The American College of Cardiology 64th Annual Scientific Session was held in San Diego, CA from March 14-16, 2015.

Major presentations at the conference included ticagrelor's (AZN) PEGASUS trial on long-term anti-platelet usage after a prior myocardial infarction, and details from selexipag's (Actelion) morbidity/mortality trial in PAH. The PCSK9 inhibitors evolocumab (AMGN) and alirocumab (REGN, SNY) were also major focuses of interest, along with ETC-1002 (ESPR), which had additional new data right after the conference.

On devices, there was exciting data from TAVR valve Sapien 3 (EW). Interesting preliminary data came from Triguard (Keystone) for cerebral protection during TAVR and Barostim (CVRx) for heart failure. The bullets below provide highlights from these and other presentations. Acute Coronary Syndrome (ACS) and Coronary Arterial Disease (CAD)

• In PEGASUS, Ticagrelor (AZN) showed a benefit on MACE in patients with a prior heart attack 1-3 years before, but the magnitude was numerically underwhelming, given what it had achieved previously against clopidogrel in PLATO. There was an increase in major bleeding of a similar absolute magnitude as the reduction in MACE.
  • KOLs and physicians had wide-ranging opinions on the implications. These included increased use of generic clopidogrel, a boost for ticagrelor as it now has the best evidence in the setting, or possible limited use only in selected high risk patients due to the bleeding risk. The results may also reinforce use of prasugrel (LLY) in some patients and there could be a case for vorapaxar (MRK), though most were trying to understand how the latter fit into the treatment paradigm.
• Mitochondrial-targeting bendavia (Stealth) failed to reduce reperfusion injury. The company is instead shifting focus to heart failure patients with kidney disease, given evidence that the drug reduces renal hypoxemia.

Pulmonary Arterial Hypertension (PAH)

• Selexipag's (Actelion) 40% reduction in morbidity/mortality--largely due to a reduction in PAH hospitalization and disease progression-- were consistent whether patients were on monotherapy or combination treatment, including a background of both an ERA and PDE5 inhibitor.
  • While not as important as morbidity, improvement in 6MWD for those on other therapies was quite modest, at a not significant 7 m. Investigators attributed this to a strict imputation, but results with other methods were not released.
  • The rate of prostacyclin associated AEs were still high, though more so in the titration phase. It is unclear from the data if selexipag is any better on this front than UTHR's orenitram, though investigators said they pushed the dose titration, which could have made AEs worse.

Dyslipidemia

• An exploratory analysis of evolocumab's (AMGN) OSLER extension trials found a promising reduction in CV events (HR 0.49). Still, a number of KOLs we spoke with thought the PCSK9 inhibitors would only be approved for familial hypercholesterolemia prior to cardiovascular outcomes trials (CVOT), though one acknowledged that no one really knows.
  • The issue could well come up at an advisory committee meeting, possibly in June, when tentative meetings for that advisory committee are listed on the FDA adcom schedule. However, it has not been revealed whether the meetings are for the PCSK9 inhibitors.
  • Some speakers referred to small increases in neurocognitive adverse effects, also seen in alirocumab's ODYSSEY LONG TERM, as a "signal," but it is still unclear whether the findings are just due to chance.
• Alirocumab's 300 mg monthly dose showed fairly good LDL-c reductions, though 14.7-19.3% required uptitration to the Q2W dose and there were higher injection site reactions (13.8-18.5%). However, with the 150 mg monthly option, which only requires one injection, half required uptitration.
  • Results for the 300 mg dose are difficult to compare to evolocumab's monthly regimen, which uses a relatively higher dose (420 mg) to maximize LDL-c reductions, but the difference may not be large.
• As released in prior top-line data, ETC-1002 (ESPR) reduced LDL-c a strong 48% in combination with ezetimibe, in patients not on statins. The company is working on a fixed-dose combination. More details are needed on drug-related AE's however, which occurred in 42% in the combination group, but because the patient numbers are small that number is not necessarily precise.
  • An add-on study with low-to-moderate dose statins presented just after the conference showed a moderate LDL-c reduction (up to 24%). Officials said their focus is still on statin intolerant patients, but talked about potential positioning for the statin add-on segment, which ultimately would require a larger partner.
  • Lack of CVOT data could of course impact ETC-1002's competitive situation, which we review. A PCSK9 advisory committee meeting, if one indeed occurs, would give additional insight on the need for a CVOT prior to approval.
    • More details are needed on ETC-1002's PK interaction with statins, but officials believe the drug can still be used with high-dose statins and the interaction would not be a hindrance to performing a CVOT, which they plan to conduct regardless, in order to convince physicians they believe in the drug.

Reversal of Anticoagulation

• Positive data for decoy receptor andexanet (PTLA) reversing rivaroxaban and earlier stage, small molecule PER977 (Perosphere) reversing low- molecular weight heparin.
  • Andexanet appears to have a greater reversal quicker, but more information is needed to assess whether that would make a clinical difference. It does have some rebound in markers of coagulation activity. This is transient and may not make any difference clinically, though more data is needed from ongoing studies with continuous infusion after the bolus.
  • PER977 using a less specific assay (WBCT rather than anti-fXa), but the company is developing a point-of-care assay, which it hopes will give it an advantage. The company touts that it only requires a single bolus for persistent activity rather than a continuous infusion like andexanet, though Portola has its own argument why the infusion may be better.
  • Use in patients who need their anticoagulation interrupted for surgical procedures is another potential market for these agents, but will not be part of the initial submissions and may require a lower price point.

Devices Transcatheter Valve Replacement (TAVR/TAVI and TMVR/TMVI)

• Panelists were impressed by low 30-day mortality and stroke rates in the single arm Sapien 3 (EW) pivotal trial. It is not completely clear how much was from improved techniques and patient selection, but the presenter made a case that a substantial benefit was from the valve itself.
  • The presenter concluded Sapien 3 should be considered as an alternative to surgery, even in patients who are not high risk---a large market opportunity for these devices, though it will cannibalize surgical valves. The issue will be more definitively determined by ongoing trials of Sapien XT and CoreValve versus surgery in intermediate risk patients.
    • On durability, updated PARTNER 1 results, also presented at the conference, showed stable hemodynamics over 5 years for the first- generation Sapien. However, the presenter noted that some novel surgical valves have shown failure after 8-10 years, so they need to observe the TAVR valve longer to be certain durability is comparable to surgical options.
  • The rate of permanent pacemaker placement was somewhat higher than older Sapien trials, but not worse than other novel valves. An investigator felt they may be able to get rates down, though. There was still substantial mild PVL, but it is unclear if other novel valves will have substantially lower rates when also tested in larger trials.
• CoreValve Evolut R's (MDT) also had positive first data presented from its CE Mark study, though the trial was small, so not as compelling as that for Sapien 3.
  • The VARC-2 device success rate was somewhat low, though that was attributed to missing data requiring some cases not to be counted as successful.
  • Rates of permanent pacemaker placement were much lower than older CoreValve trials, though registry data have shown similar rates for the older product when implanted according to "better practices."
  • 2-year data from the older generation CoreValve US High Risk Trial continued to show a mortality benefit versus surgery, with a widening of curves, despite more paravalvular leak (PVL) with CoreValve. The presenter suggested this could be a real effect due to counterbalancing factors and complications in the surgical arm that could lead to worse mortality over time.
    • Interestingly, much of the mortality benefit was in patients with an intermediate risk score. Hence, the investigator felt CoreValve will be shown to be at least non-inferior to surgery in its intermediate risk trial, which should be sufficient for approval in that group.
  • An early look at the comparison with surgery in lower risk patients (albeit still over age 70) came from the Scandinavian NOTION all- comers trial with the older generation CoreValve. It did not show a benefit over surgery, but unfortunately was underpowered to show a moderate effect. So while rates of MACE were numerically lower with CoreValve, they were nowhere close to statistically significant.
• First randomized controlled data for cerebral protection device Triguard (Keystone) increased the percent of patients free from ischemic brain lesions on MRI after TAVR and appeared to prevent cognitive decline. The study was small, though, so the results need to be confirmed in a larger US pivotal study.
  • More benefit was demonstrated when Sapien valves were used, but the investigators are still analyzing device-specific subgroups.
• On a side note, one speaker said in a presentation that a company planned to enter the US market with a $15,000 valve, substantially lower than current options.

Heart Failure

• Barostim (CVRx) baroreflex therapy had encouraging preliminary data from a small randomized, though unblinded, study in patients with heart failure and reduced ejection fraction (HFrEF).
  • The device showed significant improvements in NYHA Class, quality of life, and 6MWD.
  • There may also be a reduction in hospitalizations, but the data was complicated by different baseline rates.
• Interesting, but preliminary, results for Interatrial Septal Device (DC Devices) in heart failure with preserved ejection fraction (HFpEF) showed improvements in NYHA Class and HF hospitalizations. The study was quite small, however, and single arm.

This report covers presentations from a number of other drugs and devices, as well, including ivabradine (AMGN, Servier) LY3015014 (LLY), AMR-001 (NBS), CXL- 1427 (Cardioxyl), revusiran (ALNY, SNY, ISIS), Lotus valve (BSX), Aortix (Procyrion), Pulmonary Arterial Denervation (Pulmono) and Symplicity Renal Denervation (MDT, post- conference news).

For the full report, please download the PDF version at the top of this page. For our disclosures, please read the BioMedTracker Research Standards.