With a win in postpartum depression in the bag Sage Therapeutics’ attention with its oral GABA-A modulator SAGE-217 now turns to the big one: major depressive disorder (MDD). Data from the phase III Mountain trial are due in the fourth quarter, although this could slip into early next year.
The company needs a hit to help justify its $7bn valuation. It already sells the intravenous post-partum depression therapy Zulresso, but SAGE-217 is expected to be its biggest growth driver, with 2024 sales forecast to reach $1.8bn, according to EvaluatePharma sellside consensus. The oral project has a risk-adjusted NPV of $4.7bn.
Hopes are high going into the Mountain readout, but depression trials are notoriously tricky. The study tests two weeks' SAGE-217 at 20mg or 30mg versus placebo, with four weeks' follow-up. The primary endpoint is change from baseline in the 17-item Hamilton rating scale for depression (HAM-D) total score at 15 days; a higher score indicates more severe depression.
Sage bulls will point to the fact that the phase IIb trial of SAGE-217 in MDD met its primary endpoint, showing a seven-point improvement in HAM-D versus placebo at 15 days; in addition 64% of SAGE-217-treated patients achieved remission, compared with 23% of placebo recipients.
More recently, SAGE-217 prevailed in a phase III study in postpartum depression (JP Morgan 2019 – development shortcuts pay off for Sage, January 8, 2019). However, data from the single-arm Archway trial in bipolar depression disappointed, and Sage has chosen not to continue in this indication.
Safety will also be closely watched, as there have been reports of fainting with Zulresso, which has a similar chemical structure to SAGE-217. This would be particularly problematic for the oral drug, which would be given in an outpatient setting, whereas Zulresso is administered by a continuous intravenous infusion over 60 hours. Still, there have been no reports so far of fainting with SAGE-217.
Two further phase III trials of the oral project are looking at retreatment in MDD: Shoreline evaluates SAGE-217 on an as-needed basis, while Redwood will assess long-term dosing. Meanwhile the Rainforest study, in comorbid depression and insomnia, is also under way.
|Climbing the Mountain: selected trials of SAGE-217|
|Study||Details||Trial ID||Placebo adjusted change on HAM-D after treatment||Share price reaction|
|Robin||Phase III PPD||NCT02978326||4 points, p=0.0029||43%|
|-||Phase IIb MDD||NCT03000530||7 points, p=<0.0001||70%|
|Mountain||Phase III MDD||NCT03672175||-||-|
|MDD: major depressive disorder; PPD: postpartum depression. Source: Clinicaltrials.gov, company releases.|
Homo homini lupus
Pipeline concerns have been laying Biogen low for some time now – the company’s R&D head of three years quit this week – so any signal of efficacy from BIIB059, a mid-stage lupus candidate, would give the beleaguered biotech a much-needed boost. Phase II results are due before the end of the year, and the trial looks rigorous enough to provide some fairly reliable pointers of activity.
BIIB059 binds BDCA2, a receptor found on plasmacytoid dendritic cells, immune cells that produce large amounts of type I interferon, a key driver of lupus. Plasmacytoid dendritic cells have been shown to accumulate in the skin, and it is hoped BIIB059 will have a particularly marked impact on the rashes seen in many lupus patients.
Data from a phase I study published earlier this year found significant reductions in interferon-related gene and protein expression in patients who received BIIB059, as well as improvements in skin-related disease activity.
The phase II, double-blind, placebo-controlled trial, Lilac, has enrolled distinct lupus populations into two separate cohorts, 264 in total.
Part A assesses a 450mg dose in subjects with systemic lupus erythematosus who suffer from lupus rash and painful joints. The primary measure is change on a joint pain assessment, incorporating 28 different joints, measured over 24 weeks.
Part B tests patients with various forms of lupus skin disease, including cutaneous lupus and discoid lupus, who may or may not have systemic disease. Three different doses are being used in this cohort – 50mg, 150mg and 450mg – and the primary endpoint is an activity score used in lupus skin diseases called CLASI-A. Change in baseline is measured over 16 weeks.
Lupus has proven a very difficult field for drug developers, so any positive signals from Lilac will need to be confirmed in a much larger study. Still, the recent surprise success with Astrazeneca’s anifrolumab suggests that progress is being made (Second time lucky for Astra in lupus, August 29, 2019).
Anifrolumab also targets INF-1, binding to receptors on the interferon; by turning off INF-1 at the source BIIB059 theoretically works earlier. Whether this makes any difference should soon begin to be answered.