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20240722_184340

7 min read

TavapadonPartial agonist selectively targeting D1/D5 receptorTEMPO-3 in Late PD
TEMPO-1 (fixed dose) in early PD
TEMPO-2 (fixed dose) in early PD
pioglitazoneP2, NET-PD) FS-ZONE217 individuals with early PD (, 2015 #2076)
NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS respectively). Significant treatment effects were also observed for secondary and exploratory ...
CDNF (HERANTIS) cerebral dopamine neurotrophic factor, peptide, direct surgical implantation,
Unlike other neurotrophic factors, CDNF is not a secreted protein. It is found mainly in the lumen of the endoplasmic reticulum in cells. Studies suggest it regulates the unfolded protein response (UPR) CDNF binds to key targets that modulate UPR signaling (IRE1, PERK, ATF6 and GRP78) ie the C-terminal Domain of CDNF Binding to GRP78 and ER Lumenal Domains of IRE1a and PERK 		clinical Clinical P1/2, 'TreatER' NCT03295786
n=17, randomised, Double-Blind, Placebo Controlled,
Placebo vs mid dose vs high dose, 40w,
inclusion: presence of motor fluctuations, PDuration of PD motor syptoms 5-15 y, at least 5 daily doses of levodopa, UPDRS III 9off) between 25-50, H&Y iii (OFF), RESPONSIVE TO LEVODOPA, 		17 patients at three university hospitals in Finland and Sweden. Participants first underwent neurosurgical implantation of the infusion device in a procedure comparable to the placement of a DBS electrode in advanced PD. Then they received six monthly infusions of recombinant human CDNF, starting at 120 micrograms and escalating to 400 or 1,200 micrograms, or placebo, into their putamina. → After six months, all groups were eligible to receive CNDF monthly for an additional six months, with two years of follow-up. Twenty-four endpoints cover safety and tolerability, plus measures of clinical measures of mood, cognition, motor function, non-motor symptoms and general function; device-related safety, accuracy of implantation and infusion success; formation of anti-CDNF antibodies; DAT PET imaging; and serum and CSF levels of CDNF and α-syn. → partial results from the six-month placebo-controlled main study (presented at slide presentation). It reported no SAE related to CDNF treatment, and only mild to moderate side effects that were similar in treated and placebo groups. Two patients left the study because of serious infections requiring hospitalization, probably related to the device implantation and infusion process. Both recovered, and surgical procedures were altered to prevent future infections, the company said.
  • Full results) In March 2021 at AD/PD, 12-month TreatER trial results were presented. Compared to the first six months, fewer AE were reported during the extension phase, with no dose-limiting toxicities and no detection of anti-CDNF antibodies. Most drug-related side effects were mild to moderate, and all participants recovered. The most common were dyskinesias, headache, low-grade cold, fever, or fatigue, impulse control disorder, nausea, and weight loss. On the exploratory efficacy endpoints, treatment did not worsen symptoms, and some patients showed signs of potential benefits. The low-dose group had a reduction in bradykinesia at six months, as measured with a movement-measuring device worn on the wrist. However, there was no significant difference between groups in the UPRDS motor score. DAT levels in the low-dose group remained stable after 12 months, while the other groups declined. A proteomics analysis of TNF-α, IL-1b, IL-6, IL-10, CCL2 등 봤음, AD-PD 2021 found that changes in previously seen CSF biomarkers were more prominent in the low-dose group. In three patients, proteomics changes correlated with improvement in the UPRDS or DAT-PET.
preclinical In rodent models of toxin-induced dopaminergic cell loss, single intracerebral or chronic brain infusion of CDNF were reported to improve motor function and neuron survival and function (Lindholm et al., 2007; Voutilainen et al., 2011; Airavaara et al., 2012). Cdnf enhanced the therapeutic benefit of acute subthalamic deep-brain stimulation (DBS), a current treatment for PD, in a rat model of late-stage disease (Huotarinen et al., 2018).

The same group, as well as independent investigators, published data on a gene-therapy approach. Using viral vectors to express CDNF in the striatum protected neurons and improved motor behaviors in the 6-hydroxydopamine toxicity model of parkinsonism in rats (Bäck et al., 2013; Ren et al., 2013; Wang et al., 2017).

CDNF was reported to inhibit α-syn oligomer toxicity in cultured dopaminergic neurons (Latge et al., 2015). No data are published on CDNF in α-syn animal models.

In 6-OHDA-lesioned marmoset monkeys, CDNF treatment increased dopamine transporter (DAT) binding activity on PET scans, suggesting it protected dopaminergic neurons (Garea-Rodriguez et al., 2016).
ST-502, Sangamosyn-targeted zinc finger transcriptional repressors at ADPD 2021 conference
ANVS401 Buntanetap (Posiphen) by Annovis Bio B-amyloid precursor protein, alpha-syn inhibitor

Good summary in https://www.alzforum.org/therapeutics/posiphen 		[completed] P2a NCT04524351) AD & PD (Hoehn & Yahr ≤ 4), oral Phase 2, double-blind, placebo-controlled trial
  • The Phase 2 study (NCT04524351) of ANVS401 measured four inflammatory markers that are very prevalent in the brains of AD and PD patients. All four inflammatory markers showed statistically significant reduction after 25 days of treatment with ANVS401 as compared to baseline
    Inflammatory Marker% Change from Baseline
    Complement C3-24.9
    YKL40-22.9
    sTREM2-28.2
    GFAp-34.6
    p value column: 0.0072 / 0.0013 / 0.0108 / 0.000001
  • Annovis believes that this inflammatory marker data substantially confirms the efficacy of ANVS401 in PD patients reported in March
    • Previously in March 2021, Annovis announced interim data of the same Phase 2 study showing ANVS401 improves speed and coordination in PD patients (link)
    • This study Phase 2a study is designed to treat a combined total of 68 patients for 4 weeks with ANVS401
      • The CSF and plasma samples of the 14 PD patients and the 14 AD patients who completed treatment are still being analyzed to measure the reversal of the toxic cascade with additional data expected to be reported in the next two months
        https://www.newsfilecorp.com/release/98604/Annovis-Bio-Announces-Positive-Phase-2-Efficacy-Data-for-the-Treatment-of-Parkinsons-Disease
    • The full study data, including a dose ranging analysis in 40 PD patients, is anticipated in July/August 2021
GLP-1 agonists REVIEW {McFarthing, 2020 #1342} i) Tx binds upregulated GLP-1R in activated microglia → PI3K/protein kinase B (AKT) → FkB → ↓ microglia, ↓ cytokines → ↓ inflammation,

ii) mitogen-associated protein kinase/extracellular signal-regulated kinase (MAPK/ERK (= Ras-Raf-MEK-ERK) → ↑ synapse (LTP, stabilization of dendritic spines) 		Exenatide (Byetta and Bydureon) P2: NCT01174810., {Aviles-Olmos, 2013 #1579} single-blind study of moderately advanced PD randomized to exenatide or control group showed improvement in UPDRS part 3 scores for those who received exenatide improvement by 2.7 points versus a decline of 2.2 points in the control group. In addition, there was a improvement in the Mattis dementia rating scale improvement of 2.8 points in the exenatide treated patients, while the control group deteriorated by 3.5 points [7]. A follow upstudy of the trial cohorts showed that improvements persisted 12 months after cessation of exenatide [8].

P2: {Athauda, 2017 #1578} NCT01971242, Exenatide-PD a double-blind placebo-controlled Phase 2 study conducted in 60 patients with moderately advanced PD

→ At 60w, MDS-UPDRS III, (Off) had improved by 1.0 points (95% CI: in the exenatide group and worsened by 2.1 points (-0.6 to 4.8) in the placebo group. The study confirmed the motor benefits observed in the previous trial with an adjusted mean difference of -3.5 points ]. These effects were maintained but reduced at 12 weeks following the end of exenatide treatment. The benefits of exenatide seen in the open label study was not reproduced in the placebo-controlled posthoc analysis of a wide range of non-motor symptoms showed no significant improvement in the exenatide group when compared to placebo [10].

Jaya: met primary endpoint (sig difference in motor function in exenatide group vs placebo)
→ There remains a question of whether this observed benefit is driven ...
GT
Cell therapy
Inflammation Ongoing: one phase 1, two phase 2, and one phase 3 study. The phase 1 single-center non-placebo controlled study at the University of Florida is specifically examining the change in MRI brain metrics, in addition to symptomatic changes, of PD individuals after 1-year of exenatide treatment. A phase 2 study sponsored by Stockholm Health Care Services is investigating the effect of extended-release exenatide (Bydureon) injections versus placebo on ...

Uncertain Spans

locationtranscriptionuncertainty
CDNF clinical narrative9off) token in UPDRS III 9off)The token 9off) reads as “(off)” in context but is OCR’ed with a leading 9; preserved as printed (likely a stylized open-paren).
ANVS401 inflammatory sub-tablep-value columnThe right-most p-value column is partly cut at the right edge of the source crop; values 0.0072 / 0.0013 / 0.0108 / 0.000001 are read from the visible portion.

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