Eiger is a late-stage clinical biopharmaceutical company dedicated to developing and commercializing a series of targeted and pioneering therapies for the treatment of severe rare and ultra-rare diseases. Recently, the company announced that the US Food and Drug Administration (FDA) has accepted Zokinvy (lonafarnib) New Drug Application (NDA). The NDA seeks accelerated approval of Zokinvy for the treatment of Progeria (Progeria, also known as: Hutchinson-Guilford Progeria Syndrome, HGPS) and Progeroid Laminopathies (Progeroid Laminopathies). The FDA has granted Zokinvy NDA priority review, and has designated a prescription drug user fee method (PDUFA) target date of November 20, 2020. The FDA has notified Eiger that it does not intend to convene an advisory committee meeting to discuss NDA.
If approved, Zokinvy will become the world's first drug to treat premature aging. Currently, Zokinvy is also undergoing accelerated evaluation by the European Medicines Agency (EMA). Previously, Zokinvy has been granted orphan drug qualification (ODD) for the treatment of premature aging and premature aging-like laminopathy by the US FDA and EU EMA, breakthrough drug qualification (BTD) and rare pediatric disease qualification (RPDD) by the FDA.
Premature aging is an extremely rare and fatal disease that can cause premature aging in children. Without treatment, children with premature aging will die of heart disease, with an average age of 14.5 years. Currently, there is no approved treatment for premature aging and premature aging-like laminopathy.
Zokinvy's active pharmaceutical ingredient is lonafarnib, a pioneer, oral farnesyl transferase inhibitor (FTI) that has been shown to prolong survival in children with premature aging and young adult patients. A study published in the Journal of the American Medical Association (JAMA) in 2018 showed that in patients with premature aging, lonafarnib monotherapy reduced the risk of death by 88%, and the most common adverse reactions reported were gastrointestinal symptoms. Many premature aging patients have been receiving lonafarnib for more than 10 years.
Eiger has also established a global management access plan, which is expected to cover more than 40 countries to ensure that all children and young people with premature aging and premature aging-like laminopathy can receive treatment.
David Cory, President and CEO of Eiger, said: "The acceptance of our first NDA by the FDA is an important milestone for Eiger, and it is also a treatment for patients with progressive premature aging and progressive premature aging-like laminopathy. Children and young people have taken an important step. We want to thank the Premature Aging Research Foundation (PRF) for their commitment, perseverance and dedication. Most importantly, we thank all children and their families with premature aging who have participated The lonafarnib clinical trial makes this possible. We are preparing for the commercial launch of Zokinvy in the US and Europe. "
Leslie Gordon, PRF Medical Director, MD, said: "This milestone is the culmination of 12 years of clinical trials that have treated children with premature aging and premature aging-like laminopathy from more than 30 countries and six continents. We are very fortunate to be Eiger ’s partners in the NDA preparation and submission, and to provide continuous Zokinvy supply for children and young people with premature aging. We thank all children and their families with premature aging. Their courage inspires We are every day. "
Molecular structure of lonafarnib (Image source: Wikipedia)
Premature aging (HGPS) is a rare, fatal genetic disease that accelerates aging in children. The disease is caused by a point mutation in the LMNA gene encoding lamin A, which produces a farnesylation-prone, toxic progerin. Lamin A is a part of the nuclear structure scaffold and plays an important role in the nuclear structure and function. Children with premature aging will die from the same disease that affects millions of normal aging adults-arteriosclerosis, but the average age at which the child dies is 14.5 years. The symptoms of premature aging include severe hypoplasia, scleroderma-like skin, systemic malnutrition, hair loss, joint contracture, skeletal dysplasia, accelerated systemic atherosclerosis, decreased cardiovascular function and stroke. It is estimated that there are about 400 children with premature aging worldwide.
Progeroid-like laminopathy (progeroid laminopathies) is the inheritance of accelerated aging caused by a series of mutations in the lamin A and / or Zmpste24 gene, these mutations produce farnesylation that is different from the premature aging protein protein. Although no premature aging protein is produced, mutations in these genes can cause overlapping but distinct disease manifestations with premature aging protein. Overall, the prevalence of premature aging-like laminopathy may be higher than premature aging globally.
lonafarnib is licensed by Eiger from Merck. The drug is a distinctive, late-development stage, orally active inhibitor targeting farnesyl transferase. The process of diene is involved in the modification of proteins. Premature aging protein is an abnormal protein that is farnesylated and is thought to be uncleavable, resulting in tight binding to the nuclear membrane, resulting in changes in nuclear membrane morphology and subsequent cell damage.
lonafarnib blocks the farnesylation of premature aging protein. In the Phase I / II and Phase II studies funded by the Boston Children's Hospital Progeria Research Foundation (www.Progeria Research.org), more than 90 patients with premature aging The child was treated. The results of the two studies showed that after 2.2 years of follow-up, compared with untreated children with premature aging, lonafarnib monotherapy had a lower mortality rate of children with premature aging (3.7% vs 33.3%; HR = 0.12) and reduced risk of death 88%.
In addition to treating premature aging and premature aging-like laminopathy, Eiger is also developing lonafarnib to treat hepatitis D virus (HDV) infection. At the end of December 2018, FDA and EMA granted lonafarnib the breakthrough drug qualification (BTD) and priority drug qualification (PRIME) for the treatment of hepatitis D virus infection (HDV). Lonafarnib can inhibit the isoprene step of HDV replication in liver cells, blocking the virus life cycle during the virus assembly stage.
Data from multiple phase II clinical studies confirm the efficacy and safety of the lonafarnib-based regimen for the treatment of HDV-infected patients. The data show that the lonafarnib-based regimen has achieved The combined primary endpoint of HDV RNA levels ≥2 log10 and normalization of alanine aminotransferase (ALT) reflects the improvement of liver status and virological response. Currently, the drug is in a critical phase III clinical study of HDV.
Hepatitis D is caused by HDV infection and is the most serious type of human viral hepatitis. Hepatitis D only occurs as a co-infection in individuals who carry the hepatitis B virus (HBV), causing more serious liver disease than hepatitis B, and it can accelerate liver fibrosis, liver cancer, and liver failure. Hepatitis D is a disease that seriously affects human health worldwide, and the disease may affect approximately 15-20 million people worldwide. The prevalence of hepatitis D varies in different regions of the world. According to reports, worldwide, approximately 4.3% -5.7% of chronic hepatitis B virus carriers have HDV infection. In some regions, including Outer Mongolia, China, Russia, Central Asia, Pakistan, Turkey, Africa, Middle East and South America, the prevalence of HDV among chronic HBV-infected persons is even higher. According to reports, Mongolia and Pakistan ’s The prevalence of HDV among people with HBV infection is as high as 60%.