| Compound | Mechanism | Phase / Trial | Design / Patient info | Results | Ref | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Non-Exenatide: Liraglutide (Victoza), lixisenatide, semaglutide | Overview |
investigating the effect of extended-release exenatide (Bydureon) injections versus placebo on progression of disease, non-motor, and motor symptoms. A second phase 2 study in South Korea is studying the effect of Peptron's novel sustained release formulation of Exenatide, PT320, on motor function. [P3, UCL] important, Exenatide-PD3, ISRCTN14552789, NCT04232969, Estimated Study Completion Date : July 31, 2024 PROTOCOL: (Vijiaratnam, 2021 #2793) Sse: The sample size is based on the detectable effect size (primary outcome is the MDS-UPDRS motor subsection in the OFF medication state) for a two-arm (exenatide vs placebo) parallel-group trial design. The calculations assume a common SD of 13.5, and a correlation of 0.70 between baseline and follow-up MDS-UPDRS measurements. These estimates are reasonable based on data from the previous exenatide-PD trial.14 On this basis, 160 evaluable participants divided equally between the two groups is sufficient to detect a difference of 5.0 MDS-UPDRS part 3 points in the OFF medication state between the two groups adjusting for baseline MDS-UPDRS part 3 OFF scores, with 90% power and at a significance level of 0.05. Assuming 20% attrition (withdrawal/lost to follow-up), 200 participants will be recruited. Neuraly (D&D Phamatech)'s NLY01, is in a p2 clinical trial. This novel pegylated form of exenatide will be compared to placebo to assess its safety, tolerability, and efficacy in PD. (NCT04154072, N=240, recruitment to finish by end of the 2021 year); (cf: would like to start AD study (IND cleared, Phase 2b study), N=518): Based on previous blind data analysis (UPDRS Part 3 and Part2+3 with 157 patients), we are very much convinced of a high probability of success in this ongoing Ph2 study. - lixisenatide, liraglutide, and semaglutide are being studied in phase 2 placebo-controlled trials to assess the drugs' effects on motor outcomes in PD (studied by Toulouse University Hospital with Sanofi, Cedars-Sinai Medical Center with Novo Nordisk, and Oslo University Hospital, respectively). The trials of these three re-purposed compounds all involve early-stage PD, with the primary outcome measure of change in motor function from baseline to trial end-point. - These four p2 studies vary in their treatment duration; the study of semaglutide is the longest with 4 years of treatment, with 13.5 m for the study of liraglutide, 12m study of lixisenatide, and 9 m for the Neuraly study of NLY01. The lixisenatide study is unique amongst these four trials in that it has a washout period of 2 m after the 12-m treatment phase. | |||||||||||||||||
| lixisenatide |
P2: LIXIPARK trial (Meissner, 2024 #2771)
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| liraglutide |
P2, Cedars Sinai Medical Center: NCT02953665 https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4212371 liraglutide 1.2 or 1.8 mg SC daily, RCT, 52W, 2:1 randomization, Sixty-three subjects were enrolled and randomized to liraglutide (n=42) or placebo (n=21). There were 12 early withdrawals (9 liraglutide, 3 placebo), 4 of whom completed week 28 endpoint assessments. At 54 weeks, NMSS scores had improved by 6.6 points in the liraglutide group and worsened by 6.5 points in the placebo group, a 13.1 point adjusted mean difference (p <0.05). MDS-UPDRS part III and MDRS-2 score changes did not significantly differ between liraglutide and placebo. Secondary outcome analyses revealed a significant improvement of MDS-UPDRS part II (p=0.001), PDQ-39 (p<0.001), and Parkinson's Anxiety Scale Avoidance Behavior scores (p <0.05) in the treatment group. MDRS-2 sub-scores did not further differentiate study groups, while Delis-Kaplan Executive Function System letter fluency scores favored placebo group (p <0.05). | ||||||||||||||||||
| semaglutide | preclinical | ||||||||||||||||||
| MTK-458, Mitokinin/AbbVie, Small molecule | PINK1 activator □MTK-458 only boost the activity of active-form PINK1, and does not affect the regulatory processes involved in activating or degrading PINK1 | Will p1 SOON. | MPTP, LPS, 6-OHDA https://www.pharmacompass.com/pipeline-prospector-drugs-in-development/mitokinin | ||||||||||||||||
| isradipine | L-Type channel blocker, a dihydropyridine has the highest affinity for Cav1.3 channel, neuroprotective in in vitro and in vivo models of PD | P3, (STEADY-PD III, ), early PD (h&Y ≤2) | A Phase II safety, tolerability, and dose selection study of isradipine in early PD (Mov Disord. 2013 Nov;28(13)) N=336, one dose vs placebo, 36m, {Biglan, 2017 #1563} | Results in clinicaltrial.gov: MDS-UPDRS III off worsening 4.6 vs 4.5 — failed | |||||||||||||||
| UDCA Ursodeoxycholic Acid | P1 University of Minnesota | 4w, before & after, UDCA (50mg/kg/day) | NCT02967250: OL, single group, n=20, MRS 로 ATP 봄. MRS ATP | ||||||||||||||||
| P2 University of Sheffield, The "UP" Study, PI: Oliver Bandmann | , 48w, 30, A Phase II, Placebo Controlled, Double Blind, Randomised Clinical Trial To Assess The Safety And Tolerability Of 30mg/kg Daily UDCA in PD | NCT03840005, MDS-UDRS 3, MRS ATP, PCr, Pi | |||||||||||||||||
| Sathe 2020) OL, single-arm, Univ of Minnesota | 5 sPD patients. UDCA 6W, (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). → 3 patients: The ATP concentrations (mM) at pre/post- UDCA conditions are 2.68/2.73, 2.76/2.79, and 2.72/2.75 in subjects 1, 2 and 4, respectively. In the first 2 subjects, we also observed ↓10% and 48% in the metabolic rate of ATPase reaction, accompanied by ↑5% & 8% of the metabolic rate of creatine kinase reaction in the same brains, respectively. | ||||||||||||||||||
| CF) Parry 2010 | ALS patients, UDCA (15, 30, and 50 mg/kg of body weight per day.), about 100-200x higher drug concentration in serum than in CSF | ||||||||||||||||||
| Non-clinical, Univ of Sheffield, |
Cf) {Mortiboys, 2013 #1524} In Parkin-PD patients fibroblast, Ursocholanic acid: ↑MMP, ↑ATP, ↑mc1,2,3,4 activity, via glucocorticoid receptor with ↑phosphorylatio of Akt, UDCA: ↑ATP in Parkin-PD fibroblast (Fig6D) & in Parkin KO cortical neurons. {Carling, 2020} in sPD fibroblasts: UDCA → ↑MMP, ↑ATP, ↑mc1&4 activity {Mortiboys, 2015 #1525} in LRR2-pd fibroblasts: UDCA → restored ATP {Bell, 2018 #1526} in AD fibroblasts: UDCA → restored MMP and respiration, ↑Drp1 protein amount and localization | ||||||||||||||||||
| Animal model, |
Abdelkader 2016, in Rotenone rat model: UDCA → ↑ striatial DA and ↑ striatal ATP, UDCA reduced the rotenoneinduced nuclear factor- κ B expression and tumor necrosis factor alpha level. Furthermore, UDCA amended alterations in Bax and Bcl-2 and reduced the activities of caspase-8, caspase-9, and caspase-3, Castro-Caldas 2012, MPTP Mouse: UDCA → NEUROPROtection, ↓ ROS (striatum & midbrain). | ||||||||||||||||||
| YTX-7739 (Yumanity) a small molecule | stearoyl-CoA desaturase (SCD) | P1 (SAD) study (Trial NL8258) | • in healthy volunteers, n=40 | lxxxi) | |||||||||||||||
| Phase 1 MAD (Trial NL9172 - Part A) in HV, Part 2 will be in n=30 | Two doses, placebo-controlled, RCT, DB blind, for 14-28 days, n=16, 6:2 ratio | lxxxii) | |||||||||||||||||
| Lu AF28996, Lundbeck | Dopamine D1/D2 agonist, Phase 1 | ||||||||||||||||||
| ABBV-951, Abbvie | Dopamine Precursor (CD/LD, subcutaneous, pump-delivered levodopa-carbidopa formulation (solution) | P3 (NCT03781167, 121 patients |
Cohort 1 is complete and included 2 participants New participants will start with Cohort 2; Cohort 2 will consist of 3 participants Cohorts 3 and 4 will each consist of 4 participants lxxxiii) There is a possibility of adding 1 more cohort including 4 participants (Cohort 5)
| lxxxiv) | |||||||||||||||
| P3 (NCT04380142) 131 patients | 24-hour daily exposure of continuous subcutaneous infusion of ABBV-951 in adult participants with Parkinson's disease1 | lxxxv) | |||||||||||||||||
| comparing continuous subcutaneous infusion of ABBV-951 with oral carbidopa/levodopa tablets for the treatment of motor fluctuations in adult participants with advanced Parkinson's disease |
[results, 근데 이게 NCT0378167의 결과일지도 모름] lxxxvi) The 12-week, 130-subject phase 3 trial pitted ABBV-951 against oral levodopa-carbidopa. Subjects on ABBV-951 experienced a 2.7-hour increase in "On" time, when symptoms are well controlled, versus a one-hour improvement in the oral control cohort. The improvement was evident after one week and persisted throughout the study. | lxxxvii) | |||||||||||||||||
| TC857 (By PTC Therapeutics) | Inhibits 15-Lipoxygenase (= ALOX15), a seminal enzyme in metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. Involved in DA in nigrostriatial (Chou, 2013 #1106) | P1 HV, SAD & MAD | 20210511 The Phase 1 study in HV is now complete (including both SAD & MAD parts) • Data from this study expected in Q2 2021 | lxxxviii) | |||||||||||||||
| GBA-PD에 임상한다고 (GBA GT PRC1 narrative) | |||||||||||||||||||
| NOURIANZ (=Istradefylline, KW-6002) | Kyowa Kirin's Nourianz (istradefylline) antagonist of adenosine A2A receptors → ↑ GABA release | P1 HV, SAD & MAD | 20210802: EMA rejected, he EMA noted that "only four out of the eight studies showed a reduction in 'off' time, and the effect did not increase with an increased dose of Nouryant." | an add-on therapy to treat off periods in Parkinson's disease patients on a carbidopa/levodopa regimen. four 12-w, placebo-controlled Phase 2 and 3 clinical trials NCT00955526, NCT00455507, NCT01968031, and NCT00250393) that assessed the safety and efficiency of two doses (20 mg and 40 mg) of Nourianz to reduce the mean total hours of awake time per day spent in the off state and also lessen motor symptoms. | lxxxix) | ||||||||||||||
| Axed 202207 | xc) | ||||||||||||||||||
| KW-6356 Kyowa Kirin, | a selective antagonist of adenosine A2A receptors (distributed across the basal ganglia, next generation of | P2b , | RCT, db, pcb controlled clinical trial in Japan, 502patients | xci) | |||||||||||||||
Uncertain Spans
- 표 전체가 매우 wide column 구조이며 여러 행의 셀 경계 위치가 시각적으로 정확히 판독되지 않는 부분이 있다 (예: ABBV-951 행의 Phase/Trial 열과 Design 열 분리 위치).
- KW-6356 행 마지막 셀 “next generation of” 다음 단어는 사진 우측에서 잘려 보이지 않는다.
- 페이지 하단 (xc, xci) 행 일부는 사진 가장자리에 걸쳐 있어 footnote 표기 외 추가 셀 내용이 더 있는지 확인 어렵다.
- “Lu AF28996, Lundbeck”의 mechanism cell이 “Dopamine D1/D2 agonist, Phase 1”로 한 셀에 합쳐 보이는데, 원문에서 phase column이 별도였는지 사진만으로는 단정 어렵다.