CRHR1

Spruce Biosciences pointed to poor compliance with the treatment among patients as one possible reason for the clinical fail. Spruce Biosciences' stock has shed three-quarters of its value in the wake of the failure of a phase 2 trial for the biotech's only drug candidate. The CRF1 receptor antagonist tildacerfont was being investigated in the CAHmelia-203 trial of 96 adults with severe congenital adrenal hyperplasia (CAH), meaning they all had levels of a steroidal hormone called androstenedione over five times higher than normal. The study failed to reach the primary efficacy endpoint of causing a reduction in androstenedione levels from baseline at Week 12. As a result, Spruce explained in an accompanying full-year earnings report that the trial is ending, and 21% of the workforce will be laid off to extend the biotech's cash runway through the end of 2025. Spruce pointed to poor compliance with the treatment among patients as one possible reason for the clinical fail: “Compliance with study medication and glucocorticoids was low with approximately 50% of patients reporting 80% or greater compliance, resulting in lower-than-expected tildacerfont exposure,” the biotech said in a separate release. These results “underscore the complexities inherent in managing a patient group with challenges related to androgenic control and glucocorticoid compliance,” endocrinologist Irina Bancos, M.D., the study’s principal investigator and an associate professor of medicine at the Mayo Clinic, said in Spruce’s release. “Based on my clinical experience, patients within this group may face difficulties adhering to any therapeutic interventions, potentially impacting treatment outcomes,” Bancos said. “CAHmelia-203 is the first study of its kind to address a difficult-to-treat CAH patient population with severe and more refractory hyperandrogenemia, which is often attributed to challenging real-life compliance with daily glucocorticoids,” Spruce CEO Javier Szwarcberg, M.D., said in the same release. “We garnered important data from this study which will inform ongoing development of tildacerfont in adult classic CAH.” Szwarcberg was understandably keen to refocus attention onto another ongoing phase 2 trial, dubbed CAHmelia-204, which is assessing the ability of tildacerfont to reduce the use of glucocorticoids in adult CAH patients with close to normal levels of androstenedione. Spruce described a reduction in glucocorticoid use as a “potentially registrational endpoint,” while Szwarcberg said the company is “eager” to read out top-line data from CAHmelia-204, which are expected in the third quarter of the year. The biotech also tried to balance today’s fail with some better clinical news, announcing some “positive” preliminary data from the phase 2 CAHptain-205 trial in children that showed tildacerfont was not only safe but led to 73% of the 30 patients meeting the efficacy endpoint of either androstenedione or glucocorticoid reduction from baseline at Week 12. “Assuming positive results from CAHmelia-204 and CAHptain-205, we plan to meet with the U.S. FDA and comparable foreign regulatory authorities in early 2025 to outline the design of a registrational clinical program in adult and pediatric classic CAH,” Szwarcberg said. The promise of better results to come didn't appear to be enough to reassure investors, who sent Spruce’s stock plummeting 74% to $1.34 per share in premarket trading Thursday from a Wednesday closing price of $5.19. CAH spans a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones. Around 95% of cases are caused by a mutation that leads to a deficiency of the enzyme 21-hydroxylase, and there are currently no FDA-approved non-glucocorticoid treatments available. Spruce’s loss could be Neurocrine Biosciences' gain, according to analysts at William Blair, who pointed out that the latter’s own CRF1 receptor antagonist crinecerfont demonstrated the ability to both reduce glucocorticoid use and androstenedione levels in phase 3 trials in adults and children last year. Time is also on Neurocrine’s side as it prepares to submit an approval application in the second quarter of this year, while Spruce is not expecting to even begin discussions with the agency about pivotal trials until 2025. The William Blair analysts said they were “confident” that crinecerfont would secure approval, with a commercial launch penciled in for next year.

The US Food and Drug Administration has classified the development as a Class II recall. Credit: sumroeng chinnapan / Shutterstock.com. Sun Pharmaceutical Industries has announced a recall of 55,000 bottles of Febuxostat, a medication used to treat gout, from the US market, PTI has reported. The recall is due to deviations from current good manufacturing practice (CGMP) regulations. The US Food and Drug Administration (FDA) has classified the development as a Class II recall, meaning that exposure to the affected product may lead to temporary or medically reversible adverse health consequences. The recall encompasses 47,520 bottles of 40mg strength and 7,488 bottles of 80mg strength Febuxostat tablets. The FDA reported microbial contamination in stagnant water in the duct of the manufacturing equipment. See Also: Spruce Biosciences files patent for treatment of congenital adrenal hyperplasia using CRF1 receptor antagonist 4D Molecular Therapeutics files patent for gene therapy for fabry disease using optimized alpha-galactosidase a sequence The affected lot was manufactured at Sun Pharma’s Dadra, India plant and was intended for Northstar Rx, based in Memphis. The recall began on 4 March 2024 and has been classified as nationwide in the US. Sun Pharma is a generic pharmaceutical sector giant in the US. The US generic drug market was valued at $115.2bn in 2019. The development comes after Sun Pharma signed a definitive merger agreement in January 2024 to acquire all outstanding ordinary shares of Taro Pharmaceutical not currently owned by the company or its affiliates for $347.73m (Rs28.92bn) in cash. In an intimation letter published on 12 December 2023, Sun Pharma expressed interest in a takeover of Taro. Taro develops off-patent pharmaceuticals and supplies prescription and over-the-counter products such as tablets, capsules and topical formulations to markets including Canada, Israel and the US.

100 Patients Enrolled, Exceeding Target Enrollment of 90 Patients Topline Results for CAHmelia-204 Anticipated in the Third Quarter of 2024 SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Spruce Biosciences, Inc. (Nasdaq: SPRB), a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for rare endocrine disorders with significant unmet medical need, today announced completion of enrollment in its CAHmelia-204 clinical trial of tildacerfont for the treatment of adult classic congenital adrenal hyperplasia (CAH). “Completing enrollment in our CAHmelia-204 clinical trial marks a significant milestone in our adult classic CAH program. This achievement reinforces the continued momentum within our tildacerfont program and positions us favorably to report topline results in the third quarter of 2024,” said Javier Szwarcberg, M.D., M.P.H., Chief Executive Officer of Spruce Biosciences. “Thanks to positive engagement from our patient community and study investigators alike, the CAHmelia-204 clinical trial enrolled 100 patients, exceeding target enrollment of 90 patients.” Dr. Szwarcberg continued, “Looking ahead, assuming positive results from CAHmelia-203 in March and CAHmelia-204 in the third quarter, we plan to meet with the U.S. Food and Drug Administration (FDA) and comparable foreign regulatory authorities to discuss the potential registrational path forward for tildacerfont as a treatment for adult classic CAH.” CAHmelia-204 is a randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of tildacerfont, a potentially novel, once-daily, non-steroidal treatment option, in reducing glucocorticoid usage in 100 adults with classic CAH on supraphysiologic doses of glucocorticoids with normal or near normal levels of androstenedione (A4) at baseline. The primary endpoint of this clinical trial is the absolute change in daily glucocorticoid dose in hydrocortisone equivalents (HCe) from baseline at week 24. About CAHmelia-203 CAHmelia-203 is a randomized, double-blind, placebo-controlled, dose ranging Phase 2b clinical trial evaluating the safety and efficacy of tildacerfont in adults with classic CAH and highly elevated levels of A4 at baseline while on stable glucocorticoid dosing. This clinical trial enrolled 96 subjects with elevated levels of A4. For the first six weeks, patients will receive blinded placebo to assess their adherence to their existing glucocorticoid therapy. Patients who continue to meet all eligibility criteria at the end of this period will enter a three-part treatment period. During the placebo-controlled treatment period, patients will be randomized in a blinded manner to receive placebo, 50mg, 100mg, or 200mg tildacerfont once daily. Dosing in the placebo-controlled treatment period will continue for 12 weeks. The primary endpoint of the clinical trial is the percentage change in A4 from baseline to week 12. Following the placebo-controlled treatment period, all patients will receive tildacerfont following a dose-escalation protocol that allows dose increase to 200mg once daily over 12 weeks. Following the 12-week dose-escalation period, all patients will continue receiving tildacerfont at 200mg once daily for an additional 46 weeks. Patients who achieve control of A4 while on supraphysiologic glucocorticoid treatment will have the opportunity to reduce their glucocorticoid dosing in the open-label period according to a pre-specified algorithm in the protocol. For more information about the CAHmelia program, please visit . About CAHmelia-204 CAHmelia-204 is a randomized, double-blind, placebo-controlled Phase 2b clinical trial to evaluate the safety and efficacy of tildacerfont in reducing glucocorticoid usage in 100 adults with classic CAH on supraphysiologic doses of glucocorticoids with normal or near normal levels of A4 at baseline. This clinical trial is designed in two parts. In the first part of the clinical trial, patients will be randomized to receive 200mg tildacerfont once daily or placebo for 24 weeks. During the second part of the clinical trial, all patients will receive open-label 200mg tildacerfont once daily for 52 weeks. Throughout the trial, tapering of glucocorticoids will be guided according to a pre-specified algorithm and continue to the lowest level possible (physiologic replacement levels), as long as patients remain well controlled based on standard biomarkers and clinical assessments. The primary endpoint of this clinical trial is the absolute change in daily glucocorticoid dose in HCe from baseline at week 24. For more information about the CAHmelia program, please visit . About Congenital Adrenal Hyperplasia (CAH) CAH is an autosomal recessive disease, driven by a mutation in the gene that encodes an enzyme necessary for the synthesis of key adrenal hormones. In CAH patients, the body is not able to produce cortisol, leading to serious health consequences. The absence of cortisol alters the normal feedback cycle of the hypothalamic-pituitary-adrenal (HPA) axis and leads to excess secretion of adrenocorticotropic hormone (ACTH), hyperplasia of the adrenal gland, and consequently high levels of adrenal androgen production. As a result, CAH patients suffer from premature puberty, impaired fertility, hirsutism, acne, the development of adrenal rest tumors, and an impaired quality of life, and additionally for females, virilized genitalia and menstrual irregularities. Currently, the only way to downregulate the production of excess androgens in CAH patients is to administer supraphysiologic doses of glucocorticoids, which present specific side effects, including increased risks of developing diabetes, cardiovascular disease, stunted growth, osteoporosis, thin skin, gastrointestinal disorders, and decreased lifespan. About Tildacerfont Tildacerfont is a potent and highly selective, non-steroidal, once-daily oral antagonist of the CRF1 receptor, which is the receptor for corticotropin-releasing factor (CRF), a hormone that is secreted by the hypothalamus. The CRF1 receptor is abundantly expressed in the pituitary gland where it is the primary regulator of the HPA axis. By blocking the CRF1 receptor, tildacerfont has the potential to address the uncontrolled cortisol feedback regulatory pathway in CAH, and in turn reduce the production of ACTH in the pituitary, limiting the amount of androgen produced downstream from the adrenal gland. By controlling excess adrenal androgens through an independent mechanism, tildacerfont has the potential to reduce the unwanted clinical symptoms associated with high androgen exposure and could also enable treating physicians to lower the supraphysiologic glucocorticoid doses given to CAH patients to near physiologic levels. Tildacerfont has been evaluated in over 200 subjects across nine completed clinical trials in which it has been generally well tolerated. No drug-related serious adverse events have been reported related to tildacerfont treatment in completed studies. About Spruce Biosciences Spruce Biosciences is a late-stage biopharmaceutical company focused on developing and commercializing novel therapies for rare endocrine disorders with significant unmet medical need. Spruce is initially developing its wholly-owned product candidate, tildacerfont, as the potential first non-steroidal, once-daily therapy for patients suffering from classic congenital adrenal hyperplasia (CAH) and other endocrine disorders. To learn more, visit and follow us on X, LinkedIn, Facebook, and YouTube. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the results, conduct, progress and timing of Spruce’s clinical trials; Spruce’s expectations regarding reporting results of its clinical trials in 2024; and Spruce’s plans to meet with the FDA and comparable foreign regulatory authorities to discuss the potential registrational path forward of tildacerfont for adult classic CAH. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “anticipate”, “will”, “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Spruce’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Spruce’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Spruce’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Spruce undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.