CDNF: Phase II top-line data early but encouraging
Herantis currently has two ongoing clinical trials: a Phase I/II trial testing its recombinant CDNF (cerebral dopamine neurotrophic factor) in patients with PD and a Phase II trial testing its Lymfactin gene therapy in patients with BCAL secondary lymphedema.
Herantis recently reported preliminary data from a first-in-human Phase I/II study with CDNF in patients with advanced PD. This study has a long follow-up period of four years after the data from the main and extension studies complete. The main study read out at six months and met its primary endpoint on safety and tolerability of CDNF, with all patients volunteering to continue in an extension study, in which they will receive either lower or higher CDNF doses for another six months (Exhibit 1). Similar safety profiles to the placebo group were confirmed in the two CDNF dosing groups. However, two patients discontinued from the study due to infections that were probably related to the drug delivery device.
The secondary and exploratory endpoints of the study evaluated initial signs of efficacy. Promising signals were observed in some patients by dopamine transporter (DAT) PET imaging, which is an indirect measure of the dopaminergic function. Specifically, there was a marked difference between DAT binding potential in the putamen area of the brain between placebo and one CDNF group (-6 to -21% decrease) and the other CDNF group (increase of 17%). Two patients in the CDNF group showed a 37-51% increase in DAT binding potential in the putamen. We highlight that these data are preliminary and based on small patient numbers in a trial powered for safety and not for efficacy.
However, this is an encouraging observation at this early stage, as the patients are at an advanced disease stage and therefore less susceptible to the potential neuroprotective properties of CDNF. This suggests that dosing CDNF in patients with earlier signs of PD could be beneficial given that more dopaminergic neurons are available to potentially protect.
Exhibit 1: CDNF study design: three groups, three parts
Source: Herantis corporate presentation
Top-line results from the extension study are expected in Q320 and, if positive, will suggest that CDNF’s activity is sustained for a year after the first dose. If positive, Herantis plans to start a Phase II trial that will assess the efficacy of CDNF in earlier-stage, well characterised PD patients. This study will use a longer treatment period and recruit a larger number of patients. Patient enrolment is expected in 2021.
Neurotrophic/neuroprotective factors (such as CDNF, MANF and GDNF) are endogenous secretory proteins that have been shown to have neuroprotective and neurorestorative effects, presenting the opportunity for their use in the treatment of PD. CDNF-based therapy is being evaluated for its potential neuroprotective and neurorestorative properties in PD. CDNF is a recombinant factor, large molecule-based treatment that is unable to cross the blood-brain barrier in its current formulation. It therefore needs to be administered into the exact region of the brain (the putamen) where it can target its effect. CDNF is dosed intracranially once a month (two- to three-hour infusion in the outpatient setting) using an implanted drug delivery device with portal access located behind the patient’s ear. The novel drug delivery system (DDS) being used in the study has been developed by Renishaw, a global metrology company headquartered in the UK.
Herantis has in-licensed the global rights to a second generation of CDNF (from the University of Helsinki in July 2018). It has been developing a non-invasive way of delivering CDNF (such as subcutaneous) and has identified a number of candidates that will enter into the lead optimisation phase of preclinical development in 2020.
Lymfactin Phase II AdeLE data expected at the end of 2020
Herantis is developing its Phase II asset, Lymfactin gene therapy, as a potential therapy for BCAL, administered as a single-dose injection in combination with lymph node transfer surgery. The 12-month Phase I follow-up results announced in April 2019 demonstrated that the treatment was safe, with no serious adverse events reported. The study enrolled 15 patients from three universities in Finland (Helsinki, Tampere and Turku). 12-month data from the Phase II AdeLE (adenovirus gene therapy for the treatment of lymphedema) trial in BCAL patients is expected by the end of 2020 (enrolment has completed). If the data readout is positive, a Phase III registrational trial in BCAL could be initiated in 2021 – either by Herantis or a potential development and commercialisation partner. Furthermore, positive safety and efficacy data in BCAL would provide validation of the therapy for investigation in lymphedema from other secondary causes.