FDA clears Pombiliti plus Opfolda to treat adults with LOPD
Amicus Therapeutics' 2-component therapy will be option for eligible patients
Pombiliti (cipaglucosidase alfa) plus Opfolda (miglustat), a combination therapy formerly known as AT-GAA, has been approved by the U.S. Food and Drug Administration (FDA) to treat certain adults with late-onset Pompe disease (LOPD) who are not improving on their current enzyme replacement therapy (ERT).
Its developer, Amicus Therapeutics, plans to launch the therapy immediately in the U.S.
“Today’s FDA approval of Pombiliti and Opfolda is a testament to the power of science, medicine, and our passionate determination to improve the lives of people living with Pompe disease,” John F. Crowley, executive chairman of Amicus, said in a press release.
“This approval … is a very meaningful step for the Pompe community,” Crowley added.
The decision follows similar ones earlier this year by authorities in the U.K. and European Union, where Pombiliti plus Opfolda is approved for adults with LOPD.
Amicus will offer a patient and caregiver support program called Amicus Assist that can help with medication access and in identifying sources of financial assistance. The therapy is expected to cost about $650,000 a year.
“We look forward to rapidly bringing this new treatment regimen to all eligible adults living with late-onset Pompe disease who are not improving on their current ERT,” said Bradley Campbell, Amicus’ president and CEO.
How the two-component therapy works
Pombiliti, given as intravenous, or into-the-vein, infusions, is an ERT designed to deliver Pompe patients with a lab-made version of acid alpha-glucosidase (GAA), the enzyme they lack, particularly in muscle cells. Miglustat, an oral therapy, is a chaperone protein that stabilizes the enzyme so it stays active in the body longer.
Infusions of Pombiliti are indicated at a dose of 20 mg/kg once every two weeks. Opfolda should be taken about an hour before each Pombiliti infusion at a dose of 260 mg for patients weighing 50 kg or more (about 110 pounds), or 195 mg for patients weighing 40-49 kg. The therapy duo is indicated only for patients weighing at least 40 kg (about 88 pounds).
Amicus initiated a rolling application with the FDA late in 2o2o. Nearly a year later, in October 2021, Amicus announced it had completed applications covering each component of the therapy — a biologics license application for Pombiliti and a new drug application for Opfolda.
While decisions initially were expected last year, delays in facility inspections due to the COVID-19 pandemic pushed back the review.
Approval based on multiple study findings
Approvals for each therapy component were supported partly by findings from the Phase 3 PROPEL (NCT03729362) trial, along with data from its ongoing extension study (NCT04138277).
PROPEL compared the safety and effectiveness of AT-GAA against alglucosidase alfa (marketed as Lumizyme in U.S., and Myozyme elsewhere), Sanofi’s approved ERT for Pompe, in 123 adults at 62 sites worldwide.
Data showed that Pombiliti plus Opfolda outperformed alglucosidase alfa at increasing the distance walked in six minutes, a test of motor abilities and the study’s main goal. But this finding only reached statistical significance in the subgroup of patients on this ERT before the trial’s start. A significantly smaller decline in lung function also was reported for patients on Pombiliti plus Opfolda.
AT-GAA tended to outperform the ERT in other measures, including those of strength, coordination, mobility, and biomarkers of muscle damage and glycogen clearance, but not all measures produced statistically significant differences.
Data from the extension trial, which is expected to finish this year, showed these benefits were sustained after two years of treatment.
Positive findings from the ongoing Phase 1/2 ATB200-02 trial (NCT02675465), the first in-human trial, also backed the therapy’s clearance.
“This two-component therapy is an important new treatment for those adults living with late-onset Pompe disease and not improving on current therapies,” said Tahseen Mozaffar, MD, of the University of California Irvine and PROPEL study investigator. “I am encouraged by the evidence generated over many years of clinical research studying this therapy for ERT-experienced patients living with late-onset Pompe disease.”
Side effects and warnings for Pombiliti plus Opfolda
Common side effects associated with Pombiliti or Opfolda include headache, diarrhea, fatigue, nausea, abdominal pain, and fever.
Pombiliti comes with a boxed warning of severe allergic reactions, infusion-related reactions, and a risk of acute cardiorespiratory failure for patients with underlying vulnerabilities.
The therapy combination is contraindicated for use during pregnancy, as it may cause harm to a developing fetus.
“The FDA approval of Pombiliti and Opfolda represents a long-awaited day for people living with late-onset Pompe disease and advocating for additional therapeutic options,” said Tiffany House, president of the Acid Maltase Deficiency Association.
Two ongoing, yearlong Phase 3 studies are evaluating Pombiliti plus Opfolda in children with Pompe. Each is recruiting up to 22 eligible patients, infants to age 17.
The ZIP study (NCT03911505) in children with LOPD is recruiting at sites in the U.S., Canada, Japan, Taiwan, and Australia. The ROSSELLA study (NCT04808505) is assessing patients with infantile-onset disease, and it is enrolling at three U.S. sites.
“We are grateful to the Pompe community, particularly the patients, caregivers, families, researchers, and physicians who have contributed to the development process through their commitment to our clinical studies,” Campbell said.
For more information, Amicus has set up a website for Pombiliti plus Opfolda, as well as a site for healthcare professionals.
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