Panel Meeting For Victoza And Decision Time For Portola's Anticoagulant

Includes: NVO, PTLA
by: EP Vantage

Welcome to your weekly digest of approaching regulatory and clinical readouts. Novo Nordisk's Victoza will go before a US panel meeting on June 20 with the aim of getting a cardiovascular benefit added to its label. The GLP-1 agonist still has a bigger battle on its hands - convincing payers that it is worth the price.

And by June 24 Portola (NASDAQ:PTLA) will know the FDA's decision on betrixaban. A phase III trial testing the factor Xa inhibitor's ability to prevent blood clots in acute medically ill patients produced mixed results, and with a rejection for another of its drugs Portola will want to avoid another setback.

Cardio benefit

An advisory committee will determine on June 20 whether Victoza can have cardiovascular safety added to its label, before its PDUFA date in August. In its outcomes trial, Leader, Victoza's benefit was largely down to prevention of cardiovascular death, while no effect was shown on non-fatal strokes or heart attacks (Novo slumps as Leader looks more like a follower, June 14, 2016).

FDA briefing documents released today make it clear that there will be questions over how Victoza met the primary endpoint without showing a benefit on heart attacks and stroke. On the safety front the FDA notes that longer term follow-up is needed to characterize the relationship between GLP-1s and the development of pancreatic cancer, a known risk factor with the class.

Rivalry in the GLP-1 space is heating up, though Victoza would have the edge with a superiority claim. In its own outcomes trial, Astrazeneca's Bydureon was shown to be non-inferior to placebo on the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke - but it did not show superiority. A cardiovascular outcomes study for Lilly's Trulicity will read out next year.

Competition from the SGLT2 inhibitor class is likely to become even stiffer - Lilly and Boehringer's Jardiance is so far the only diabetes drug to boast a benefit on cardiovascular outcomes on its label. It too was proven to prevent cardiovascular death without significant effect on non-fatal strokes or heart attacks. J&J's Invokana recently showed a cardiovascular benefit, but this came with an increased risk of amputation (ADA - Canvas paints a mixed picture for J&J's Invokana, June 12, 2017).

Another battle for Victoza will be convincing payers; it is still barred under the national formulary of Express Scripts, the biggest US pharmacy-benefit manager. Getting the cardiovascular claim on its label could persuade payers to start thinking differently.

GLP-1 cardiovascular outcomes trial readouts
Product Company Study Status Trial ID
Lyxumia Sanofi Elixa Met non-inferiority vs placebo NCT01147250
Victoza Novo Nordisk Leader Met superiority vs placebo NCT01179048
Injectable semaglutide Novo Nordisk Sustain 6 Met superiority vs placebo NCT01720446
Bydureon Astrazeneca Exscel Met non-inferiority vs placebo NCT01144338
Oral semaglutide Novo Nordisk Pioneer 6 Primary completion Apr 2018 NCT02692716
Trulicity Eli Lilly Rewind Primary completion Jul 2018 NCT01394952

Portola's date with the FDA

Betrixaban is an oral, once-daily factor Xa inhibitor, and the FDA will decide by June 24 whether to approve its use to prevent blood clots in acutely medically ill patients with associated risk factors.

The project stumbled through its phase III study, Apex, failing to show superiority over the much older drug Lovenox in preventing blood clots in hospitalized patients at the highest risk - those with elevated d-dimer protein - but succeeding in the overall study population, including lower-risk patients. Shares fell 30% on the news (Precision medicine takes a scalp as Portola's results confuse, March 24, 2016).

The company released further analyses two months later reporting improved efficacy when using central d-dimer testing; shares rose 5%. It will be difficult to guess how the FDA will receive the data, but it is notable that no advisory committee meeting was scheduled.

P-values for primary efficacy endpoint* in the Apex study
Using local laboratory d-dimer testing Using central laboratory d-dimer testing
Cohort 1 (patients with elevated d-dimer) 0.054 0.002
Cohort 2 (patients with elevated d-dimer and aged >75 years) 0.029 0.007
Cohort 3 (overall population) 0.006 0.006
*Composite of asymptomatic proximal DVT, symptomatic DVT, non-fatal PE, and VTE-related death through Visit 3. Source: NEJM article NCT01583218.

The factor Xa field is dominated by Bayer's Xarelto and Bristol-Myers Squibb's Eliquis. However, both the big pharma factor Xa pills have failed to show any benefit in acutely medically ill patients. Betrixaban was able to beat the standard of care and the company could be rueing its decision to focus on the narrow population.

2022 forecasts sit at $579m, according to EvaluatePharma consensus, with an NPV of $1.6bn or 77% of Portola's market cap. It is now Portola's biggest growth driver after the FDA rejected its other project, Andexxa, an anticoagulant reversal agent, last August.