FDA Lifts Clinical Hold on LogicBio’s Trial in Pediatric Patients with Methylmalonic Acidemia
May 9, 2022
Rare Daily Staff
The U.S. Food and Drug Administration has lifted the clinical hold on LogicBio Therapeutics’ LB-001 Investigational New Drug Application (IND), allowing patient enrollment to resume in the phase 1/2 SUNRISE trial for pediatric patients with methylmalonic acidemia.
In its letter, the FDA acknowledged that the company satisfactorily addressed all clinical hold issues. The company has initiated activities to resume dosing as soon as possible.
“We are pleased that the FDA has completed its review of the information we provided and that the hold on our LB-001 IND has been lifted,” said Frederic Chereau, president and CEO of LogicBio. “We look forward to dosing the next patient in our SUNRISE trial, which we expect will occur in the third quarter of 2022.”
Methylmalonic acidemia (MMA) is a rare and life-threatening genetic disorder affecting approximately 1 in 50,000 newborns in the United States. In the most common form of MMA, a mutation in a gene called methylmalonyl-CoA mutase (MMUT) prevents the body from properly processing certain fats and proteins. As a result, toxic metabolites accumulate in the liver, in muscle tissue and in the brain. Symptoms include vomiting, lethargy, seizures, developmental delays and organ damage. There is no approved medical therapy addressing the underlying cause of the disease. To manage the symptoms, patients go on a severely restrictive, low-protein, high-calorie diet, often through a feeding tube. Even with aggressive management, these patients often experience life-threatening metabolic crises that can require recurrent hospitalizations and cause permanent neurocognitive damage. Because of this risk for irreversible damage, early intervention is critical, and newborns are screened for MMA in every state in the United States.
LB-001 is an investigational, first-in-class, single-administration, genome editing therapy for early intervention in methylmalonic acidemia (MMA) using LogicBio’s proprietary GeneRide drug development platform, which utilizes a natural DNA repair process called homologous recombination that enables precise editing of the genome without the need for exogenous nucleases and promoters that have been associated with an increased risk of immune response and cancer. LB-001 is designed to non-disruptively insert a corrective copy of the methylmalonyl-CoA mutase (MMUT) gene into the albumin locus to drive lifelong therapeutic levels of MMUT expression in the liver, the main site of MMUT expression and activity. LB-001 is delivered to hepatocytes intravenously via liver-targeted, engineered recombinant adeno-associated virus vector (rAAV-LK03).
Preclinical studies found that LB-001 was safe and demonstrated transduction of hepatocytes, site-specific genomic integration, and transgene expression. LB-001–corrected hepatocytes in a mouse model of MMA demonstrated preferential survival and expansion (selective advantage), thus contributing to a progressive increase in hepatic MMUT expression over time. LB-001 resulted in improved growth, metabolic stability, and survival in MMA mice. The U.S. Food and Drug Administration (FDA) granted fast track designation, rare pediatric disease designation and orphan drug designation for LB-001 for the treatment of MMA. In addition, the European Medicines Agency (EMA) granted orphan drug designation for LB-001 for the treatment of MMA.
As previously disclosed, the FDA placed the IND for LB-001 on clinical hold following the occurrence of two serious adverse events, categorized as cases of thrombotic microangiopathy (TMA), in the company’s SUNRISE trial. Both cases of TMA resolved within weeks.
In connection with the lifting of the clinical hold, LogicBio amended the SUNRISE protocol in a manner that reflected its dialogue with the FDA. LogicBio expects to proceed with dosing after it implements the changes to the SUNRISE protocol, which include enhanced monitoring measures, such as frequent testing for complement activation, a characteristic of TMA, as well as the use of a complement inhibitor in the event there are laboratory findings indicating a potential TMA. LogicBio plans to treat the next patients, who may be as young as six months old, at the 5e13 vg/kg dose and continually assess safety outcomes.
Following the lifting of the clinical hold, the company announced that it is reinstating its previous guidance and expects to present interim clinical data from the SUNRISE trial by the end of the second quarter of 2022.
Photo: Frederic Chereau, president and CEO of LogicBio Therapeutics
Sign up for updates straight to your inbox.