Welcome to your weekly digest of approaching regulatory and clinical readouts. Pivotal data are due in the second half of the year with Astrazeneca’s lupus project anifrolumab, an earlier trial of which gave mixed results. Astra will be eager to offer a glimmer of hope for a disease with a dismal track record.
Astellas and Pfizer, meanwhile, are awaiting a US FDA approval decision this month on Xtandi in pre-metastatic castration-resistant prostate cancer. The jury is out on how lucrative this setting is, since Zytiga is due to lose market exclusivity later this year and is already being being used in ever-earlier disease.
Because systemic lupus erythematosus (SLE) is an inflammatory automimmune disorder immune suppression has been one strategy for treating it. With anifrolumab Astrazeneca is targeting the interferon alpha receptor, hoping to shut down signalling more completely than could be done by targeting the ligand.
Astra’s pivotal Tulip programme will report in the second half of the year. Tulip SLE 1 enrolled 450 adults with moderate to severe, autoantibody-positive SLE, given 150mg or 300mg of anifrolumab every four weeks for 13 doses versus placebo. The second trial, Tulip SLE 2, tests just the higher dose versus placebo in 360 patients, all continuing on standard of care such as steroids.
The primary measure in both studies is the proportion of patients achieving an SLE responder index score of 4 (SRI-4) or greater at week 52. This composite endpoint includes measurements of disease activity, manifestations in organ systems and physician's global assessment.
In phase II the 300mg dose met the composite primary endpoint – SRI-4 at day 169 with a sustained reduction of oral corticosteroid use between day 85 and 169 versus placebo. 34.3% of patients receiving the MAb had a response versus 17.6% for placebo (p=0.014), but dose response was lacking, with a 1,000mg dose missing statistical significance.
To identify patients who might be more likely to benefit from treatment the MAb is being developed with an interferon gene signature test. Efficacy in phase II was primarily seen in high expressers, who account for 70-80% of patients, according to Bernstein analysts.
Notable recent flops in SLE include Immupharma’s Lupuzor, while earlier this month Neovacs released questionable data with IFNα-Kinoid (Beleaguered Neovacs still has it all to do, July 3, 2018). GSK’s Benlysta got a US green light based on a 9-14 percentage point difference from placebo in the responder index after 52 weeks. However, sales remain weak owing to its modest efficacy, high price tag and risk of infection and anaphylaxis.
|Tulip SLE 1||NCT02446912|
|Tulip SLE 2||NCT02446899|
The shift of novel prostate cancer drugs to earlier stages is nearing its logical conclusion. Xtandi, locked in a battle with Johnson & Johnson’s Zytiga for the biggest sales in this space, faces the next catalyst in this endeavour, a US FDA decision that could allow it to be used in pre-metastatic castrate-resistant patients.
The commercial and clinical relevance of approval is debatable, however, given uncertainties about the number and detection of non-metastic castrate-resistant patients and because of the use of Zytiga in early disease settings, before anti-androgen treatments lose their effectiveness, thanks to findings from the Stampede trial (Asco-GU – J&J’s Zytiga follow-on strategy crumbles on Spartan, February 5, 2018).
The picture will be complicated further with the advent of Zytiga generics when the branded drug loses patent protection this year. And the non-metastatic setting is on the radar of the US pricing watchdog Icer, which yesterday put out draft guidance comparing the three agents.
Still, Pfizer and Astellas have pressed ahead, pushing up the timeline for readout of Xtandi's Prosper trial – no doubt aware that not only was Zytiga being tested in the pre-metastatic population, but also that J&J’s follow-on drug, Erleada, was bidding to hit pre-metastatic patients.
Prosper tested Xtandi on top of androgen deprivation therapy (ADT), and achieved a metastasis-free survival of 36.6 months, versus 14.7 months with ADT alone. This is lower than the 40.5 months achieved by Erleada, which was also on an ADT backbone, but both have similar hazard ratios, 0.29 and 0.28 respectively.
|WW sales ($m)|
|Erleada||Johnson & Johnson||72||824||1,506||2,115|
|Zytiga||Johnson & Johnson||3,122||2,049||1,527||382|
However, Zytiga plus ADT is now an emerging first-line standard of care in hormone-sensitive patients thanks to Stampede, where it scored a 43.9-month failure-free survival number – again, with an HR of 0.29. The fact that the J&J drug's sales are due to fade away as generics enter could be bad news all round.