This is a randomized, double-blind, multi-center, placebo-controlled dose-ranging clinical trial of two IkT-001Pro doses in patients with PAH designed to assess safety, tolerability and efficacy. It will enroll approximately 150 participants at up to 50 sites globally. The study consists of two parts, a 26 week placebo controlled treatment period (Part A) followed by a 36 month extension period (Part B).

Start Date30 Jun 2025

Sponsor / Collaborator

Inhibikase Therapeutics, Inc.

NCT06454409 / Not yet recruitingPhase 1IIT

A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

Start Date20 Mar 2025

Sponsor / Collaborator

City of Hope National Medical Center

[+1]

100 Clinical Results associated with PDGFRα x ABL x c-Kit x PDGFRβ

100 Translational Medicine associated with PDGFRα x ABL x c-Kit x PDGFRβ

0 Patents (Medical) associated with PDGFRα x ABL x c-Kit x PDGFRβ

Literatures (Medical) associated with PDGFRα x ABL x c-Kit x PDGFRβ

01 Jan 2018·Small Molecules in Hematology

Dasatinib

Article

Author: Lindauer, Markus ; Hochhaus, Andreas

Dasatinib is an oral available short-acting inhibitor of multiple tyrosine kinases. It was designed to inhibit ABL and SRC, but also has activity in multiple other kinases, including c-KIT, PDGFR-α, PDGFR-β, and ephrin receptor kinases. Dasatinib is a very potent inhibitor of BCR-ABL and an effective treatment for the BCR-ABL-driven diseases chronic myeloid leukemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), characterized by the constitutively active tyrosine kinase, BCR-ABL. Dasatinib is approved for the treatment of CML (all phases) including children and for the treatment of Ph+ ALL, resistant or intolerant to prior imatinib treatment. Randomized trials in CML comparing dasatinib with imatinib show that first-line dasatinib causes significantly deeper and faster molecular remissions. In accelerated and blastic phase CML, as well as in Ph+ ALL, dasatinib frequently induces complete hematologic and cytogenetic remissions even in imatinib pretreated patients. Remissions however are often short. Dasatinib is administered independent of food intake as a once-daily dose of 100 mg in chronic phase CML and 140 mg in Ph+ ALL or blastic phase. Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. The review presents the preclinical and clinical activity of dasatinib with a focus on clinical studies in CML.

01 Nov 2017·PharmacogenomicsQ4 · MEDICINE

Precision Oncology: Neither a Silver Bullet nor a Dream

Q4 · MEDICINE

Review

Author: Sánchez, Nora S ; Mills, Gordon B ; Mills Shaw, Kenna R

Precision oncology is not an illusion, nor is it the magic bullet that will eradicate all cancers. Precision oncology is simply another weapon in our growing armament against cancer. Rather than honing in on the failures of a relatively young field, one should advocate for integrating its successes into widespread clinical practice, especially for indications, such as: ABL, ALK, BRAF, BRCA1, BRCA2, EGFR, KIT, KRAS, PDGFRA, PDGFRB, ROS1, BCR-ABL, FLT3 and ROS1, where aberrations have been shown to alter responses to US FDA approved drugs – that is, level 1 data. Moreover, to truly assess the promise of precision oncology, we must first begin by defining our expectations for this field. Importantly, we must recognize that the conception of precision oncology arose as an antithesis of the ‘one-size fits all’ cancer therapeutics approach. Consequently, tools used for evaluating these conventional, large-scale trials, are not directly transferable for assessing nonconventional, smaller-scale trials needed for evaluating precision oncology. Hence, a thorough vetting of precision oncology as another tool of the trade, must first begin by reassessing our expectations for this field, as well as current clinical trial designs and end point measurements. Importantly, we must recognize that most targeted therapy approaches are in their infancy, with only monotherapy approaches being assessed and combination therapies likely being necessary to fulfill the promise of precision oncology.

01 Nov 2016·LeukemiaQ1 · MEDICINE

Aberrations identified by genomic arrays in normal karyotype CMML can be detected in 40% of patients, but do not add prognostic information to molecular mutations

Q1 · MEDICINE

Letter

Author: Meggendorfer, M ; Vetro, C ; Haferlach, C ; Kern, W ; Nadarajah, N ; Haferlach, T ; Zenger, M

Chronic myelomonocytic leukemia (CMML) is a chronic clonal disease characterized by myelodysplastic (MDS) and myeloproliferative (MPN) features.It is defined by the occurrence of peripheral blood (PB) monocytosis (>1 × 10⁹/l) without BCR-ABL1 fusion oncogene or PDGFRA or PDGFRB rearrangements.Cases are further subclassified in CMML-1 (<10% blasts in the bone marrow (BM)) and CMML-2 (10-19% blasts), accounting for 80 and 20% of cases, resp.The genetic landscape is highly heterogeneous.Most frequently mutated genes are TET2 (59-60% of cases), SRSF2 (50-51%), ASXL1 (40-45%), RAS (30%), CBL (15-21%) and SETBP1 (6-15%), whereas TP53 mutations are rare (1%).Majority of patients (up to 70%) show normal karyotype (NK), whereas clonal cytogenetic abnormalities have been identified in almost 30% of cases.Most frequent abnormalities are trisomy 8 (23%), loss of the Y chromosome (20%), monosomy 7 or 7q deletion (14%), complex karyotype (10%), trisomy 21 (8%), abnormalities of chromosome 3 (8%) and 20q deletion (8%).On the basis of the cytogenetic findings, the Spanish group defined three risk classes, i.e., low (-Y and NK), intermediate (karyotype not classified as low or high risk) and high risk (+8 or monosomy 7).Balanced rearrangements have been described rarely.However, chromosome banding anal. (CBA) shows some limits related to the necessity of in vitro replication of the abnormal clone.Moreover, spatial resolution is limited to 10 MB size.Therefore, submicroscopic cytogenetic aberrations cannot be detected.Genomic arrays do not rely on proliferating cells and provide a very high spatial resolution, up to few Kb.Furthermore, arrays can detect not only copy number abnormalities (CNAs), i.e., losses and gains, but also copy neutral loss of heterozygosity (CN-LOH).However, at least 15% of cells should harbor the genomic abnormality to allow a reliable detection.On the basis of these premises, we aimed to evaluate genomic abnormalities in CMML patients with normal CBA through the application of genomic array.One hundred and forty patients have been analyzed.Diagnosis has been performed on morphol. evaluation of PB and BM smears according to the WHO classification (2016).Cytogenetic and genomic array evaluation was performed on BM, and gene sequencing has been performed only on BM in 137 cases and BM/PB in three cases.Samples were referred to MLL Munich Leukemia Laboratory between Oct. 2005 and Feb. 2015.Morphol. and cytogenetic evaluation as well as survival information were available for every patient.Median follow-up was 2.4 years.Cases with normal CBA were further studied with genomic array (SurePrint G3 ISCA CGH+SNP (4 × 180 K), Agilent, Waldbronn, Germany) and data were analyzed using Nexus Copy Number Software v. 6.1 (Biodiscovery, Inc., El Segundo, CA, USA) according to manufacturer's recommendations.Amplicon-based next generation sequencing or polymerase chain reaction were applied to detect TET2, SRSF2, ASXL1, RUNX1, CBL, SETBP1, KRAS, NRAS, JAK2, EZH2, KIT, U2AF1, SF3B1, DNMT3A, SMC1A and CSF3R mutations in all patients.Library preparation was performed with Access Array Technol. (Fluidigm, South San Francisco, CA, USA) and sequencing with MiSeq Instrument (Illumina, San Diego, CA, USA).Part of patients was the validation set published by Itzykson etal.⁸ and were also included in Meggendorfer et al.All patients gave written informed consent for use of data for scientific evaluations.The study was approved by the Internal Review Board and adhered to the tenets of the Declaration of Helsinki.Dichotomous variables were compared between different groups using χ²-test and continuous variables by Student's t-test.Significance was set at P<0.05.Reported P-values are two-sided.Kaplan-Meier method was applied for overall survival (OS) curves and results were analyzed applying the two-sided log-rank test.Cox regression anal. was performed for multivariate anal., including parameters significant (P<0.05) at univariate anal.Median age was 74 years and 95 patients out of 140 (68%) were male.Mean white blood cell (WBC) count was 17 × 10⁹/l (±20 s.d.) with a mean percentage of monocytes of 29% (±12).The mean absolute monocyte count (AMC) was 5.2 × 10⁹/l (±6.1).Thirty-one patients (22%) showed CMML-2 morphol.Ninety-five out of one hundred and forty patients (71%) showed a NK by CBA, whereas the remaining 41 patients (29%) showed CBA abnormalities.These two groups did not differ for age, gender, WBC, AMC, Hb and CMML subtype.However, the group with abnormalities showed lower platelet count (mean 186 vs 131 × 10⁹/l, P=0.004).In NK subgroup, mutations were identified at the following frequencies: TET2 (76/99, 77%), SRSF2 (55/99, 56%), ASXL1 (47/99, 48%), RUNX1 (20/99, 20%), CBL (14/99, 14%), SETBP1 (8/99, 8%), KRAS (12/99, 12%), NRAS (10/99, 10%), JAK2 (10/99, 10%), EZH2 (5/99, 5%), KIT (5/99, 5%), U2AF1 (5/99, 5%), SF3B1 (4/99, 4%), DNMT3A (2/99, 2%) and SMC1A (2/99, 2%).No mutations were detected on CSF3R gene.TET2 mutations were more frequent in NK subset (77 vs 56%, P=0.024), whereas SETBP1 mutations were more frequent in abnormal CBA subset (8 vs 22%, P=0.04).No statistical differences were evident regarding remaining genes.Applying genomic array in all 99 cases with NK, we detected 50 CNA/CN-LOH in 40/99 patients (40%).These encompassed 28 CNA (22 deletions and 6 gains) in 24 patients and 22 CN-LOH in 20 patients.The median CNA size was 0.79 MB (range 0.07-159).Only in one case, the abnormality was >10 MB, i.e., a case with monosomy 7 not detected by CBA, probably due to insufficient in vitro proliferation of aberrant clone.The median CN-LOH size was 66.6 MB (range 10.14-135.44).In 19 cases, CN-LOH ranged to telomere and in three cases, it was interstitial.Majority of patients had one aberration (31/40, 78%), eight patients showed two aberrations and one patient showed three aberrations (all gains).Except for mutual exclusion between NRAS mutations and CNA/CN-LOH, no other association with recurrently mutated genes was evident.Moreover, the number of addnl. mutations did not differ between normal and abnormal genomic array subgroups.Most frequently recurrent aberration was the CN-LOH of chromosome 4q22.3q32.2 (97 791 611-190 803 979) in six patients involving TET2 gene (five harbored TET2 mutations and one patient showed SRSF2 mutation), followed by 11q13.5q25 CN-LOH (76 150 205-134 195 978) involving CBL gene (all of them showing CBL mutation) in four patients and 17q22q24.1 CN-LOH (53 404 930-63 868 162) in three patients, involving MPO gene.Moreover, 4q24 deletion (105 479 140-106 215 692), also involving TET2 gene, was found in three patients, all showing TET2 mutation.Two patients showed 7q21.3q36.3 CN-LOH (7 368 205-159 118 566) and other two patients showed 7q22.1q22.1 deletion (101 262 074-101 951 902) encompassing the CUX1 gene, a tumor suppressor gene frequently deleted in myeloid neoplasms.Two further patients showed Xp22.2p22.2 deletion (15 748 556-16 686 778) involving the ZRSR2 gene.The aforementioned findings are in line with the study by Tiu et al., reporting a rate of aberrations of 37% in 55 CMML patients with normal CBA and Gondek et al., indicating a rate of CN-LOH, among 24 unselected MDS/MPN patients, of 35%.Furthermore, we confirmed the recurrence of 11q, 7q, 17q CN-LOH.No specific mol. profile related to recurrent abnormalities, except for CBL mutation (n=14) that was strongly related to 11q CN-LOH (10 out of 95 patients without 11q CN-LOH, 11% vs 4 out of 4 with 11q CN-LOH, 100%, P=0.001).From the 14 patients with mutated CBL, four patients (28.6%) showed 11q CN-LOH, whereas only 2 of the 10 patients without 11q CN-LOH (20%) had two CBL mutations.This is in line with data stating that 11q CN-LOH strictly relates to CBL mutations.Among the 76 patients with mutated TET2, eight patients showed 4q CNA/CN-LOH.Five of these eight patients with CN-LOH showed TET2 homozygosity and three patients with deletions showed TET2 hemizygous status, whereas, among the 69 patients without 4q aberrations, 48 (70%) showed two TET2 mutations, corroborating the finding that TET2 acts as tumor suppressor gene.Noteworthy, only one patient did show neither any gene mutation nor any genomic array aberration.Overall survival anal. showed a neg. impact of ASXL1 (median 5.6 vs 1.7 years, P=0.008), EZH2 (4.3 years vs 4 mo, P=0.03), RUNX1 (6.6 vs 1.5 years, P=0.014) and NRAS (4.3 vs 1.4 years, P=0.015) mutations.However, at Cox multivariate anal., only ASXL1 mutation retained statistical significance (hazard ratio 2.1; 95% confidence interval 1.02-4.4, P=0.04), in line with previous observations.On the other hand, no differences in OS were detected between normal and abnormal genomic array subgroups, also considering numbers of aberrations or recurrent lesions.Recently, Palomo et al. investigated the impact of genomic array in 117 low-risk cytogenetic CMML (NK and loss of chromosome Y) and 11 cases with failed karyotyping.Even though they found aberrations at higher frequency compared with our series (i.e., 67%), they did not find any correlation with OS, regarding either the occurrence of any aberrations or their number, confirming our results.In conclusion, genomic array anal. can detect aberrations in 40% of CMML patients with NK at CBA, enriching the genomic scenario.Recurrent genomic array aberrations were detected at 4q, 7q, 17q, 11q and Xp.However, the prognostic role of mol. genetic markers, in particular, ASXL1 mutations, overcomes the prognostic significance of any genomic aberration in terms of OS.

News (Medical) associated with PDGFRα x ABL x c-Kit x PDGFRβ

04 Dec 2023

·www.biospace.com

Inhibikase Therapeutics Granted Pre-NDA Meeting with the FDA for IkT-001Pro

- Pre-NDA Meeting to discuss requirements for a 505(b)(2) NDA submission for IkT-001Pro in up to eight blood and stomach cancer indications - - Bioequivalence to 400 mg and 600 mg imatinib mesylate completed with minimal adverse events - BOSTON and ATLANTA, Dec. 04, 2023 (GLOBE NEWSWIRE) -- Inhibikase Therapeutics, Inc. (Nasdaq: IKT) (“Inhibikase” or “Company”), a clinical-stage pharmaceutical company developing protein kinase inhibitor therapeutics to modify the course of Parkinson's disease, Parkinson's-related disorders and other diseases of the Abelson Tyrosine Kinases, today announced the U.S. Food and Drug Administration has granted a pre-New Drug Application (pre-NDA) meeting to be held in January 2024 to discuss the requirements for approval of IkT-001Pro and to review the data establishing doses of IkT-001Pro bioequivalent to 400 mg and 600 mg imatinib mesylate. The Company expects to provide an update following the meeting. “We are pleased that the FDA has granted a pre-NDA meeting to discuss the parameters for approval of IkT-001Pro,” stated Dr. Milton Werner, President and Chief Executive Officer of Inhibikase Therapeutics. “Our completed ‘501’ study has identified the bioequivalent doses of IkT-001Pro to 400 mg and 600 mg imatinib mesylate and has demonstrated that there were minimal adverse events observed at all doses. We believe these data support the potential approval of IkT-001Pro and we intend to submit an NDA for up to 8 indications in adults with blood or stomach cancers, similar to the adult indications for imatinib mesylate.” The 501 bioequivalence study evaluated IkT-001Pro at four single ascending doses of 300, 400, 500 and 600 mg in 27 healthy subjects ranging in age from 18 to 55, followed by a pivotal phase comparing the 600 mg of IkT-001Pro to 400 mg imatinib mesylate in 31 healthy volunteers. The study also evaluated an additional cohort of 8 healthy subjects to determine the bioequivalent dose of IkT-001Pro to 600 mg imatinib mesylate, a dose that is poorly tolerated in patients. This additional cohort identified 900 mg of IkT-001Pro as bioequivalent. Across all doses, there were only mild adverse events observed, including just two adverse events for IkT-001Pro at the highest dose comparison. Imatinib delivered by IkT-001Pro demonstrated a slower rise time to maximum plasma concentration (Tmax) of 6 hours, compared to the 4-hour Tmax of 400 mg imatinib mesylate. Pharmacokinetic profiles for imatinib delivered by IkT-001Pro and imatinib mesylate were similar at equivalent doses. Imatinib mesylate is currently approved for treatment of Philadelphia chromosome positive chronic myelogenous leukemia and acute lymphoblastic leukemia, adults with myelodysplastic or myeloproliferative disease associated with mutations in the PDGFR genes, mastocytosis associated with mutations in the c-Kit gene and stomach cancers that arise from mutations in the c-Kit or PDGFR genes. About IkT-001Pro IkT-001Pro is a prodrug formulation of imatinib mesylate and has been developed to improve the safety of the first FDA-approved Abelson (Abl) kinase inhibitor, imatinib (marketed as Gleevec®). Imatinib is commonly taken for hematological and gastrointestinal cancers that arise from Abl kinase mutations found in the bone marrow or for gastrointestinal cancers that arise from c-Kit and/or PDGFRa/b mutations in the stomach; c-Kit, PDGFRa/b and Abl are all members of the Abelson Tyrosine Kinase protein family. IkT-001Pro has the potential to be a safer alternative for patients and may improve the number of patients that reach and sustain major and/or complete cytogenetic responses in stable-phase CML and/or reduce the relapse rate for these patients. In preclinical studies, IkT-001Pro was shown to be as much as 3.4 times safer than imatinib in non-human primates, reducing burdensome gastrointestinal side effects that occur following oral administration. Imatinib delivered as IkT-001Pro was granted Orphan Drug Designation for stable-phase CML in September, 2018. About Inhibikase ( ) Inhibikase Therapeutics, Inc. (Nasdaq: IKT) is a clinical-stage pharmaceutical company developing therapeutics for Parkinson's disease and related disorders. Inhibikase's multi-therapeutic pipeline focuses on neurodegeneration and its lead program IkT-148009, an Abelson Tyrosine Kinase (c-Abl) inhibitor, targets the treatment of Parkinson's disease inside and outside the brain as well as other diseases that arise from Ableson Tyrosine Kinases. Its multi-therapeutic pipeline is pursuing Parkinson's-related disorders of the brain and GI tract, orphan indications related to Parkinson's disease such as Multiple System Atrophy, and drug delivery technologies for kinase inhibitors such as IkT-001Pro, a prodrug of the anticancer agent imatinib mesylate that the Company believes will provide a better patient experience with fewer on-dosing side-effects. The Company's RAMP™ medicinal chemistry program has identified a number of follow-on compounds to IkT-148009 to be potentially applied to other cognitive and motor function diseases of the brain. Inhibikase is headquartered in Atlanta, Georgia with offices in Boston, Massachusetts. Social Media Disclaimer Investors and others should note that we announce material financial information to our investors using our investor relations website, press releases, SEC filings and public conference calls and webcasts. The company intends to also use X, Facebook, LinkedIn and YouTube as a means of disclosing information about the company, its services and other matters and for complying with its disclosure obligations under Regulation FD. Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking terminology such as "believes," "expects," "may," "will," "should," "anticipates," "plans," or similar expressions or the negative of these terms and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based on Inhibikase's current expectations and assumptions. Such statements are subject to certain risks and uncertainties, which could cause Inhibikase's actual results to differ materially from those anticipated by the forward-looking statements. Important factors that could cause actual results to differ materially from those in the forward-looking statements include factors that are discussed in our periodic reports on Form 10-K and Form 10-Q that we the U.S. Securities and Exchange Commission. Any forward-looking statement in this release speaks only as of the date of this release. Inhibikase undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. Contacts: Company Contact: Milton H. Werner, PhD President & CEO 678-392-3419 info@inhibikase.com Investor Relations: Alex Lobo Stern Investor Relations, Inc. alex.lobo@sternir.com

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