A phase 3 study evaluating the efficacy and safety of crinecerfont in adults with classic congenital adrenal hyperplasia (CAH) met its primary and key secondary endpoints.

In 95% of cases, patients with CAH have a mutation that causes severe deficiency of the 21-hydroxylase (21-OHD) enzyme. This results in the inability of the adrenal glands to produce cortisol, and in a majority of cases, aldosterone. Crinecerfont an oral, selective corticotropin-releasing factor type 1 receptor antagonist, is expected to decrease the production of adrenal androgens and potentially improve the symptoms of classic CAH, allowing for lower doses of glucocorticoids, the current standard of care.

The CAHtalyst study (ClinicalTrials.gov Identifier: NCT04490915) included 182 adult patients with CAH due to 21-OHD who were on a stable regimen of steroidal treatment. Study participants were randomly assigned to receive either crinecerfont or placebo orally twice daily for 24 weeks, followed by active treatment with crinecerfont for at least 1 year.

Findings showed a statistically significant reduction in daily glucocorticoid dose at week 24 (primary endpoint) in patients treated with crinecerfont compared with placebo (P <.0001). Crinecerfont treatment also resulted in a statistically significant decrease in androstenedione at week 4 vs placebo (P <.0001). Moreover, a greater percentage of patients treated with crinecerfont achieved a glucocorticoid daily dose to physiologic levels at week 24 (~63% vs 18% for placebo; P <.0001). The most common adverse events reported during the trial were fatigue, headache, and coronavirus infection.

“For physicians, the current treatment paradigm is problematic, relying on glucocorticoids for a dual purpose: not only to address the underlying cortisol deficiency but typically at supraphysiologic doses to treat androgen excess resulting in well-known complications over the long-term,” said Eiry Roberts, MD, Chief Medical Officer at Neurocrine Biosciences. “The CAHtalyst phase 3 adult data bring us one step closer to a new approach to treating CAH with a therapy that has demonstrated the ability to substantially reduce glucocorticoid doses while maintaining or improving androgen control.”

Additional information from the CAHtalyst adult trial will be presented at a future medical meeting. Data from the phase 3 CAHtalyst pediatric study (ClinicalTrials.gov Identifier: NCT04806451) are expected in the fourth quarter 2023.

Tesamorelin is a growth hormone-releasing factor analog that is used to treat excess abdominal fat in adults with HIV who have lipodystrophy. The product was originally approved under the brand name Egrifta^®. The F8 formulation is 8 times more concentrated than Egrifta and 2 times more concentrated than the current F4 formulation, Egrifta SV^®. 

The F8 presentation of tesamorelin is intended to replace Egrifta SV, enabling a smaller volume of administration and simplified dosing. The sBLA is supported by pharmacokinetic studies that show bioequivalence between the F8 formulation and the F1 formulation. 

In the CRL, the FDA requested clarifications related to the chemistry, manufacturing and controls concerning the microbiology, assays, impurities and stability of both the lyophilized F8 product and the reconstituted drug. Questions regarding the potential impact of the F8 formulation on immunogenicity risk were also raised.

“While we are disappointed to receive a Complete Response Letter from the FDA for the F8 formulation of tesamorelin containing questions that were not raised during the review process, we plan to address these new comments as swiftly as possible,” said Christian Marsolais, PhD, Senior Vice President and Chief Medical Officer at Theratechnologies. “We remain focused on bringing this new formulation of tesamorelin to market as part of our commitment to innovate and simplify treatments for people with HIV.”

Egrifta SV continues to be commercially available in the US.

This month’s case focuses on how a physician handled continuing a patient’s medication after she was released from a hospital stay. It’s a reminder that when a Boxed Warning is involved, extra care should be taken when prescribing that particular medication.

Just the Facts

The patient, Ms B, 73, had been seeing a rheumatologist since the early 2000’s, and had been diagnosed with rheumatoid arthritis. As of 2016, Ms B was taking the corticosteroid prednisone to compensate for the effects of a pituitary tumor that had caused adrenal insufficiency.

Starting in 2012, Ms B began seeing an internist, Dr R. Over the next 4 years, Dr R treated the patient for a variety of issues, including an earache, cat bite, cough, pre-operative clearance for hand surgery, and hip pain.

In late November 2016, Ms B contacted Dr R with complaints of high fever, weakness, and difficulty moving. The physician recommended that she go to a hospital emergency department, which she did. The emergency department physician diagnosed the patient with severe community-acquired pneumonia, sepsis secondary to pneumonia, and effusion. The hospital physician consulted with an intensive care unit physician and pulmonologist who recommended treating the patient with levofloxacin.

Ms B was admitted to the hospital as an inpatient for 5 days, with Dr R listed as the admitting physician. During this time, the patient was administered 750mg of levofloxacin every 48 hours for 5 days, and continued on her existing medications, including prednisone. Dr R examined Ms B in the hospital between November 24 and November 26, 2016.

The hospital physicians adjusted Ms B’s prednisone dose after noting findings consistent with an inflammatory response to poorly controlled rheumatoid arthritis. The plaintiff’s arthritis was improved after that, and she was discharged from the hospital on November 28, 2016, in stable condition, with a prescription for prednisone, and instructions to follow up with Dr R, her internist.

She saw Dr R the day after she was discharged, November 29, and he provided her with a continuation prescription for levofloxacin, one 750mg tablet every 48 hours for 6 days. She filled the prescription and took the medication. Within a month, Ms B suffered from an acute rupture of the gluteus medius tendon, requiring her to undergo 2 major surgeries leaving her unable to walk without assistance, and suffering from numerous disabilities.

Tendon rupture is a known risk of fluoroquinolones such as levofloxacin, and the risk is increased in patients over the age of 60 and in those taking corticosteroids, such as prednisone. This information has been the subject of a Boxed Warning which was added to the dispensing information in 2008.