Lonafarnib (1) – Zokinvy®

• Clinical trials
  • ProLon1 is an open-label, single-arm, single-centre Phase II trial in which 28 patients with Hutchinson-Gilford progeria syndrome or progeroid laminopathy received lonafarnib for up to 30 months.
  • ProLon2 is an open-label, single-centre Phase II trial without a control arm.

Patients aged 12 months or older with a genetically confirmed diagnosis of Hutchinson-Gilford progeria syndrome or progeroid laminopathy with a processing defect associated with a heterozygous LMNA mutation causing Progerin-like protein accumulation or a homozygous or compound heterozygous ZMPSTE24 mutation

• Overall, a hint of non-quantifiable additional benefit is derived for lonafarnib, as the scientific evidence does not permit quantification.
• Overall, therefore, only a hint of additional benefit can be inferred.
• mortality
  • Fatalities were recorded as part of the safety monitoring in the ProLon1 and ProLon2 studies.
  • In the ProLon1 study, one death occurred in a child with classic HGPS aged 9 years, and in the ongoing ProLon2 study, four deaths had occurred by the analysis date of 4 February 2020.
  • It is not possible to interpret or evaluate the mortality data due to the lack of a control group.
  • Consequently, no conclusions regarding the extent of the additional benefit can be drawn for the mortality category.
• morbidity
  • Short stature and severe growth failure, combined with reduced body weight compared with the general population, are key clinical characteristics of progeria.
  • Anthropometric measures, or deviations from them, are therefore regarded as patient-relevant parameters in this therapeutic indication.
  • The primary endpoint of the ProLon1 and ProLon2 studies was defined as achieving an increase in the annual rate of body weight gain of at least 50 per cent compared with baseline.
  • As the pharmaceutical manufacturer’s current analyses present only absolute values (and no standardised values), the endpoint cannot be used for benefit assessment due to the lack of a valid comparison.
  • For the endpoints ‘change in BMI’ and ‘change in height’, only absolute values were presented for the changes from baseline, as opposed to norm-referenced values (e.g. z-scores).
  • As there is no valid comparison, this endpoint cannot be taken into account for the benefit assessment either.
  • Consequently, no conclusions can be drawn regarding the extent of the additional benefit for the morbidity category.
• quality of life
  • No results on quality of life were presented.
• Side effects
  • The median duration of treatment was 809 days in the ProLon1 study and was only slightly shorter at 755 days in the ProLon2 study.
  • All participants experienced AEs during the course of the studies.
  • Severe AEs of CTCAE grade ≥ 3 were common in both studies.
  • Serious adverse events affected 43% of participants in the ProLon1 study and 34% in the ProLon2 study, with ‘cerebral ischaemia’ (7 per cent) in the ProLon1 study and ‘myocardial infarction’ (11 per cent) in the ProLon2 study were the most common preferred terms.
  • It can be assumed that a significant proportion of the AEs are attributable to the symptoms of the underlying condition.
  • No analyses are available in which aspects of the underlying condition have been factored out of the AEs.
  • Furthermore, particularly for the ProLon2 study, it is unclear whether it was possible to record all AEs in full, given the relatively long intervals between telephone follow-ups.
  • Given the lack of a valid comparison, the small sample size and the limitations in the collection and analysis of safety data regarding the recording of disease symptoms, no conclusions can be drawn regarding the extent of the additional benefit for the ‘side effects’ category.
• Overall assessment / Conclusion
  • For lonafarnib for the treatment of patients aged 12 months and over with Hutchinson-Gilford progeria syndrome (HGPS) or progeroid laminopathy, results are available from the open-label, single-arm Phase II intervention studies ProLon1 and ProLon2 for the endpoint categories of mortality, morbidity and side effects.
  • In addition, the pharmaceutical manufacturer has submitted a further study in which patients with HGPS treated with lonafarnib are compared with untreated controls in terms of survival, based on data from the Progeria Research Foundation’s ‘International Progeria Registry’.
  • This is a non-adjusted indirect comparison without a bridge comparator.
  • The indirect comparison submitted cannot be taken into account due to the limitations described.
  • For the mortality category, no conclusions regarding the extent of the additional benefit can be drawn due to the absence of a control group.
  • In the morbidity category, no conclusions regarding the extent of the added benefit can be drawn for the endpoints ‘rate of weight gain’, ‘change in BMI’ and ‘change in height’, as only absolute values – as opposed to norm-referenced values (e.g. z-scores) – were presented for the extent of the additional benefit, and a valid comparison is therefore lacking.
  • No results were presented in the quality of life category.
  • Given the lack of a valid comparison, the small sample size and the limitations in the collection and analysis of safety data regarding the recording of disease symptoms, no conclusions regarding the extent of the additional benefit can be drawn for the ‘Side effects’ category.
  • It is not possible to quantify the extent of the additional benefit on the basis of the data provided.
  • Overall, a non-quantifiable additional benefit is inferred for lonafarnib, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.