In 2019, Xtalks profiled six Parkinson’s biotech companies that were leading the way in disease research and drug development. Two years later, we wanted to check in on the progress these companies have made in developing treatments for the progressive neurodegenerative disorder.
Like other neurodegenerative disorders, such as Alzheimer’s disease and dementias, Parkinson’s disease research has been immensely challenging for biotechs, with a high rate of late-stage attrition in trials leading to a lack of disease-modifying therapies being approved.
Read on to learn about the latest updates from Parkinson’s biotech companies Prevail Therapeutics, Axovant Gene Therapies, Voyager Therapeutics, Inflazome, Denali Therapeutics and Neuropore Therapies, and also find out about some emerging players in the Parkinson’s disease space.
1. Prevail Therapeutics
In late March 2019, New York-based Parkinson’s biotech company Prevail Therapeutics had just secured $50 million in investments in a Series B financing round. The gene therapy company was focused on applying adeno-associated virus (AAV) vectors to developing a one-time treatment for patients with Parkinson’s disease who have specific genetic mutations.
Genes encoding lysosomal enzymes were targets for their gene therapy candidates, as lysosomal dysfunction leads to the buildup of toxic waste materials in cells, which is thought to contribute to the onset and progression of neurodegenerative diseases like Parkinson’s.
Acquired by Eli Lilly for $880 million in December 2020, Prevail Therapeutics currently has three compounds under development, one of which is designed to treat Parkinson’s. Currently being tested in the Phase I/II PROPEL trial — announced in June 2019 — PR001 is the company’s first compound and is being developed to treat patients with Parkinson’s disease with confirmed mutations in the GBA1 gene (PD-GBA).
GBA1 encodes for beta-glucocerebrosidase (GCase), a lysosomal enzyme that is responsible for regulating the organelle’s ability to get rid of glycolipids. Cellular accumulation of α-synuclein is a hallmark of Parkinson’s, and it’s been postulated that dysfunction of GCase in neurons could contribute to build-up of the protein and the resulting inflammation and neurodegeneration characteristic of the disorder.
In fact, mutations in the GBA1 gene are currently the most significant risk factor for the development of Parkinson’s disease, with up to 12 percent of Parkinson’s patients worldwide having at least one mutation in the gene. According to Prevail, this amounts to 90,000 patients in the US, making GBA1 an obvious target for gene therapy.
Prevail’s gene therapy is designed to compensate for the dysfunctional copy of GBA1 and restore the normal functioning of GCase in neurons. PR001 is administered via a single injection into the cisterna magna, a cerebrospinal fluid-filled space on top of the spinal canal.
In July 2019, PR001 was granted Fast Track Designation from the US Food and Drug Administration (FDA), and the company’s composition of matter patent for PR001 was approved in November 2020. The randomized PROPEL trial is recruiting up to 16 patients with moderate to severe PD-GBA, with a subset of patients having already been enrolled and dosed.
In early March 2020, Prevail released a statement saying that interim data from the trial would be released late last year; however, that was pushed back until the middle of this year. The PROPEL trial was almost certainly affected by the COVID-19 pandemic, which forced drug developers to increasingly adopt a decentralized model — something not possible for the route of administration required for this kind of therapeutic. Though dosing was halted at the start of the pandemic, Prevail resumed the trial in late November 2020.
2. Axovant Gene Therapies
In early March 2019, New York-based Parkinson’s biotech company Axovant Gene Therapies had just reported positive interim results from its Phase II SUNRISE-PD trial of an investigational gene therapy for the treatment of the disorder. AXO-Lenti-PD made use of a retroviral vector that originates in lentiviruses to provide host cells with the ability to produce three enzymes involved in dopamine synthesis (tyrosine hydroxylase, cyclohydrolase 1 and aromatic L-amino acid decarboxylase).
The company’s Parkinson’s disease therapeutic development program focused on stabilizing dopamine levels in the brain, an approach well-supported by research and the fact that L-dopa is a mainstay in the management of Parkinson’s symptoms. AXO-Lenti-PD was designed to be a one-dose, long-lasting dopaminergic strategy to treating the disease, which could reduce patients’ reliance on daily L-dopa medication.
Indeed, Axovant’s interim results from the SUNRISE-PD trial supported its gene therapy approach; low-dose AXO-Lenti-PD was associated with an average improvement of 42 percent in patients’ Unified Parkinson’s Disease Rating Scale (UPDRS) Part III score. However, this first cohort included just two patients with advanced Parkinson’s disease, one of whom saw double the improvement in the UPDRS scale compared to the other.
After closing a $74.7 million public offering in February of last year, Axovant entered the beginning of the pandemic on solid footing with all four patients enrolled in the second cohort of their SUNRISE-PD trial having already been dosed with AXO-Lenti-PD, and with remote data collection being an option they were prepared for.
In October of last year, Axovant shared positive half-year follow-up data from this second cohort, which included “meaningful improvements in quality-of-life measures.” However, COVID-19 impacted one patient’s ability to participate in all aspects of the trial, while another refused to do the UPDRS assessments.
By November 2020, Axovant had rebranded to Sio Gene Therapies citing cumulative changes to both its scientific approach to drug development and its corporate leadership team as reasons for the name change.
Though the company expected to begin enrollment into a sham-controlled EXPLORE-PD Phase II trial this year, manufacturing delays experienced by its CDMO partner Oxford Biomedica have made it unlikely that this AXO-Lenti-PD study will begin by the end of 2021. Unrelated to the manufacturing problems with AXO-Lenti-PD, Oxford Biomedica has also been busy accelerating production of AstraZeneca’s COVID-19 vaccine at its OxBox site in the UK.
3. Voyager Therapeutics
Like Prevail, Massachusetts-based Voyager Therapeutics is another Parkinson’s biotech company that was also focused on applying AAV vector technology to the treatment of Parkinson’s disease. And while the company had taken a dopaminergic approach like Sio, its Parkinson’s program is unique.
Voyager’s gene therapy relies on the principle that it’s not just the amount of dopamine — and its precursor, levodopa — in the brain that matters, but also levels of aromatic l-amino acid decarboxylase (AADC), the enzyme responsible for converting levodopa into dopamine.
While the most common treatment strategy for Parkinson’s is currently dopamine replacement therapy through daily administration of levodopa medications, this is less effective for patients with advanced stages of the disease who have lower concentrations of AADC in the brain.
Voyager’s investigational gene therapy VY-AADC (also referred to as NBIb-1817) is also a one-time treatment that makes use of an AAV vector to deliver the gene that encodes the AADC enzyme into neurons. The hope is that this will compensate for the lack of endogenous AADC and help improve patients’ response to levodopa medications, resulting in better motor function.
Two years ago, Voyager had just announced a strategic partnership with Neurocrine Biosciences, a San Diego-based Parkinson’s biotech company developing their own adjunctive therapy to levodopa. The company published promising interim results from an open-label Phase Ib trial of VY-AADC in Annals of Neurology in March 2019, but by this point had already moved the gene therapy into a Phase II randomized study, dubbed RESTORE-1, in December of the previous year.
Their goal was to enroll up to 100 patients in the RESTORE-1 trial and simultaneously conduct a Phase III trial (RESTORE-2), based on feedback from the FDA.
Much has changed for Voyager’s Parkinson’s program since then. In April 2020, just after the start of the first wave of the COVID-19 pandemic in the US, Voyager stopped enrolling new patients into RESTORE-1 in an effort to reassess their protocol in the face of the outbreak. Still, the Parkinson’s biotech company was confident that RESTORE-2 would commence on schedule later that year.
By September, the company had released three-year follow up data on VY-AADC from its Phase Ib trial. The results looked good: patients treated with NBIb-1817 showed sustained improvement in UPDRS Part III scores, reliance on Parkinson’s medication was reduced by up to 441.2 mg/day and patients experienced real quality-of-life improvements in the form of more “on” time without dyskinesia, the involuntary movements that are a hallmark of Parkinson’s disease.
Voyager and Neurocrine planned to restart enrollment in the RESTORE-1 trial closer to the end of 2020, and things were looking up. University of California professor Dr. Chad Christine, lead investigator on the study, went so far as to say, “it is our hope that NBIb-1817 has the potential to become the first gene therapy for Parkinson’s disease.”
But just three months later, Voyager faced another stumbling block in the form of an FDA-mandated clinical hold on the trial. An investigational new drug (IND) Safety Report submitted to the regulator detailed “MRI abnormalities” in some of the Parkinson’s patients treated with NBIb-1817, which prompted the independent Data Safety Monitoring Board (DSMB) to ask Voyager to stop dosing patients in RESTORE-1, which had only just started enrolling again since the beginning of the pandemic.
What followed was Neurocrine cutting ties with Voyager Parkinson’s program in February of this year, though the companies will still collaborate on other gene therapies to treat the rare disease Friedreich’s ataxia. But according to the biotech, “Voyager’s understanding is that Neurocrine’s decision to terminate the NBIb-1817 (VY-AADC) program was based on a portfolio review and prioritization of its current pipeline assets.”
It’s now in Voyager’s hands to provide a complete response to the FDA regarding the MRI abnormalities identified in the RESTORE-1 trial and how NBIb-1817 could have contributed to their development. In addition, the Parkinson’s biotech company must make a plan for how to mitigate the risk of these adverse events and “justify [to the FDA] that a favorable benefit/risk profile remains for the product.”
Irish biotech firm Inflazome’s approach to treating Parkinson’s disease was to target the brain inflammation associated with the neurodegenerative disorder. Unlike the other Parkinson’s biotech companies covered in this, and the previous article, Inflazome was working to develop small molecule drugs designed to inhibit pro-inflammatory proteins involved in the innate immune system pathway known collectively as the NLRP3 inflammasome.
Its lead candidate, an NLRP3 inhibitor called inzomelid, is capable of passing through the blood-brain barrier to deliver the drug to affected neurons. In March 2019, the company secured over $1 million in funding from the Michael J. Fox Foundation to support research into the development of a specific tracer for NLRP3 to aid in PET imaging of neuroinflammation. If developed, this tracer would enable Inflazome to detect NLRP3-mediated inflammation in the brain and use it as a biomarker to support recruitment and enrollment of suitable patients into their clinical trials.
In November 2019, Inflazome advanced inzomelid into a Phase I trial assessing the safety and tolerability of the small molecule inhibitor in healthy adults. By March of the following year, the company had released results from the study which found that inzomelid had a favorable safety profile.
While the early-stage trial did not look at the compound’s efficacy in treating Parkinson’s, they did share some preliminary findings on inzomelid’s ability to treat a single patient with cryopyrin-associated periodic syndrome (CAPS), a rare autoinflammatory disease against which Inflazome believed the drug could be effective. Within hours of treatment, the patient’s CAPS-related flare was improved, and they achieved remission within a matter of days.
The results caught the eye of pharma giant Roche, who, in September 2020, inked a deal to acquire Inflazome and its Parkinson’s pipeline for €380 million, plus milestone payments down the line. The last update on the clinical development of inzomelid came in December when a pharmacokinetic (PK) study initiated by Inflazome in early April was withdrawn by Roche, who attributed it to a “strategic decision by sponsor.”
5. Denali Therapeutics
Denali Therapeutics, a San Francisco-based Parkinson’s biotech company, had three small molecular drugs in development in early 2019: one targeting α-synuclein (ATV:aSyn) which accumulates in the neurons of those with Parkinson’s, and two drugs designed to inhibit leucine-rich repeat kinase 2 (LRRK2). ATV:aSyn is designed to bind to α-synuclein and prevent it from dispersing throughout the brain and forming Lewy bodies. Mutations in the gene that encodes LRRK2 are involved in most cases of Parkinson’s disease, including autosomal dominant and sporadic types.
Despite being implicated in many cases of Parkinson’s disease, the function of LRRK2 is not fully understood, though it’s thought to regulate lysosomal function. However, a number of mechanisms have been proposed for its involvement in Parkinson’s disease, including in the aggregation of α-synuclein in Lewy bodies, and in microglia activation associated with neuroinflammation.
In December 2018, Denali had just commenced a Phase Ib trial of DNL201, the company’s lead LRRK2 inhibitor candidate at the time. The study included Parkinson’s patients with and without mutations in the LRRK2 gene to assess the safety and PK/PD of the compound.
Despite meeting both preclinical and clinical data requirements collected to-date, the company made the decision in August 2020 to put development of DNL201 on the backburner in an effort to focus on its other LRRK2 inhibitor, DNL151. Having started a Phase Ib trial for DNL151 in September 2019, the company selected this compound for further development in late-stage clinical trials because of its “pharmacokinetic properties that provide additional dosing regimen flexibility.”
To bolster patient engagement and recruitment efforts, Denali has also launched Engage Parkinson’s, a website designed to educate those with the neurodegenerative disorder and act as a patient registry for the company’s trials.
As of January of this year, Denali announced they would be sharing the results of their Phase Ib study of DNL151 at an upcoming conference. The company also shared they’ll be partnering with biotech industry veteran Biogen in the late-stage development of the LRRK2 inhibitor, with trials slated to commence later this year. The deal is worth $560 million in upfront payments, with an addition $465 million in the form of an equity investment into Denali.
So what about Denali’s α-synuclein blocker ATV:aSyn? According to the company’s pipeline page, the antibody drug is still in the drug discovery stage of development.
6. Neuropore Therapies
One of the California-based Parkinson’s biotech companies Neuropore Therapies took an approach similar to other companies profiled here by targeting inflammation and the accumulation of protein aggregates like α-synuclein. In 2018, the company published data from a preclinical study in a mouse model of Parkinson’s disease of its α-synuclein misfolding inhibitor and lead candidate NPT200-11.
In collaboration with Belgian biopharma UCB, Neuropore also completed a Phase I trial of NPT200-11, which found the compound was well-tolerated in a cohort of 55 healthy volunteers.
The company has benefited from two grants — one in 2017 and one in 2018 — awarded by The Michael J. Fox Foundation for Parkinson’s Research. Both were in support of its toll-like receptor 2 (TLR2) antagonist program, with the goal of discovering novel small molecules capable of addressing neuroinflammation in diseases like Parkinson’s, which were in the lead optimization stage at the time the second grant was awarded.
Since 2019, Neuropore has focused on early-stage development of other small molecule drugs in their pipeline that target neuroinflammation. NPT200-11, now named UCB0599, continues to be developed, with the last update having come in May 2019 when UCB commenced a Phase Ib trial of the small molecule drug.
In the same month, Neuropore started a Phase I study of NPT520-34, a small molecule drug designed to decrease inflammation by targeting microglia and astrocytic markers in the brain. The study was completed in January 2020, which found that the compound was safe and well-tolerated in heathy adults.
According to Neuropore’s pipeline page, both UCB0599 and NPT520-34 remain in Phase I clinical development.
Promising Parkinson’s Biotech Companies for 2021
Dozens of other biotech startups have entered the Parkinson’s disease space recently, many of which are still in the research and preclinical phases of development.
New York City-based Brainstorm Cell Therapeutics is taking a cellular therapy approach to Parkinson’s disease through its proprietary NurOwn platform. Currently in preclinical development, Brainstorm’s technology relies on the collection of a patient’s own mesenchymal stem cells (MSC) which are then differentiated into MSC-NTF cells capable of secreting neurotrophic factors (NTF). These NTFs may activate neuroprotective pathways once they’re reinfused into the patient, potentially slowing disease progression.
Established in 2016 with nearly $20 million in Series A financing, Axial Therapeutics is focused on using biotherapeutics which target the gut microbiome to treat neurological disorders like Parkinson’s. Research suggests that some gut bacteria can increase levels of α-synuclein in the brain through the production of amyloids. Axial’s lead Parkinson’s candidate AB-4166 seeks to block Lewy body formation and help treat colonic dyskinesia and other gastrointestinal symptoms of the disease.
Like other Parkinson’s biotech companies, Boston-based Yumanity Therapeutics is also focused on preventing α-synuclein aggregation in order to slow the process of neurodegeneration. Their small molecule drug YTX-7739 — currently in Phase I of clinical development — is designed to inhibit stearoyl-coa desaturase (SCD), an enzyme involved in the synthesis of desaturated fatty acids. By decreasing the activity of this enzyme, YTX-7739 may be able to prevent α-synuclein from interacting with membranes, thereby reducing aggregation and the formation of Lewy bodies in the brain.
And it’s not just pharmacological therapies that are in development for the treatment of Parkinson’s disease. Medical device company Cala Health believes that neuromodulation through a bioelectronic wearable could be a more tailored treatment for essential tremor associated with Parkinson’s disease compared to currently available medication.
Cala Trio is an FDA-approved device that’s worn on the wrist and that has been shown to reduce tremor power by 50 percent in patients using the device. According to Cala Health, this reduction in tremors is consistent with the benefits of pharmacotherapies without the potential side effects. The company is now investigating the effectiveness of the bioelectronic wearable for treating action tremor, a symptom of Parkinson’s whereby patients experience involuntary movements while trying to perform a task.
In the life science industry, so much can change in a short period of time. The business and clinical development shifts experienced by these Parkinson’s biotech companies from early 2019 until now highlight the agility and adaptability of this industry. However, the COVID-19 pandemic’s toll on drug development also emphasizes the fragility of these processes and underscores the importance of investing in approaches like decentralized trials that can help insulate the industry in the future.
For further analysis of these Parkinson’s biotech companies, listen to this episode of the Xtalks Life Science Podcast.