Strongbridge Biopharma (SBBP) is a small-cap ($161 million) commercial-stage biopharmaceutical company developing innovative therapies for rare diseases affecting the neuromuscular and endocrine systems (i.e., acromegaly and Cushing’s syndrome). Commercial products include Keveyis, an oral carbonic anhydrase inhibitor for treating hyperkalemic, hypokalemic, and related variants of primary periodic paralysis in the United States; and Macrilen, an oral growth hormone secretagogue receptor agonist for use in the diagnosis of patients with adult growth hormone deficiency.
Cushing’s syndrome is a metabolic disease triggered by excess secretion of cortisol. RECORLEV (levoketoconazole) is an investigational cortisol synthesis inhibitor being evaluated in a Phase 3 clinical trial. Top line data is expected by Q1/2020.
Cortisol: Adrenocorticotropic hormone (ACTH, also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone secreted by the anterior pituitary gland in the brain. ACTH stimulates the adrenal cortex of the adrenal gland to produce cortisol from cholesterol in response to signaling from the hypothalamus, also located in the brain. This is referred to as the hypothalamic pituitary adrenal axis.
Excessive Cortisol: Endogenous Cushing’s Syndrome
This is rare and triggered by something inside your body, such as a disorder, rather than something outside your body, such as pharmacological agents. Specifically, Cushing’s syndrome is mediated or induced by excess cortisol secretion that is not dependent on ACTH stimulation but by overproduction of ACTH due to a disorder(s) of the adrenal glands. The most common of these disorders is a noncancerous benign tumor of the adrenal cortex, called an adrenal adenoma.
As depicted in Fig. 1, symptoms may include weight gain and fatty deposits in certain areas of the body, such as the face, below the back of the neck, called a buffalo hump, and in the abdomen; thinning arms and legs; purple stretch marks on the abdomen; facial hair; fatigue; muscle weakness; easily bruised skin; high blood pressure; diabetes; and other health issues.
Fig. 1: Overview of Cushing’s syndrome (Source: Strongbridge)
RECORLEV: Mechanism of Action
Ketoconazole, an antibiotic used in the treatment of fungal infections, has been used for over 30 years to treat Cushing's syndrome globally except in US (not approved). About 50-75% of the individuals with Cushing's syndrome treated with ketoconazole have their cortisol levels normalized. Ketoconazole is an effective drug that is limited by associated mild liver toxicity which normalizes when discontinued.
RECORLEV (levoketoconazole) is an investigational cortisol synthesis inhibitor currently being evaluated in two Phase 3 clinical trials, LOGICS and SONICS, for endogenous Cushing’s syndrome. Levoketoconazole (RECORLEV; Fig. 2 right) is a pure enantiomer of Ketoconazole (Fig. 2 left), meaning it is a mirror copy of Ketoconazole that differs in its R, S configuration (see Fig. 2).
Fig. 2: Chemical Structures of Ketoconazole and Levoketoconazole (RECORLEV)
RECORLEV (levoketoconazole) is presumed to have a favorable efficacy, enhanced potency and improved safety signals (i.e., lower risk of hepatotoxicity) over Ketoconazole for the following reasons. Mechanistically, it suppresses glucocorticoid biosynthesis and circulating levels to therapeutically resolve Cushing's syndrome. Equally important, its presumed good safety signals have been attributed to reduced potency at suppressing CYP7A1, rate-limiting enzyme for bile acids synthesis from cholesterol, eliminating the risk of liver toxicity.
The Phase 3 Clinical Trials
Strongbridge is currently conducting two Phase 3 clinical trials, LOGICS (i.e., double-blind controlled trial) and SONICS (i.e., single-arm open study), on the therapeutic effect of RECORLEV in patients with Cushing’s syndrome. The two Phase 3 trials were requested by the FDA for potential NDA submission based on the information obtained from the 10-Q form.
RECORLEV is being pitched as an improved drug candidate over the conventional therapeutic, Ketoconazole, currently used elsewhere in the clinic for patients with Cushing’s syndrome. Data from the Phase 3 SONICS (i.e., single-arm open study) trial has validated the clinical benefit for RECORLEV in Cushing’s syndrome by achieving its primary endpoint of normalized mean urinary free cortisol (mUFC) after 6 months of maintenance therapy in 29 of 94 (~31%) patients. There were some serious adverse events, including one patient with liver toxicity which was not unexpected. The absence of a placebo-controlled group was a limitation of the study, which is why the second Phase 3 LOGICS study is similarly important.
The second Phase 3 LOGICS study has a placebo group, which will make it easier to compare against any perceived adverse events by RECORLEV in patients with Cushing’s syndrome. Strongbridge expects data readout for LOGICS Q1/2020 and should submit an NDA for RECORLEV in Q3/2020 that will include data from both trials.
Clinically, some patients with Cushing's syndrome have hepatic steatosis or NAFLD/fatty liver. Cushing's syndrome exhibits similar features of the metabolic syndrome (central obesity, hypertension, insulin resistance and dyslipidemia) and is associated with a 20% prevalence of NAFLD. Data from the Phase 3 SONICS trial showed that RECORLEV was associated with improvement in dyslipidemia (i.e., LDL-C and HDL-C levels) and markers of insulin sensitivity.
Notably, there was increased weight loss in patients who received RECORLEV treatment. These clinically meaningful benefits of RECORLEV in limiting some risks of the metabolic syndrome could translate to a potential therapeutic benefit at improving liver steatosis reported in some patients with Cushing's syndrome. Given the weight loss in these patients, it remains to be seen whether Strongbridge will similarly evaluate any clinical effect of RECORLEV on potential liver steatosis.
Based on the liver safety profiles (slide 15), RECORLEV’s safety signals may not be perceived as a significant improvement over Signifor, or perhaps Ketoconazole, an antibiotic used to treat Cushing's syndrome globally except in US for the last 30 years. However, Cushing's syndrome is a rare disease with a sequela of symptomatic clinical events, making it difficult to discern if any potential investigative drug candidate(s) can ever be developed without documented safety signals reported for RECORLEV and others.
Institutional Investors, Insiders Purchase, And Analyst Ratings
At the end of Q1/2019, Strongbridge had $104.3 million in cash and cash equivalents. Sale revenues of $4.3 million were reported at the end of Q1/2019. The company estimates revenue guidance in 2019 of $18-20 million.
Based on the 13F filing, institutional ownership presently stands at 50.12%, with Caxton Corp. and NEA Management Company the two top shareholders. A Strong Buy is recommended by 3 analyst firms with a 12-month price consensus of $15.
RECORLEV has orphan designations from the FDA and the European Medicines Agency. Strongbridge anticipates Phase 3 LOGICS top line data by the end of Q1/2020, and it will submit an NDA for RECORLEV in Q3/2020 that will include data from each of the SONICS and LOGICS trials.
This article has specifically focused on Strongbridge and RECORLEV in its therapeutic approach to Cushing’s syndrome. This is a small cap with a promising pipeline in rare diseases, including acromegaly. Patients with orphan diseases such as Cushing’s syndrome are typically underserved. Limited or non-existent FDA approved therapeutic options provide a unique therapeutic gap for drug candidates like RECORLEV.
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