In U-turning on its previous refusal to approve Nerlynx the EU regulator sent the drug’s maker, Puma, up 24% yesterday. This is surprising given that just 18% of Nerlynx’s forecast 2024 global sales of $1.5bn will come from Europe, according to EvaluatePharma sellside consensus.
On the other hand, Puma is worth a fraction of what it was in its heyday, so positive events have an exaggerated impact. But the regulatory volte-face should not have been quite so unexpected; after Roche’s rival Perjeta got the EU green light this month a reversal of the regulator’s negative stance on Nerlynx had become a distinct possibility.
For years Nerlynx and Perjeta, and their respective Extenet and Aphinity studies, had been pitted as arch rivals in the setting in question – extended adjuvant treatment of breast cancer. In the event the modest but statistically significant result of Extenet trumped an even more borderline effect in Aphinity.
Both drugs came before the EMA, which in January announced a “negative trend vote” on Nerlynx, indicating that a positive opinion was unlikely. Sure enough, a month later the filing was turned down, with the regulator saying Nerlynx’s invasive disease-free survival benefit in Extenet might lack clinical relevance.
At the same time, it became apparent that Roche’s Aphinity data with Perjeta were also to have been discussed by the regulator, but no announcement had been made, and the Swiss firm was cagey about proceedings (Europe blocks Nerlynx, Perjeta up next, January 24, 2018).
Puma requested a re-examination of the EMA’s negative decision in March. While the regulator deliberated, however, it approved Perjeta in the extended adjuvant setting on June 1, apparently without raising major questions about Aphinity.
It is not known what arguments Puma used, but after a drug with arguably even less clinical relevance than Nerlynx was approved the die was cast, and the EMA yesterday adopted a positive trend vote on Nerlynx.
Even before Perjeta’s thumbs-up Stifel analysts noted that EU regulatory U-turns after initially negative decisions were not unheard of. Indeed, of 20 negative opinions that had appealed for re-examination since 2014, four have been overturned.
|EU regulatory U-turns: negative opinions overturned after re-examination 2014-18|
|Product||Company||Indication||Reason for rejection||Reason for U-turn|
|Nerlynx||Puma||Extended adjuvant breast cancer||Lack of clinical relevance||Not yet known|
|Sialanar||Proveca||Drooling in children with CNS disease||Lack of benefit in mild to moderate disease||Positive in severe drooling|
|Ninlaro||Takeda||Multiple myeloma||Lack of benefit||Conditional approval with request for confirmatory data|
|Translarna||PTC Therapeutics||Duchenne muscular dystrophy||Lack of benefit||Evidence of effectiveness seen at 40mg dose|
|Linoladiol N||Unclear||Vaginal atrophy||Concern about existing overuse||Limited treatment to four weeks|
Reasons behind the other four U-turns range from re-examination of a medicine’s effect on a narrower patient population to limiting toxicity by restricting the treatment dose. One problem the regulator might have seen with Extenet is that Nerlynx’s efficacy was driven by breast cancer patients who were hormone receptor-positive, or who had high nodal status.
Still, this process usually does not work in companies’ favour. The most recent test of the EU regulator’s resolve was Pharmamar’s Aplidin. Its marketing authorisation for multiple myeloma was refused in December, and in March the decision was upheld on re-examination.
The full scope of the regulatory blessing to Nerlynx will only become apparent as and when a formal decision is given. Of course, even if the EMA decides that Nerlynx is, after all, relevant beyond the narrow patient populations, whether it actually is will be down to doctors and payers.