Strongbridge Biopharma reckons that pivotal data on its Cushing’s syndrome project Recorlev are so encouraging that the US FDA might grant accelerated approval. This sounds optimistic, though the results so far look good enough to win Recorlev a green light at some point.
Speed might not be the most important factor here. With a cheap generic already available, and a strong competitor in the shape of Novartis, Recorlev needs to pass the finishing line with a first-line label and no liver toxicity warnings. Should Strongbridge fail to achieve either of these, accelerated approval will be irrelevant.
Liver toxicity is an issue because Recorlev's active ingredient, levoketoconazole, is an enantiomer of ketoconazole, an antifungal that has been for used off-label for years to treat Cushing’s but is associated with liver injury and carries a black box warning.
Recorlev and ketoconazole work by blocking cortisol synthesis; sustained raised levels of cortisol, which in around 75% of patients are caused by a benign pituitary tumour, lead to a range of problems including hypertension, dyslipidaemia and diabetes.
While ketoconazole is very effective at reducing cortisol – effectiveness is thought to be around 50-60% – its side effects mean that physicians are reluctant to use it for long periods.
Results released yesterday from Strongbridge’s Sonics trial suggest that Recorlev does not have the same issues: ALT elevations of >3x the upper limits of normal (ULT) were noted in 10.6% of patients, and >5x in 3.2% of patients. Rigorous studies of ketoconazole have never been done, but Strongbridge has pointed to a trial that observed ALT elevations of >5x in 13% of patients.
A big question is whether the FDA will be comfortable with Recorlev, given its association with ketoconazole. Strongbridge executives noted that the label for Novartis’s Signifor, which will be Recorlev’s main branded competitor, details ALT elevations of 14% and 5%, for >3x and >5x ULT respectively.
These levels are higher than those seen in Sonics, and Signifor does not carry a black box warning of liver toxicity. Strongbridge does not appear to think that Recorlev will be hit with a liver warning.
“Safety is mission critical to payers across this category,” Matthew Pauls, Strongbridge's chief executive, told investors yesterday. “These data, particularly the liver data, are going to put us in a very good spot with payers.”
Of course regulators have to be convinced on efficacy as well as safety, and here Recorlev also looks good. The primary endpoint of Sonics was the proportion of patients achieving normal cortisol levels (measured by urinary free cortisol, UFC) over a six-month maintenance period; 30% of the 94 patients recruited hit this target.
This ruled the trial a success, and the numbers improved further when patients who needed dose adjustments were included, something that the company claims reflects a real-world clinical setting. 76% of the 55 evaluable patients at the end of the study achieved partial or complete UFC normalisation from baseline.
Signifor was approved on the back of a single-arm trial showing a 26% UFC response rate at six months at its highest dose, and is associated with diabetes and gastrointestinal issues, so is far from a perfect drug.
Faster AND better?
Whether this all amounts to a product worthy of accelerated approval is a question for the FDA, and on this point Strongbridge expects to know more before the end of the year. The Cushing's market is not entirely without options, so there is a chance that the regulator will decide to await further data; Strongbridge has a placebo-controlled withdrawal study, Logic, due to report early next year.
Accelerated approval would be a big boost for this wannabe rare disease player. But, to really compete with the deep pockets of Novartis, Recorlev needs to win the same first-line label, devoid of liver warnings.
Perhaps there is one other reason why Strongbridge is keen to rush to market. Novartis has a phase III follow-on asset, osilodrostat, which is also due to report pivotal data this year. The Swiss pharma giant could soon become an even stronger competitor.