A Phase 1, Open-label, Dose-escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered TG101348 in Patients With Primary, Post-polycythemia Vera, or Post-essential Thrombocythemia Myelofibrosis

The purpose of this study is to evaluate the safety and tolerability of orally administered TG101348 in patients with myelofibrosis.

Start Date01 Jan 2008

Sponsor / Collaborator

TargeGen, Inc.

NCT00509548 / TerminatedPhase 2

An Open-Label Randomized Pilot Study of Safety and Preliminary Efficacy of TG100801 in Patients With Choroidal Neovascularization Due to Age-Related Macular Degeneration

Wet age-related macular degeneration (AMD) is caused by the formation and growth of abnormal blood vessels (angiogenesis) in the retina. The new blood vessels have fragile walls and can leak fluid into the retina. The build-up of fluid (edema) under the macula can distort vision or cause vision loss. TG100801 is a topical (eye drop) therapy that has been shown to inhibit ocular angiogenesis, vascular leak, and inflammation in laboratory studies. The primary purpose of this pilot study is to evaluate the ability of topical administration of TG100801 to reduce the amount of fluid in the retina in patients with AMD following 30 days of treatment. An additional objective is to evaluate the safety of TG100801 in patients with AMD.

Start Date01 Jul 2007

Sponsor / Collaborator

TargeGen, Inc.

NCT00414999 / CompletedPhase 1

A Phase 1, Double-Masked, Placebo-Controlled, Dose-Escalation Study (in Two Parts) of TG100801 and a Colored Vehicle in Adult Healthy Volunteers

The formation of new blood vessels (angiogenesis), blood vessel leakage, and inflammation contribute to the progression of the eye disease, age-related macular degeneration (AMD), which is the leading cause of irreversible, severe loss of vision in people 55 years of age and older in the developed world. TG100801 is a new drug that inhibits ocular angiogenesis, vascular leak, and inflammation in laboratory studies, and may have great utility in the treatment of diseases such as AMD.
The purpose of this study is to assess the safety, ocular tolerability, and blood pharmacokinetics of TG100801 at escalating doses in healthy volunteers.

Start Date01 Nov 2006

Sponsor / Collaborator

TargeGen, Inc.

100 Clinical Results associated with TargeGen, Inc.

0 Patents (Medical) associated with TargeGen, Inc.

Literatures (Medical) associated with TargeGen, Inc.

19 Nov 2010·Blood

Longer-Term Follow up with TG101348 Therapy In Myelofibrosis Confirms Sustained Improvement In Splenomegaly, Disease-Related Symptoms, and JAK2V617F Allele Burden

Author: Gilliland, D. Gary ; Pardanani, Animesh ; Shorr, Jolene ; Gotlib, Jason R ; Tefferi, Ayalew ; Stone, Richard M ; Talpaz, Moshe ; Silverman, Michael H ; Jamieson, Catriona ; Cortes, Jorge E.

AbstractAbstract 459Background:A Phase I study of TG101348, a potent, oral JAK2-selective inhibitor in patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF) recently completed enrollment. Data from the dose escalation cohort (n=28; 30–800 mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 16 to 34 hours. The dose-limiting toxicity was reversible asymptomatic grade 3 or 4 amylasemia/lipasemia; the maximum tolerated dose was 680 mg. We now present updated results from an extension study in which subjects continued treatment beyond six 28-day cycles.Result:In the entire study, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 21 (36%) patients were transfusion-dependent at study enrollment. Forty three (73%) subjects continued treatment on the extension study; the median (range) cumulative exposure to TG101348 was 380 days (170-767); the number of cycles of treatment completed ranged from 7–29, and the proportion of subjects who completed 12, 18, and 24 cycles of treatment was 72%, 28%, and 14%, respectively. The median (range) treatment dose at data cutoff was 440 mg/day (120 to 680 mg/day; n = 35).Toxicity:TG101348 was well tolerated. Non-hematologic, at least possibly related adverse events included nausea (69%; Grade 3=3%), diarrhea (64%; Grade 3=10%), and vomiting (58%; Grade 3=3%), that were dose-dependent; the symptoms were self-limited or controlled with symptomatic treatment and/or dose reduction. Also observed were asymptomatic increases in serum lipase (27%), AST/ALT (27%/25%), creatinine (24%), and alkaline phosphatase (17%). Grade 3/4 hematological adverse events possibly related to TG101348 included treatment-emergent anemia (35% of patients who were not transfusion dependent at baseline), thrombocytopenia (24%), and neutropenia (10%).Spleen:During cycles 1–6, 42% of patients achieved Clinical Improvement (CI) per the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for spleen response. The CI rate for the 43 subjects who continued treatment beyond 6 cycles was 65%, and the median time (range) to CI was 140 days (77-802). After 12 cycles, 36 (95%) of the 38 evaluable patients had some degree of spleen size reduction; 32 (85%), 26 (68%), and 10 (26%) of subjects had a minimum 25%, 50%, and 100% decrease in palpable splenomegaly.JAK2V617F allele burden:Of the 48 JAK2V617F mutation-positive subjects, 23 (48%) had a baseline mutant allele burden of >20%. Of these, 20 subjects with a baseline median allele burden (range) of 62% (23% to 100%) completed at least 6 cycles of treatment. Sixteen subjects (80%) exhibited a median 62% (range 6% to 96%) decrease in JAK2V617F burden, including 9 (45%) with a ≥50% decrease; 4 subjects (20%) had increases (range 18% to 58%). Eighteen subjects (78%) completed 12 cycles of treatment; 13 (72%) had a median 50% decrease (range 29% to 82%), including 7 (39%) subjects with a ≥50% decrease; 5 subjects (28%) had no change or increases (range 0% to 22%) in JAK2V617F.Constitutional symptoms:For patients with data at baseline and cycle 6, early satiety, fatigue, night sweats, cough, and pruritus were reported by 56%, 47%, 24%, 22%, and 19% of subjects, respectively. Improvement (complete resolution) rates observed at cycle 6 were: 75% (40%), 65% (29%), 89% (89%), 88% (75%), and 100% (57%) for the aforementioned symptoms, respectively.Leukocytosis/Thrombocytosis:Leukocytosis was present at baseline in 33 subjects; following 6 and 12 cycles of therapy, 57% (n=28) and 56% (n=25) achieved normal WBC counts. Thrombocytosis was noted at baseline for 10 (17%) subjects; following 6 and 12 cycles of therapy, 90% (n=10) and 88% (n=8) achieved normal platelet counts.Conclusion:The current study provides proof-of-concept that selective JAK2 inhibition has anti-myeloproliferative/anti-clonal activity in myelofibrosis. The majority of subjects treated with TG101348 for more than 6 cycles experienced a rapid, significant, and durable decrease in splenomegaly, normalization of leukocyte/platelet counts, and improvement of disease-related symptoms, all within the context significantly decreased JAK2V617F burden.Disclosures:Off Label Use: There is no FDA approved drug for Myelofibrosis.All the drugs discussed will be off-label. Stone:Novartis: Consultancy. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership.

02 Mar 2010·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRβ/B-RAF

Q1 · CROSS-FIELD

Article

Author: Klemke, Richard L. ; Dneprovskaia, Elena ; Murphy, Eric A. ; Cheresh, David A. ; Bouvet, Michael ; Acevedo, Lisette M. ; Majeti, Bharat Kumar ; Walsh, Breda ; Shields, David J. ; Tsigelny, Igor ; Hoffman, Robert M. ; Stoletov, Konstantin ; Vogt, Peter K. ; Arnold, Lee ; Wrasidlo, Wolfgang ; Anand, Sudarshan ; McElroy, Michele ; Greenberg, Joshua I. ; Lindquist, Jeff ; Saldanha, Adrian

Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, and several kinase inhibitors are now approved for various cancer indications. Typically, kinase inhibitors are selected via high-throughput screening using catalytic kinase domains at low ATP concentration, and this process often yields ATP mimetics that lack specificity and/or function poorly in cells where ATP levels are high. Molecules targeting the allosteric site in the inactive kinase conformation (type II inhibitors) provide an alternative for developing selective inhibitors that are physiologically active. By applying a rational design approach using a constrained amino-triazole scaffold predicted to stabilize kinases in the inactive state, we generated a series of selective type II inhibitors of PDGFRβ and B-RAF, important targets for pericyte recruitment and endothelial cell survival, respectively. These molecules were designed in silico and screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model. Dual inhibition of PDGFRβ and B-RAF cellular signaling demonstrated synergistic antiangiogenic activity in both zebrafish and murine models of angiogenesis, and a combination of previously characterized PDGFRβ and RAF inhibitors validated the synergy. Our lead compound was selected as an orally active molecule with favorable pharmacokinetic properties which demonstrated target inhibition in vivo leading to suppression of murine orthotopic tumors in both the kidney and pancreas.

20 Nov 2009·Blood

A Phase I Evaluation of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis: Clinical Response Is Accompanied by Significant Reduction in JAK2V617F Allele Burden.

Author: Gilliland, D. Gary ; Pardanani, Animesh D. ; Gotlib, Jason R ; Shorr, Jolene ; Tefferi, Ayalew ; Cortes, Jorge ; Talpaz, Moshe ; Stone, Richard ; Silverman, Michael H ; Jamieson, Catriona

AbstractAbstract 755Background:TG101348 is a potent, orally bioavailable, JAK2-selective small molecule inhibitor, that is currently being evaluated in a Phase I study for the treatment of myelofibrosis. Data from the dose escalation cohort (n=28; 30-800mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 20 to 52 hours. The dose-limiting toxicity was asymptomatic grade 3 or 4 amylasemia/lipasemia that was reversible, and the maximum tolerated dose (MTD) was 680mg. The most frequent non-hematological toxicities were mild nausea, vomiting, and/or diarrhea that were easily controlled or resolved spontaneously. Grade 3/4 neutropenia and thrombocytopenia were observed in 14% and 25% of patients, respectively. TG101348 had activity in reducing spleen size, leukocyte count, and JAK2V617F (VF) allele burden. Here, we present updated results with a focus on data from the dose confirmation cohort who initiated treatment at a dose of 680mg/day.Results:Fifty nine patients (median age=66 years; range 43-86) have been treated – 28 in the dose escalation phase, and 31 in the dose confirmation phase. Overall, 44 patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were VF-positive. Median palpable spleen size was 18cm and 22 patients were RBC transfusion-requiring at study enrollment. After a median follow-up of 12 weeks (range <1-76), 18 (31%) patients have discontinued treatment due to toxicity (n=7; thrombocytopenia=3, neutropenia=1), comorbidities (n=5), withdrawal of consent (n=4), or non-compliance/lack of response (1 each). The remaining 41 patients are currently at the following dose levels: 680mg (n=14), 520-600mg (n=16), 360-440mg (n=10), and 240mg (n=1). The cumulative drug exposure to date is 362 patient-months; exposure at or above MTD (≥680mg) is 154 patient-months. Forty patients (68%) started treatment at ≥680mg.Toxicity:TG101348 is well tolerated. Of the patients who started at ≥680mg, Gr3/4 neutropenia was observed in 15/0% and Gr3/4 thrombocytopenia in 20/10%. Twenty four (60%) patients did not require RBC transfusions at baseline (median Hgb=9.6g/dL; range 7.4-13.1); of these, 42% and 8% of patients developed Gr3 and Gr4 anemia, respectively. The majority of patients who started at ≥680mg developed mild nausea (1 Gr3), vomiting (1 Gr3), and/or diarrhea (3 Gr3) that were self-limited or easily controlled. Other non-hematological toxicities included Gr1/2 transaminitis (38%), Gr1/2 serum creatinine elevation (38%), and asymptomatic hyperlipasemia (33%).Efficacy:Thirty three patients who started at ≥680mg have completed at least 3 cycles of treatment; at 3 months, reduction in palpable spleen size (baseline median=18cms; range 6-32) was at least 50% in 22 (67%) patients; the spleen became non-palpable in 9 (27%) patients. All 21 patients with leukocytosis at baseline (WBC range 11 to 203 ×109/L) who started at ≥680mg have experienced a marked reduction in their WBC count (range 4 to 90); 70% had a normal WBC count at their last follow-up visit. Overall, 48 of the 51 VF-positive patients completed at least 1 cycle and were evaluable for response in VF allele burden; at last available follow-up, the median decrease in granulocyte mutant allele burden was 48%; 21 (44%) patients have had a ≥50% reduction, and in the group who started treatment at ≥680mg, 48% have had a ≥50% reduction. Of those evaluable, there was clinically significant benefit or resolution of constitutional symptoms, including early satiety, fatigue, cough, pruritus, and night sweats.Conclusions:TG101348 continues to be well tolerated in patients with myelofibrosis. Spleen and leukocyte responses are frequent, observed early, and produce substantial clinical benefit for patients. These responses are associated with significant decrease in VF allele burden and point to activity of TG101348 against the malignant clone in myelofibrosis.Disclosures:Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Gotlib:TargeGen: Research Funding. Jamieson:Merck: Research Funding; Pfizer: Research Funding; Wintherix: Consultancy; TargeGen: Research Funding; Celgene: Research Funding. Cortes:Targegen: Research Funding. Stone:Cephalon: ad hoc advisory board. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership. Gilliland:Merck: Employment. Tefferi:TargeGen: Research Funding.

News (Medical) associated with TargeGen, Inc.

16 Jan 2024

·www.prnewswire.com

Plexium Announces Appointment of Michael Martin, Ph.D. as President and CEO

SAN DIEGO, Jan. 16, 2024 /PRNewswire/ -- Plexium, Inc. (Plexium), a leading next-generation targeted protein degradation (TPD) company, today announced the appointment of Michael Martin, Ph.D. as President and Chief Executive Officer, and a member of the Board of Directors. Dr. Martin joins Plexium following his 12-year tenure at Takeda Pharmaceuticals, serving most recently as the Global Head of the Center for External Innovation where he was a key member of Takeda's Leadership Team. While in this role, he was responsible for external research & development activities including Business Development, Search & Evaluation, Strategy & Operations, Academic Alliances, and Takeda Ventures, Inc. "Mike brings tremendous experience to Plexium as a scientific executive, global R&D leader, venture investor and corporate board member. He has led the strategic, global development of highly innovative therapies, with significant expertise in accelerating and establishing valuable pipelines driven by novel biology and drug targets," said Mike Grey, Executive Chairman of Plexium. "I look forward to working with Mike to advance our clinical-stage pipeline and progressing more TPD programs against important cancer targets into the clinic." Dr. Martin added, "I am proud to join the established team at Plexium and am eager to work together towards developing transformative therapies for difficult to treat cancers and other diseases. I believe that Plexium is well positioned for success with the recent advancement of PLX-4545 into Phase 1 and the advancing preclinical pipeline of small molecule monovalent degraders of SMARCA2, CDK2 and c-Raf. I am excited to lead Plexium and continue to build a leading TPD company focused on improving patients' lives." Dr. Martin joined Takeda in 2012 and prior to his most recent role, he was President of Takeda Ventures, Inc., Takeda's corporate venture capital company. Dr. Martin also previously held executive and scientific roles with Intellikine Inc. (acquired by Takeda), TargeGen, Inc. (acquired by Sanofi-Aventis), Arena Pharmaceuticals, Inc. (acquired by Pfizer) and Monsanto Corporation (acquired by Bayer). Dr. Martin holds a Ph.D. in Medicinal Chemistry from University of Illinois, a M.S. in Analytical Chemistry and B.S. degrees in Chemistry and Mathematics. Dr. Martin has extensive experience as a corporate board member, for both private and publicly traded companies, and has acted as an advisor to several notable biotech investment funds in the United States, Europe, and Japan. About Plexium Inc. Plexium Inc. is the premier, next-generation Targeted Protein Degradation (TPD) company seeking to discover monovalent direct degraders and molecular glues to address difficult-to-drug targets for the treatment of cancer. The company's proprietary drug discovery platform is designed to identify novel small molecules that induce selective degradation of pathogenic proteins through E3 ligase mediated proteasomal degradation. Plexium is advancing a pipeline of novel targeted monovalent direct degraders and molecular glues for the treatment of cancer and has also entered into a strategic collaboration with AbbVie to expand the potential of TPD to neurological conditions. For more information, visit and engage with us on LinkedIn. Plexium Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Plexium

Executive ChangePhase 1

10 Jan 2021

·www.healthcareglobal.com

Biopharma company Celgene is set to acquire Impact Biomedicines

Celgene has recently announced that it is set to acquire Impact Biomedicines and its drug fedratinib, which will be added to Celgene’s therapies for myelofibrosis (a type of bone marrow cancer) and polycythemia vera. Further payment opportunities will arise upon the drug’s sales performance worldwide. Celgene will pay approximately $1.1 billion upfront and up to $1.25 billion in contingent payments based on regulatory approval milestones for myelofibrosis. The acquisition is one of the largest in the company’s history. "Myelofibrosis is a disease with high unmet medical need as the number of patients who are ineligible for or become resistant to existing therapy continues to increase," commented Nadim Ahmed, President, Haematology and Oncology for Celgene. See also "We believe fedratinib is uniquely positioned as a potential treatment for myelofibrosis and it provides strategic options for us to build leadership in this disease with luspatercept and other pipeline assets." Impact’s Chief Executive, John Hood, is one of the co-inventors of fedratinib when working at TargeGen Inc. Now involved in the sale of fedratinib for the second time, Hood has observed its potential for treating patients with myelofibrosis. “We launched Impact Biomedicines and based on our thorough review of the data, fedratinib presents a compelling risk benefit profile in both treatment-naïve patients and patients who are resistant or intolerant to other JAK2 therapies,” he said. "We believe Celgene is the ideal organisation to follow through on our mission of maximizing fedratinib's potential for patients with myelofibrosis."

Acquisition

30 Jul 2007

·www.biospace.com

TargeGen, Inc. Initiates Multi-Center Phase II Clinical Trial Of TG100801, a Topically Applied Kinase Inhibitor In Macular Degeneration Patients

SAN DIEGO, July 30 /PRNewswire/ -- TargeGen, Inc. today announced that the Company has initiated a multi-center Phase II clinical trial of topically applied TG100801 in patients with age-related macular degeneration (AMD). (Logo: ) AMD is the leading cause of blindness in adults with more than 3.5 million estimated patients worldwide. Currently approved treatments for macular degeneration require repeated injection into the eye and act primarily by reducing VEGF mediated retinal leakage. TG100801 is administered non-invasively as an eye drop and is designed to suppress VEGF mediated leakage and additional kinase targets associated with inflammation, edema, and angiogenesis which are the pathological hallmarks of AMD and other back of the eye diseases including diabetic macular edema and proliferative diabetic retinopathy. "The initiation of this trial is a significant milestone for TargeGen," stated Peter G. Ulrich, President, CEO and Co-Founder of TargeGen. "TG100801 is an important drug candidate that potentially addresses the leading causes of debilitating vision loss in adults in a more comprehensive way and may eliminate or reduce the requirement for repeated injections into the eye." In addition to TG100801, TargeGen is developing TG101348, an oral Jak2 inhibitor for the potential treatment of myeloproliferative diseases and TG100115, a PI3K inhibitor for the potential treatment of certain inflammatory disorders. A second topically applied compound for eye disease, TG100948, is in early development. About TargeGen, Inc. TargeGen, Inc. is a privately held vascular biology-focused biopharmaceutical company based in San Diego, CA. TargeGen primarily develops small molecule kinase inhibitors that target vascular leakage (edema), vascular proliferation (angiogenesis) and inflammation. Edema, angiogenesis and inflammation are involved in the pathology of many major human diseases. TargeGen initiated operations in 2002 and has raised capital from top tier venture capital sources. Current investors include VantagePoint Venture Partners, Forward Ventures, Enterprise Partners, Chicago Growth Partners, BB BIOTECH, Innovis Investments, H&Q Capital Management, Pappas Ventures and other investors. Photo: NewsCom: AP Archive: PRN Photo Desk, photodesk@prnewswire.comTargeGen, Inc. CONTACT: TargeGen, Inc., +1-858-678-0760, fax, +1-858-678-0160,info@targegen.com Web site:

Small molecular drug

100 Deals associated with TargeGen, Inc.

100 Translational Medicine associated with TargeGen, Inc.

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Pipeline Snapshot as of 23 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Drug(Targets)	Indications	Global Highest Phase

TG-100801 ( SRC x VEGFR2 )	Diabetic macular oedema More	Preclinical
TG-100115 ( PI3Kγ x PI3Kδ )	Reperfusion Injury More	Preclinical
TG-101001 ( Raf kinase )	Neoplasms More	Pending
TG100435 ( SRC )	Neoplasms More	Pending

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