Levodopa hydrate

iStock, masterzphotois While some drugmakers continue to walk the alpha-synuclein antibody path, others like AC Immune opt for new approaches that could bring the first-ever disease-modifying therapy for Parkinson’s disease. The hunt for a therapy that can alter the course of Parkinson’s disease has been long and arduous, riddled with failed attempts and existential questions about the best way to approach the complex neurological condition. Now, several drugmakers are taking aim at the disease for a stake in what Jefferies analysts see as a potentially $8 billion market by 2035. In a recent note, the firm called the indication “one of the largest untapped opportunities in neuroscience.” Despite years of investment and a patient population expected to exceed 2 million across the U.S. and Europe in the next 10 years, the Parkinson’s pipeline has remained challenged by the intricacies of the disease, including an often late diagnosis, slow progression and varied biology across patients, Jefferies equity analyst Alyna Shamsi told BioSpace . “These challenges have contributed to a long list of clinical failures despite having compelling biological targets,” Shamsi said. “That’s why Parkinson’s has been a very difficult field for pharma as a whole to approach.” The gold standard treatment for Parkinson’s remains the dopamine replacement drug levodopa, which is limited to managing motor symptoms rather than addressing the underlying biology of the disease. Sneha Mantri, chief medical officer at the Parkinson’s Foundation, agreed that a challenging diagnosis journey has greatly complicated the search for new treatments. “One of the big reasons why disease-modifying drugs have failed over and over is because of a delay in recognition and diagnosis,” she told BioSpace , noting that it’s always easier to preserve function that you have than to regain something that you’ve lost. Biogen and Denali Therapeutics announced one such clinical failure in May. The partners were developing BIIB122, also known as DNL151, which was designed to inhibit the protein LRRK2. Dysfunction of LRRK2 is thought to influence the accumulation of misfolded alpha-synuclein protein. Biogen and Denali discontinued a Phase 2b trial of the asset after it failed to slow progression of the disease. The result was the latest in a string of disappointments in the space. Many of these efforts have been aimed at alpha-synuclein, casting doubt on what was once a target thought to be the most promising route to a disease-modifying therapy. Mixed expectations That doesn’t mean alpha-synuclein is down and out in Parkinson’s disease. Swiss pharma giant Roche, which has long focused on the target, boasts the most advanced clinical program in its late-stage antibody candidate prasinezumab, partnered with Prothena Biosciences. While new targets have emerged elsewhere, “alpha-synuclein continues to be backed by the strongest biological evidence in Parkinson’s disease,” the Jefferies analysts said in their Aug. 7 note. But despite Roche and Prothena’s push into Phase 3 , prasinezumab missed primary endpoints in two prior trials called Pasadena and Padova for motor progression in patients with the disease. For Shamsi, these results weaken the alpha-synuclein thesis, and she expressed caution with regard to the ongoing Phase 3 Paraiso trial. “The main concern here is that they had quite mixed Phase 2 results, and we just don’t feel very confident that this massive Phase 3 study is going to be able to resolve the absence of that clear dose response relationship that we saw a lack of in the Pasadena trial, and then in Padova, which was meant to address those limitations,” she said. Results for Paraiso are expected to read out in 2029, according to Jefferies. Beyond antibodies like prasinezumab, other companies such as AC Immune are taking a different approach to misfolded alpha-synuclein. In AC Immune’s case, researchers are developing a vaccine that “could more effectively address the underlying biology” of Parkinson’s disease, Jefferies noted. As an active immunotherapy, the company’s ACI-7104 “is ideally suitable for treatment at early disease stages where long-term treatment to prevent progression is needed,” Martin Zügel, interim CEO at AC Immune, told BioSpace in an email. The FDA last week granted ACI-7104 Fast Track status , and results from part one of an ongoing Phase 2 trial are expected to read out by the end of the year. Zügel said the vaccine stands out in the current Parkinson’s pipeline with a durable antibody response that allows for fewer treatments and therefore a favorable safety and tolerability profile. Still, classic Parkinson’s challenges remain. “The early diagnosis of Parkinson’s is a challenge the whole field faces and represents a significant hurdle, particularly as Parkinson’s progresses relatively slowly,” Zügel said. He pointed to imaging advances such as DAT-SPECT to find dopamine transport in specific regions of the brain as well as tests for misfolded alpha-synuclein proteins to seek out underlying pathology, but added that variability from patient to patient also makes Parkinson’s difficult to identify in early stages. The road ahead AC Immune is also exploring a different target altogether with ACI-19764, which targets inflammation caused by the intracellular sensor protein NLRP3. The company will report results from a Phase 1 study in healthy volunteers soon, according to Zügel, before moving to a second part of the trial in patients with elevated inflammation. Results from that part of the study are expected toward the end of the year. Zügel said the company will “absolutely” look to combination approaches between the two drug candidates down the road, targeting the complementary pathways in a manner similar to oncology drug combinations. Others are also seeking a foothold in NLRP3 targeting. These include Eli Lilly—which announced plans to acquire Ventyx Therapeutics for $1.2 billion earlier this year—as well as Roche , NodThera , the AI-driven drugmaker Insilico Medicine and Brenig Therapeutics . And despite the failure of Biogen and Denali’s highly anticipated LRRK2-targeting asset, several companies are still aiming in that direction, including Denali, which will continue to independently run a mid-stage study in patients who carry the appropriate gene variant. Other contenders include Brenig , Neuron23 and Ionis Pharmaceuticals . When it comes to the overall Parkinson’s picture, Shamsi draws a comparison to Alzheimer’s disease drug development, which has similarly focused on a select few mainstream targets over the years with mixed results. Like in the Alzheimer’s space, Parkinson’s drugmakers are now pouring their effort into different biomarkers that could change the way the disease is approached. “People are trying to think a little bit out of the box, because if alpha-synuclein targeting hasn’t worked for a long time, maybe we’re entering this era of diversification, recognizing that Parkinson’s involves multiple overlapping biological processes,” Shamsi said. “It’s quite a complex area.” At AC Immune, the team has learned lessons from failed trials not just in Parkinson’s but also in Alzheimer’s, “where markers of disease progression can also reliably monitor therapeutic effects.” Mantri also sees an apt comparison in the progress—and lack thereof—in Alzheimer’s disease, specifically with regard to leaps in understanding of Parkinson’s disease biology. “People have been talking about disease-modifying therapies for Alzheimer’s since I was in medical school, and everything failed, failed, failed until these recent anti-amyloid immunotherapies,” she said. “Maybe that’s the direction we need to go with Parkinson’s, because there’s something different about Parkinson’s that we’re not capturing very well in our current understanding of the disease.”