The American College of Cardiology (ACC) 66th Scientific Session was held in Washington, DC from 17–19 March 2017. The highlight of this year's conference was details from Repatha's (AMGN, Astellas) cardiovascular outcomes trial (CVOT), the first PCSK9 inhibitor CVOT to report. Main results were modest, but the investigators attributed that to the relatively short duration of follow up and inclusion of certain endpoints. Some landmark data were more consistent with what would be expected for its low-density lipoprotein cholesterol (LDL-C) lowering. Despite the positive findings, payers for the most part did not anticipate major changes to prior authorization (PA) for PCSK9 inhibitors, which has been hampering uptake of the class. Our survey of cardiologists indicated there should be a significant increase in demand, though revenues are likely to remain limited unless PA changes. Full data from the Phase II study of another PCSK9 inhibitor, inclisiran (MDCO, ALNY) led company officials to confirm two times/year dosing. The anticoagulant Xarelto (JNJ, BAYRY) had positive data versus aspirin in extended treatment of venous thromboembolism (VTE), but mixed earlier-stage data in acute coronary syndrome (ACS), where the company had been hoping to revive its prospects for US approval. Our survey of primary care physicians and specialists suggests the drug could pick up moderate share in the extended treatment of VTE. On the device front, Medtronic's (MDT) CoreValve/Evolut R had encouraging data in intermediate-risk patients undergoing transcatheter versus surgical aortic valve replacement, which should help in its competition with the Sapien franchise. On the other hand, the bioresorbable scaffold Absorb (ABT) had negative data at the conference, and shortly thereafter, that led to an FDA warning letter and restricted use in Europe. Prospects for the device will depend on data from ongoing trials with improved patient selection and implantation technique. Data on instantaneous wave-free ratio (iFR) using Philips Volcano's Verrata Pressure Guide Wire suggested it was comparable on clinical outcomes to fractional flow reserve (FFR) when used to assess the significance of coronary atherosclerotic lesions, which could help boost use of such technology. We highlight these and other presentations below. Surveys and interviews that we have conducted mentioned in the report will be available in BMT's special reports section in the future, available free of charge to KOL Insight subscribers. Dyslipidemia

• The main composite endpoints for Repatha's CVOT were modest, which investigators attributed to the relatively short duration of follow-up and inclusion of certain endpoints. Some landmark data were more consistent with what would be expected for its LDL-C lowering.
  • Feedback from payers suggested that while there may be some loosening of restrictions, it would not be major, so manufacturers will still have to struggle against PA barriers. The report has highlights from our payer interviews.
    • Claims database and survey data presented at the conference outline issues with PA leading to high rejection rates of claims.
  • Even if PA does not change, prescription demand from physicians is likely to be higher as the PCSK9 inhibitors gain labeling for their CVOTs, as outlined in our cardiology survey conducted after the conference. However, revenue could still be fairly limited without substantial PA changes.
  • It is unclear whether the FDA might broaden Repatha's indication for LDL-C lowering to more primary prevention patients. It had originally not wanted to due to uncertainty that the LDL-C-lowering effects would reduce outcomes. A number of contacts think the agency will not broaden the indication, or would only do so for higher-risk patients.
    • If the FDA does broaden it, Medicare plans will be required to cover the expanded patient population, though there are additional financial barriers to patient use in the program.
  • Data from one of bococizumab's (PFE, HALO) discontinued CVOTs, where patients were treated long enough and started from relatively high LDL-C levels at baseline, helped confirm the benefit for the class, though the drug was suspended due to anti-drug antibodies associated with an attenuated LDL-C effect over time and increased injection site reactions.
• Final inclisiran, Phase II data bolstered company plans to pursue twice-a-year dosing, though questions still remain about the PK/PD modeling.
  • The planned CVOT will use lessons learned from FOURIER, and patients are expected to start from a higher baseline LDL-C for numerically stronger headline results.
    • The report gives projections on inclisiran usage from our survey, as well as the impact of the CVOT design.
  • Company officials also speculated about yearly dosing in lower-risk patients.
• Just after the conference, Esperion announced the FDA would be willing to approve ETC-1002 prior to CVOT results, but said timing of the announcement was coincidental due to a meeting they had with the FDA the week before (prior to the release of FOURIER details).
  • Initial approval would be in atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH), with a CVOT in statin-intolerant patients expected to provide a statin intolerance indication, which the FDA has not given out in the past.
  • Our survey suggests moderate use in ASCVD patients prior to CVOT results, with a substantial increase afterwards, if CVOT data come out as planned.
• Details from CER-001's (Cerenis) atherosclerosis imaging study did not show any hint of a benefit or suggestion of what may have caused the drug to fail. While that does not necessarily mean other high-density lipoprotein (HDL)-mimetics will fail, there is not much hope given the similar failure of MDCO-216 last year.

Anticoagulation

• Xarelto showed encouraging Phase III data against aspirin in the extended treatment of VTE (EINSTEIN-CHOICE), with markedly lower rates of recurrent VTE and no statistically significant increase in major bleeding. However, results of another shot at ACS – using a strategy of adding Xarelto to a P2Y12 antagonist and testing against aspirin in a Phase II trial (GEMINI-ACS-1) – were mixed and the value of the approach is up in the air.
  • Our survey of primary care physicians and specialists does suggest the drug could pick up moderate share in extended treatment of VTE, even among some prescribers currently using Eliquis (BMY, PFE) at least as much.
• Positive results for Pradaxa (Boehringer) in the Phase IV RE-CIRCUIT trial of patients undergoing catheter ablation, though that is unlikely to reverse share losses in stroke prevention in atrial fibrillation (SPAF).

Heart Failure

• Details from Simdax's (TENX, Phyxius, ORINY, ABBV) failed pivotal trial in patients with left ventricular dysfunction undergoing cardiac surgery showed a signal for a reduction in low cardiac output syndrome and 90-day mortality, though the latter was not statistically significant and investigators acknowledged it was uncertain.
  • The company will speak with the FDA, but it seems quite unlikely the drug will be approved in the US without another trial, which could be difficult to find funding for.

Cardiovascular Outcomes Trials (CVOTs) of Diabetes Drugs

• A real-world retrospective study (CVD-REAL) showed patients started on SGLT2 inhibitors had a 39% lower rate of hospitalization for heart failure and a 51% lower rate of all-cause death than those newly started on other glucose-lowering drugs.
• With the positive CVOT data from Jardiance (Boehringer, LLY) and Victoza (NVO), there is interest from organizations like the ACC to have cardiologists more actively involved in diabetes treatment, per a speaker, though cardiologists are concerned about the lack of infrastructure to educate and follow up on diabetic patients, as well as infringing on the role of the primary diabetes provider.
  • Educational programs could help, though they may only change behavior in a sizable minority of cardiologists. In a small survey we conducted, only one-third of cardiologists said that becoming convinced of a substantial CV benefit would lead to a large increase in their prescribing of such drugs or urging their patients' primary diabetes providers to prescribe them.
  • Cardiologists could play an important role in using these medications in ACS patients previously undiagnosed for diabetes.

DEVICES Transcatheter and Surgical Aortic Valve Replacement/Implantation (TAVR/TAVI, SAVR)

• The SURTAVI trial in intermediate-risk patients demonstrated non-inferiority for CoreValve/Evolut R relative to surgical valve replacement, with signs of an advantage in a number of secondary clinical outcomes and complications, including 30-day stroke, but higher rates of permanent pacemaker implantation and paravalvular leak.
  • The trial should gain the CoreValve franchise an indication in intermediate-risk patients, like competitor Sapien, and help reinforce further use of TAVR in that group, though the focus is likely to still be on elderly patients.
  • The Sapien franchise has had some numerically better comparisons with surgery, but there are counter-arguments Medtronic could use, and one of the session panelists called the SURTAVI results "spectacular."
  • Medtronic's next-generation Evolut PRO appears to have lower rates of permanent pacemaker implantation, and competition between the franchises will now move to studies in low-risk patients.
• In the largest dataset on subclinical leaflet thrombosis, which is from two registries, evidence of the phenomenon based on CT imaging was found in 12% of patients undergoing TAVR/SAVR.
  • Anticoagulation with warfarin or novel oral anticoagulants (NOAC), but not standard-of-care antiplatelet treatment with dual antiplatelet therapy (DAPT), was effective in preventing and treating the issue, but a number of questions remain.

Coronary Stents

• Disappointing two-year results from the ABSORB III trial of the bioresorbable scaffold Absorb showed inferiority on target-lesion failure and numerically higher stent thrombosis compared to the metallic stent Xience (ABT).
  • The FDA released a "Dear Doctor" warning letter at the same time, and shortly after the conference, two-year results published for the all-comers trial AIDA showed an elevated rate of stent thrombosis for Absorb, prompting Abbott to restrict use of the device in Europe to the clinical registry setting at select sites/institutions that will play a pivotal role in monitoring the device until Summer 2018.
  • The company is counting on ABSORB IV, with better patient selection and implantation technique, to revive prospects for the stent.

Fractional Flow Reserve (FFR) and Instantaneous Wave-Free Ratio (iFR)

• Philips Volcano's iFR was non-inferior to FFR as a tool for guiding coronary revascularization in two trials. The results could help iFR, which avoids the need for the drug adenosine and its concomitant side effects, become a new standard and expand use of such technology.
• In Compare-Acute, FFR measurements (predominantly using St. Jude/ABT's PressureWire Aeris) to guide complete revascularization of all the coronary arteries in STEMI patients, compared to a conventional strategy based on clinical findings, reduced the primary MACCE endpoint, but this was driven by a lowering of the risk for another revascularization.
  • Moreover, if the extra procedures done initially in the full revascularization group are included, that strategy actually increased the rate of overall percutaneous coronary intervention (PCI).
  • There was a trend for a benefit on myocardial infarction, but larger trials are needed to determine the impact on that endpoint or CV mortality, as well as subgroups most likely to benefit from the strategy.

This report also has data on Simdax (TENX, Phyxius, ORINY, ABBV) and additional TAVR/SAVR studies (real-world comparison, microbleeds with TAVR, and embolic protection with Embol-X [EW] and CardioGard [CardioGard Medical] in SAVR). Like our report? Have any questions or feedback? Please let us know at askanalyst@sagientresearch.com.

For our disclosures, please read the Biomedtracker Research Standards.