issues with the drug.

DEVICES

Transcatheter Mitral Valve Repair

• MitraClip's (ABT) MITRA-FR failed to show a benefit in patients with severe MR secondary to heart failure at the ESC, but the follow-on trial COAPT, presented soon afterwards at TCT 2018, was more positive, and will be submitted by the company to expand the label.
  • The device is indicated for primary mitral regurgitation, but outside the US, is often used for secondary MR in patients with heart failure.
  • Patients in COAPT had more severe mitral regurgitation but not as dilated ventricles as those in MITRA-FR, so the impact of MitraClip could have been greater. MITRA-FR patients were not as severe (mortality in the control arm was lower) and the MR may just have been a bystander.
    • While the results could expand usage in the US, they also raise questions whether use should be narrower than currently outside the US.
    • More data will come from Reshape-HF2.

Coronary Interventions

• In five-year data from the all-comers BIOSCIENCE trial, BIOTRONIK's Orsiro stent failed to show a benefit over Abbott's Xience Prime durable-polymer stent. This was somewhat disappointing for the product, as more benefit was hoped to show up after the polymer degrades, which occurs between 12 and 24 months. However, the stent should be extending its reach to the US market based on the pivotal BIOFLOW V, where two-year data presented soon after at TCT 2018 extended the positive findings from the trial presented at last year's ESC meeting.
  • In BIOSCIENCE, Orsiro actually had higher rates of all-cause mortality, but this was driven by deaths from cancer. The investigators acknowledged while it may be a chance finding, it warrants observation in long-term follow-up of other ongoing studies.
  • In contrast, two-year data from BIOFLOW V at the TCT found continued benefits on a number of measures seen at year one, with some additions, though the superiority analysis on the primary endpoint was post-hoc (the primary endpoint was non-inferiority, including control data from other trials). The pivotal trial should help the stent enter the US market at a time when disappointment in ABT's first generation fully bioresorbable vascular scaffold (BVS) has opened the door to less dramatic innovations, though it will need to face three established competitors.
    • While a more sensitive definition of MI could have contributed to the difference in the primary endpoint findings on target lesion failure (TLF) between the two trials, the difference in target lesion revascularization (TLR) is more difficult to explain, and investigators did not have a good reason. However, since other comparative trials have not shown superiority, the positive BIOFLOW V findings could also be due to chance.
• B. Braun's SeQuent, a drug-coated balloon, demonstrated non-inferiority to second-generation paclitaxel drug-eluting stents (Xience or Taxus Element), raising the potential for a stent-free option that could avoid problems with tissue growth and clot formation. Patients will be followed at least two more years, though, and the study was modest sized, leading to variability in some of the individual endpoints.

This report also has early data on MEDI6012 (AZN), a recombinant human lecithin:cholesterol acyltransferase for bolstering reverse cholesterol transport, and dutogliptin (Recardio), which is planned to be used with granulocyte-colony stimulating factor (G-CSF) for acute myocardial infarction. For devices, there is also quality-of-life and symptom data from the Arctic Front Catheter's (MDT) CRYO4PERSISTENT AF.

For our disclosures, please read the Biomedtracker Research Standards.