The Food and Drug Administration (FDA) has granted Fast Track designation to AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy is a rare, genetic muscle disorder caused by an abnormal expression of DUX4 (double homeobox 4) leading to skeletal muscle wasting and progressive muscle function loss. AOC 1020 is designed to reduce the expression of DUX4 mRNA and DUX4 protein in muscles. The investigational treatment consists of a monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a small interfering RNA targeting DUX4 mRNA.

The Company is currently investigating AOC 1020 in the phase 1/2 FORTITUDE study in adults with facioscapulohumeral muscular dystrophy. The double-blind, placebo-controlled study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AOC 1020 administered intravenously. Though the study is not powered to assess functional benefit, assessments of efficacy will be made using key biomarkers, including magnetic resonance imaging measures of muscle volume and composition. Mobility, muscle strength, patient reported outcomes, and quality of life measures will also be analyzed.

“The FDA Fast Track designation for AOC 1020 reinforces the importance of finding an effective treatment to help people living with FSHD, a devastating and debilitating muscular dystrophy disorder with no treatment options,” said Steve Hughes, MD, chief medical officer at Avidity. “AOC 1020 is designed to directly target the disease-causing gene, DUX4, to address the underlying cause of FSHD. We look forward to working collaboratively with the FDA to bring the first RNA therapy directly targeting DUX4 to patients as quickly as possible.”

Reference

Avidity Biosciences granted FDA Fast Track designation for AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy. News release. Avidity Biosciences. Accessed January 18, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-granted-fda-fast-track-designation-for-aoc-1020-for-the-treatment-of-facioscapulohumeral-muscular-dystrophy-301724062.html.

The Food and Drug Administration (FDA) has accepted the supplemental New Drug Application (sNDA) for vosoritide for the treatment of children less than 5 years of age with achondroplasia, a genetic disorder that results in disproportionate short stature and significant health complications.

The sNDA is supported by data from a double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov Identifier: NCT03583697) that evaluated the efficacy and safety of vosoritide in patients less than 5 years of age with achondroplasia. Patients were randomly assigned to receive either vosoritide subcutaneously once daily (n=43) or placebo (n=32). The primary endpoint was the change from baseline in height Z-scores at 52 weeks.

Findings showed that treatment with vosoritide increased height Z-score by 0.30 (95% CI, 0.07-0.54) and annualized growth velocity of 0.92cm/year (95% CI, 0.24-1.59). Improvement in height Z-score was found to be consistent with that seen after 1 year of treatment in patients over the age of 5. Compared with placebo, no significant treatment effect was observed on upper-to-lower body segment ratio with vosoritide.

“We are pleased that the FDA has accepted our sNDA and are working closely with the agency to facilitate completion of the review in a timely manner,” said Hank Fuchs, MD, president, Worldwide Research and Development at BioMarin. “There are currently no approved pharmacological treatments in the United States for children under 5 with achondroplasia and this approval could potentially extend access to all children with achondroplasia, whose growth plates are not closed.”

A Prescription Drug User Fee Act target date of October 21, 2023 has been set for the application.

Vosoritide, an analogue of C-type natriuretic peptide, is currently marketed under the brand name Voxzogo to increase linear growth in children 5 years of age and older with achondroplasia and open epiphyses.

References

1. FDA accepts BioMarin’s supplemental New Drug Application to expand use of Voxzogo^® (vosoritide) for injection to treat children with achondroplasia under the age of 5. News release. BioMarin Pharmaceutical. Accessed March 8, 2023. https://www.prnewswire.com/news-releases/fda-accepts-biomarins-supplemental-new-drug-application-to-expand-use-of-voxzogo-vosoritide-for-injection-to-treat-children-with-achondroplasia-under-the-age-of-5-301765021.html.
2. BioMarin announces favorable results from global phase 2 study of Voxzogo (vosoritide) for injection in infants and young children with achondroplasia at The Endocrine Society Annual Meeting, ENDO 2022 (June 11-14), in Atlanta. News release. BioMarin Pharmaceutical. June 13, 2022. Accessed March 8, 2023. https://investors.biomarin.com/2022-06-13-BioMarin-Announces-Favorable-Results-from-Global-Phase-2-Study-of-VOXZOGO-TM-vosoritide-for-Injection-in-Infants-and-Young-Children-with-Achondroplasia-at-The-Endocrine-Society-Annual-Meeting,-ENDO-2022-June-11-14-,-in-Atlanta.

The Food and Drug Administration (FDA) has approved Bylvay^® (odevixibat) for the treatment of cholestatic pruritus in patients 12 months of age and older with Alagille syndrome (ALGS).

Bylvay is an ileal bile acid transporter (IBAT) inhibitor.  Although the mechanism by which odevixibat improves pruritus in ALGS is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids.

The approval was supported by data from the phase 3 ASSERT study (ClinicalTrials.gov Identifier: NCT04674761), which included 52 patients aged 6 months to 15 years with a confirmed diagnosis of ALGS and presence of pruritus at baseline. Patients were randomly assigned to receive odevixibat 120mcg/kg (n=35) or placebo (n=17) orally once daily for 24 weeks.

Results showed that treatment with odevixibat met the primary endpoint demonstrating a statistically significant reduction in pruritus at month 6, as measured by the observer-reported outcome scratching score, compared with placebo (mean difference vs placebo, -0.9 [95% CI, -1.4, -0.3]; P =.002). The most common adverse reactions reported with treatment included diarrhea, abdominal pain, hematoma, and decreased weight.

“Physicians urgently need more options to treat patients with Alagille syndrome and this approval from the US FDA spotlights the robustness of the phase 3 ASSERT clinical study results,” said Nadia Ovchinsky, MD, Chief of the Division of Gastroenterology and Hepatology, Hassenfeld Children’s Hospital at NYU Langone and ASSERT Principal Investigator. “The ASSERT study showed that Bylvay reduced pruritus associated with ALGS, which is so common among this patient population and one of the leading indications for a liver transplant.”

Bylvay is supplied in capsules (400mcg and 1200mcg) and oral pellets (200mcg and 600mcg). The contents of the shell containing the oral pellets should be mixed with soft food or liquid; children should not swallow the unopened shells containing the oral pellets.

Bylvay is also indicated for the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis.

The findings of the PROPEL study (ClinicalTrials.gov Identifier: NCT03729362) supported the benefits of cipaglucosidase/miglustat vs enzyme replacement therapy (ERT) and placebo in the treatment of ambulatory patients with late-onset Pompe disease.

Researchers of the current open-label extension study (ClinicalTrial.gov Identifier: NCT04138277) aimed to determine the long-term safety and efficacy of cipaglucosidase/miglustat in patients with Pompe disease.

Study outcomes were 6-minute walk distance, forced vital capacity (FVC), creatine kinase, and hexose tetrasaccharide (Hex4) levels; and safety of cipaglucosidase/miglustat.

Changes from baseline in the PROPEL study to week 104 in the current study were recorded (Table).

Overall, 119 participants (91 ERT-experienced) from the PROPEL trial were enrolled in the current analysis. Of the total cohort, 82 participants continued to receive cipaglucosidase/miglustat and 39 who received placebo in the PROPEL trial were switched to cipaglucosidase/miglustat.

Table: Mean percentage changes (SD) in outcomes from the PROPEL to open-label trial.

ERT: enzyme replacement therapy; FVC: forced vital capacity

Both creatine kinase and Hex4 levels improved with cipaglucosidase/miglustat as well.

With regard to safety, 3 patients discontinued the study due to adverse reactions, including urticaria, hypotension, and anaphylaxis; however, no new safety signals were found.

Overall, the researchers concluded, “Data demonstrate treatment with cipa/mig [cipaglucosidase/miglustat] up to 104 weeks was associated with a durable effect and was well tolerated … [among] patients with LOPD [late-onset Pompe disease].”

Disclosure: This research was supported by Amicus Therapeutics, Inc.

Cystic Fibrosis Treatments

HealthDay News — For patients with erythropoietic protoporphyria or X-linked protoporphyria, dersimelagon at doses of 100 and 300mg significantly increases the duration of symptom-free sunlight exposure, according to a study published in the April 13 issue of the New England Journal of Medicine.

Manisha Balwani, MD, from the Icahn School of Medicine at Mount Sinai in New York City, and colleagues conducted a randomized phase 2 trial involving patients with erythropoietic protoporphyria or X-linked protoporphyria aged 18 to 75 years to examine the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure. A total of 102 patients were randomly assigned to receive placebo or dersimelagon at 100 or 300mg once daily for 16 weeks in a 1:1:1 ratio; 90% completed the treatment period.

The researchers observed a significant increase in the mean daily time to the first prodromal symptom associated with sunlight exposure with dersimelagon: least-squares mean difference from placebo in the change from baseline to week 16, 53.8 and 62.5 minutes in the 100- and 300mg dersimelagon groups, respectively. Patients receiving dersimelagon had improved quality of life compared with those receiving placebo. Nausea, freckles, headache, and skin hyperpigmentation were the most common adverse events that occurred or worsened during treatment.

“Results from this phase 2 trial support the effectiveness and safety of dersimelagon and its further development as a potential oral treatment option for increasing light tolerance in patients with erythropoietic protoporphyria or X-linked protoporphyria,” the authors write.

The study was funded by Mitsubishi Tanabe Pharma, the manufacturer of dersimelagon.

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