Welcome to your weekly roundup of approaching clinical readouts. In the fourth quarter Novartis will report the first phase III data with fevipiprant, an oral DP2 inhibitor, in severe asthma.
The company hopes that the project can bridge the gap between inhaled therapies and biologicals. However, previous failures with this class have made investors wary. If Novartis might be able to brush off a clinical trial flop, the same might nto be true for Gossamer Bio, whose lead project, GB001, also hits DP2.
The first pivotal data with fevipiprant will come from the Zeal 1 and 2 trials, in patients with moderate to severe asthma. The primary endpoint of both is change in forced expiratory volume in one second (FEV1), a measure of lung function, at 12 weeks versus placebo.
Leerink analysts reckon a best-case scenario for both Novartis and Gossamer would be FEV1 improvements versus placebo of 200ml or more – putting fevipiprant on a par with Sanofi/Regeneron’s Dupixent in asthma – although they added that a 100ml improvement could also hit statistical significance.
But history is not on the companies’ side. Several DP2 inhibitors have been discontinued after failing to show a benefit in asthma, including Astrazeneca’s AZD1981 and Amgen’s vidupiprant/AMG 853. Leerink blamed “suboptimal pharmacology” with these older agents. Meanwhile, Novartis believes that it could have a better chance with fevipiprant as it is targeting more severe patients and those with high eosinophils, a marker of allergic asthma.
However, even in allergic asthma data have been mixed, with no clear dose response seen on FEV1 in a phase II trial, despite an overall win. Gossamer is already trying to play down the importance of FEV1 as an endpoint, but this looks like clutching at straws.
Fevipiprant is in two more pivotal trials, Luster 1 and 2, which Gossamer and its backers believe could be more relevant for GB001. However, investors in the smaller group might still be in for a rocky ride if the Zeal trials fall short.
|Upcoming readouts with DP2 inhibitors|
|Project||Company||Trial||Indication||Primary endpoint||Data due||2024e sales ($m)|
|Fevipiprant/ QAW039||Novartis||Zeal 1||Moderate to severe asthma (Gina 3/4)||FEV1 at 12 weeks||Q4 2019||619|
|Zeal 2||Moderate to severe asthma (Gina 3/4)||FEV1 at 12 weeks||Q4 2019|
|Luster 1||Severe eosinophilic asthma (Gina 4/5)||Exacerbations at one year||Q1 2020|
|Luster 2||Severe eosinophilic asthma (Gina 4/5)||Exacerbations at one year||Q1 2020|
|GB001||Gossamer Bio||Leda (phII)||Moderate to severe eosinophilic asthma (Gina 4/5)||Asthma worsening composite||2020||272|
|Gina: Global Initiative on Asthma; Source: EvaluatePharma, clinicaltrials.gov.|
Alnylam sees the light
Alnylam is due to report from its pivotal Illuminate-A trial of lumasiran in primary hyperoxaluria type 1 (PH1), a rare inherited disease, by the end of the year.
Lumasiran is an RNAi therapeutic designed to reduce levels of the enzyme glycolate oxidase, preventing the formation of oxalate; in PH1 this substance builds up in combination with calcium to form kidney and bladder stones, causing kidney problems and, eventually, end-stage renal disease.
There are three types of primary hyperoxaluria that differ in severity and genetic cause. Lumasiran targets only PH1, which is caused by a mutation in the AGXT gene. There are no approved therapies for the disease, and some patients have to undergo liver and kidney transplants.
The Illuminate trial compares subcutaneous lumasiran versus placebo in 30 adults and children. The primary measure is the percentage change in 24-hour urinary oxalate excretion from baseline to 6 months, a surrogate endpoint. Key secondary endpoints include additional measures of urinary oxalate, estimated glomerular filtration rate, safety and tolerability.
In terms of competition lumasiran is neck and neck with Dicerna’s DCR-PHXC, another RNAi contender that is in a pivotal trial called Phyox2 in 36 patients with PH1 and PH2. Dicerna hopes that its candidate could be used in all genetic subtypes of PH. DCR-PHXC targets a different enzyme, lactate dehydrogenase A, inhibition of which is said to reduce oxalate levels.
Dicerna’s trial also uses the 24-hour urinary oxalate excretion as an endpoint, but the study measures levels at 3, 4, 5 and 6 months to give an average value over time; this could help mitigate variability and placebo effect.
If Illuminate-A proves positive Alnylam expects to file early next year.
|Selected trials in primary hyperoxaluria type 1|
|Illuminate-A NCT03681184||30 adults and children, three monthly 3mg/kg doses or placebo, followed by quarterly maintenance doses||YE 2019|
|Illuminate-B NCT03905694||20 patients aged under six, dosing based on weight||Mid 2020|
|Illuminate-C||Single arm study in patients with severe renal impairment||Initiate by YE 2019|
|Lumasiran Phase I/II NCT02706886||20 patients, 1mg/kg monthly, 3mg/kg monthly and 3mg/kg quarterly||Reported: mean maximal reduction in urinary oxalate of 75% relative to baseline across all cohorts|
|Phyox2 NCT03847909||36 patients with PH1 or PH2. Multiple fixed doses of DCR-PHXC||Study completion May 2020|
|Source: EvaluatePharma, clinicaltrials.gov.|