SNY/REGN: When to Expect Outcomes Data for Praluent

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Richard Evans / Scott Hinds / Ryan Baum

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@SSRHealth

June 16, 2015

SNY/REGN: When to Expect Outcomes Data for Praluent

  • Last week’s Advisory Committee vote implies the Praluent and Repatha labels might be somewhat restricted until their outcomes trials are completed. Presumably positive outcomes data would lead to de-restriction of the labels
  • The Praluent trial (ODYSSEY) has a scheduled completion date of January 2018, however the trial includes two interim assessment points which occur after approximately 50% and 75% of the expected number (1,613) of cardio- and cerebrovascular events has occurred
  • The trial can end at the 50% assessment only for futility; it cannot end at this point with a positive finding. We estimate that a finding of futility at the 50% point, if it occurred, should occur no later than October of this year
  • The trial can end at the 75% assessment point either for futility, or because sufficient evidence of efficacy exists. A finding for futility, if it occurred, should occur no later than September of 2016. A finding that sufficient evidence of efficacy exists at the 75% assessment should occur no earlier than November of 2016
  • Assuming a July approval, we’ll have to wait at least 15 months for positive outcomes data, and the wait could be as long as 29 months
  • We remain bullish on PCSK9’s generally, and on Praluent specifically. Even with restricted labels, for practical reasons we expect large numbers of persons to take the PCSK9’s even ahead of outcomes evidence. These include patients with high CV risks scores who still have high LDL-C’s despite aggressive statin therapy, and patients with high LDL-C’s who are intolerant to statins
  • The feasibility of limiting the PCSK9’s to persons with familial hypercholesterolemia is limited by the fact that very few heterozygous patients are formally diagnosed. And, despite the Advisory Committee’s legitimate suspicion that many patients claiming to be statin intolerant could tolerate statins if carefully re-challenged, such careful re-challenges rarely occur in clinical practice – and become even less likely to occur once PCSK9’s exist as an alternative

Where we’re BULLISH: Biopharma companies with undervalued pipelines (e.g. VRTX, BMY, SNY, ROCHE); Biopharma companies with pending major product approvals (e.g. ALIOF, ALKS, AMGN, BDSI, ENDP, HLUYY, HSP, ICPT, JAZZ, NVS, PTCT, RLYP, RPRX, TSRO, UCBJY, VRTX); ABBV and ENTA on sales prospects in Hep C; SNY on undervalued basal insulin franchise and sales potential for Praluent (alirocumab), in addition to its undervalued pipeline; AZN and LLY on the likelihood that excess SG&A/R&D spending must be reined in, in addition to pending major product approvals; CFN, BCR, CNMD and TFX on rising hospital patient volumes; XRAY and PDCO on rising dental patient volumes and rising average dollar values of dental products and services consumed per visit; CNC, MOH and WCG on bullish prospects for Medicaid HMOs; and, DVA and FMS for the likely gross margin effects of generic forms of Epogen; RAD as an acquisition target as WBA and CVS seek to defend against narrowing retail networks

Where we’re BEARISH: Biopharma companies with overvalued pipelines (e.g. GILD, ALXN, SHPG, REGN, CELG, NVO, BIIB); PBMs facing loss of generic dispensing margin as the AWP pricing benchmark is replaced (e.g. ESRX, CTRX); Drug Retail as dispensing margins are pressured by narrowing retail networks and replacement of AWP (e.g. WBA, CVS, RAD); Research Tools & Services companies as growth expectations and valuations are too high in an environment of falling biopharma R&D spend (e.g. CRL, Q, ICLR); and, suppliers of capital equipment to hospitals on the likelihood hospitals over-invested in capital equipment before the roll-out of the Affordable Care Act (e.g. ISRG, EKTAY, HAE)

Last week’s FDA Advisory Committee meeting raises the prospect of somewhat restricted ‘pre-outcomes’ labels for the PCSK9’s. Being bullish on SNY, we’re especially interested in when Praluent (alirocumab) outcomes data are likely to become available, since favorable outcomes data would essentially de-restrict the drug’s label

Praluent’s ODYSSEY Outcomes trial began in October of 2012, and is scheduled to recruit 18,000 patients. Recruitment is ongoing. The trial will continue either until approximately 1,613 primary endpoint[1] events have occurred, or until stopped at either of two interim assessment points

The first interim assessment takes place when approximately 50% of primary endpoint events have occurred. The 50% assessment deals only with futility; if at this point the rate of events in the alirocumab arm is more than 1.008x the rate in the placebo arm, the trial will be stopped. Assuming a constant rate of recruitment since the trial initiated, background event rates at the levels anticipated in the trial design[2], and attrition at the rate anticipated in the trial design, we would expect the 50% interim assessment to occur in October[3] of this year, if the efficacy comparison is futile (Exhibit 1). If the ODYSSEY trial continues well past this date we would take this as an indication that the trial is unlikely to be stopped (at the 50% interim assessment) for reasons of futility

The second interim assessment takes place when approximately 75% of primary endpoint events have occurred. At this assessment point, the Data Safety Monitoring Board (DSMB) considers both futility and efficacy. The trial can be stopped for reasons of futility if the event rate in the alirocumab arm is more than 95.1% of the event rate in the placebo arm. All else (recruitment and attrition rates, and background rate of cardiovascular events) equal, if the trial is going to be stopped for futility at the 75% assessment point, we would expect this to occur no later than September of 2016. If the trial continues past this date we would take this as an indication that the trial is unlikely to be stopped for futility

The ODYSSEY trial could also be stopped at the 75% assessment point if alirocumab is found to be substantially more effective than the 15% efficacy rate assumed in the trial design. Specifically, if the rate of events on alirocumab is 80.2% or less than the placebo event rate, the trial would stop at the 75% assessment point with a positive finding. We estimate that the earliest the trial could be stopped for efficacy is November of 2016[4] (again Exhibit 1). If the trial were not stopped at the 75% assessment point it would run to completion, which is currently projected (by SNY/REGN on clinicaltrials.gov) to occur in January of 2018

  1. Coronary heart disease death, major nonfatal coronary event, or ischemic stroke
  2. 3.8% at 12 months, 6.4% at 24 months, 8.9% at 36 months, and 11.5% at 48 months
  3. Estimates of the dates on which futility might be determined tend to be the latest feasible dates – because if alirocumab efficacy were worse than needed to establish futility, events would occur more rapidly. Conversely estimates of when the trial might be stopped because of efficacy tend to be earliest feasible dates – because greater efficacy means fewer events, and more time needed to reach the point at which 75% of events have occurred
  4. This date assumes the alirocumab event rate is EXACTLY 80.2% of the placebo rate. The larger alirocumab’s efficacy advantage, the longer it takes for 75% of events to occur
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