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The FDA has declined to approve CUTX-101 (copper histidinate) to treat Menkes disease in paediatric patients, Fortress Biotech and its subsidiary Cyprium Therapeutics said on Wednesday. In late 2023, Cyprium sold commercial and developmental rights for CUTX-101 to Sentynl Therapeutics, a subsidiary of Zydus Life Sciences, for $4.5 million upfront. Under the deal, Cyprium was eligible for up to $129 million in development and sales milestones, plus tiered royalties; the company will also retain a priority review voucher if issued by the FDA upon approval of CUTX-101.According to Fortress, the complete response letter (CRL) was due to current Good Manufacturing Practice (cGMP) deficiencies at the facility where CUTX-101 is manufactured. The unnamed site has provided responses to a re-inspection in September.Issues related to chemistry, manufacturing and controls are the most frequent reason for an FDA rejection, a recent FirstWord analysis found; Biogen's high-dose Spinraza was hit with a similar complaint last month. The US regulator in July posted a batch of CRLs associated with more than 200 new drug applications, and deficiencies at manufacturing facilities or subpar quality of the manufactured drug product led to a combined 60% of all rejections (see – Vital Signs: What we learned from the FDA's CRL data dump).The CRL for CUTX-101 didn't flag any issues with the efficacy or safety, and Sentynl is planning to meet with the FDA to discuss resubmitting its application for the drug.The agency had granted the initial filing a priority review in January based on data showing that CUTX-101 led to a median overall survival of 177.1 months in patients with Menkes disease, a statistically significant result compared with the 16.1 months seen for an untreated historical control cohort.

iStock, undefined undefined As with recent rejections for Biogen and Scholar Rock, manufacturing issues stymied a regulatory bid from Fortress Biotech and Sentynl Therapeutics. Fortress said the FDA did not flag problems with the drug’s safety or efficacy. The FDA has rejected Fortress Biotech and Sentynl Therapeutics’ investigational treatment for Menkes disease, a rare, genetic disorder that usually leads to death by 3 years of age. In its complete response letter, the regulator cited issues at the manufacturing facility where the drug is produced, Fortress announced Wednesday, noting that the plant in question has already responded to these observations. The FDA did not find any other deficiencies with the application, nor did it flag problems with the drug’s efficacy or safety data, according to Fortress. Manufacturing has become a recurring theme in recent FDA rejections. Biogen’s high-dose formulation for Spinraza and Scholar Rock’s apitegromab were both also rejected due to issues at a manufacturing site, as opposed to anything about the therapies themselves. Sentynl acquired the asset, called CUTX-101, in February 2021 for $20 million . The company plans to seek a meeting with the agency to discuss a resubmission. If approved, Fortress, through a subsidiary, will be entitled to up to $129 million in aggregate development and sales milestones, plus royalties on net sales. Afflicting 1 in 100,000 infants, Menkes disease is characterized by sparse and depigmented hair, seizures, intellectual disability and developmental delays. Patients with the disease also fail to gain weight or grow as expected and suffer from the deterioration of the nervous system. Menkes disease is caused by mutations to the ATP7A gene, which under healthy conditions produces a protein that helps maintain levels of copper throughout the body. Genetic alterations in Menkes disease disrupt the otherwise normal distribution of copper, resulting in deficiencies in some organs but toxic excesses in others. CUTX-101 is a subcutaneous formulation of copper histidinate, which in an October 2021 readout reduced the risk of death by 80% in treated patients as compared with untreated historical controls. The midstage trial also found that early intervention with CUTX-101 resulted in a median overall survival of 177.1 months, versus 16.1 months in controls. The FDA in January 2020 gave CUTX-101 its rare pediatric disease designation. If approved, the drug could receive a priority review voucher, which Sentynl has agreed to transfer to Fortress. The rare disease space has seen a rush of activity in recent months. FDA Commissioner Marty Makary has publicly said multiple times that his office is open to granting expedited approval for drugs in this space, but drugmakers are still being hit with surprise rejections. In July, for instance, Capricor’s Duchenne muscular dystrophy drug was turned away , and Ultragenyx was handed a denial in Sanfilippo syndrome type A. The following month, however, the FDA signed off on four industry firsts in the rare disease space: Jazz Pharmaceuticals’ Modeyso for Glioma, Insmed’s Brinsupri for non-cystic fibrosis bronchiectasis, Precigen’s Papzimeos for recurrent respiratory papillomatosis and Ionis’ Dawnzera for hereditary angioedema.