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RWE Decision Alert

French HTA Approves ZOKINVY® (Lonafarnib) Based on Evidence Package Including RWE


On March 22, 2023, ZOKINVY® (lonafarnib) was approved for reimbursement in France, and real-world evidence (RWE) played a key role in this decision. Our expert team has reviewed the decision process and shared its highlights.

The French National Health Authority/Haute Autorité de santé (HAS) recently reviewed and approved ZOKINVY for reimbursement for treating Hutchison-Gilford progeria syndrome (HGPS) and processing deficient progeroid laminopathy (PDPL). The decision was based on data from two open-label single-arm trials compared with an external control arm based on real-world data.

Eiger BioPharmaceuticals Inc., the ZOKINVY ‘s EU market authorization holder, utilized real-world data (RWD) from the Progeria Research Foundation’s International Registry as an external control to conduct an indirect comparison study, which played a significant role in the HAS decision. ZOKINVY is now reimbursed in France for the treatment of patients aged 12 months and older with a confirmed genetic diagnosis of HGPS or PDPL, displaying either a heterozygous LMNA mutation with progerin-like protein accumulation or a homozygous or composite heterozygous ZMPSTE24 mutation. The HAS concluded that ZOKINVY offers a minor improvement in actual benefit (ASMR IV) for HGPS and PDPL compared to the current therapeutic.

ZOKINVY was designated as an ”orphan medicine” on December 14, 2018, by the European Medicines Agency (EMA) for HGPS and PDPL. ZOKINVY received EMA approval under exceptional circumstances in July 2022 based on positive results, including an increase in the lifespan of treated patients compared to historical untreated patients (external control), from two separate single-arm cohorts. Eiger BioPharmaceuticals is thus committed to conducting a post-authorization safety study (PASS) to confirm the benefits and safety of ZOKINVY.

HGPS is an ultra-rare genetic disorder characterized by rapid aging in children. It is caused by a mutation in the LMNA gene, producing an abnormal protein called progerin. This protein affects cell structure and leads to premature aging symptoms, including growth retardation, hair loss, skin wrinkling, joint stiffness, cardiovascular complications, and a shortened average lifespan of 14.5 years. PDPL refers to a broader range of disorders caused by mutations in the LMNA gene, which share similar features with progeria but may exhibit variations in clinical manifestations and disease progression.

RWE Study

In a post-hoc indirect comparison study, ZOKINVY monotherapy treatment of HGPS patients from ProLon1 and ProLon2 was compared to a matched untreated natural history cohort of patients (Gordon et al., 2018). The untreated cohort served as an external control arm, allowing an assessment of whether ZOKINVY monotherapy treatment in ProLon1 and ProLon2 reduced mortality in patients with HGPS when compared to the matched control natural history cohort.

The treated cohort consisted of patients from two single-arm, single center trials, ProLon1 (N=27) and its subsequent extension study, ProLon2 (N=35). These patients received oral ZOKINVY (150 mg/m2) twice daily. In addition, a total of 258 patients were identified from the Progeria Research Foundation’s International Registry (n=211) and published scientific literature (n=47) who only received supportive care for symptom management. For the primary analysis, 81 untreated patients born in 1991 or later were selected as contemporaneous controls. The matching criteria included age, sex, and continent of residency, ensuring that the selected untreated patients were alive at the initiation of ZOKINVY treatment and matched the same sex and continent of residency.

The study found 8.1% (n=5/62) of patients in the treated group had died versus 25.9% (n=21/81) of patients from the natural history cohort. The truncated mean lifespan at 3 years of patients with HGPS treated with ZOKINVY monotherapy increased by 0.49 years (2.83 versus 2.34 years; HR = 0.17; 95% CI = [0.060; 0.478]) at the primary 3-year follow-up analysis. Furthermore, in a recent post-hoc analysis conducted in August 2021 (median follow-up time 7.44 years), the mean survival time for patients with progeria treated with ZOKINVY increased by 4.3 years (10.1 vs. 5.73; HR = 0.28; 95% CI = [0.154, 0.521]) compared to the natural history cohort.

RWE Study Assessment and Conclusions

The external control group was criticized by HAS for not properly limiting the role of bias; namely, for the lack of a pre-defined hypothesis regarding the potential survival benefit, for not adequately matching the treated and untreated populations due to unknown patient characteristics and limited matching factors, and for differences in care management since the 1990s. The HAS recognized that due to the data uncertainty, the true benefit of ZOKINVY could be less than reported, and it also pointed out the lack of a clinically relevant morbidity endpoint. The HAS concluded that, despite the fact that the efficacy data was based on a biased indirect comparison, and the limited generalizability of the results, ZOKINVY has an impact on mortality but not on morbidity. Considering the absence of available treatments, as well as the extreme rarity of HGPS and PDPL, the HAS recommended ZOKINVY as a first-line treatment for patients aged 12 months and older in France.

Author: Rithvik Badinedi, Consultant, Market Access and Real-World Evidence


  1. HAS Opinion of ZOKINVY (Ionafarnib)
  2. EMA Overview of ZOKINVY (Ionafarnib)
  3. FDA Integrated Review of ZOKINVY (Ionafarnib)
  4. Gordon LB, Shappell H, Massaro J, D’Agostino RB Sr, Brazier J, Campbell SE, Kleinman ME, Kieran MW. Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018 Apr 24;319(16):1687-1695. doi: 10.1001/jama.2018.3264. PMID: 29710166; PMCID: PMC5933395.
About RWE Decision Alerts

RWE Decision Alerts provide subscribers with timely analyses of published reports from HAS, AEMPS, NICE, EMA, and the FDA where RWE is used to support HTA and regulatory decision-making. We identify if a submission included RWE and assess the value of the RWE submitted.

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