Tiana Tran, PharmD

On August 31, 2022, the FDA approved olipudase alfa-rpcp (Xenpozyme) for intravenous (IV) infusion in pediatric and adult patients with acid sphingomyelinase deficiency (ASMD),

 a rare genetic disease that causes premature death due to the accumulation of a complex lipid called sphingomyelin. Olipudase alfa-rpcp is an enzyme replacement therapy and provides an exogenous source of ASM. It is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD. Olipudase alfa-rpcp received fast track, breakthrough therapy, priority review, and orphan drug designations from the FDA.

Investigators evaluated the efficacy of olipudase alfa-rpcp across 3 clinical trials. The first, ASCEND (NCT02004691), a multicenter, randomized, double-blinded, placebo-controlled, repeat-dose phase 2/3 study, evaluated adults with ASMD in 2 groups: a treatment group, receiving olipudase alfa-rpcp for 104 weeks (n = 13), and the placebo group (n = 18). At week 52, patients in the placebo group crossed over to receive olipudase alfa-rpcp treatment to reach the targeted maintenance dose of 3 mg/kg.

By week 104, patients who were initially in the placebo group had received olipudase alfa-rpcp for 52 weeks and demonstrated the following mean changes from baseline: predicted diffusion capacity of the lungs for carbon monoxide (DLco) increased by 26.8%; spleen volume reduced by 36.5%; liver volume reduced by 29.5%; and platelet count increased by 19.5%.

Patients in the previous olipudase alfa-rpcp group demonstrated improvement from baseline in the following parameters: predicted DLco increased by 34.1%; spleen volume reduced by 48.3%; liver volume reduced by 31.7%; and platelet count increased by 24%.

Trial 2, ASCEND-Peds (NCT02292654), enrolled 8 pediatric patients who received an IV infusion of olipudase alfa every 2 weeks over a 64-week period. During a 6-month extension study (Trial 3; NCT02004704), efficacy analyses showed continued improvements in the 3 patients evaluated for percent predicted DLco, the 6 patients evaluated for platelet counts, and all 8 patients evaluated for spleen and liver volumes, compared with baseline.

Two pediatric patients reported a serious adverse event (anaphylactic reaction). The most frequently reported adverse drug reactions in adults were headache, cough, diarrhea, hypotension, and ocular hyperemia. In pediatric patients, these reactions included pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis.

Treatment-related serious adverse events, hypersensitivity reactions including anaphylaxis, and infusion-associated reactions occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than adult patients.

Olipudase alfa-rpcp is administered via IV infusion every 2 weeks for adult and pediatric patients. In adults, the recommended starting dose is 0.1 mg/kg on day 1/week 0. The recommended maintenance dose is 3 mg/kg every 2 weeks. The dose escalation regimen is as follows: 0.3 mg/kg at week 2 and week 4; 0.6 mg/kg at week 6 and week 8; 1 mg/kg at week 10; 2 mg/kg at week 12; and 3 mg/kg at week 14 and thereafter.

In pediatric patients, the recommended starting dose is 0.03 mg/kg on day 1/week 0. The recommended maintenance dose is 3 mg/kg every 2 weeks. The dose escalation regimen is as follows: 0.1 mg/kg at week 2; 0.3 mg/kg at week 4 and week 6; 0.6 mg/kg at week 8 and week 10; 1 mg/kg at week 12; 2 mg/kg at week 14; and 3 mg/kg at week 16 and thereafter.

Reconstituted olipudase alfa-rpcp vials not used immediately and diluted solutions not to be administered immediately should be refrigerated at 2 to 8 °C (36-46 °F) for up to 24 hours, or at room temperature at 20 to 25 °C (68-77 °F) for up to 12 hours.

FDA approves first treatment for acid sphingomyelinase deficiency, a rare genetic disease. News release. FDA. August 31, 2022. Accessed October 2, 2022. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-acid-sphingomyelinase-deficiency-rare-genetic-disease

Xenpozyme. Prescribing information. Genzyme; 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761261s000lbl.pdf

Articles

Acid sphingomyelinase deficiency is a rare, progressive genetic disease associated with significant morbidity and mortality.

FDA Approves Olipudase Alfa-rpcp for Acid Sphingomyelinase Deficiency

On January 7, 2022, the FDA approved daridorexant (Quviviq) for the treatment of adults with insomnia.

 The approval was based on findings from a phase 3 clinical trial program in which the drug successfully demonstrated significant improvement in sleep onset, sleep maintenance, and patient- reported total sleep time.

Two multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trials (study 1, NCT03545191; study 2, NCT03575104) evaluated efficacy. Investigators randomly assigned 1854 patients to receive daridorexant or placebo once in the evening for 3 months. Study 1 included 930 participants who received daridorexant 50 mg, 25 mg, or placebo (n = 310 for all). Study 2 participants received daridorexant 25 mg, 10 mg, or placebo (n = 309, 307, and 308, respectively).

The primary efficacy end point was change from baseline in latency to persistent sleep (LPS)

and wake after sleep onset (WASO), measured by polysomnography at months 1 and 3. Secondary end points included patient-reported subjective total sleep time (sTST), recorded using a validated sleep diary questionnaire.

At months 1 and 3, study 1 participants who received 25 mg or 50 mg demonstrated statistically significant improvements in LPS, WASO, and sTST; study 2 results showed that 25 mg led to a statistically significant improvement vs placebo in WASO and sTST. No statistically significant improvement was noted in the 10 mg group.

The safety profile of daridorexant was established through 3 placebo-controlled studies: study 1, study 2, and a phase 3, 9-month extension study of eligible patients from the first 2 studies (NCT03679884). In the extension study, 804 participants were randomly assigned to receive daridorexant 50 mg, 25 mg, or 10 mg; placebo; or daridorexant 25 mg/ex-placebo.

The most common adverse events in the 25-mg, 50-mg, and placebo groups, respectively, were headache (6%, 7%, 5%), somnolence/fatigue (6%, 5%, 4%), dizziness (2%, 3%, 2%), and nausea (0%, 3%, 2%). Rare occurrences of sleep paralysis were reported in the 25-mg and 50-mg groups, and hypnagogic/hypnopompic hallucinations were reported in the 25-mg group.

A randomized, double-blind, placebo- and active-controlled 4-way crossover study assessed the next-day effects of the medication on driving after doses of 50 mg and 100 mg. The difference in performance after the first dose, measured by change in standard deviation of lateral position, was significant compared with placebo for both dose groups. However, the mean effect after 4 days of treatment was not significant. Patients should be cautioned about next-day driving impairment when initiating treatment.

The use of daridorexant is contraindicated in patients with severe hepatic impairment; a maximum daily dose of 25 mg is recommended in those with moderate impairment. Concomitant use with strong CYP3A4 inhibitors should be avoided. Concomitant use with moderate inhibitors of CYP3A4 may be considered, but the maximum daily dose should not exceed 25 mg.

Daridorexant is a schedule IV medication with potential for abuse due to its central nervous system depressant effects.

Daridorexant is for the treatment of adult patients with insomnia and is supplied as an arc triangle–shaped, film-coated oral tablet. The recommended dosage range is 25 mg to 50 mg taken by mouth, no more than once per night within 30 minutes of going to bed. There should be at least 7 hours remaining prior to planned awakening. Time to sleep onset may be delayed if daridorexant is taken with or soon after a meal.

1. QUVIVIQ [package insert]. Radnor, PA. Idorsia Pharmaceuticals US Inc. January 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf

2. Idorsia receives US FDA approval of QUVIVIQ (daridorexant) 25 and 50 mg for the treatment of adults with insomnia. News release. Idorsia. January 10, 2022. Accessed May 11, 2022. 

https://www.idorsia.com/media/news-details?newsId=2665386

Daridorexant demonstrated significant reduction in daytime sleepiness among
other measures.