The highlight of this year's conference was results from Praluent's (REGN, SNY) ODYSSEY cardiovascular outcomes trial (CVOT), which were interesting to compare to Repatha's (AMGN, Astellas) FOURIER results presented at last year's conference. While the benefit on the primary endpoint was similarly modest, unlike FOURIER, there were signs of a mortality benefit, and patients with higher baseline LDL-C levels showed relatively strong results. However, the biggest news was that, in exchange for reduced barriers from US payers, the sponsors plan to negotiate net price down into a range based on a cost-effectiveness analysis for high-risk patients concurrently released by the ICER organization. We discuss the implications of these developments, including highlights from interviews with payers and comments from KOLs.
There was also updated data from AndexXa's single-arm Phase III trial ANNEXA-4, but little more information to help gauge whether the FDA will require a randomized controlled trial pre- or post-approval.
On the device front, results from VEST, the first randomized trial of Zoll's LifeVest wearable cardioverter defibrillator for prevention of sudden cardiac death, were mixed, triggering a great deal of discussion among cardiologists. Positive long-term results were also presented for HeartMate 3 (ABT), bolstering the left ventricular assist device (LVAD) in its competition against Medtronic's HeartWare HVAD.
We highlight these and other presentations below.
- Praluent's ODYSSEY trial in recent ACS patients demonstrated a modest 15% hazard reduction in its primary outcome, but also evidence for an all-cause mortality benefit and stronger results in those starting with LDL-C of at least 100mg/dl despite maximally tolerated statins. However, the big news was that REGN/SNY announced that for US payers willing to remove barriers to access for such high-risk patients with elevated LDL- C, they would negotiate net pricing into a range based on a cost-effectiveness analysis for high-risk patients concurrently released by the ICER organization ($4,500-8,000/year), though they did not specify how low in the range they would be willing to accept.
- It had been hoped that the main results would be somewhat stronger, since the trial was longer than FOURIER, which investigated more chronic patients, and the benefit with LDL-C lowering grows after the first year. However, there was an upward drift in LDL-C in the Praluent group due to protocol-specified down-titration for very low LDL-C levels, and possibly due to ACS patients being more recently started on high- intensity statins that were then down-titrated.
- In addition, it took longer for the event curves to separate in ODYSSEY, possibly since many events in the first year of ACS are due to thrombosis, and so risk may not be as modifiable by LDL-C reduction.
- Nevertheless, other presentations at the ACC looking at landmark analyses noted that results for ODYSSEY and FOURIER were what would be expected for the LDL-C lowering and duration of the studies according to Cholesterol Treatment Trialists' (CTT) meta-analyses of statin trials.
- While somewhat stronger results for those with higher LDL-C levels were expected, there was not a significant benefit for Praluent in those with LDL-C less than 100mg/dl. This contrasted to FOURIER, where patients with lower LDL-C levels did show a benefit similar from Repatha compared to other groups.
- Since these patients also have lower event rates so more patients need to be treated to prevent a CV event, a prominent KOL thought these ODYSSEY findings will be used by payers to push back against treating patients with lower LDL-C levels. However, a payer noted that would depend on net pricing.
- The group with lower baseline LDL-C levels may also have included more patients whose dose had to be down-titrated, which could have lowered efficacy, though the investigators did not provide details.
- Many physicians we spoke with at the conference said that after seeing the observed mortality benefit in high-risk patients, they will be putting additional pressure on payers in order to ensure their patients are able to secure treatment.
- Lowering the net price into the ICER range listed above for high-risk patients could well reduce some barriers, but payers either thought the price would need to drop further to remove prior authorization (PA) completely or that there was not a realistic price where PA could be removed.
- If only physician attestation is required for prior authorization, that could well help increase usage, but that will be moderated by the fact that any PA may still be a hassle for cardiologists, whose offices may not be set up to process them efficiently.
- Another expert had mentioned that while Medicare prior authorizations are not terribly difficult, the copays are too high for many patients. Reducing the net price sufficiently would move the drugs off the specialty tier, which would provide significant relief to those who do not already receive assistance.
- Most physicians we spoke with did not view the cardiovascular benefit for Praluent as any different from Repatha.
- The report discusses these topics further, as well as implications for other competitors.
- Phase II data for AKCEA-APOCIII-LRx (AKCA, IONS, NVS) for hypertriglyceridemia were largely incremental, though provided more details on different doses. It was encouraging to see an almost 30% reduction in non-HDL-C, but questions remain as to whether the mechanism will improve CV outcomes.
- A pharmacogenetic analysis from CETP-inhibitor evacetrapib's (LLY) failed CVOT raises questions for dalcetrapib's (DalCor Pharmaceuticals, RHHBY, Japan Tobacco) ongoing Phase III trial in a genetically defined population.
- Updated results were presented from AndexXa's (PTLA) single-arm Phase III trial, ANNEXA-4, but there was little to inform the major issue facing the drug, announced a couple weeks prior to the conference, of whether a new FDA requirement for a randomized controlled trial will need to be pre- or post-approval.
- Questions have been raised as to whether such a trial would even be ethical, but that would be even more of an issue if it were conducted post-approval.
- One issue under discussion with regulators is the discrepancy between the number of patients that experience complete biomarker reversal as compared to the number of patients achieving excellent or good hemostatic efficacy, though it was not clear if there are other issues the FDA is concerned about.
- This discrepancy did not appear to be much different than the case for approved Praxbind (Boehringer), but there is a different section of the agency evaluating AndexXa.
- Officials explained a higher rate of thrombotic events in ANNEXA-4 by differences in the proportion of VTE patients compared to other trials, as well as differences in re-anticoagulation, but more details are needed to bolster the argument.
- Inorganic nitrite Aironite (SVRA) failed to show any benefit in the INDIE study of patients with heart failure and preserved ejection fraction (HFpEF), an indication that has seen many failures.
- Mavacamten (MYOK, SNY) had positive new efficacy results from the single-group PIONEER trial in the orphan indication obstructive hypertrophic cardiomyopathy (oHCM), also presented by the company to investors a week before the conference.
- In the new lower-dose cohort, where patients were allowed to continue beta-blockers, efficacy parameters were generally positive, though not all were as strong as in the previous higher-dose cohort, where beta-blockers had to be discontinued. One caveat is that the trial was uncontrolled.
- On safety, though, there were more patients in the combined cohorts who had atrial fibrillation deemed related to drug, though a company representative noted hypertrophic cardiomyopathy patients are prone to the condition and asserted that rates are in line with the literature.
- Dosing in Phase III is expected to be titrated based on echocardiographic imaging of the impact of the drug.
- JVS-100 (Juventas), a plasmid encoding stromal cell-derived factor-1 (SDF-1), failed its Phase II trial in critical limb ischemia patients. While investigators are looking to six-month data, there was no indication of a benefit to place hopes on.
- In Uloric's (Takeda, ABBV, Teijin, Ipsen, Menarini, Astellas) CV safety study, although the primary endpoint of non-inferiority to allopurinol in MACE was met, which had been required due to an imbalance in events in its pivotal program, a higher rate of all-cause mortality due to an excess in CV deaths was worrying.
- Preliminary findings had already been announced in November in an FDA Drug Safety Communication, noting that the agency would conduct a comprehensive review.
- While the FDA has the power to pull the drug from the market, the agency may be less stringent, given needs in patients with chronic kidney disease (the imbalance was not seen in those with moderate CKD, albeit just on subgroup analysis), or those with hypersensitivity reactions to allopurinol.
- Results of VEST, the first randomized, multi-center trial of Zoll's LifeVest wearable cardioverter defibrillator for prevention of sudden cardiac death following a heart attack, missed its primary endpoint, a reduction in sudden cardiac deaths. However, patients randomized to LifeVest had lower overall risk of mortality than the patients randomized to standard medical therapy. The conflicting results triggered a lot of discussion among cardiologists.
- The presenter noted that some of the sudden-cardiac deaths in the trial may have been misclassified, and the company's press release and advertising at the conference highlighted the difference in overall mortality.
- This outraged some cardiologists at the meeting, however, with one KOL pointing out that the greatest advantage in mortality was stroke- related deaths, which is difficult to explain, and removing them rendered results no longer significant.
- Results of the all-comers MOMENTUM 3 trial show Abbott's HeartMate 3 (ABT) left-ventricular device can provide long-term circulatory support for advanced heart failure patients with fewer complications than the second-generation HeartMate II (ABT).
- HeartMate 3 demonstrated superiority in its primary endpoint composite (disabling stroke, device malfunction requiring surgery to replace or remove it, and death from heart failure), though this was driven by a lower rate of device malfunction, related to fewer pump thromboses.
- HeartMate 3 also had a significantly lower rate of strokes, but this was only due to fewer that were non-disabling.
- With these strong results, it is likely that HeartMate 3 will be able to secure a destination-therapy indication, bolstering it in its competition against HeartWare HVAD in this segment.
- Two-year results from the South Korean DEFENSE PRO trial of the Amplatzer PFO Occluder (ABT), in patients with a high-risk PFO who suffered a cryptogenic stroke, found an appreciable reduction in stroke recurrence compared to medical therapy, a benefit that occurred much earlier than in prior major studies.
- Though the study was small, differences in the groups were fairly pronounced, and the investigators concluded that patients who benefit most from the device can be identified on the basis of the size of the PFO and the movement of the heart wall around it.
Praluent (alirocumab; REGN, SNY) - Approved
HIGHLIGHTS FROM PAYER INTERVIEWS ON PCSK9 INHIBITORS
Evacetrapib (LLY) - Suspended
Dalcetrapib (DalCor Pharmaceuticals, RHHBY, Japan Tobacco) - Phase III
AKCEA-APOCIII-LRx (AKCA, IONS, NVS) - Phase II
AndexXa (andexanet alfa; PTLA) -Phase III
Aironite (sodium nitrite inhalation solution; SVRA) - Suspended
Mavacamten (MYOK, SNY) - Phase II
Acute Coronary Syndrome
Peripheral Arterial Disease
JVS-100 (Juventas) - Phase II
CV Safety in Gout
Uloric (febuxostat; Takeda, ABBV, Teijin, Ipsen, Menarini, Astellas) - Approved
LifeVest Wearable Cardioverter Defibrillator (ZOLL Medical) - Approved
Left Ventricular Assist Devices (LVAD)
HeartMate 3 (ABT) - Approved
Patent Foramen Ovale (PFO) Closures
Amplatzer PFO Occluder (ABT) - Approved
Transcatheter Aortic Valve Replacement (TAVR/TAVI)
CoreValve (MDT) - Approved