It is rare for a small, European biotech to go all the way to have a drug approved in the US, but this is precisely what Oncopeptides managed in February with the multiple myeloma chemotherapy Pepaxto. Now a bizarre chain of events could scupper its efforts.
Key to Pepaxto’s success is expansion into early treatment lines, but this has been called into question by new results from the Ocean study, toplined this morning, showing patients living longer on Pomalyst than on Pepaxto. While some will hope that the problem will be resolved as soon as poorly performing subgroups can be weeded out, others will see a negative read-across to the entire programme, including its approved indication.
For now the negative OS signal has resulted in the FDA putting Ocean and other Pepaxto trials on clinical hold. This includes the Lighthouse and Anchor trials, combining the drug with Darzalex, Velcade or Pomalyst, as well as the Ascent trial in AL amyloidosis. Separately, an early study of OPD5, Oncopeptides’ second peptide-drug conjugate project, is also on hold.
On an investor call this morning Oncopeptides said it was working with the FDA to restart trials, but said realistically the delay would last months. Its stock, which on Pepaxto’s approval had stood 300% above its February 2017 IPO, sank 24% today.
|Selected studies of Pepaxto (melflufen)|
|Study||Setting||Design||Primary endpoint||Key secondary||Data/status|
|Horizon||≥5L||Single cohort||ORR||PFS & OS||Accelerated approval on basis of 24% ORR|
|Ocean||3L to 5L||Vs Pomalyst||PFS||OS||HR 0.792 for PFS, 1.104 for OS; on clinical hold|
|Lighthouse||≥3L||Darzalex combo, vs Darzalex||PFS||OS||On clinical hold|
|Anchor||2L to 5L||Velcade or Darzalex combo, uncontrolled||ORR||PFS & OS||On clinical hold|
|Source: company information & clinicaltrials.gov.|
How the situation came about is even stranger than the fact that the OS discrepancy has arisen at all.
Pepaxto’s US label is based on the Horizon study, and effectively amounts to a salvage setting in multiple myeloma patients who have failed at least four lines of therapy. The drug, a souped-up version of the chemotherapy melphalan, carries 2026 revenue forecasts of $490m, according to Evaluate Pharma sellside consensus, but Jefferies reckons the Horizon setting accounts for only 22% of peak sales.
This is why Oncopeptides started a series of trials in earlier therapy lines. Of these Ocean was the most interesting since it pitted Pepaxto head to head against Bristol Myers Squibb’s Pomalyst, which Oncopeptides argued was the most prescribed drug in the relapsed-refractory setting.
However, in May it emerged that, while investigator-assessed PFS in Ocean suggested superiority to Pomalyst, independent review indicated a lower relative benefit, amounting only to non-inferiority. This prompted a reanalysis, which discovered that imaging results for 29 of the 495 Ocean patients had not been provided to the independent review committee.
When these were provided the committee reassessed its findings, and decided that Ocean’s primary PFS endpoint did, after all, show superiority over Pomalyst.
|Ocean's moving PFS result|
|Date||Type of review||PFS hazard ratio vs Pomalyst||p value||Outcome|
|25 May||Investigator||0.790 (0.639-0.976)||0.029||Superiority|
|25 May||Independent||0.817 (0.659-1.012)||0.064||Non-inferiority|
|8 June||Independent||0.792 (0.640-0.979)||0.031||Superiority|
But alongside this came news that early analysis of Ocean’s key secondary OS endpoint had revealed that patients on Pepaxto were 10.4% more likely to die than those on Pomalyst. Though there was no statistical significance here the FDA slapped its clinical hold on the programme.
Typically a discrepancy between PFS and OS can be accounted for by an efficacious therapy increasing toxicity and thus mortality, or by an imbalance in subsequent therapies. Indeed, Ocean is notable for not including anti-CD38 therapy, and maybe progressing control arm patients got Darzalex or Sarclisa sooner and thus lived longer than those on Pepaxto, who progressed later.
However, Oncopeptides appeared to rule this out, instead putting the discrepancy down to wildly differing performance in subgroups. It claimed that one group was doing better on Pepaxto, with a 0.5 hazard ratio for OS, while another favoured Pomalyst (HR around 1.5), and the latter drove the overall negative OS result.
Though it did not reveal what these subgroups were, Ocean is known to have stratified for age, prior therapy lines, and disease staging, criteria that could also comprise prespecified subgroups. All will be revealed at September’s International Myeloma Working Group meeting, for which Oncopeptides has submitted the full data as a late-breaker.
For investors the clinical hold is just one problem. Another is that the hold could derail Pepaxto’s approved fifth-line indication, which was to some extent reflected in Ocean’s third to fifth-line population. Though Oncopeptides insists that the label represents a much later-stage setting, the possibility of the FDA revoking the drug’s accelerated approval cannot be dismissed.
Even if this does not happen, it is abundantly clear that Pepaxto’s target population is rather smaller than first hoped for.
This story has been updated to correct the design of the Anchor trial.