Spotlight − late-stage challengers in Parkinson’s disease

Biogen and Denali stand out among small developers targeting Parkinson's.

Few big developers are seriously pursing Parkinson’s disease, so news last week that Biogen and Denali had canned a phase 3 study of BIIB122 was a blow for this space. A dive into the remaining late-stage pipeline reveals a handful of small companies or academic groups testing a diverse range of mechanisms, all of which are trying to improve on current dopaminergic therapies. 

A long-researched project from the tiny listed developer Annovis Bio is among the most advanced, alongside a couple of repurposed drugs in investigator-sponsored studies. A bit further behind, Anavex and Biovie are hoping to move into pivotal studies soon.

Improving SoC 

Levodopa is the gold-standard dopaminergic therapy in Parkinson’s disease and is often given in combination with an enzyme inhibitor called carbidopa. However, after a few years of treatment many patients experience "off" states when the levodopa wears off in between doses, leading to the re-emergence of motor symptoms such as rigidity and tremor, and non-motor symptoms like anxiety and fatigue. 

As such, the hunt is on for options to turn to when levadopa fails.

By year end Annovis Bio should release topline pivotal data on buntanetap, which is said to work by inhibiting the translation of neurotoxic aggregating proteins.  

Buntanetap's phase 3 study has already passed a blinded interim analysis, conducted on 132 patients who had received two months of therapy on a background of standard of care. The study recently completed enrolment of 520 early patients, and its primary endpoint is MDS-UPDRS parts 2 and 3 at six months. 

In an earlier dose-ranging study the project showed some improvements in total MDS-UPDRS scores, with the biggest effect at 10mg and 20mg, which are being tested in phase 3. Lack of dose response could be a red flag here: the highest two doses, 40mg and 80mg, and the lowest, 5mg, did not score higher than placebo on total MDS-UPDRS. 

Other notes of caution include Annovis's small $126m market cap − a sign of investor scepticism − and buntanetap's long history. The agent was formerly known as Posiphen, went into the clinic more than a decade ago, and has passed through several hands. 

Elements of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
Part 1 Non-motor experiences of daily living, including but not limited to memory loss, problems sleeping, pain, depression & anxiety
Part 2 Motor experiences of daily living such as chewing, getting dressed & walking
Part 3 Motor examination (includes gait, posture, speech, rigidity & tremor)
Part 4 Complications caused by motor symptoms (dyskinesia & motor fluctuations)
Note: a higher score indicates more severe Parkinson disease symptoms. More details here.

Investigator sponsored 

University College London is involved in two phase 3 studies of repurposed drugs.

Most advanced is the Exenatide-PD3 trial, testing the GLP-1 receptor agonist Bydureon. The type 2 diabetes therapy has shown neuroprotective effects in preclinical Parkinson's models.  

Exenatide-PD3's primary endpoint is MDS-UPDRS part 3 in an off-medication state, when patients have not taken their dopaminergic therapy for at least eight hours. 

Patients taking exenatide in the phase 2 Exenatide-PD trial showed a modest improvement in motor symptoms in an off-medication state, with placebo patients worsening. 

A second study also involving UCL, called ASpro-PD, is due to start in September. The trial tests ambroxol, an ingredient found in cough medicine. Ambroxol is said to increase the activity of an enzyme called GCase that could improve the clearance of waste proteins that build up in brain cells. 10-15% of Parkinson’s patients have mutations in the GBA1 gene that result in a lower production of GCase. 

ASpro-PD will recruit patients with both positive and negative GBA1 mutation status, with status confirmed before screening. Other academic centres are also pursuing ambroxol, with the University Medical Center Groningen recently starting a phase 2/3 study that selects for patients with a GBA1 mutation. 

Late-stage setback?

Biogen and Denali are also exploring genetic subtypes of Parkinson's with the LRRK2 inhibitor BIIB122; LRRK2 mutations occur in about 1% of sporadic disease, and 4% of familial cases of the disease. 

The partners recently abandoned the phase 3 Lighthouse trial, which had aimed to enrol 400 patients with this mutation, blaming the “study’s complexity including the long timeline”; completion had been set for in 2031. Efficacy and safety of BIIB122 had nothing to do with the decision, they said. 

The phase 2b Luma study of BIIB122, in early-stage idiopathic disease, will continue and will now also include patients with a LRRK2 mutation. Berenberg analysts estimate that topline data will come in 2025. The primary measure is the time to confirmed worsening in MDS-UPDRS parts 2 and 3 combined score. 

Next stop pivotal 

Two more companies have said they hope to head into late-stage testing soon: Anavex and Biovie.

Biovie’s NE3107 is believed to inhibit neuroinflammation, and two clinical studies in levodopa-naïve patients are planned. The phase 2b Sunrise-1 trial will start in the third quarter, and next year the phase 3 Sunrise-2 will begin. For both the primary endpoint will be MDS-UPDRS part 3 score at six months.  

In an earlier small study more patients given NE3107 plus levodopa were assessed as being in the “on” state in the morning versus those on levodopa alone. The combination also showed improvements in the part 3 score. 

This year Anavex is also expecting to start a six-month pivotal study in Parkinson’s patients with and without dementia. The primary endpoint is expected to be MDS-UPDRS parts 2 and 3.

Previously Anavex reported results with Anavex2-73, a sigma-1 receptor activator, in a phase 2 blinded study and open-label extension in patients with dementia. Patients were allowed to stay on their stable regimen of background medications. In the 14-week blinded study there was an improvement on MDS-UPDRS total score with the high 50mg dose. Details from the lower 30mg have not been disclosed.

Gene therapies? 

The end goal of Parkinson's treatments is a disease-modifying approach, rather than therapies that merely delay symptoms. Here gene therapies could be key; the likes of Meiragtx’s AAV-GAD and Lilly’s LY3884961 are in phase 1/2.

Selected late-stage Parkinson's disease projects
Product Pharma class Company Note
Buntanetap (Posiphen/ANVS401, phenserine) Amyloid precursor protein, a-synuclein & tau inhibitor Annovis Bio Ph3 in early disease, topline data expected by end of year
Exenatide  GLP-agonist University College London Ph3 Exenatide-PD3, PCD Feb 2024
Ambroxol GCase-modulator University College London Ph3 ASPro-PD set to start in Sept 2023, PCD 2027
University Medical Center Groningen Ph2/3 Great, started May 2023, PCD 2025 in patients with GBA1 mutation
BIIB122/ DNL151 Leucine-rich repeat kinase 2 inhibitor Biogen/Denali Ph2b Luma in idiopathic early disease, since the termination of Ph3, Luma will now also include patients with a LRRK2 genetic mutation, PCD 2025
Pivotal planned

Anavex2-73 (blarcamesine)

Muscarinic & sigma-1 receptor agonist Anavex Life Sciences Reported Ph2 blinded and open-label data in Parkinson's disease dementia, plans to start pivotal study
NE3107 Extracellular signal regulated kinase 1 & 2 inhibitor Biovie Recent Ph2 data, preparing to launch pivotal studies
Excludes dopaminergic therapies. PCD=primary completion date. Source: Evaluate Pharma, clinicaltrials.gov & company releases.

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