Amgen still in play with Endeavor to expand Kyprolis

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Amgen had already made strides to boost Kyprolis’s relevance in the multiple myeloma market, and the most important aspect of yesterday’s interim analysis of the Endeavor study is that it allays the worst fears about the drug’s cardiotoxicity.

Indeed, sharp-eyed industry watchers will have noted that Kyprolis’s progression-free survival benefit in Endeavor had already slipped out at December’s ASH meeting. The data will allay some concerns that Amgen had overpaid for Onyx, and set the stage for readout of the Clarion trial of Kyprolis in the first-line setting.

Of course, Celgene’s Revlimid, with sales of nearly $5bn last year, is not about to be toppled as the powerhouse of multiple myeloma therapy. Rather, the question is with which agents it should be combined as novel treatments move higher up the lines of treatment and patient outcomes improve.

Kyprolis had already staked a claim, its combination with Revlimid demonstrating PFS of 26.3 months in the second-line Aspire trial. At ASH in December the Mayo Clinic’s Dr Keith Stewart said this combo should become standard of care in relapsed disease.

At the same time he compared the benefit against Endeavor, in which he said Kyprolis had shown around a 19-month PFS in similar patients (ASH – Multiple myeloma therapy goes combo, December 6, 2014). Though Endeavor was an open-label trial the formal result from its planned interim analysis was not revealed until yesterday.

Head to head

This showed Kyprolis to have generated an 18.7-month PFS, versus 9.4 months for J&J/Takeda’s Velcade, giving a 47% reduction in risk of progression.

Kyprolis is approved in later settings and is awaiting registration for second-line use. It is important for Amgen to show superiority over Velcade because the J&J/Takeda drug is set to lose patent protection in 2017.

If Kyprolis’s second-line efficacy had already been taken as read, attention should fall on safety: Amgen said Endeavor had shown comparable adverse event discontinuations and deaths between the two arms, with similar rates of cardiac and renal failure to Aspire, and increased hypertension and dyspnoea in the Kyprolis arm versus Velcade and that seen in Aspire.

While the finer details of this increase will be subjected to intense scrutiny when the full data are presented at Asco, the lack of a specific added safety signal is important in itself. This is because Endeavor had dosed Kyprolis at 56mg/m2 – over twice the approved 27mg/m2 tested in Aspire.

And it makes Amgen look a little better in having paid a generous-looking $10.4bn to acquire Kyprolis’s developer, Onyx Pharmaceuticals; the price tag had been criticised after Celgene had dropped the sellside hints about Kyprolis’s emerging cardiotoxicity profile back in 2013.

Still, the best way for investors to have played the Endeavor result was not via Amgen – up 1% yesterday – but by trading Ligand Pharmaceuticals, which via a deal with Proteolix, the biotech bought by Onyx in 2009, retains a small interest in Kyprolis. Ligand closed up 15% yesterday.

Front line

Amgen’s attention thus now turns to Clarion, another head-to-head trial against Velcade, this time testing Kyprolis in newly diagnosed multiple myeloma. This doses Kyprolis at 36mg/m2 and should read out next year.

While Clarion could secure Amgen even more against Velcade generics there is little to suggest that Celgene’s dominance is about to be challenged. EvaluatePharma’s consensus data point to sales of Revlimid, recently approved first line, reaching $8.4bn in 2020, when the drug will still have eight years’ patent life.

In Pomalyst Celgene has a multiple myeloma drug approved in a similar setting to Kyprolis, though it is treading carefully since this has three years’ less generic exclusivity than Revlimid. Of greater importance to the firm’s lifecycle management will be Revlimid combos with novel agents, such as the anti-CD38 MAb MOR202, which it licensed from MorphoSys.

The trick Kyprolis has to pull off is not to beat Revlimid but to join it.

Amgen's plan to move Kyprolis into front-line multiple myeloma
Study Design Trial ID
Aspire 780 second-line pts, Kyprolis added to Revlimid NCT01080391
Endeavor 898 second-line pts, Kyprolis vs Velcade NCT01568866
Clarion 882 first-line pts, Kyprolis vs Velcade NCT01818752

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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