Clinical trials suggest peptide may halt ‘relentlessly progressive’ Parkinson’s
Most people think of Parkinson’s disease purely in terms of its effects on motor function. In fact, the condition negatively impacts a wide range of body systems. What’s more, no two patients look exactly alike. This makes developing a cure a considerable challenge.
At the moment, medications can mask symptoms, but are not "disease-modifying" – that is, they cannot slow the progression of Parkinson's. Some evidence has shown that neurotrophic factors like cerebral dopamine neurotrophic factor (CDNF) may offer new disease-modifying avenues for intervention. Unfortunately, getting these proteins into the brain can be difficult.
In response, Finnish biotech company Herantis Pharma has developed a CDNF-mimicking peptide called HER-096. Preclinical data shows that the nine amino acid-molecule easily transcends the blood-brain barrier (BBB) and does the job of its larger cousin despite being just ~5% of its length.
For more on Parkinson’s and HER-096’s development, check out the first part of this story at Tides Global.
Now, with the help of the Michael J. Fox Foundation and Parkinson’s UK, their drug candidate has moved into clinical trial. Herantis CEO Antti Vuolanto was at TIDES Europe in Hamburg, Germany, to share preliminary results.
Clinical optimism
According to a Herantis webinar from October 2023, Phase I clinical trials for HER-096 are split into two parts. In Phase Ia, the goals are to ensure that HER-096 can effectively get past the BBB and to monitor the tolerance of one dose of the peptide. Phase Ib will look at the safety impact and pharmacokinetics of multiple doses. This part of the trial will also investigate the biological effects of the therapeutic.
Early results from Phase Ia studies are positive, Vuolanto reported. He noted that HER-096 appears to be well-tolerated in patients. He even offered a preview of Phase Ib, which is currently underway. He says this phase will involve “up to 24 early- to mid-stage Parkinson's patients” and “two administrations per week for four weeks, with subcutaneous administration.”
Of note, Herantis chief scientific officer Henri Huttunen conceded to Tides Global that Herantis isn’t entirely sure what allows HER-096 to cross the BBB. “There is nothing special in the formulation the drives BBB penetration,” he said. “We currently do not fully understand the molecular mechanism.” Nevertheless, he and Vuolanto revealed that their clinical trials indicate strong BBB penetrance.
One of the key questions around HER-096 is when it should be given to Parkinson’s patients. “The potential of HER-096 is firstly being trialed in people with early-stage Parkinson’s, whose condition is stable,” Arthur Roach, director of the Parkinson’s Virtual Biotech at Parkinson’s UK, explained toTides Global. “This is quite common in clinical trials looking at potentially disease-modifying therapies in Parkinson’s as this group of people have lost less dopamine-producing brain cells than those with more advanced Parkinson’s. This makes it easier to see whether potential treatment might be protective."
“As these treatments (as far as we know) do not promote neurogenesis, it is quite likely that best efficacy would be seen in early-stage patients,” Huttunen added. “Currently, we do not know if there is a certain stage in the disease process after which the efficacy would gradually be lost. If there is, it could be also very variable as Parkinson’s is an etiologically highly heterogeneous disease.”
Huttunen said patient inquiries regarding HER-096 are already beginning to snowball. “A good example of the interest is that for the ongoing Phase Ib study that just started patient recruitment, we are looking for 24 Parkinson’s patients,” he said. “In a short time, more than 100 patients contacted the site and volunteered for the study, even though they know that it is only a short safety study, not a long-term treatment for them.”
Jesse Cedarbaum, professor, neurologist, and clinical trialist at Yale School of Medicine, told Tides Global that current treatments mostly focus on symptoms. “We have very good symptomatic treatments for the disease, primarily motor manifestations,” he said. “But underneath this, the disease is relentlessly progressive.” For this reason, he is encouraged by new medicines like HER-096 that seek to halt or even reverse the damage done by Parkinson’s rather than merely manage how it manifests.
For individuals and families eager for these ostensibly game-changing treatments, the drug development process can be overwhelming. “Overall, the sentiment among Parkinson’s patients is at the same time hopeful but also somewhat frustrated with slow or no progress so far in the development of disease-modifying therapies,” Huttunen said.
To this end, he believes “2029–2030 is probably the earliest” this drug could hit the market.
Liminal limitations
One important point to highlight with HER-096 is that while it shows efficacy in addressing symptoms and potentially even halting disease progression, it can’t save neurons destroyed by inflammation. This means patients with advanced Parkinson’s could see limited benefits versus those at earlier stages.
Vuolanto illustrated the issue in numbers. “At the time the first symptoms appear in Parkinson's disease, you have a loss of approximately 50% of the dopaminergic activity already,” he said. “When it progresses for ten years, you might have maybe 10% left of the activity.”
Antti Vuolanto, CEO, Herantis Pharma
“Our treatment definitely cannot grow new neurons,” he emphasized. “They can, in a way, reprogram those neurons that are not functional. But if a neuron is dead, it is dead. Stem cell therapy would be the only option there.”
Cedarbaum also highlighted potential critiques of HER-096 based on what he has seen so far. “This molecule has a very short half-life,” he said. “They need to work through – and maybe they have – how to go from a two-hour half-life drug to something that stays onboard to continuously suppress the unfolded protein response [UPR]. They could use a hyaluronic acid formulation that would give it a longer residence time in the tissue.”
On the other hand, a short half-life may be a bug rather than a feature. “Maybe their theory is that you only want to do this intermittently,” he continued. “They mentioned that a potential downside with chronic administration would be blocking the UPR. The UPR is something you want to have active if you have a tumor, so there's a yin and yang with neurodegeneration and oncogenes. That's a liability they're going to have to deal with down the line.”
Moreover, Herantis is really the only game in town when it comes to taking this specific UPR-focused approach. “They're the only lab that's doing this. I can't say that a totally independent lab has taken the trouble to reinvent their reagents and repeat the experiments,” Cedarbaum said. “I can tell you that the phenomena in animal models and cell culture are robust.”
Nevertheless, Cedarbaum believes the underlying hypothesis of HER-096 seems viable, even if it’s only one of many opportunities to tackle Parkinson’s. “The unfolded protein response, proteostasis in general, is one of the things that's messed up in Parkinson's disease, for sure,” he said. “And it probably also has knockon effects on mitochondrial function, lysosomal function, et cetera. So it is a point of attack.”
And Cedarbaum has another prediction: HER-096 may be a peptide now, but it might not remain one forever.
“If you've got a cryo-EM structure, you know how you're docking with your ligand, and you've got good synthetic chemists – which I think they know how to find – then you can go from what they've got to an agonist or an allosteric modulator that will do the same job,” he speculated. “But that's several years’ worth of work.”
“[HER-096] may turn into a drug, but if it doesn't, they're already well on the way to finding small non-peptide molecules that could do this.”
In the meantime, even if HER-096 doesn’t succeed in clinical trial, Vuolanto noted that the company has four backup peptide formulations to try in its place.
Paying for peptides
There are outstanding questions about how accessible HER-096 will ultimately be when and if it makes its way to patients. If Cedarbaum is right about a future pivot to small molecules, this could also affect pricing in a positive way.
“Obviously, the holy grail are small molecules,” he said. “Novartis has one which may or may not go forward. There are a number of small molecules targeting some genetic targets, like LRRK2 and glucocerebrosidase. Roche has a small molecule targeting the proteasome, an analogous approach to [HER-096]. Small molecules will be more accessible, depending on how companies end up pricing them.”
One of the other rate-limiting factors is regulatory approval. “There are a number of groups working with the US Food and Drug Administration and the European Medicines Agency to try to smooth out the process for clinical trials for disease modification of Parkinson's,” Cedarbaum elaborated. “[These trials have] an additional layer of difficulty because you have the availability of these symptomatic drugs which work very early in the disease and screw up your ability to measure disease progression. So trial design is a big, big issue.”
However, he is optimistic that HER-096 will eschew some of the pitfalls of other drug candidates. “Many of the drugs that are in development are antibodies,” he said. “These are going to require infusions and be very, very costly. This drug will probably be cheaper to produce.”
Roach further pointed out that initial price tags aren’t always the final word on drug affordability.
“Even if a new treatment starts out as an expensive patent-protected drug,” he said, “that patent will expire and the inexpensive generic forms will become available with multiple manufacturers in competition, which will lead to low prices.”
He added that Parkinson’s UK has a role to play in this process by advocating for and platforming patients and their interests. The charity is also invested in reducing costs by investigating currently approved drugs for potential “repurposing” in the context of Parkinson’s.
As for Herantis, their focus remains on drug development for the time being. “We have not been able to address issues like accessibility of treatments in developing countries yet,” Huttunen said. “We believe that what we can do best is to develop disease-modifying treatments in indications where there is a major unmet medical need.”
