On 20 June, Annovis Bio announced that the company had received a positive safety review of their Phase III trial of buntanetap in patients with early Parkinson’s disease (PD) (NCT05357989) from the Data and Safety Monitoring Board (DSMB). As such, the DSMB recommended that the trial continue as originally designed. Should buntanetap demonstrate good efficacy and safety profiles, the drug could be the first α-synuclein-targeting product to enter the market. GlobalData forecasts that buntanetap will launch in the US and 5EU (France, Germany, Italy, Spain, and the UK) in Q4 2026 and Q4 2028, respectively.

The six-month prospective, randomised, double-blind, placebo-controlled clinical trial investigating the efficacy, safety, and tolerability of buntanetap in patients with early PD was initiated in August 2022. During the DSMB safety evaluation, a total of 414 patients were enrolled in the US and Europe. The DSMB found that each adverse event (AE) was less than 2% of the enrolled study population and there were no reports of buntanetap-related serious AEs. Furthermore, a 6% drop-out rate was observed. The positive safety review enables the trial to move forward as planned and the study is estimated to be completed by December 2023.

The current medications used for the treatment of PD are limited to dopaminergic therapies that provide only symptomatic relief of motor symptoms, leaving ample opportunities for new entrants into the PD market. The need for disease-modifying therapies (DMTs) is one of the highest unmet needs in the field and was consistently highlighted by key opinion leaders (KOLs) previously interviewed by GlobalData. Aggregates of α-synuclein present inside Lewy bodies have been identified as the pathological hallmark of PD and play an important role in disease pathogenesis and neurodegeneration. Buntanetap is being developed to be a first-in-class oral product that may possess disease-modifying properties by inhibiting neurotoxic proteins, including α-synuclein, potentially preventing the formation of toxic aggregates and in turn halting disease progression.

Set to compete with buntanetap is Roche/Prothena’s prasinezumab, a monoclonal antibody targeting α-synuclein, administered as an intravenous infusion. Prasinezumab is currently being studied in a multicenter, randomized, double-blind, placebo-controlled study called PASADENA (NCT03100149), consisting of three parts. It will evaluate the efficacy of prasinezumab against placebo over 52 weeks in participants with early PD. Part two of prasinezumab’s trial PASADENA did not meet its primary endpoint of reducing motor and non-motor symptoms in early-stage PD. However, it provided enough signs of efficacy in secondary outcome measures and had a good safety profile, leading the company to advance it into a further global Phase IIb study called PADOVA (NCT04777331), with a primary completion date of July 2024. GlobalData forecasts that prasinezumab will launch in the US in Q4 2029.

KOLs agreed that if a disease-modifying or neuroprotective agent was approved for PD, it could bring a major shift in the way these patients are treated. However, KOLs also expressed concerns about their likelihoods of success, largely because it is unclear whether targeting extracellular α-synuclein protein with buntanetap or prasinezumab will slow the progression of PD and offer enough functional benefit to PD patients. Additionally, the lack of validated endpoints and biomarkers measuring disease-modifying properties remains a major hurdle in the development of novel treatments. Unfortunately, unlike amyloid imaging for Alzheimer’s disease, an α-synuclein imaging tool is not available. As such, advancement in assessing α-synuclein as a biomarker for PD is considered to be a very important step toward developing DMTs. So far, α-synuclein levels have mainly been tested in cerebrospinal fluid, which adds a major challenge to studies due to the invasive process of collecting these samples. Therefore, alternative methods are needed that will enable α-synuclein tracing in plasma, blood, or saliva.

Targeting α-synuclein as a mechanism of action has yet to be proven in larger Phase III clinical trials, and previous attempts to target this protein have failed. For example, Biogen’s cinpanemab failed in its Phase II trial SPARK (NCT03318523) in February 2021, leading the company to halt its development for PD. However, companies developing DMTs in PD will be heavily rewarded from the investment in this risky R&D space. If found to slow PD disease progression, buntanetap and prasinezumab have the potential to revolutionise the treatment of PD.

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