August 28th, 2014

Predicting PARADIGM-HF, or What to Expect When You’re Expecting

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The wait is almost over. For the last 5 months the most eagerly awaited trial in the cardiovascular universe has been PARADIGM-HF, the large (8,500 patient) trial of a new and novel heart failure drug from Novartis. If reality lives up to the early hope and hype, the drug, LCZ696, could completely reshape the heart failure landscape and give Novartis that rarest of gems, a new and genuine blockbuster cardiovascular drug.

The main results of the trial will first be presented at a press conference in Barcelona, Spain this Saturday in connection with the annual meeting of the European College of Cardiology. As I have previously reported, the PARADIGM-HF trial was stopped because of a highly statistically significant reduction in cardiovascular mortality in patients taking LCZ696 (a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor) instead of the current gold standard of treatment, an ACE inhibitor.

Until we see the data it is impossible to reach any conclusions, but, as might be expected, Wall Street analysts have been reading the tea leaves and trying to figure out likely outcomes.

One analyst, Timothy Anderson of Sanford Bernstein, remains cautious, despite “investor excitement” over comments made by the company and the co-principal investigator of PARADIGM-HF, Milton Packer. He noted that Novartis “has sometimes overpromised and underdelivered,” so he’s waiting to see the results. He currently thinks LCZ696 could reach annual sales of 2.4 billion in 2020. His estimates could grow if the results of PARADIGM are extremely impressive. Currently, according to Anderson, “analysts’ opinions are jelling around a high teens to 20%” reduction in the primary endpoint of cardiovascular death and heart failure hospitalizations.

“This would be viewed as meaningful—anything more would be fantastic,” said Anderson. Of course the analysts, along with everyone else, will also be looking at other issues like safety and tolerability, including, especially “any red flags about angioedema,” which ruined a similar BristolMyers Squibb drug, omipatrilat, some years ago.

One striking feature of the current situation is that LCZ696 stands alone. Anderson is unaware of any other similar drugs in mid or late phase development. On the one hand, this may be good for Novartis. “The runway is very clear for a very long time,” said Anderson. On the other hand, Novartis won’t benefit from the combined effect—seen with both ACE inhibitors and ARBs in the past—of multiple companies working to develop the market. Efforts “to supplant” the very well established ACE inhibitors and ARBs will require “a paradigm shift… that could take a long time to take into effect.”

Another analyst, Larry Biegelsen at Wells Fargo, wrote that PARADIGM-HF is “arguably the most important heart failure drug trial in almost 25 years.”

Morgan Stanley analysts calculate that Novartis’s stock price now assumes expected peak sales of LCZ696 of more than $5.5 billion. To achieve these sales the drug “would need to be used in ~75% of the eligible patient population.” Morgan Stanley then surveyed cardiology key opinion leaders (KOLs). In order to replace ACE inhibitors as the standard of therapy, they said the trial would need to show at least a 25% relative risk reduction in the primary endpoint and at least a 20% reduction in cardiovascular death.

The Morgan Stanley survey also notes that KOLs (and, surely, plain old cardiologists as well) will be just as interested in the absolute differences between the two treatment arms, as reflected in the number needed to treat, or NNT, as in the relative risk reductions. The KOLs said an NNT of 25-30 would encourage a shift to LCZ696.

Novartis has told analysts that LCZ696 could become the biggest product in the company’s history. The current record holder is Diovan (valsartan), which had peak sales of $6 billion.

One thing we know for certain: I’ve been told by a reliable source that LCZ696 will not gain a new name at the ESC. For now we’re stuck with this awkward moniker.

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