Welcome to your weekly digest of approaching regulatory and clinical readouts. Dermira’s excessive underarm sweating project glycopyrronium tosylate is due before the US regulators by June 30, and after the failure of an acne treatment in March the group can ill afford another setback.
Shortly afterwards, by July 10, the FDA is to review a supplemental filing of Bristol-Myers Squibb’s Opdivo plus Yervoy in MSI-high colorectal cancer. Opdivo is already approved in this setting, and if Yervoy’s added toxicity is acceptable a combo could allow Bristol to challenge Merck & Co’s Keytruda in this tumour type.
Don’t sweat it
Dermira’s glycopyrronium tosylate (DRM04) is an anticholinergic drug formulated in a topical wipe that inhibits the interaction between acetylcholine and cholinergic receptors responsible for sweat gland activation.
The filling is based on two phase III trials, Atmos-1 and 2, in a combined 697 subjects aged nine and older with primary axillary hyperhidrosis. Patients were instructed to apply 3.75% glycopyrronium tosylate or vehicle to each underarm once daily for four weeks.
Atmos-2 produced statistically significant improvements in the co-primary endpoints of proportion of patients who had an improvement in sweating severity measured by an axillary sweating daily diary, and change in gravimetrically measured sweat production.
Secondary endpoints, the proportion of patients who had an improvement in hyperhidrosis disease severity scale and at least a 50% reduction in sweat production, were also both hit.
Atmos-1, meanwhile, met statistical significance on both secondary but only one co-primary endpoint, missing change in measured sweat production, with p=0.065. However, a sensitivity analysis excluding extreme outlier data from one analysis centre, comprising 14 patients, yielded p=0.001, the company said.
The most frequent adverse events for both trials were consistent with those for oral anticholinergics, including blurred vison, urinary hesitation, dry eyes and dry skin. There were low discontinuation rates in the trials of 3.5-3.8%.
Allergan’s Botox is marketed in hyperhidrosis and is administered via 15-20 injections per underarm, typically twice a year. If approved Dermira’s topical product could present a welcome self-administered alternative.
2024 forecasts for glycopyrronium tosylate sit at $239m, according to EvaluatePharma consensus, yielding an NPV of $340m, or 75% the company’s market cap. The asset became Dermira’s lead when its acne project olumacostat glasaretil failed earlier in the year, causing shares to plummet 66% (Dermira in a spot of bother after acne failure, March 5, 2018).
Dermira has enough cash to last until mid-2020, but this excludes the cost of advancing its anti-IL-13 MAb lebrikizumab into phase III; another setback would be costly.
Adding Yervoy in MSI-high
In May 2017 Merck & Co’s Keytruda secured US approval in tumours that have either microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency, becoming the first oncology drug available without specifying a particular cancer type.
Two months later Bristol’s Opdivo made up some ground, with an approval for second-line colorectal tumours that are MSI-high. Now Bristol wants to challenge its rival, seeking to extend its reach in MSI-high colorectal cancer to an approval for a combination of Opdivo with Yervoy.
The basis is the Checkmate-142 trial, which for Opdivo monotherapy yielded a 32% overall remission rate (Keytruda’s next advance encroaches on Opdivo and Tecentriq territory, May 24, 2017). In the Yervoy combination cohort the remission rate was higher – 55% – irrespective of PD-L1 expression.
Safety should play a large part of the regulator’s deliberations; Yervoy is known to be toxic, and a third of all subjects in the combo cohort experienced grade 3 or 4 treatment-related adverse events, most commonly liver enzyme elevations.
Since MSI-high/MMR-deficient tumours mainly comprise colorectal cancer Keytruda and Opdivo are playing for a similar market. However, an AACR paper found that MSI is seen in 3.8% of all cancers, with a particularly strong showing in endometrial tumours (31.4%) and gastric adenocarcinoma (19.1%).
The FDA accepted Bristol’s filing in March, and has set July 10 as the action date. Checkmate-142 also includes a cohort getting Opdivo plus the anti-Lag3 agent BMS-986016, though this has yet to face regulators.
|Studies in MSI-high colorectal cancer|
|Keynote-016||Merck & Co||3rd-line (n=40), Keytruda monotherapy||52%||NCT01876511|
|Keynote-164||Merck & Co||>2nd-line (n=61), Keytruda monotherapy||28%||NCT02460198|
|Checkmate-142||Bristol-Myers Squibb||2nd-line (n=74), Opdivo monotherapy||32%||NCT02060188|
|Checkmate-142||Bristol-Myers Squibb||3rd-line (n=119), Opdivo+Yervoy||55%||NCT02060188|
|VHIO16001-EORTC 1604||Roche||2nd-line (n=10), Tecentriq+Avastin||40%||NCT02982694|
|Source: AACR 2018.|