Abstract
Introduction
Protein kinases are a group of molecules that play a crucial role in regulating several cellular functions by modulating various protein structures. Kinases mainly act by phosphorylating specific amino acids of the target protein utilizing adenosine triphosphate (ATP) as a phosphate source. This brings about a conformational change turning the target proteins from inactive to active [1]. Such changes alter the signaling cascades, thus bringing the desired effect. Abnormal kinase activation is associated with the pathogenesis of various diseases, with most of the work done in oncology [2]. Preclinical and human studies have demonstrated the abnormal activity of various kinase systems playing a role in Parkinson’s disease (PD) pathogenesis [2]. There are many kinase proteins implicated in PD pathogenesis like c-Jun N-terminal kinases, glycogen synthase kinase 3β, colony-stimulating factor 1 receptor, Leucine-Rich Repeat Kinase 2 (LRRK2), and Abelson Murine Leukemia Viral Oncogene Homolog 1(c-Abl), to name a few [2]. Targeting kinase inhibition as disease modification in PD has garnered increasing interest in the scientific community. Appraising all kinase systems is beyond the scope of the current review, and as such, the focus will be on LRRK2 and c-Abl kinases based on the molecules currently in trial.
Mutations in the LRRK2 gene are linked to the most common autosomal dominant cause of familial PD. LRRK2 is a large multi-domain protein expressed heavily in the immune cells, lungs, and kidneys in addition to the brain. It has two main enzymatic domains, kinase and GTPase, along with other protein interaction domains. In addition to directly regulating proteins via phosphorylation, LRRK2 also modulates cellular processes like autophagy, vesicular trafficking, inflammation, and mitochondrial functions indirectly via a distal downstream effect [3]. While the exact pathogenic pathway is not well understood, increased LRRK2 kinase activity is central to the majority of disease-associated mutations and variants.
Additionally, increased LRRK2 activity is associated with sporadic PD as well [4]. As such, achieving LRRK2 inhibition may result in reduced neuronal degradation. However, developing direct inhibitors has been challenging as LRRK2 expression is not just limited to the brain. Safety concerns exist due to renal and lung histological changes reported in animal studies [5,6]. The molecules studied have been ATP-competing LRRK2 inhibitors, speculated to alter vesicular transportation negatively [7]. This has raised concerns regarding the long-term safety of such inhibition. A proposed solution includes targeting GTP-binding and potential allosteric inhibition of LRRK2 instead [7]. DNL201 and DNL151 are two small molecule LRRK2 inhibitors that have been moved into human trials. LRRK2 inhibition is also being targeted via the antisense oligonucleotide (ASO) against specific LRRK2 mutations to reduce the increased protein expression and the kinase activities. BIIB094 is one such ASO that has been moved into clinical trials.
c-Abl is another kinase system that plays an essential role in normal cellular functioning and maintains a minimally active state at baseline. Preclinical studies demonstrate increased alpha-synuclein aggregation and neuronal degradation in response to aberrant c-Abl activation. While c-Abl acts via multiple pathways, two main interactions are central to neurodegeneration related to increased alpha-synuclein aggregation and reduced clearance. The changes in response to c-Abl activation include increased phosphorylation of alpha-synuclein leading to increased alpha-synuclein aggregation, and phosphorylation of parkin leads to reduced synuclein clearance [3,4,8]. c-Abl molecules on the market were developed for oncology, not central nervous system (CNS) indications, so low blood-brain barrier (BBB) penetrance poses a challenge for PD therapeutics.
Nilotinib is currently approved to treat Philadelphia chromosome-positive chronic myeloid leukemia in the USA. Though not the most penetrant among other c-Abl inhibitors, Nilotinib has been shown to reduce synuclein pathology across different animal models and ostensibly also targets other kinases like discoidin domain receptors (DDR), which has also been linked to PD pathogenesis [9]. Two recently concluded Phase 2 studies of Nilotinib in PD have established a reasonably safe drug profile when tested in a carefully selected population [10,11]. Though both the studies had similar effects, the two have diverged paths in regard to decision for future trials due to target engagement evidence interpretation. Nilotinib studies have been published and, as such, will not be included in this review [10,11]. A few c-Abl inhibitors are currently being developed for neurodegenerative disorders with attention to CNS exposure, which will be discussed in this review.
Kinases play an intricate role in PD pathogenesis, and kinase inhibition presents as a promising target. Among other challenges to developing effective therapy, CNS penetration and selective or preferential kinase inhibition to avoid arresting multiple cellular functions are of prime concern.
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Overview of clinical trials for kinase inhibitors
LRRK2 inhibitors
Despite the relatively high profile of LRRK2 in the PD research field, there are only three programs at the clinical stage of development for LRRK2 inhibitors, one from Biogen (BIIB094) and two from Denali Therapeutics (DNL151 and DNL201). All three programs are in phase 1.
BIIB094 is an ASO to the mRNA of LRRK2, aimed at reducing the production of LRRK2. It is being developed by Biogen in collaboration with Ionis Pharmaceuticals. IONIS-HTTRx has demonstrated safety, tolerability, and target engagement of the ASO Ionis technology platform in Huntingdon’s disease and is now in a phase 3 trial in collaboration with Roche [1].
DNL151 and DNL201 are orally-delivered selective brain penetrant small molecule inhibitors of LRRK2. Denali has conducted two phase 1 trials each for DNL151 and DNL201. The first set of studies evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics in healthy volunteers. The DNL201 study (NCT04551534) completed in August 2018 and the DNL151 version (NCT04557800) is still in progress and recruiting. The second is a phase 1b design in people with Parkinson’s (PwP) to evaluate the same parameters. The DNL201 study finished in December 2019 (NCT03710707) and that for DNL151 ended in December 2020 (NCT04056689). The number of dose levels in the Denali healthy volunteer studies is not specified; the phase 1b study of DNL151 in PwP evaluated three dose levels while the same trial design for DNL201 tested two levels.
Safety and tolerability data from phase 1 studies have shown that both molecules meet the criteria set for progression to the next stage. Denali released top line conclusions in August 2020 following an interim review of data from the first 162 volunteers in the DNL151 Phase 1 [3]. Based on these data, DNL151 appears to have an acceptable safety and tolerability profile, and has met the target engagement goals. DNL151 will be moved forward to two phase 2 trials in 2021, as it has pharmacokinetic properties that provide more flexible dosing compared to DNL201. One phase 2 study will recruit patients with LRRK2 mutations, and the other will recruit patients with idiopathic PD. Biogen and Denali are collaborating on the future development of DNL151 [2].
Biogen’s ASO BIIB094 study is a combination of single ascending dose (SAD) and multiple ascending dose (MAD), evaluating six dose levels in the SAD stage and three in the MAD. The drug is administered by intrathecal injection.
The Biogen study is recruiting PwP of up to seven years’ duration with a Hoehn & Yahr (H&Y) score 3. Both Denali phase 1b trials also required a H&Y score of up to three. The completed DNL201 phase 1b also required a sub-group of PwP with a LRRK2 mutation and one without, as does the Biogen BIIB094 phase 1.
Biogen’s phase 1 study is assessing adverse events up to 253 days from baseline. The phase 1 study of DNL201 had a treatment duration of 10 days, extended to 42 days in the phase 1b. Both DNL151 studies extended treatment to 42 days, and both active molecules are being tested at two dose levels. Establishing safety of LRRK2 inhibitors is even more important than usual, given preclinical data in PD models raised toxicity issues [4].
The preclinical pipeline is more reflective of the research interest in the LRRK2 pathway. Arrien Pharma, E-Scape Bio, GSK, Merck, Neubase, and Neuron 23 all have LRRK2 inhibitor programs in the preclinical stage. In addition, Cerevel Therapeutics, Lead Discovery Center, and Servier (in partnership with OncoDesign) have discovery programs under way.
c-Abl tyrosine kinase inhibitors
Four companies have c-Abl inhibitor projects at the clinical stage. Sun Pharma Advanced Research Company Limited (SPARC)’s K0706 (vodobatinib/SCC-138) and Il Yang’s radotinib are in phase 2, while 1st Biotherapeutics’ 1st-101 (FB101) and Inhibikase’s IkT-148009 are both in phase 1. All four experimental treatments are taken orally.
K0706 is a small molecule, brain penetrant, and orally available c-Abl inhibitor that has successfully completed phase 1 [5]. It is now being evaluated in the PROSEEK phase 2b study. Radotinib is already approved for use in Chronic Myeloid Leukaemia (CML), and K0706 is in phase 2 for CML.
K0706 has successfully completed two phase 1 studies with no significant adverse events in either (NCT02970019 and NCT03445338). Preliminary pharmacokinetic data indicate the presence of active drug in cerebrospinal fluid (CSF), suggesting BBB permeability, an important parameter for c-Abl inhibitors, given the issues in previous studies of Nilotinib [6]. Radotinib is also reported to be brain penetrant. A phase 2 study in Dementia with Lewy bodies (DLB) is under way for K0706 in collaboration with Georgetown University in the USA (NCT03996460).
The PROSEEK study is evaluating two dose levels of K0706 versus placebo in a large study of 504 PwP, with outcome measures focused on early efficacy defined as a change in MDS- UPDRS Part II+III over a 40-week intervention period. The trial is recruiting PwP yet to start dopaminergic treatment, and an H&Y score of 2. The treatment period is 40 weeks, a relatively short period for disease-modifying trials. The age criterion is for PwP over the age of 50.
The Radotinib phase 2a is a smaller study with 40 PwP, focusing on safety and pharmacokinetic parameters. There are secondary measures of efficacy at a six-month timepoint, again a relatively short duration, but complemented by a series of biomarker assessments. The age criteria for recruitment are broader at 40-80 years, with an H&Y score 2.5.
As would be expected in phase 1 studies, the outcome measures for FB-101 and IkT-148009 relate to safety, tolerability, and pharmacokinetics. IkT-148009 will also be evaluated for brain penetrance through CSF measurements. FB-101 will be tested in 48 healthy subjects between the ages of 18 and 55. IkT-148009 will be tested in 112 healthy volunteers between the ages of 55 and 70.
Treatment-emergent adverse events will be measured after seven days of treatment with FB-101 and after 14 days with IkT-148009. Both studies will measure similar pharmacokinetic parameters with measurements in single ascending dose (SAD) and multiple ascending dose (MAD) protocols.
We were not able to identify any other c-Abl inhibitors in the preclinical pipeline
[1] Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, Rosser A, Kordasiewicz HB, Czech C, Swayze EE, Norris DA, Baumann T, Gerlach I, Schobel SA, Paz E, Smith AV, Bennett CF, Lane RM. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N Engl J Med. 2019 380(24):2307-2316.
[2] Denali therapeutics press release. Denali Therapeutics Announces Closing of Collaboration and Share Purchase Agreements with Biogen. https://www.denalitherapeutics.com/investors/press-release?id=7766, Last updated October 10, 2020. Accessed on February 28, 2021
[3] Denali therapeutics press release. Denali Therapeutics Announces Decision to Advance DNL151 into Late Stage Clinical Studies in Parkinson’s Patients. https://www.denalitherapeutics.com/investors/press-release?id=7661. Last updated August 6, 2020. Accessed on February 28, 2021.
[4] N. Whiffin, I.M. Armean, A. Kleinman, J.L. Marshall, E. v. Minikel, J.K. Goodrich, N.M. Quaife, J.B. Cole, Q. Wang, K.J. Karczewski, B.B. Cummings, L. Francioli, K. Laricchia, A. Guan, B. Alipanahi, P. Morrison, M.A.S. Baptista, K.M. Merchant, J. Alföldi, I.M. Armean, E. Banks, L. Bergelson, K. Cibulskis, R.L. Collins, K.M. Connolly, M. Covarrubias, B. Cummings, M.J. Daly, S. Donnelly, Y. Farjoun, S. Ferriera, L. Francioli, S. Gabriel, L.D. Gauthier, J. Gentry, N. Gupta, T. Jeandet, D. Kaplan, K.J. Karczewski, K.M. Laricchia, C. Llanwarne, E. v. Minikel, R. Munshi, B.M. Neale, S. Novod, A.H. O’Donnell-Luria, N. Petrillo, T. Poterba, D. Roazen, V. Ruano-Rubio, A. Saltzman, K.E. Samocha, M. Schleicher, C. Seed, M. Solomonson, J. Soto, G. Tiao, K. Tibbetts, C. Tolonen, C. Vittal, G. Wade, A. Wang, Q. Wang, J.S. Ware, N.A. Watts, B. Weisburd, N. Whiffin, C.A. Aguilar-Salinas, T. Ahmad, C.M. Albert, D. Ardissino, G. Atzmon, J. Barnard, L. Beaugerie, E.J. Benjamin, M. Boehnke, L.L. Bonnycastle, E.P. Bottinger, D.W. Bowden, M.J. Bown, J.C. Chambers, J.C. Chan, D. Chasman, J. Cho, M.K. Chung, B. Cohen, A. Correa, D. Dabelea, M.J. Daly, D. Darbar, R. Duggirala, J. Dupuis, P.T. Ellinor, R. Elosua, J. Erdmann, T. Esko, M. Färkkilä, J. Florez, A. Franke, G. Getz, B. Glaser, S.J. Glatt, D. Goldstein, C. Gonzalez, L. Groop, C. Haiman, C. Hanis, M. Harms, M. Hiltunen, M.M. Holi, C.M. Hultman, M. Kallela, J. Kaprio, S. Kathiresan, B.J. Kim, Y.J. Kim, G. Kirov, J. Kooner, S. Koskinen, H.M. Krumholz, S. Kugathasan, S.H. Kwak, M. Laakso, T. Lehtimäki, R.J.F. Loos, S.A. Lubitz, R.C.W. Ma, D.G. MacArthur, J. Marrugat, K.M. Mattila, S. McCarroll, M.I. McCarthy, D. McGovern, R. McPherson, J.B. Meigs, O. Melander, A. Metspalu, B.M. Neale, P.M. Nilsson, M.C. O’Donovan, D. Ongur, L. Orozco, M.J. Owen, C.N.A. Palmer, A. Palotie, K.S. Park, C. Pato, A.E. Pulver, N. Rahman, A.M. Remes, J.D. Riou, S. Ripatti, D.M. Roden, D. Saleheen, V. Salomaa, N.J. Samani, J. Scharf, H. Schunkert, M.B. Shoemaker, P. Sklar, H. Soininen, H. Sokol, T. Spector, P.F. Sullivan, J. Suvisaari, E.S. Tai, Y.Y. Teo, T. Tiinamaija, M. Tsuang, D. Turner, T. Tusie-Luna, E. Vartiainen, J.S. Ware, H. Watkins, R.K. Weersma, M. Wessman, J.G. Wilson, R.J. Xavier, J.S. Ware, A.S. Havulinna, B. Iliadou, J.J. Lee, G.N. Nadkarni, C. Whiteman, M. Agee, A. Auton, R.K. Bell, K. Bryc, S.L. Elson, P. Fontanillas, N.A. Furlotte, B. Hicks, D.A. Hinds, K.E. Huber, E.M. Jewett, Y. Jiang, K.H. Lin, N.K. Litterman, M.H. McIntyre, K.F. McManus, J.L. Mountain, E.S. Noblin, C.A.M. Northover, S.J. Pitts, G.D. Poznik, J.F. Sathirapongsasuti, J.F. Shelton, S. Shringarpure, C. Tian, J.Y. Tung, V. Vacic, X. Wang, C.H. Wilson, M. Daly, T. Esko, C. Hultman, R.J.F. Loos, L. Milani, A. Palotie, C. Pato, M. Pato, D. Saleheen, P.F. Sullivan, J. Alföldi, P. Cannon, D.G. MacArthur, The effect of LRRK2 loss-of-function variants in humans, Nature Medicine. 26 (2020) 869–877. https://doi.org/10.1038/s41591-020-0893-5.
[5] Andrew Goldfine, Robert Faulkner, Vasu Sadashivam, OmidOmidvar, John Hill, Singaravelu Jagadeesan, Anil Sharma, Siu-Long Yao. Results of a Phase 1 Dose-Ranging Trial, and Design of a Phase 2 Trial, of K0706, a Novel C-Abl Tyrosine Kinase Inhibitor for Parkinson’s Disease. Neurology Apr 2019, 92 (15 Supplement) P2.8-047
[6] Sparc: Update on R&D pipeline, https://www.sparc.life/sites/default/files/2020-09/SPARC_Update_on_R%26D_pipeline.pdf. Last updated September 10, 2020. Accessed February 28, 2021
LRRK2 Inhibitors
Biogen BIIB094
The single ascending dose (SAD) is evaluating six dose levels of BIIB094, and the multiple ascending dose (MAD) will test three dose levels. The study is planned to complete in September 2023.
Secondary outcomes are: Serum concentrations of BIIB094. Area under the concentration-time curve from time zero extrapolated to infinity (AUCinf). Area under the concentration-time curve from time zero to last quantifiable concentration (AUClast). Maximum concentration (Cmax). Time to reach maximum concentration (Tmax). Terminal elimination half-life (t1/2).
The timeframe for each of the secondary outcomes for the SAD is pre-dose through day 57; and for the MAD, pre-dose through day 169.
BIIB094 is the first ASO drug to reach the clinical phase of development for PD. The ultimate goal is to attempt to modify the course of PD, slowing or even stopping the progression. Establishing safety and tolerability parameters with a relatively new technology are thus crucial.
[1] Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, Rosser A, Kordasiewicz HB, Czech C, Swayze EE, Norris DA, Baumann T, Gerlach I, Schobel SA, Paz E, Smith AV, Bennett CF, Lane RM. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N Engl J Med. 2019 380(24):2307-2316.
Denali DNL151
Background: Four phase 1 trials have been conducted on DNL151 and DNL201, summarized in the table below.
Denali reported that DNL151 has completed dosing of 162 healthy volunteers in an ongoing Phase 1 study, and completed a phase 1b in 25 PwP [1]. Denali is currently completing further dose escalation cohorts in an expanded Phase 1 and an additional cohort in the Phase 1b study to define the full therapeutic window. Based on the clinical data to date, DNL151 appears to have an acceptable safety and tolerability profile, and has met desired target engagement goals.
DNL201 successfully completed a Phase 1 study in 122 healthy volunteers (NCT04551534) in August 2018 and a Phase 1b study in 28 PwP (NCT03710707) December 2019. Results are yet to be published, but the company has stated that DNL201 has been generally safe and well tolerated in the doses tested and met target engagement and biomarker goals.
Denali has decided that, while DNL201 meets the criteria for progression into further clinical studies, the development will be put on hold in favor of moving DNL151 into two phase 2 studies based on pharmacokinetic properties that provide additional dosing flexibility. The phase 1 study of DNL151 in healthy volunteers is described in more detail below.
Outcome Measures: There are seven primary and two secondary outcome measures. The primary ones are: Incidence of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and discontinuations due to TEAEs. Maximum observed concentration (Cmax) in plasma. Time to maximum observed concentration (Tmax) in plasma. The area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞) in plasma (SAD only). Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC [0-last]) in plasma. The area under the concentration-time curve over a dosing interval (AUC0- Apparent terminal elimination half-life (t1/2) in plasma.
The timeframe for the measures above is up to 42 days.
Secondary outcome measures are the concentration of DNL151 in CSF (following selected single and multiple doses) up to 13 days from initiation; and the pharmacodynamics of DNL151 in whole blood as measured by the percent change from baseline in pS935, up to 42 days.
[1] Denali therapeutics press release. Denali Therapeutics Announces Decision to Advance DNL151 into Late Stage Clinical Studies in Parkinson’s Patients. https://www.denalitherapeutics.com/investors/press-release?id=7661. Last updated August 6, 2020. Accessed on February 28, 2021
c-Abl inhibitors
Radotinib
The study will include dopaminergic drug naïve PwP between 40-80 years of age with Hoehn and Yahr stage of 2.5. They will utilize the MDS clinical diagnostic criteria with a positive DAT scan for inclusion. In addition to standard exclusionary criteria, individuals on certain drugs will be excluded. The comprehensive list of exclusionary drugs includes strong CYP3A4 inhibitors and inducers, P-glycoprotein inducers, and medications that prolong QT interval.
The study is being conducted across seven centers in France.
The secondary outcome measures assess the effect in two main domains, pharmacokinetic and clinical. Pharmacokinetic assessments will be done at 14 days after dose administration, and meas-urements include peak observed drug concentration, time to reach peak drug concen-tration, trough plasma concentration, the area under plasma concentration-time curve, elimination half-life, apparent total drug clearance, and apparent volume distribution. Clinical assessment will include Change in MDS-UPDRS parts I-III at 6 months. Time to initiation of dopamine replacement therapy assessed at 6 months Patient reported outcome will include a change in the quality of life via PDQ-39 and the subject’s clinical global impression scale at 12 months.
Other outcome measures will include the following: Change in Brain DaT SPECT scan CSF concentration of the following at 6 months: alpha-synuclein, Tau, phospho-Tau (p-181), beta-amyloid peptide 1-42. CSF and plasma concentration of Radotinib Serum concentration of NF-L
Radotinib is a potential c-Abl inhibitor alternative drug for PD owing to its superior brain penetration [2,3]. The current study is exploring doses lower than the approved dose for CML. Compared to other kinase inhibitors, Radotinib exerts its effect via c-Abl inhibition only [3]. It is undetermined whether the road to effective alpha-synuclein reduction is via multiple or selective kinase inhibition. While there is conflicting preclinical data regarding Radotinib efficacy, whether this translates to human efficacy is yet to be seen.
[1] A.E. Eskazan, D. Keskin, Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update, Therapeutic Advances in Hematology. 8 (2017) 237–243. https://doi.org/10.1177/2040620717719851.
[2] S. Lee, S. Kim, Y.J. Park, S.P. Yun, S.H. Kwon, D. Kim, D.Y. Kim, J.S. Shin, D.J. Cho, G.Y. Lee, H.S. Ju, H.J. Yun, J.H. Park, W.R. Kim, E.A. Jung, S. Lee, H.S. Ko, The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson’s disease mouse model, Human Molecular Genetics. 27 (2018) 2344–2356. https://doi.org/10.1093/hmg/ddy143.
[3] A.J. Fowler, M. Hebron, A.A. Missner, R. Wang, X. Gao, B.T. Kurd-Misto, X. Liu, C.E.H. Moussa, Multikinase Abl/D.D.R./Src Inhibition Produces Optimal Effects for Tyrosine Kinase Inhibition in Neurodegeneration, Drugs in R and D. 19 (2019) 149–166. https://doi.org/10.1007/s40268-019-0266-z.
[4] YR Do, J.Y. Kwak, J.A. Kim, H.J. Kim, J.S. Chung, H.J. Shin, S.H. Kim, U. Bunworasate, C.W. Choi, D.Y. Zang, S.J. Oh, S. Jootar, A.H. Reksodiputro, W.S. Lee, Y.C. Mun, J.H. Kong, P.B. Caguioa, H. Kim, J. Park, D.W. Kim, Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE), British Journal of Haematology. 189 (2020) 303–312. https://doi.org/10.1111/bjh.16381.
[5] Safety, Tolerability, Pharmacokinetics and Efficacy Study of Radotinib in Parkinson’s Disease - Full Text View - ClinicalTrials.gov, (n.d.). https://www.clinicaltrials.gov/ct2/show/NCT04691661?term=NCT04691661&draw=2&rank=1. Accessed February 28, 2021.
K0706 (Vodobatinib/SCC-138) - PROSEEK TRIAL
The drug is administered orally once-daily, and participants will be assigned to one of the three arms: Low dose K0706 High dose K0706 Placebo
The study visits will include at least 1 screening visit, 10 study treatment visits, and 1 follow-up visit 4 weeks post final study visit. The study is being conducted across 79 centers in the USA and Europe
The secondary outcome measure will assess the change at 40 weeks from baseline in the following: MDS-UPDRS Time to initiation of symptomatic treatment Health-related quality of life as measured by the European quality of life questionnaire 5 lev-el version Clinician global impression severity Parkinson’s disease- autonomic questionnaire Level of K0706
The study will also include other exploratory measures, including effect of the drug on the DaT Scan, Skin biopsy, blood, and CSF levels of K0706. Following exploratory measures will be included: Effect of the active drug on Dopamine Transporter Single Photon Emission Computed Tomog-raphy (DaT SPECT) CSF K0706 levels of progression
[1] O. Antelope, NA. Vellore, A.D. Pomicter, A.B. Patel, A. van Scoyk, P.M. Clair, M.W. Deininger, T. O’Hare, BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia, Experimental Hematology. 77 (2019) 36-40.e2. https://doi.org/10.1016/j.exphem.2019.08.007.
[2] Sparc.life, Research Programs SCC-138 (n.d.). https://www.sparc.life/research-programs/scc-138. Accessed February 13, 2021.
[3] PROSEEK: A Phase 2 Study In Early Parkinson’s Disease Patients Evaluating The Safety And Efficacy Of Abl Tyrosine Kinase Inhibition Using K0706 - Full Text View - ClinicalTrials.gov, (n.d.). https://www.clinicaltrials.gov/ct2/show/NCT03655236?term=Sun+Pharma+K0706&draw=2&rank=3. Accessed February 13, 2021.
FB-101
[1] 1ST BIOTHERAPEUTICS, INC – 퍼스트바이오, 테라퓨틱스, 1stbio, (n.d.). Research and pipeline. http://www.1stbio.com/#press. Accessed February 28, 2021.
[2] Neuraly, (n.d.). Pipeline, NLY02. https://www.neuralymed.com/pipeline. Accessed February 28, 2021.
[3] Safety, Tolerability, and Pharmacokinetics of Oral FB-101 in Healthy Subjects - Full Text View - ClinicalTrials.gov, (n.d.). https://clinicaltrials.gov/ct2/show/NCT04165837. Accessed February 28, 2021.
IkT-148009
[1] IkT-148009 for Parkinson’s Disease and GI complications?: Inhibikase Therapeutics, Inc. (IKT), (n.d.). https://www.inhibikase.com/pipeline/ikt-148009-for-parkinsons-disease-and-gi-complications. Accessed February 28, 2021
[2] A Study to Assess Single and Multiple Doses of IkT-148009 in Healthy Elderly Participants - Full Text View - ClinicalTrials.gov, (n.d.). https://clinicaltrials.gov/ct2/show/NCT04350177?term=ikt148009&draw=2&rank=1. Accessed February 28, 2021