Zokinvy™ for Progeria and
Progeroid Laminopathies

Stage
PDUFA Date November 2020
MAA Filed
Disease
Progeria and Progeroid Laminopathies
Prevalance
1 in 20 million (Progeria)
1 in 36 million (Progeroid Laminopathies)
Mechanism of Action
Prenylation Inhibitor
Regulatory Designations
  • Orphan in US and EU
  • Breakthrough Therapy in US
  • Rare Pediatric Disease in US
About Progeria

Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria) and Progeroid Laminopathies

Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is an ultra-rare and rapidly fatal genetic condition of accelerated aging in children. Progeria is caused by a point mutation in the LMNA gene, encoding the lamin A protein, yielding the farnesylated aberrant protein, progerin. Lamin A protein is part of the structural scaffolding that holds the nucleus together. Researchers now believe that progerin may make the nucleus unstable, and that cellular instability may lead to the process of premature aging in Progeria.

Untreated children with Progeria have a life expectancy of 14 years

Disease manifestations include severe failure to thrive, scleroderma-like skin, global lipodystrophy, alopecia, joint contractures, skeletal dysplasia, global accelerated atherosclerosis with cardiovascular decline, and debilitating strokes. It is estimated that 1 in 20 million individuals have Progeria with approximately 400 cases worldwide.

Progeroid Laminopathies are genetic conditions of accelerated aging caused by a constellation of mutations in the lamin A and/or ZMPSTE24 genes yielding farnesylated proteins that are distinct from progerin. While non-progerin producing, these genetic mutations result in disease manifestations with phenotypes that have overlap with, but are distinct from Progeria. It is estimated that 1 in 36 million individuals have a Progeroid Laminopathy.

Zokinvy

Zokinvy™ (lonafarnib) is a well characterized inhibitor of farnesyltransferase, an enzyme involved in modification of proteins through a process called prenylation

Zokinvy blocks the farnesylation of the aberrant protein, progerin, and has been dosed in over 80 children with Progeria in Phase 1/2 and Phase 2 studies. Zokinvy is generally well tolerated. Most commonly reported adverse events to date are diarrhea and nausea. Side effects can be well managed with prophylactic treatment with antidiarrheals and antiemetics. Longest duration of dosing is > 10 years.

ZOKINVY™ (lonafarnib) Blocks the Production of Progerin; Progerin Causes Progeria

Zokinvy Blocks

172 children with Progeria or Progeroid Laminopathies have been identified worldwide

  • 43 patients identified reside in either the US or EU with Progeria or Progeroid Laminopathies
  • Estimated 400 cases worldwide
  • Approximately 90 children have been treated with Zokinvy™ (lonafarnib) in Phase 2
  • Zokinvy has been dosed in children with Progeria for > 10 years
World Map PRF By The Numbers. Progeria Research Foundation; 2020.

Zokinvy™ (lonafarnib) clinical studies in Progeria

Zokinvy has been dosed in more than 90 children with Progeria in 5 Phase 1/2 and Phase 2 studies.

Lonafarnib treatment vs no treatment with mortality rate in children with Progeria

An observational cohort study assessed the mortality rate of children with Progeria treated with Lonafarnib monotherapy (n=63) vs those not treated with Lonafarnib (n=63). Treated children were contemporaneously matched by gender, age, and continent of residency with untreated patients. Children were treated with Lonafarnib monotherapy (150 mg/m2 twice daily) .
Young Child

77% reduction in risk of mortality with Lonafarnib treatment compared with no treatment.

In this analysis there were 4 deaths (6.3%) among 63 Lonafarnib-treated patients and 17 deaths (27%) in the untreated matched group. Children treated with Lonafarnib had a 77% reduction in the risk of mortality compared with the untreated matched controls over an average follow-up period of 2.2 years (Hazard ratio 0.23; P=0.04). Results were published in the Journal of American Medical Association (JAMA) 2018. Lonafarnib is generally well tolerated. Most commonly reported adverse events to date are diarrhea and nausea. Side effects can be well managed with prophylactic treatment with antidiarrheals and antiemetics. Longest duration of dosing is > 10 years.

Lonafarnib improved survival in progeria

77% Reduction in Risk of Mortality Compared with No Treatment Survival Probability

Eiger’s commitment is to provide access to Zokinvy™ (lonafarnib) to every child and young adult in the world with Progeria

Patients with Progeria and Progeroid Laminopathies have been identified in over 40 countries around the world. Eiger is seeking regulatory approval for Zokinvy in the US with FDA and in the EU with EMA. The company will assess additional countries in the future.

Eiger is committed to ensuring that every eligible patient has access to Zokinvy. Eiger has partnered with Clinigen Group PLC, a global pharmaceutical services company, to launch a worldwide Zokinvy Managed Access Program (MAP) for patients with Progeria and Progeroid Laminopathies. For more information, please visit www.progeriaresearch.org.