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Lonafarnib
Clinical data
Trade namesZokinvy
Other namesSCH 66336
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.204.509 Edit this at Wikidata
Chemical and physical data
FormulaC27H31Br2ClN4O2
Molar mass638.83 g·mol−1
3D model (JSmol)
  • C=12CCC=3C=C(C=C(C3[C@H](C1N=CC(=C2)Br)C4CCN(CC4)C(=O)CC5CCN(CC5)C(N)=O)Br)Cl
  • InChI=1S/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1 checkY
  • Key:DHMTURDWPRKSOA-RUZDIDTESA-N checkY

Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age and older.[3][4] It is under trial for its use as combination treatment for Hepatitis D Virus.[5]

The most common side effects included nausea, vomiting, headache, diarrhea, infection, decreased appetite and fatigue.[3]

Lonafarnib was approved for medical use in the United States in November 2020,[3][6] and in the European Union in July 2022.[2] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[7]

Medical uses

[edit]

Lonafarnib is indicated to be used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain other processing-deficient progeroid laminopathies in people one year of age and older.[3][4]

Contraindications

[edit]

Lonafarnib is contraindicated for co-administration with strong or moderate CYP3A inhibitors and inducers, as well as midazolam and certain cholesterol-lowering medications.[3]

History

[edit]

Lonafarnib, a farnesyltransferase inhibitor, is an oral medication that helps prevent the buildup of defective progerin or progerin-like protein.[3] Its effectiveness for the treatment of Hutchinson–Gilford progeria syndrome was supported by clinical data and comparisons with untreated patients from a natural history study.[3][4] Lonafarnib's approval for the treatment of certain processing-deficient progeroid laminopathies was based on similarities in the underlying genetic mechanism of disease and other available data.[3]

The U.S. Food and Drug Administration (FDA) granted the application for lonafarnib priority review, orphan drug, and breakthrough therapy designations.[3] In addition, the manufacturer received a rare pediatric disease priority review voucher.[3] The FDA granted the approval of Zokinvy to Eiger BioPharmaceuticals, Inc.[3]

Society and culture

[edit]
[edit]

On 19 May 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Zokinvy, intended for the treatment of patients with progeroid syndromes.[8][9] The applicant for this medicinal product is EigerBio Europe Limited.[8] It was approved for medical use in the European Union in July 2022.[2][10]

Research

[edit]

Lonafarnib is a farnesyltransferase inhibitor (FTI) that has been investigated in a human clinical trial as a treatment for progeria, which is an extremely rare genetic disorder in which symptoms resembling aspects of aging are manifested at a very early age.[11][12] For those with progeria, research has shown that the drug reduces the prevalence of stroke and transient ischemic attack, and the prevalence and frequency of headaches while taking the medication.[13] A phase II clinical trial was completed in 2012, which showed that a cocktail of drugs that included lonafarnib and two other drugs met clinical efficacy endpoints that improved the height and diminished the rigidity of the bones of progeria patients.[citation needed]

Lonafarnib is a synthetic tricyclic halogenated carboxamide with antineoplastic properties.[14] As such, it is used primarily for cancer treatment.

Hepatitis D

[edit]

Ongoing studies and clinical trials have found a correlation of lonafarnib treatment with cure of hepatitis D (HDV). Up to now, the trials have proven an efficacy of lonafarnib on HDV if combined with ritonavir, as a supportive treatment for pegylated interferon alpha therapy. [5]

Cancer

[edit]

Lonafarnib (also known as SCH 66336) is an orally bioavailable, non-peptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational farnesylation of proteins such as Ras, RhoB, and centromere-binding proteins. This modification is essential for the membrane localization and activation of these proteins, many of which are implicated in oncogenesis. Originally developed by Merck & Co. in the late 1990s as an anticancer agent targeting Ras-driven malignancies, lonafarnib aimed to block oncogenic signaling pathways. However, despite promising preclinical data, its clinical development for cancer was largely discontinued due to insufficient efficacy as monotherapy in advanced solid tumors and hematologic malignancies. It is now FDA-approved (as Zokinvy™) for Hutchinson-Gilford progeria syndrome (HGPS) and certain progeroid laminopathies, with ongoing investigations inhepatitis D virus (HDV) infection. Below is an overview of its use in cancer patients based on historical and recent data.[15]

Mechanism of Action in Cancer

[edit]

Lonafarnib inhibits FTase, preventing the farnesylation of Ras proteins, which are mutated in approximately 30% of human cancers (e.g., pancreatic, colorectal, lung). This disrupts Ras-mediated signaling pathways involved in cell proliferation, survival, and metastasis. Emerging evidence suggests broader effects, including modulation of RhoB (a tumor suppressor), inhibition of autophagy flux (e.g., via ATG3-mediated cyclin D1 degradation), and reduction of tau inclusions in tauopathy models, which may have implications for certain cancers. Preclinical studies demonstrated anti-proliferative effects on Ras-independent tumor cell lines (e.g., lung, pancreas, colon, prostate, bladder, and hematologic cancers). Notably, lonafarnib has shown synergistic potential with chemotherapeutics by enhancing sensitivity to agents like sorafenib, paclitaxel, and docetaxel, potentially overcoming drug resistance through increased lysosomal activation and efflux pump inhibition.

Clinical Trials and Efficacy

[edit]

Lonafarnib entered clinical development for cancer in the early 2000s, with extensive phase 1-3 trials evaluating it as monotherapy or in combinations. Early phase 2 studies showed modest activity, but larger randomized trials failed to meet efficacy endpoints, leading to halted oncology programs by the mid-2010s. Key findings include:

Monotherapy
[edit]

In advanced breast cancer (phase 2, n=76 women post-chemotherapy/endocrine therapy), continuous or intermittent oral dosing (200 mg BID) yielded objective response rates of 10-14%, but no progression to phase 3 due to limited durability. Refractory head and neck cancer (phase 2, n=15): Minimal responses (<10% partial responses). Advanced pancreatic, colorectal, and non-small cell lung cancer (phase 2): Response rates <10%, with no robust survival benefit. Hematologic malignancies (e.g., acute myeloid leukemia [AML], chronic myelogenous leukemia [CML]): Promising early signals in AML/CML, but phase 3 trials (e.g., with tipifarnib, a related FTI) did not confirm superiority over standard care.

Combination Therapy
[edit]

Non-small cell lung cancer (NSCLC): Phase 2 data with paclitaxel showed encouraging response rates in taxane-pretreated patients, but a phase 3 trial (paclitaxel +carboplatin ± lonafarnib) was terminated for futility. Hepatocellular carcinoma (HCC): In vitro/in vivo models showed lonafarnib synergizes with sorafenib, inducing autophagic flux and cyclin D1 degradation, reducing HCC cell growth by >50% at low doses (e.g., 5-10 μM). A phase 2 trial suggested potential to lower sorafenib doses and mitigate resistance, extending survival by 3-5 months in responsive subsets (~30% of patients), though clinical trials are limited and preclinical. Prostate cancer: Intermittent dosing with docetaxel potentiated efficacy in models, but human data were inconclusive. Urothelial cancer: Phase 2 with gemcitabine showed feasibility but no significant improvement in salvage settings. Overall, while preclinical synergy is evident, clinical efficacy has been "weak" or "not robust" in solid tumors, with development discontinued for myelodysplastic syndromes, leukemia, and most solid tumors due to lack of survival benefit. No cancer indications are currently approved, and ongoing trials are rare (e.g., NCT00773474 for metastatic breast cancer, completed but unpublished results).

Side Effects and Safety Profile
[edit]

Lonafarnib is generally well-tolerated at oncology doses (100-200 mg BID orally), but dose-dependent toxicities limit its use. Common adverse events (≥20% incidence) include:

Adverse Event Frequency Notes
Fatigue 40-60% Dose-limiting; often grade 1-2
Diarrhea 30-50% Manageable with antidiarrheals
Nausea/Anorexia 20-40% Dose-dependent; supportive care effective
Myelosuppression (neutropenia, thrombocytopenia) 10-30% More common in combinations
QTc Prolongation <5% Rare (1/15 in head/neck trial); monitor ECG
Elevated ALT/AST 20-35% Transient, mild (≤3x ULN in 5%); no Hy's law cases in cancer trials

Serious risks include nephrotoxicity, retinal toxicity, and embryo-fetal harm (contraindicated in pregnancy). Drug interactions are significant: Strong CYP3A4 inhibitors (e.g., ketoconazole) increase exposure (AUC up 4-5x), while inducers (e.g., rifampin) decrease it. In cancer trials, discontinuations due to toxicity were ~10-15%. LiverTox data confirm no clinically apparent acute liver injury, though monitoring is advised.

Current Status and Future Directions

As of 2025, lonafarnib is not approved or routinely used for cancer treatment. Its oncology legacy informs research into FTase inhibitors for Ras-mutant cancers (e.g., KRAS G12C), but successors like tipifarnib have also faltered. Interest persists in combinations for HCC and drug-resistant tumors, with preclinical data supporting trials. Patients should consult oncologists for alternatives like targeted therapies (e.g., sotorasib for KRAS-mutated NSCLC). For progeria or HDV, it remains a standard option.

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lonafarnib

View on Grokipedia
from Grokipedia
Lonafarnib, sold under the brand name Zokinvy, is an oral farnesyltransferase inhibitor approved for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies in patients aged 12 months or older with a of at least 0.39 m². It functions by inhibiting the enzyme farnesyltransferase, which prevents the farnesylation of prelamin A and thereby reduces the accumulation of the toxic protein characteristic of these disorders. First approved by the U.S. (FDA) on November 20, 2020, and by the (EMA) on July 18, 2022, lonafarnib represents the first for HGPS and related conditions, offering improved survival outcomes compared to historical untreated cohorts. Originally developed by Merck & Co. as an anticancer agent in the early 2000s, lonafarnib's oncology applications were largely discontinued due to limited efficacy, but it was repurposed by Eiger BioPharmaceuticals—under license from Merck—for rare genetic diseases involving abnormal protein farnesylation, and later acquired by Sentynl Therapeutics in 2024. Preclinical studies in mouse models demonstrated that lonafarnib extends lifespan and improves cardiovascular function by mitigating progerin-induced cellular damage, paving the way for clinical evaluation in humans. Phase 2 clinical trials, including open-label studies involving dozens of pediatric patients, showed that lonafarnib treatment increased mean survival by approximately 2.5 years over an 11-year period relative to untreated individuals, with benefits in weight gain, bone density, and cardiovascular parameters. The drug is administered orally as 50 mg or 75 mg capsules, typically starting at 115 mg/m² twice daily and potentially escalating to 150 mg/m² after four months, with dosing adjustments for drug interactions involving CYP3A modulators. Common adverse effects include gastrointestinal disturbances such as , , and , as well as and decreased , which are generally manageable but can lead to in young patients. More serious risks encompass elevations in liver enzymes (observed in about 35% of HGPS patients, typically mild and transient), potential , retinal vascular changes, and impaired , necessitating regular monitoring of electrolytes, renal function, liver tests, and ophthalmologic exams during therapy. Lonafarnib is also under investigation for chronic virus infection, where it has shown reductions in HDV levels in clinical trials, though it remains unapproved for this indication as of 2025. As an , its approval highlights advancements in precision medicine for ultra-rare diseases, with ongoing research exploring its broader applications in laminopathies.

Pharmacology

Mechanism of action

Lonafarnib is a selective, orally bioavailable farnesyltransferase inhibitor (FTI) that potently blocks the activity of the (FTase) with an IC50 of 1.9 nM for farnesyl protein transferase. This inhibition occurs through reversible binding to the CAAX-binding site on FTase, preventing the enzyme from catalyzing the transfer of a farnesyl lipid group from to the residue in the C-terminal CAAX motif (where C is , A is an aliphatic , and X is any ) of substrate proteins. In the context of Hutchinson-Gilford progeria syndrome (HGPS), lonafarnib targets the underlying defect by inhibiting the farnesylation of prelamin A, the precursor to the protein lamin A. The HGPS-associated LMNA mutation leads to aberrant splicing, producing —a truncated form of prelamin A that retains the CAAX motif and undergoes farnesylation, resulting in its persistent accumulation at the and disruption of nuclear structure. By blocking this , lonafarnib prevents progerin from anchoring to the inner nuclear membrane, thereby reducing its toxic effects and addressing the core biochemical pathology of the disease. This mechanism yields observable cellular benefits in HGPS models, including improvements in aberrant nuclear morphology, such as reduced blebbing and lobulation of the in patient-derived fibroblasts treated with lonafarnib. Additionally, lonafarnib enhances cellular , promoting the clearance of aggregates, and contributes to the reversal of phenotypes, such as restored proliferative capacity and diminished DNA damage markers in HGPS cell lines and animal models.

Pharmacokinetics

Lonafarnib is rapidly absorbed following , with a time to maximum plasma concentration (T_max) of 2 hours at the recommended dose of 115 mg/m² twice daily in patients with Hutchinson-Gilford progeria syndrome (HGPS). In these patients at , the mean maximum plasma concentration (C_max) is 1777 ± 1083 ng/mL, and the area under the plasma concentration-time curve over the dosing interval (AUC_τ) is 12,365 ± 9,135 ng·h/mL. is achieved after approximately 3 days of twice-daily dosing. Although absolute has not been determined, administration with a high-fat decreases C_max by 53% and AUC by 28%, while a low-fat decreases C_max by 22% and AUC by 17%; nonetheless, lonafarnib is recommended to be taken with to improve tolerability. The apparent at is approximately 90 L in healthy subjects, indicating moderate tissue distribution. Lonafarnib is highly bound to plasma proteins (>99%) over a concentration range of 0.5 to 40 μg/mL. It penetrates various cell types, including those affected in . Preclinical studies have shown reduced levels in tissues following lonafarnib treatment. Lonafarnib undergoes extensive hepatic metabolism, primarily via the enzyme , which accounts for 43% to 86% of its biotransformation, with minor contributions from , , CYP2C8, , , and CYP2E1. Major metabolites include oxidative products such as HM17 and HM21, which represent about 15% and 14% of plasma radioactivity, respectively. This involvement contributes to potential drug interactions. The terminal elimination of lonafarnib is 4 to 6 hours at . Elimination occurs predominantly via (approximately 62%), with less than 1% excreted unchanged in , reflecting primarily hepatic clearance. In pediatric patients with HGPS, clearance is influenced by (BSA), with exposure varying by up to 1.4-fold across BSA ranges of 0.25 to 0.9 . Dosing in special populations, such as children with HGPS aged 12 months or older, is adjusted based on BSA of at least 0.39 , with pharmacokinetics showing high interpatient variability potentially due to factors like sex and food intake, though no clinically significant age or sex effects on exposure have been identified in this group.

Medical use

Indications

Lonafarnib is indicated to reduce the risk of mortality in patients aged 12 months or older with a of at least 0.39 who are diagnosed with Hutchinson-Gilford syndrome (HGPS) or processing-deficient progeroid laminopathies (PDPL) resulting from heterozygous LMNA mutations that code for progerin-like proteins or from homozygous or compound heterozygous ZMPSTE24 mutations. This approval is supported by evidence from two open-label, single-arm phase II trials demonstrating improvements in key clinical outcomes compared to historical untreated controls. In the first trial (NCT00425607, conducted 2007–2011), 25 children with HGPS received lonafarnib for an average of 2.2 years, resulting in an estimated 1.6-year extension in lifespan, alongside enhancements in vascular stiffness (measured by ) and bone mineral density. A confirmatory study (NCT00916747) involving 35 treatment-naïve participants with HGPS further showed a 60% reduction in mortality incidence (P=0.0064) and improvements in rates, cardiovascular parameters (including reduced prevalence), , and vascular stiffness after up to 11 years of follow-up. Overall, these trials indicated an average survival benefit of 2.5 years for treated HGPS patients versus untreated historical controls. Lonafarnib is not indicated for processing-proficient progeroid laminopathies or for other lacking the specific mutations (heterozygous LMNA variants producing progerin-like proteins or homozygous/compound heterozygous ZMPSTE24 mutations) that cause accumulation of farnesylated abnormal prelamin A or progerin-like proteins, as the drug's mechanism relies on inhibiting farnesylation of these specific abnormal proteins.

Dosing and administration

Lonafarnib is administered orally at a starting dose of 115 mg/m² twice daily, approximately 12 hours apart in the morning and evening, with meals to minimize gastrointestinal adverse reactions. After 4 months of treatment, the dose is increased to 150 mg/m² twice daily, with the total daily dose rounded to the nearest 25 mg increment based on (BSA). This BSA-based dosing applies to patients 12 months of age and older with a BSA of 0.39 m² or greater, and capsules are available in 50 mg and 75 mg strengths to facilitate accurate administration. Treatment initiation occurs at the full starting dose without a required ramp-up period, with ongoing monitoring for tolerability to guide any necessary adjustments; therapy is continued indefinitely unless contraindicated or poorly tolerated. For growing pediatric patients, BSA should be reassessed periodically to adjust the dose accordingly, ensuring alignment with changes in body size. If gastrointestinal reactions such as or lead to or , the dose may be reduced to 115 mg/m² twice daily. Capsules must be swallowed whole with sufficient water and should not be chewed or crushed. For patients unable to swallow capsules whole, the contents of the capsule(s) may be opened and mixed with 5 to 10 mL of Ora-Plus, Ora-Blend SF, , or 1 to 2 teaspoonfuls of ; the mixture should be prepared fresh and consumed immediately, within 10 minutes. or products containing oranges should be avoided due to potential interactions affecting exposure. In the event of a missed dose, it should be taken as soon as possible if less than 8 hours have elapsed since the scheduled time; otherwise, the dose should be skipped, and the regular dosing schedule resumed without doubling up. Regular monitoring during lonafarnib therapy includes electrocardiograms (ECGs) to assess before initiation and periodically thereafter, renal function tests at routine intervals, liver enzyme evaluations, and levels to manage potential abnormalities. Complete blood counts may also be checked periodically.

Safety and tolerability

Adverse effects

Lonafarnib is associated with a range of adverse effects, primarily gastrointestinal, which are common in patients treated for progeria. In clinical trials involving children with Hutchinson-Gilford progeria syndrome (HGPS), the most frequent adverse reactions occurred at high incidences, reflecting the drug's tolerability profile in this population. Common adverse effects, reported in more than 10% of patients, include gastrointestinal disturbances such as nausea (56%), vomiting (90%), diarrhea (81%), abdominal pain (48%), and decreased appetite (53%) leading to weight loss (37%). Neurological effects encompass fatigue (51%) and headache (37%), while infections, particularly upper respiratory tract infections (51%), are also prevalent. Dermatological reactions feature rash (18%) and pruritus, alongside other effects like cough (33%) and electrolyte abnormalities (43%). Cardiovascular effects include hypertension (29%), and hematologic effects involve myelosuppression (35%) and anemia (18%). These events were generally manageable and did not lead to high discontinuation rates, with only 4 out of over 100 patients stopping treatment due to side effects in progeria studies. Serious adverse effects, though less common, include QTc prolongation (risk of torsades de pointes, arrhythmias, and sudden death; avoid in patients with bradycardia, hypokalemia, hypomagnesemia, or congenital long QT syndrome, and with other QT-prolonging drugs; obtain baseline ECG and monitor periodically; withhold if QTc ≥500 ms until <470 ms), severe vomiting (2%), severe diarrhea (8%), and severe liver enzyme increases (ALT 12%, AST 5% >5-20x ULN). Hepatic elevations in transaminases (aspartate aminotransferase 35%, alanine aminotransferase 27%), renal concerns like decreased estimated glomerular filtration rate and nephrotoxicity, and ocular vision decline due to potential retinal toxicity were observed in progeria clinical trials and preclinical studies, with no fatalities directly attributed to the drug. Management of adverse effects typically involves dose interruption or reduction for grade 3-4 events, such as severe gastrointestinal symptoms causing or , with resumption at a lower dose (115 mg/m² twice daily) once resolved. Supportive care, including antiemetics and hydration for gastrointestinal issues, is recommended, alongside routine monitoring of electrolytes, blood counts, liver enzymes, renal function, , ECGs prior to treatment and periodically for QTc, and ophthalmological evaluations for vision changes. Long-term data from trials, with cumulative exposure exceeding 128 patient-years and some patients treated for over 10 years, show no new safety signals beyond initial observations, though potential impacts on remain possible based on and have not been fully evaluated in humans.

Contraindications and interactions

Lonafarnib is contraindicated in patients taking strong CYP3A inhibitors, such as or , due to significantly increased exposure leading to enhanced risk of adverse reactions. It is also contraindicated with strong or moderate CYP3A inducers, including rifampin, as these reduce lonafarnib plasma concentrations and may diminish efficacy. Concomitant use with is prohibited owing to lonafarnib's potent inhibition of CYP3A, which elevates levels and risk of prolonged sedation. Additionally, lonafarnib should not be coadministered with , simvastatin, or because of the heightened risk of and from increased exposure. For moderate CYP3A inhibitors like or , avoid coadministration if possible. If unavoidable, no dosage adjustment for lonafarnib is recommended, but monitor closely for adverse reactions, particularly during the first 7 days after initiating lonafarnib; consider an alternative therapy if adverse reactions occur. Lonafarnib is a sensitive CYP3A substrate, and interactions are primarily mediated through this pathway, with over 500 known drug interactions reported. Use with QTc-prolonging drugs, such as , is not recommended; if necessary, assess risk and monitor ECGs closely, as lonafarnib can prolong the QTc interval. For other statins like , employ the lowest possible dose and monitor for signs of . Food interactions must be considered for optimal safety and efficacy. Grapefruit, Seville oranges, and their juices should be avoided, as they inhibit CYP3A and can increase lonafarnib exposure, heightening toxicity risk. Conversely, lonafarnib capsules should be taken with a fatty meal to enhance bioavailability, as food increases absorption by approximately twofold. Precautions are essential in specific patient populations. Lonafarnib has not been studied in patients with hepatic impairment. No dosage adjustment is recommended, but use with caution and monitor liver function closely. Lonafarnib may cause fetal harm based on showing embryolethality and malformations; is not recommended, and effective contraception is required during treatment and for one month after discontinuation for females of reproductive potential and males with pregnant partners. is not advised, as lonafarnib is excreted in the of lactating rats with no human data available. All patients should undergo baseline and periodic monitoring of s, ECGs, liver enzymes, renal function, and complete blood counts to detect potential complications like QT prolongation or imbalances.

History

Development and early trials

Lonafarnib, also known as SCH 66336, was initially discovered and developed by Schering-Plough Research Institute in the 1990s as an oral farnesyltransferase inhibitor targeting Ras protein farnesylation to disrupt oncogenic signaling pathways in cancer cells. Following the acquisition of Schering-Plough by Merck & Co. in 2009, Merck continued its advancement as a potential anticancer agent, focusing on its ability to inhibit farnesylation-dependent membrane localization of Ras proteins implicated in various malignancies. Early clinical development in the 2000s emphasized phase I and II trials evaluating lonafarnib's safety, pharmacokinetics, and preliminary efficacy across solid tumors and hematologic cancers. Phase I studies established dosing regimens, such as 100 mg twice daily when combined with paclitaxel for advanced solid tumors, demonstrating acceptable tolerability but modest antitumor activity. Phase II trials extended to non-small cell lung cancer, where lonafarnib combined with paclitaxel yielded a median progression-free survival of 16 weeks but no significant overall survival benefit, and to chronic myeloid leukemia, showing limited responses in accelerated-phase patients. Additional phase II investigations in myelodysplastic syndrome and secondary acute myeloid leukemia confirmed dose-dependent inhibition of farnesylation but insufficient clinical efficacy to warrant broad advancement. These trials highlighted challenges, including gastrointestinal toxicities and the emergence of alternative prenylation pathways, such as geranylgeranylation by geranylgeranyltransferase, which allowed Ras and other small GTPases to evade inhibition and sustain oncogenic activity. By 2010–2011, Merck discontinued lonafarnib's program after multiple trials, including those in and pancreatic cancers, failed to demonstrate meaningful improvements in progression-free or overall survival compared to standard therapies. The lack of efficacy stemmed from incomplete Ras blockade due to compensatory mechanisms, leading to no regulatory approvals for cancer indications as of 2025. Prior to this pivot, preclinical studies in 2005 demonstrated that farnesyltransferase inhibitors, including analogs of lonafarnib, reversed nuclear blebbing and envelope abnormalities in Hutchinson-Gilford (HGPS) fibroblasts by inhibiting progerin farnesylation, sparking interest in repurposing the drug for this rare genetic disorder.

Approval for progeria

The repurposing of lonafarnib for treatment was initiated by the Progeria Research Foundation (PRF) in 2007, shifting its focus from to addressing Hutchinson-Gilford syndrome (HGPS) and progeroid laminopathies. This effort led to the launch of the first pediatric (NCT00425607), a phase II open-label study involving 25 children with HGPS who received lonafarnib for at least two years, demonstrating improvements in vascular stiffness, bone mineral density, and hearing ability. Key evidence supporting lonafarnib's efficacy emerged from the 2012 phase II trial results published in PNAS, which showed preliminary benefits in cardiovascular, skeletal, and auditory parameters using surrogate endpoints such as and echodensity. A 2018 further revealed that lonafarnib monotherapy extended median survival by 2.5 years compared to historical untreated controls, with a 77% reduction in mortality risk based on data from 62 patients followed for up to 11 years. These findings, derived from single-arm trials and historical comparisons, formed the basis for regulatory evaluation, emphasizing surrogate markers of disease progression due to the rarity of HGPS. Regulatory milestones accelerated lonafarnib's path to approval. The U.S. (FDA) granted designation on December 12, 2018, designation on July 3, 2019, and for its in May 2020. The (EMA) awarded orphan designation on December 14, 2018. On November 20, 2020, the FDA provided accelerated approval for lonafarnib (branded as Zokinvy) as the first for HGPS and processing-deficient progeroid laminopathies in patients aged 12 months and older, relying on surrogate endpoints and historical controls to address the unmet need in this fatal pediatric disease. Post-approval, the EMA granted marketing authorization under exceptional circumstances on July 18, 2022, making lonafarnib the first approved treatment in the for these conditions. Japan's Ministry of Health, Labour and Welfare (MHLW) approved it in January 2024, expanding access for affected children. In May 2024, Sentynl Therapeutics acquired global rights to Zokinvy from BioPharmaceuticals, ensuring continued access for patients. Additionally, PRF has facilitated programs to provide lonafarnib to eligible patients outside clinical trials, ensuring broader availability amid ongoing confirmatory studies.

Society and culture

In the United States, lonafarnib, marketed as Zokinvy, was approved by the (FDA) on November 20, 2020, for reducing the risk of mortality in patients 12 months of age and older with a of 0.39 m² or greater who have (HGPS) or processing-deficient progeroid laminopathies (PDPL). The drug is available by prescription and is not classified as a under the . Lonafarnib received designation from the FDA, which includes incentives such as exemption from certain user fees for new drug applications. In the , the (EMA) granted marketing authorization for Zokinvy on July 18, 2022, for the treatment of HGPS and PDPL in patients 12 months of age and older. This authorization was issued under exceptional circumstances due to the rarity of the conditions and the limited availability of data at the time of approval, requiring the marketing authorization holder to conduct post-authorization studies and submit annual reports on efficacy and safety to support ongoing renewal. Lonafarnib also holds orphan medicinal product designation in the EU. In , the Ministry of Health, Labour and Welfare (MHLW) approved Zokinvy on January 19, 2024, for the treatment of HGPS and PDPL in pediatric patients, representing the first regulatory approval of the in Asia. The approval includes designation by the MHLW. As of November 2025, lonafarnib has not received regulatory approval in , , or most developing countries. In these regions, limited access may be possible through compassionate use or programs, such as the Managed Access Program offered by Sentynl Therapeutics in collaboration with the Research Foundation for eligible patients outside approved markets. The drug has obtained status in additional jurisdictions beyond the , , and to facilitate development for these rare conditions. No generic versions of lonafarnib are currently available, with patent protections and regulatory exclusivities estimated to prevent generic entry until approximately July 2029.

Commercial aspects

Lonafarnib is marketed under the brand name Zokinvy for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies, following its licensure to Eiger BioPharmaceuticals from Merck & Co. in 2010 for non-oncology indications. Previously, during oncology clinical trials, the compound was known as Sarasar. In May 2024, Sentynl Therapeutics acquired global rights to Zokinvy from Eiger, assuming responsibility for its commercialization worldwide. Zokinvy is formulated as oral capsules available in 50 mg and 75 mg strengths, enabling weight-based dosing for pediatric and adult patients. The drug is manufactured by third-party contractors under current good manufacturing practices (cGMP) to ensure quality and compliance with regulatory standards. Following the 2024 acquisition, Sentynl Therapeutics oversees the , including production and distribution logistics. The annual cost of Zokinvy for an average patient is approximately $1 million USD, based on typical dosing regimens that may require up to 300 mg daily, reflecting its status and limited patient population. Patient assistance programs mitigate this burden; the Progeria Research Foundation (PRF) provides full coverage of medication costs for eligible patients worldwide through its Managed Access Program, while Sentynl Cares offers copay support and financial aid for commercially insured U.S. patients. High pricing poses significant access challenges, restricting availability primarily to approved markets despite global demand, as the ultra-rare nature of HGPS limits . The PRF addresses international barriers by and for patients seeking treatment at specialized centers. No generic versions are available due to seven-year exclusivity granted by the FDA upon approval in 2020, extending market protection until at least 2027. Zokinvy is commercially available in the United States (since 2021), the and (since 2022), and (since 2024), with approximately 200 identified patients living with HGPS and related progeroid laminopathies worldwide as of mid-2025. Revenues from these markets, though modest due to the small patient base, have historically supported ongoing efforts for lonafarnib in rare diseases.

Research

Ongoing progeria studies

Ongoing research into lonafarnib for progeria emphasizes combination therapies to augment its farnesyltransferase inhibition and address residual disease progression. A phase II clinical trial (NCT00916747) evaluated lonafarnib in combination with pravastatin and zoledronic acid in children with Hutchinson-Gilford progeria syndrome (HGPS), demonstrating additive benefits over lonafarnib monotherapy, including improved weight gain rates, enhanced hearing thresholds, and reduced cardiovascular stiffness as measured by carotid intima-media thickness. Similarly, a phase I/II trial (NCT02579044) assessed lonafarnib combined with everolimus, an mTOR inhibitor, with preclinical data from iPSC-derived vascular models showing reduced reactive oxygen species, decreased DNA damage, and improved cellular proliferation in HGPS cells, supporting potential synergistic effects on vascular pathology (trial status unknown as of 2023). Recent preclinical studies in 2025 have explored lonafarnib in combination with , a JAK inhibitor, using LmnaG609G/G609G mice. This dual therapy synergistically reduced accumulation, attenuated via JAK-STAT pathway inhibition, preserved colonic , and extended median lifespan by approximately 25% compared to monotherapy, highlighting the role of in non-farnesylation-dependent effects. The Progerinin trial, a phase 2a study initiated in 2024, positions lonafarnib (Zokinvy) as the therapeutic backbone combined with Progerinin, a novel small-molecule inhibitor of -lamin A binding that mimics statin-like blockade. Authorized by the FDA for enrollment of 10 patients with HGPS and progeroid laminopathies, the trial aims to assess safety, dosing, and preliminary efficacy in further disrupting progerin toxicity beyond farnesylation inhibition. Long-term follow-up through the Progeria Research Foundation (PRF) registry tracks over 5-year survivors on lonafarnib monotherapy, revealing sustained benefits such as a 30-35% lifespan extension in those treated for 10+ years. Recent analyses focus on cardiac outcomes, with 2025 data indicating lonafarnib induces to partially reverse in mouse hearts and human iPSC-derived cardiomyocytes, reducing and improving contractile function despite ongoing safety monitoring for gastrointestinal effects. Current studies address gaps in managing non-farnesylated effects, such as persistent and mislocalization, with no new monotherapies emerging; instead, combinations like those with or Progerinin target these pathways to potentially achieve approximately 25% further lifespan extension in preclinical models, building on baseline efficacy from prior approval trials.

Investigations in other conditions

Lonafarnib has been investigated for the treatment of chronic hepatitis delta virus (HDV) , a condition lacking FDA-approved therapies as of 2025. In phase 2 LOWR trials, lonafarnib combined with boosting demonstrated virologic responses (defined as undetectable HDV RNA or ≥2 log10 IU/mL decline) in approximately 30-40% of patients at certain doses over 24-48 weeks, though gastrointestinal side effects were common. The pivotal phase 3 D-LIVR trial, completed in 2022, evaluated lonafarnib 50 mg twice daily with 100 mg twice daily versus in 314 patients; the primary composite endpoint (HDV RNA below the lower limit of quantitation and normalization at week 48) was met by 10.1% in the lonafarnib/ arm (p=0.0044 versus placebo) and 19.2% in the combination arm with pegylated (p<0.0001 versus placebo). BioPharmaceuticals sought accelerated FDA approval for HDV in 2023 based on these data, but the application was not granted due to concerns over , profile including hepatobiliary events, and the need for further evidence of durable response. Ongoing efforts focus on optimizing dosing to improve tolerability and efficacy for HDV. The phase 2 NCT05229991 , initiated in 2022, is evaluating once-daily lonafarnib 50 mg co-administered with 200 mg in up to 30 adults with chronic HDV and compensated over 48 weeks, aiming to assess antiviral activity and ; as of November 2025, the remains active but not recruiting, with no published results yet. This regimen seeks to reduce gastrointestinal toxicities associated with twice-daily dosing while maintaining virologic suppression, positioning HDV as the most advanced non-progeria indication for lonafarnib. Investigations into lonafarnib for have been limited following early failures. Originally developed as an anticancer agent targeting farnesyltransferase to inhibit RAS signaling, phase 3 trials in the showed insufficient efficacy in advanced solid tumors, halting further development in that area until efforts. Recent phase 1/2 studies have explored lonafarnib in HRAS-mutant tumors, such as head and neck , where preclinical data suggest potential synergy with immunotherapies like PD-1 inhibitors by modulating ; however, no phase 3 trials have advanced since 2011, and clinical responses remain modest without regulatory pursuit. Exploratory research has examined lonafarnib in other conditions involving aberrant protein farnesylation or . Preclinical studies indicate potential benefits in by inhibiting cyst growth through blockade, but no clinical trials have been initiated. A 2025 preprint reported that lonafarnib partially reversed cardiac in human induced pluripotent stem cell-derived cardiomyocytes and mouse models by activating and reducing accumulation, though safety concerns including limited its effects; no approvals or advanced trials exist for these indications. Repurposing lonafarnib beyond faces challenges, including dose-limiting toxicities in adults that exceed those tolerated in pediatric patients. In adult and HDV trials, doses of 200 mg twice daily caused , , and severe vomiting, necessitating reductions, whereas children safely received up to 150 mg/m² twice daily (equivalent to 115-250 mg) with primarily mild gastrointestinal effects. Additionally, patent protections for novel formulations (e.g., boosting for HDV) and sponsor transitions—from to BioPharmaceuticals, which faced financial difficulties and discontinued related trials in 2023—have slowed broader repurposing efforts.

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