Novel Therapy Eases Cushing’s Symptoms in Pivotal Trial

by Kristen Monaco, Staff Writer, MedPage Today

LOS ANGELES — An investigational therapy improved quality of life and reduced disease symptoms for patients with endogenous Cushing’s syndrome, according to new findings from the phase III SONICS study.

Patients taking oral levoketoconazole twice daily had significant reductions in mean scores for acne (-1.8), peripheral edema (-0.4), and hirsutism (-2.6), all secondary endpoints of the pivotal trial (P<0.03 for all), reported Maria Fleseriu, MD, of Oregon Health and Science University in Portland.

“We’re looking forward to see the results of further studies and to add this therapy to the landscape of Cushing’s,” Fleseriu said here during a presentation of the findings at AACE 2019, the annual meeting of the American Association of Clinical Endocrinologists. “We have a newer medication and still we cannot make a dent in the outcomes of Cushing’s, especially for patient-reported outcomes.”

Free testosterone levels significantly decreased in women taking levoketoconazole (a ketoconazole stereoisomer and potent steroidogenesis inhibitor), from an average of 0.32 ng/dL down to 0.12 ng/dL (0.011 to 0.004 nmol/L, P<0.0001). Men had a non-significant increase: 5.1 ng/dL up to 5.8 ng/dL (0.177 to 0.202 nmol/L).

There were no significant changes from baseline to the end of maintenance for other secondary endpoints in the analysis: moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation, and dysmenorrhea. However, significant improvements after 6 months of therapy were seen in patient-reported quality of life compared with baseline (mean 10.6 change on the Cushing QOL questionnaire) as well as a significant reduction in depressive symptoms (mean -4.3 change on the Beck Depression Inventory II).

The open-label, multicenter SONICS (Study of Levoketoconazole in Cushing’s Syndrome) trial included 94 adult men and women with a confirmed diagnosis of Cushing’s syndrome and elevated 24-hour mean urinary free cortisol (mUFC) levels at least 1.5 times the upper limit of normal.

In the dose-titration phase of the study (weeks 2 to 21), patients were titrated up to a max dose of 600 mg levoketoconazole twice daily until mUFC normalization. A 6-month maintenance phase followed with no dose increases, but decreases were allowed if adverse events emerged. An additional 6-month extended evaluation phase followed thereafter.

The study met it’s previously reported primary endpoint, with 30% of patients achieving normalized mUFC levels after 6 months of maintenance therapy without a dose increase (95% CI 21%-40%, P=0.0154).

Levoketoconazole was well tolerated, with only 12.8% of patients discontinuing treatment due to adverse events. The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17%), and fatigue (16%), some of which were expected due to steroid withdrawal, Fleseriu said.

Serious adverse events were reported in 14 patients, including prolonged QTc interval in two patients, elevated liver function in one patient, and adrenal insufficiency in another, events similar to those seen with ketoconazole (Nizoral) therapy.

Fleseriu explained that drug-drug interaction is a problem in Cushing’s, as all of the available medications prolong QT interval.

She noted that in SONICS, QT prolongation with levoketoconazole was observed in few patients. It’s still a “concern,” said Fleseriu, especially for patients on other drugs that prolong QT.

Although not yet approved, levoketoconazole has received orphan drug designation from the FDA and the European Medicines Agency for endogenous Cushing’s syndrome. The tentative brand name is Recorlev.

The study was supported by Strongbridge Biopharma.

Fleseriu reported relationships with Strongbridge, Millendo Therapeutics, and Novartis. Co-authors also disclosed relevant relationships with industry.

From https://www.medpagetoday.com/meetingcoverage/aace/79465

New Phase 3 Data Further Support Recorlev’s Ability to Safely Lower Cortisol Levels in Cushing’s Patients

Strongbridge Biopharma released additional positive results from a Phase 3 trial evaluating whether the company’s investigational therapy Recorlev (levoketoconazole) is safe and effective for people with endogenous Cushing’s syndrome.

The latest results were presented in the scientific poster “Safety and Efficacy of Levoketoconazole in Cushing Syndrome:  Initial Results From the Phase 3 SONICS Study,\” at the 18th Annual Congress of the European NeuroEndocrine Association (ENEA), which took place in Wrocław, Poland, last month.

The SONICS study (NCT01838551) was a multi-center, open-label Phase 3 trial evaluating Recorlev’s safety and effectiveness in 94 patients with endogenous Cushing’s syndrome.

The trial consisted of three parts: a dose-escalation phase to determine the appropriate Recorlev dose that achieved normalization of cortisol levels; a maintenance phase in which patients received the established dose for six months; and a final extended phase, in which patients were treated with Recorlev for an additional six months, with the possibility of dose adjustments.

Its primary goal was a reduction in the levels of cortisol in the patients’ urine after six months of maintenance treatment, without any dose increase during that period. Among secondary goals was a reduction in the characteristically high risk of cardiovascular disease in these people, through the assessment of multiple cardiovascular risk markers.

Strongbridge announced top-line results of the SONICS study in August, which showed that the trial had reached its primary and secondary goals. It concluded last month.

After six months of maintenance therapy, Recorlev successfully lowered to normal the levels of cortisol in 30% of patients without a dose increase. It also led to statistically and clinically significant reductions in cardiovascular risk biomarkers, including blood sugar, cholesterol levels, body weight, and body mass index.

Maria Fleseriu, MD, director of the Oregon Health Sciences University Northwest Pituitary Center, presented additional and detailed results of SONICS at the congress.

Additional analyses showed that among the 77 patients who completed the dose-escalation phase and entered the study’s maintenance phase, 81% had their cortisol levels normalized.

At the end of the six months of maintenance treatment, 29 (53%) of the 55 patients who had their cortisol levels assessed at the beginning of the study and at the end of the maintenance phase had achieved normalization of cortisol levels, regardless of dose increase.

Among all patients who completed maintenance treatment (including patients with some missing data) and regardless of dose increase, 38% had achieved normalization of cortisol levels and 48% recorded a 50% or more decrease or normalization.

The results also highlighted that Recorlev substantially reduced patients’ cortisol levels regardless of their levels at the study’s beginning (which were on average about five-fold higher than the upper limit of normal). In those patients with the highest levels of cortisol in their urine, Recorlev led to a median reduction of more than 80%.

As previously reported, Recorlev was found to be generally well-tolerated, with no new safety concerns, and only 12 participants (12.8%) stopped treatment due to adverse events.

Ten patients had three- or five-fold increased levels of alanine aminotransferase — a liver enzyme used to assess liver damage — which were fully resolved without further complications. These liver-related adverse events “were all noted in the first 60 days, thus suggesting a timeline interval for monitoring,” Fleseriu said in a press release.

“We continue to be encouraged by the positive efficacy results of SONICS and the overall benefit-to-risk profile of Recorlev and look forward to sharing additional planned analyses from the study in the near future,” said Fredric Cohen, Strongbridge’s chief medical officer.

From https://cushingsdiseasenews.com/2018/11/01/new-data-from-phase-3-trial-supports-recorlev-ability-to-safely-treat-cushings-syndrome/

Drug trial begins for Cushing’s syndrome therapy

Participant enrollment has concluded for a phase 3 trial investigating the safety and efficacy of levoketoconazole, a cortisol synthesis inhibitor, for the treatment of endogenous Cushing’s syndrome, according to a press release from Strongbridge Biopharma, the drug’s developer.

The single-arm, open-label SONICS study will include the 90 enrolled participants and may allow a small number of other patients to enroll also, according to the release.

After titration to a therapeutic dose of levoketoconazole (Recorlev), participants will maintain treatment for 6 months, the primary efficacy endpoint. Longer-term evaluation for safety will extend to 1 year. A planned 6-month double blind, placebo-controlled, randomized withdrawal extension, dubbed LOGICS, will include approximately half of the participants from SONICS.

“The need for a safe and effective, next-generation cortisol synthesis inhibitor, such as Recorlev, in the treatment of Cushing’s syndrome is substantial. Through achieving target enrollment in the SONICS study, we are one step closer to better understanding the clinical value of Recorlev and potentially bringing a new therapeutic treatment option to this community,” said Matthew Pauls, president and chief executive officer of Strongbridge Biopharma.

The company expects to announce results of SONICS in the second quarter of 2018 and of LOGICS in the third quarter, according to the release.

For more information:

Clinicaltrials.gov/ct2/show/NCT01838551

From https://www.healio.com/endocrinology/adrenal/news/online/%7Bdddb8b5b-e4c8-412f-b4b8-82acde8f21a2%7D/drug-trial-begins-for-cushings-syndrome-therapy

%d bloggers like this: