Pipeline of PD — gene therapy and cell therapy (continued)
| Treatment (sponsor) | phase | patients | Admin route | Start | status | Pt # | Design | Tx duration | Primary outcome m | Secondary | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|
| (Axovant) ProSavin | Diagnosis of PD > five years H&Y 3 and 4 UPDRS (Part III) of between 20 and 60 in the "OFF" state | n: AADC + TH + GTP-cyclohydrolase 1 | ProSavin is a gene therapy designed to delivery three key enzymes involved in the synthesis of dopamine - Primary: safety (1y) - Secondary: UPDRS (6m) Results: A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. | (Palfi, 2014 #1043 (원문 x) | |||||||
| P1/2 | H&y 3 or 4, UPDRS) (III) score of between 30 and 60 in the "OFF" medication Presence of motor fluctuations and/or dyskinetic movement | 32 | two parts to this phase 1/2 study. The second phase will take the optimal dose from part one into a RCT, DB phase in which patients will receive either active AXO-Lenti-PD or an imitation surgical procedure (ISP). | SUNRISE-PD, NCT03720418 | |||||||
| NINDS - AAV2-GDNF | P1 | 25 | OL, Dose escalation (4 doses) | NCT01621581 | |||||||
| AAV2-GDNF, AskBio (a subsidiary of Bayer) | P1b, | ○ The study has two cohorts (Earlier-stage PD and Late-stage PD): 6 patients will be dosed in each cohort | 10 | lxxii) Primary Endpoint: The incidence of treatment-emergent adverse events (TEAEs, 5y) lxxiii) Secondary: MDS-UPDRS, NMSS, DATSCAN: all 18 M ○ AAV2-GDNF gene therapy delivered to the putamen as a single dose infusion using novel bilateral image-guided neurosurgical delivery technology | NCT04167540 |
Cell therapy
| Treatment (sponsor) | type | phase | patients | Admin route | Start | status | Pt # | Design | Tx duration | Primary outcome m | Secondary |
|---|---|---|---|---|---|---|---|---|---|---|---|
| bemdaneprocel (BRT-DA01): BlueRock Tx, a subsidiary of Bayer, (/Memorial Sloan Kettering Cancer Center (MSK)) | Allogeneic Stem cell, human embryonic stem cell-derived mid-brain dopamine neuron cell therapy (MSK-DA01) | 1 NCT04802733) | MSK-DA01 will be administered using a device that is used for injection of fluids into the brain (surgical transplantation), advanced PD The study enrolled 12 patients, with ages ranging from 60 to 78 in the U.S. and 50 to 78 in Canada. These patients had been diagnosed with Parkinson's disease for a duration of three to 20 years and had previously been treated with levodopa, but experienced incomplete response to the medication. | using a device that is used for injection of fluids into the brain (surgical transplantation) | 10 | OPEN LABEL | □ The primary objective: safety and tolerability of DA01 cell transplantation at 1y post-transplant □ The secondary objectives will be to assess the evidence of transplanted cell survival and motor effects at one- and two-years post-transplant, to evaluate continued safety and tolerability at two years, and to assess feasibility of transplantation 20230703: WAS SAFE | ||||
| Aspen | Autologous (patients' own ) iPSC → | ||||||||||
| Novo nordisk | allogeneic |
(Bartus, 2014 #642)
Table 2 Summary of gene therapy clinical programs for Parkinson’s disease
| Treatment (approach) | Trial design | Year began | Subject # dosed | Highest total dose (vg) | Target(S) | Largest volume (μl)/site | Safety results | Efficacy outcomes |
|---|---|---|---|---|---|---|---|---|
| AAV2/GAD | Ph1-uncontrolleda | 2003 | 12 | 1×1012 | Subthal Nuc (unilat) | 50 | Acceptable | Advanced to Ph2 |
| Ph2-double-blindb | 2008 | 22/16* | 1×1012 | Subthal Nuc (Bilat) | 35 | Acceptable | Mixed results; program suspended | |
| AAV2/AADC | Ph1-uncontrolledc | 2004 | 10 | 0.3×1012 | Putamen (Bilat) | 50 | Acceptable | Program suspended; revised Ph1 recently announced |
| AAV2/AADC | Ph1-uncontrolledd | 2007 | 6 | 0.3×1012 | Putamen (Bilat) | 50 | Acceptable | No further testing; revised Ph1 recently announced by USA group |
| AAV2/NRTN | Ph1-uncontrollede | 2005 | 12 | 0.54×1012 | Putamen (Bilat) | 5(10)** | Acceptable | Advanced to Ph2 |
| Ph2A-double-blindf | 2006 | 38 | 0.54×1012 | Putamen (Bilat) | 5(10)** | Acceptable | Mixed results; revised Ph1 designed | |
| Ph1-uncontrolledg | 2009 | 6 | 2.4×1012 | Put + SN (Bilat) | 50 | Acceptable | Advanced to Ph2 | |
| Ph2B-double-blindh | 2010 | 24 | 2.4×1012 | Put + SN (Bilat) | 50 | Acceptable | Program suspended | |
| LENTI/AADC-TH-CH1 | Ph1/2-uncontrolledi | 2008 | 15 | Lentivirus dosing is not comparable to that of AAV## | Putamen (Bilat) | Acceptable | Program suspended; additional work to optimize vector ongoing | |
| AAV2/GDNF | Ph1-uncontrolledk | 2013 | Ongoing | 0.7×1012 | Putamen (Bilat) | 150 | N/A | N/A |
| Synopsis | Total of seven phase 1 and three phase 2 trials | 2003–2013 | >139 | Tested up to 1×1012 vg AAV | Targets have included subthalamic nucleus, putamen and SN | 50 μl (most common); 150 μl (largest) | No safety issues or serious side effects noted | Efficacy outcomes generally disappointing |
AAV, adeno-associated virus; SN, substantia nigra.
aKaplitt et al.13. bLeWitt et al. 201116. cChristine et al.22. dMuramatsu et al.28. eMarks et al.40. fMarks et al.38. gBartus et al.39. hBartus et al.37. iPalfi et al.71. kLonser90.
*Twenty-two subjects were dosed but six were eliminated from efficacy analysis due to mistargeting of cannula. **Two 5 μl volumes infused via single needle tract ~4 mm apart. # Described as a Phase 1/2 trial, this open label (uncontrolled) study does not differ substantially from many dose-escalation Phase 1 safety studies that include secondary efficacy endpoints; thus, the distinction appears to be more a semantic preference than a reflection of a substantial difference in study design.
A five-fold dose range was tested involving 3 dose levels (1.9X107 transducing units (TU); 4.0X107 TU; 1.0X108 TU).
Inflammation
| Target | Treatment | type | phase | mechanism | In vivo results |
|---|---|---|---|---|---|
| NPT520-34 (Neuropore) | Small molecule | P1 (HV) | In PD : TLR activation → DAMPs release, SLC22A8 (transporter) inhibitor → ↓inflammation (astrocytic & microglial neuroinflammation markers) |
기타 MOA들
| Target | Treatment | type | phase | patients | Admin route | Start | status | Pt # | Design | Tx duration | Primary outcome m | Secondary | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CEP-1347 | MLK inhibitor (precept) | P2/3 | Modified Hoehn and Yahr stage less than or equal to 2.5 ( | oral | Futility analysis 결과 조기 discontinuation | 806 | DB, RCT, 10 mg BID, 25 mg BID, or 50 mg BID, or matching placebo, (ie e POC없었네!) | 4W | time to the development of disability requiring dopaminergic therapy (survival analysis): placebo 군 539일, Tx군: 364-457일, (오히려 치료군이 shorter) | lxxiv) Updrs lxxv) DATScan over 22m | lxxvi) |
| Target | Treatment | Mechanism | Design | Reference |
|---|---|---|---|---|
| MTX325 and MTX652, ough, Mission Therapeutics | MTX325 and MTX652 both inhibit USP30, a mitochondrial de-ubiquitylating enzyme (DUB), a deubiquitylating enzyme localised to mitochondria which is a negative regulator of mitophagy. for increasing damage-associated mitochondrial ubiquitylation to promote mitophagy → | announces the start of a Phase I first-in-human clinical trial of MTX325,). has now completed dosing the first cohort of HV in a multi-part, adaptive Phase I study evaluating safety, tolerability, pharmacokinetics and brain penetration of MTX325. Single ascending, multiple dose ascending and elderly HV cohorts are planned in 2024, whereas PD patients will be the focus of the trial in 2025. lxxvii) FDA declined approval 20230326 | ||
| ABBV-951 (AbbVie) | carbidopa-levodopa | |||
| M-Au8® (Clene) | orally-administered, concentrated suspension of clean-surfaced catalytically-active | REPAIR-MS (n=11) REPAIR-PD (n=13) 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the | (Ren, 2023 #2624) |
Uncertain Spans
- “(Axovant) ProSavin” — this row’s left target/category cell is cut off above the visible top of the page; the visible drug-name cell reads “(Axovant) ProSavin”.
- “CEP-1347” — the leftmost edge of the row is truncated by the tile boundary; only “EP-1347” is fully visible. Transcribed as the standard literature name “CEP-1347” (Cephalon’s MLK inhibitor); the leading “C” is inferred but not visible in this page’s crop.
- “MTX325 and MTX652, ough, Mission Therapeutics” — the company name appears wrapped across lines as “…ough, Mission” + “…erapeutics”; transcribed as “Mission Therapeutics” with the partial “…ough” prefix preserved; the prefix may correspond to an earlier word (“Forbough”/“…ough”) that is cut off at the left edge.
- “M-Au8® (Clene)” Primary outcome — sentence ends mid-clause “the mean NAD+/NADH ratio in the …”; the continuation falls outside this page.