Lonafarnib/Ritonavir for HDV

Stage

Phase 3 Completed
Positive Pre‑NDA Meeting with FDA
Partnering opportunity

Disease

Hepatitis Delta Virus Infection

Prevalence

100K in the US
200K in the EU

Mechanism of Action

Prenylation Inhibitor

Regulatory Designations

Orphan in US and EU
Breakthrough Therapy in US
PRIME in EU

About Hepatitis Delta Virus

HDV is the most severe form of viral hepatitis

Hepatitis Delta is caused by infection with the Hepatitis Delta Virus and leads to the most severe form of viral hepatitis. HDV occurs only as a co-infection in individuals infected with Hepatitis B Virus (HBV). HDV leads to more severe liver disease than HBV alone and is associated with accelerated liver fibrosis, liver cancer, and liver failure. Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not affect HBsAg, and have no impact on HDV.

Lonafarnib is the first and only oral agent in development for HDV

Lonafarnib is a well-characterized, first-in-class, inhibitor of farnesyl-transferase, an enzyme involved in modification of proteins through a process called prenylation. HDV uses this host cell process inside liver cells to complete a key step in its life cycle. Lonafarnib inhibits the prenylation step of HDV replication inside liver cells and blocks the virus life cycle at the stage of assembly.

Global Phase 3 D-LIVR Study completed
FDA Breakthrough Therapy designation
EMA Prime designation

Lonafarnib has been granted Orphan Drug Designation by the US FDA and European Medicines Agency (EMA), as well as Fast Track and Breakthrough Therapy Designation by the US FDA and PRIME Designation by the EMA. Lonafarnib is licensed from Merck Sharp & Dohme Corp. (known as MSD outside of the United States and Canada). 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.

HDV replication and prenylation

After HDV enters a target cell hepatocyte, the genome is translocated to the nucleus where genome replication occurs without the need of any gene products from HBV. An important interaction between HDV and HBV proteins has been shown to depend on the presence of the last 4 amino acids of the large delta antigen, comprising a CXXX box motif, where C represents cysteine and X denotes any other amino acid. This amino acid sequence is required for the protein to be post-translationally modified by farnesyltransferase (FT), an enzyme which covalently attaches a 15-carbon prenyl-lipid farnesyl moiety to the cysteine of the CXXX box. Prenylation of the large delta antigen renders it more lipophilic, promotes its association with HBsAg, and is essential for initiating the HDV particle formation process.

The HDV Lifecycle

Reference: Elazar M, Glenn JS. Confronting new and old antiviral threats: broad spectrum potential of prenylation inhibitors. In: Torrence PF, ed. Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats. Hoboken, NJ: John Wiley & Sons; 2005:249-261.

HDV Prevalence

Hepatitis Delta is a disease with a significant impact on global health, which may affect up to 20 million people worldwide

The prevalence of HDV varies among different parts of the world. Globally, HDV infection is reported to be present in approximately 4% to 6% of chronic Hepatitis B carriers. The prevalence of HDV in patients infected with chronic HBV is even higher in certain regions, including certain parts of Mongolia, China, Russia, Central Asia, Pakistan, Turkey, Africa, Middle East, and South America, with an HDV prevalence as high as 60% being reported in HBV-infected patients in Mongolia and Pakistan.

Globally, HDV infection is reported to be present in approximately 4% to 6% of chronic hepatitis B carriers.

Hdv worldwide prevalence: 15-20 million

References: 1. Fattovich G, Boscaro S, Noventa F, et al. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis. 1987;155(5):931-5. 2. Calle Serrano B, Grosshennig A, Heidrich B, et al. Comparing the long-term outcome of hepatitis delta and HBV monoinfection: Is HDV-infection really worse? Poster presented at: The International Liver Congress™ 2011; March 31, 2011; Berlin, Germany. 3. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31-40.

HDV causes the most rapid liver disease progression

70% of HDV-infected patients will progress to cirrhosis within 5 to 10 years and >50% of patients are cirrhotic at diagnosis.

HDV: MOST RAPID PROGRESSION OF DISEASE

50% of HDV-Infected Patients are Cirrhotic at Diagnosis

Lonafarnib in HDV clinical studies

Lonafarnib (LNF) is the first and only oral agent in development for HDV. It is well-characterized and has been previously administered to > 2000 patients in oncology and > 90 children with Progeria. Most common adverse events are gastrointestinal. In our HDV program, we discovered that co-dosing Lonafarnib with ritonavir (RTV), an inhibitor of its metabolism, allows for lower doses of Lonafarnib to be administered with higher concentrations of Lonafarnib in the liver and systemic circulation. Lonafarnib has been dosed in over 400 HDV-infected patients in Phase 2 and Phase 3 HDV studies. 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.

Learn more about the phase 2 program

POC Study (Placebo-controlled LNF monotherapy) (N=14)
LOWR-1 Study (Combination: LNF with RTV or PEG IFN-alfa-2a) (N=21)
LOWR-2 Study (Dose Finding: LNF + RTV + PEG IFN-alfa-2a) (N=58)
LOWR-3 Study (QD Dosing: LNF + RTV) (N=21)
LOWR-4 Study (BID Dose-Escalation: LNF + RTV) (N=15)

About the Phase 3 D-LIVR study

D-LIVR is a global Phase 3 study with the only oral agent in development for HDV. D-LIVR evaluates an all-oral arm of LNF boosted with RTV and a combination arm of LNF boosted with RTV combined with pegylated interferon-alfa-2a (PEG IFN-alfa-2a), with each arm to be compared with a placebo arm (background HBV nucleos[t]ide only), in HDV-infected patients.

STUDY COMPLETE

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D-LIVR Landmark Phase 3 Global Study

EVALUATION OF TWO LONAFARNIB-BASED REGIMENS AS POTENTIAL FINITE THERAPIES

Primary Endpoint Achieved with Significance in BOTH Arms

% PATIENTS ACHIEVING COMPOSITE ≥2 LOG DECLINE IN HDV RNA + ALT NORMALIZATION AT WEEK 48

Importantly, statistically significant improvement in histology observed with the combination regimen

Overall Safety through Week 48

BOTH LONAFARNIB-TREATMENT REGIMENS WERE WELL-TOLERATED

PTWK24 (End of Study) Response for Both Lonafarnib Regimens

COMPOSITE ENDPOINT, RANDOMIZED POPULATION, N=338

Increase in response rate post-treatment vs at end of treatment may partially be explained by beneficial flares occurring in approximately 10% of the oral and 20% of the combo arm after stopping treatment.
Durability of response at 24-week post-treatment suggests that finite therapy may be possible in a subset of patients with chronic HDV.

Lonafarnib / RitonavirHepatitis Delta Virus (HDV) Infection