DUBLIN – By late 2019, early stage Finnish biotech firm Herantis Pharma plc aims to have a readout from its lead development program, which involves the intracerebral delivery of a first-in-class neurotrophic growth factor to Parkinson's disease patients, and to have completed recruitment onto a phase I/II trial of a novel gene therapy in patients with lymphedema arising from breast cancer treatment.
It's a full agenda for a company operating on a shoestring budget. If European biotech has historically been the poor relation of its U.S. counterpart (although that situation is changing), Finnish biotech has been among the poorest of those poor relations. Herantis CEO Pekka Simula attributes the funding gap to the absence of a strong pharma tradition in Finland. But Finland has a strong tradition of academic research. Espoo-based Herantis rests on the research of two academic superstars based at the University of Helsinki, Kari Alitalo, long one of Europe's most highly cited researchers and a foreign associate member of the U.S. National Academy of Sciences, and Mart Saarma, who identified cerebral dopamine neurotrophic factor (CDNF), a growth factor for dopaminergic neurons, over a decade ago.
The company is halfway through the recruitment process for the CDNF trial in Parkinson's and expects to complete the task by year-end. The study is assigning 18 patients to one of three arms – placebo or one of two doses of CDNF, delivered to the putamen. Although the primary endpoint is safety, Herantis is also looking out for early efficacy signals.
The delivery method it is employing is unusual for the type of therapy involved. Rather than using a gene therapy vector – an approach first undertaken in Parkinson's as far back as 2007 – it is collaborating with Wotton-Under-Edge, U.K.-based Renishaw plc, which has developed a surgically implanted catheter-based drug delivery device. That is connected to a drug port, fitted behind the patient's ear, which can be connected to a drug pump for monthly infusions.
Gene therapy, Simula told BioWorld, is still too immature for his liking in this particular setting. "Still today, there are not any robust technologies to switch off expression," he said. "We didn't feel it was the right ethical approach, especially in a first-in-human study." The surgical procedure required for implanting the Renishaw system is akin to that used in deep brain stimulation. "There's a lot of acceptance for the procedure," Simula said.
Upwards of a dozen gene therapy trials in Parkinson's have, so far, not delivered any clear-cut clinically meaningful benefit to patients. The disparate approaches undertaken have variously delivered genes encoding enzymes involved in neurotransmitter metabolism (e.g., glutamic acid decarboxylase and aromatic L-amino acid decarboxylase (AADC)) or growth factors that may protect neuronal death (glial-derived neurotrophic factor and neurturin). Several programs are ongoing, including Voyager Therapeutics Inc.'s VY-AADC, which has received regenerative medicine advanced therapy (RMAT) designation from the FDA and which is now progressing to a pivotal program.
CDNF, Simula said, addresses three different aspects of Parkinson's pathology: It protects or restores dopaminergic neurons from endoplasmic reticulum (ER) stress, which arises from the accumulation of misfolded proteins, especially mutant forms of alpha-synuclein; it is also active in alpha-synuclein models of the condition; and it also inhibits neuroinflammation. A key issue is to administer therapy before too many dopaminergic neurons undergo irreversible apoptosis – the goal of therapy is to rescue neurons that may have lost their phenotype but have yet to enter a cell death pathway.
In a nonhuman primate model – the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model – the approach led to a twofold improvement in living dopaminergic neurons. CDNF was administered several months after the introduction of the lesion that models the disease. The clinical trial, in contrast, is recruiting patients with a five- to 15-year history of motor symptoms. It is not clear, Simula said, how many dopaminergic neurons are lost at time of disease onset. "Obviously it's a high-risk approach," he said.
The company is also researching an alternative, subcutaneous formulation of CDNF, which has been altered to enable the protein to cross the blood-brain barrier. That program is at the lead optimization stage, but the company is not releasing further details until it completes the necessary patent filings.
Its gene therapy program, based on one aspect of Alitalo's wide-ranging work on cancer and vascular biology, involves the adenoviral vector delivery of vascular endothelial growth factor C (VEGF-C) to breast cancer patients who have experienced damage to their lymphatic system following mastectomy or radiotherapy. Current therapies are symptomatic at best – they include physiotherapy, massage and the use of compression garments. Herantis aims to stimulate the regrowth of damaged lymphatic vessels. "VEGF-C, which is the focus of our work, is highly specific to lymph angiogenesis," Simula said.
The present study began recruiting patients in Finland over the summer and will start recruiting patients in neighboring Sweden later this year. The enrollment target is 40 subjects, who will be randomized on a 1-to-1 basis to a treatment arm or a placebo arm.
Herantis is listed on Nasdaq Helsinki, but its valuation is at this point decidedly modest – at about €34.4 million (US$40.5 million). It exited the second quarter with €4 million in cash. A European Commission research grant is funding most of the cost of the CDNF study, but the company will need to make an additional cash call in the near future.