Amgen’s Arch trial was assumed to be a rubber stamping exercise ahead of osteoporosis drug romosozumab’s July PDUFA decision – an event many saw as a foregone conclusion. Instead, the study that was supposed to bolster the drug’s credentials in non-vertebral fracture and improve its commercial prospects has proved its undoing. Serious cardiovascular side effects were observed in the romosozumab arm, leading the FDA to demand more safety data.
This now leaves romosozumab, which has been renamed Evenity, at best facing a severely delayed approval with numerous safety warnings on a very restricted label, or at worst being discontinued completely.
The regulators' concerns were raised over the reported imbalance of serious cardiovascular events with 2.5% for Evenity compared with 1.9% in the control arm. Amgen, which has suffered from pipeline setbacks and slow starts to the drugs it has launched saw its shares fall by 2% when the US market opened
The pain came earlier and much harder for UCB, Amgen’s partner, whose shares fell by 18% in European trading. UCB had acquired romosozumab as part of its acquisition of Celltech and was set to get 50% of sales following approval of Evenity, a sum that would have helped offset the impending biosimilar competition to its rheumatoid arthritis drug Cimzia.
Analyst Umer Raffat at Evercore reacted to the news by removing all Evenity sales from forecast models. The drug was expected to have sales of $917m in 2022 according to consensus forecasts from EvaluatePharma.
Size does matter
The 4,100 patient Arch study saw participants take Evenity for 12 months followed by alendronate for a further 12 months and the number of vertebral and non-vertebral fractures observed at 24 months. The drug met its primary endpoint of reducing vertebral fractures and, more importantly, non-vertebral fractures were reduced by 19%, reversing the drug’s earlier miss in the Frame trial.
However, the fact there were no significant imbalances in cardiovascular events in the much larger 7,180-patient Frame study made the safety signals in the smaller Arch trial such a surprise.
Mr Raffat hypothesised that the Evenity’s mechanism of action, binding and inhibiting sclerostin, could have had an impact on vascular calcification. While Geoffrey Porges of Leerink speculated that it could conversely be bisphosphonates' ability to lower arterial calcification, that “the comparison in the new trial may have heightened those differences”.
Mr Porges also pointed to the higher number of adverse events in the Frame trial as a potential warning to the Arch results. Another theory was the difference in age of the trial participants, with Arch patients being older than those in the Frame trial and therefore potentially at higher cardiovascular risk.
No time soon
As the Arch data will now be included in the submission for Evenity, analysts are expecting the process of reviewing the data and refiling could delay approval until the middle of 2018, or even later. As a biologic in a largely generic market Evenity already had a lot to prove to payers. Even if the drug does eventually get approved, with a worrying safety profile this task has now become event harder
|Top 5 osteoporosis products in 2022|
|Annual Sales WW (Indication) ($m)|
|Product||Company||Pharmacological Class||2016||2022||WW Indication Status|
|Prolia||Amgen||Anti-receptor activator of nuclear factor-kappaB ligand (RANKL) MAb||1,635||2,821||Marketed|
|Tymlos (Abaloparatide SC)/Abaloparatide TD||Radius Health/Undiclosed Partner Sales||Parathyroid hormone||9||570||Approved (subcutaneous)/Phase II (transdermal)|
|Forteo||Eli Lilly||Parathyroid hormone||1,500||554||Marketed|
|Viviant||Pfizer||Selective oestrogen receptor modulator (SERM)||133||489||Marketed|
|Source: EvaluatePharma *Forecasts prior to Arch results NCT01631214|
The setback for Amgen, however, is a huge opportunity for Radius Health’s newly approved abaloparatide, now Tymlos, to capitalise on the patent expiry of Eli Lilly’s Forteo in 2018. Amgen had been hoping a July approval for Evenity would help it take some share from Forteo. Instead Tymlos, which which not only managed to hit its endpoint in non-vertebral fractures, but has also shown no safety signals could be the one taking up this opportunity.