EGFR C797S inhibitors(Epidermal Growth Factor Receptor C797S inhibitors), EGFR T790M inhibitors(EGFR T790M inhibitors), EGFR exon 19 deletion inhibitors

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication

AdenocarcinomaBronchogenic CarcinomaEGFR positive non-small cell lung cancer+ [2]

Inactive Indication-

Originator Organization

Blueprint Medicines Corp.

Active Organization

Blueprint Medicines Corp.

Inactive Organization

Zai Lab (Shanghai) Co., Ltd.Patheon Development Services, Inc.

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

Structure

Molecular FormulaC28H37FN6O3S

InChIKeyLIMFPAAAIVQRRD-BCGVJQADSA-N

CAS Registry2660250-10-0

Clinical Trials associated with Tigozertinib

NCT04862780 / Active, not recruitingPhase 1/2

A Phase 1/2 Study Targeting Acquired Resistance Mechanisms in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-945, a selective EGFR inhibitor, as monotherapy or in combination with osimertinib.

Start Date29 Jun 2021

Sponsor / Collaborator

Blueprint Medicines Corp.

CTR20221771 / SuspendedPhase 1/2

一项治疗EGFR突变型非小细胞肺癌获得性耐药的I/II期研究

[Translation] A phase I/II study for the treatment of acquired drug resistance in EGFR-mutant non-small cell lung cancer

在携带有EGFR突变的NSCLC患者中评估在RP2D下BLU-945单药治疗的抗肿瘤活性等

[Translation]

Evaluate the antitumor activity of BLU-945 monotherapy at RP2D in NSCLC patients with EGFR mutations, etc.

Start Date-

Sponsor / Collaborator

Zai Lab (Shanghai) Co., Ltd.

[+2]

100 Clinical Results associated with Tigozertinib

100 Translational Medicine associated with Tigozertinib

100 Patents (Medical) associated with Tigozertinib

Literatures (Medical) associated with Tigozertinib

01 Jan 2024·Therapeutic Advances in Medical Oncology

BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer

Article

Author: Cho, Byoung Chul ; Tavera-Mendoza, Luz E. ; Stevison, Faith ; Zalutskaya, Alena ; Oh, Seung Yeon ; Hsieh, John ; Yun, Mi Ran ; Rotow, Julia ; Lim, Sun Min ; Park, Sewon ; Dineen, Thomas A. ; Albayya, Faris ; Millet, Yves A. ; Zhang, Zhuo ; Woessner, Rich ; Lee, Dae-Ho ; Schalm, Stefanie S. ; Conti, Chiara ; Goto, Koichi ; Lee, Eun Ji

Introduction::

Despite the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), most patients with non-small-cell lung cancer (NSCLC) eventually develop resistance to these agents. Notably, EGFR_C797S mutations confer resistance to the third-generation EGFR-TKI osimertinib and no approved post-osimertinib targeted pharmacology options are currently available. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI that selectively targets EGFR-activating ( EGFRm) and resistance mutations (including EGFR_C797S) with nanomolar potency while sparing wild-type EGFR in vitro.

Methods::

In vitro activity of BLU-945 as a single agent and in combination with osimertinib was tested in engineered EGFR-mutant cell lines as well as patient-derived cells and patient-derived organoids. In vivo activity was evaluated in osimertinib-resistant patient-derived xenograft mouse models. Three patient cases from the global, first-in-human, phase I/II SYMPHONY trial (NCT04862780) demonstrating the clinical efficacy of BLU-945 were reported.

Results::

In vitro BLU-945 demonstrated inhibited cell viability and growth of EGFR-mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR_L858R/C797S and third line: EGFR_ex19del/T790M/C797S and L858R/T790M/C797S) both as monotherapy and in combination with osimertinib. BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial.

Conclusion::

Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFRm NSCLC progressing on previous EGFR-TKIs.

25 Dec 2023·Journal of chemical information and modeling

Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations

Article

Author: Shao, Xueguang ; Zhou, Huaxin ; Fu, Haohao ; Cai, Wensheng

The overexpression or mutation of the kinase domain of the epidermal growth factor receptor (EGFR) is strongly associated with non-small-cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) have proven to be effective in treating NSCLC patients. However, EGFR mutations can result in drug resistance. To elucidate the mechanisms underlying this resistance and inform future drug development, we examined the binding affinities of BLU-945, a recently reported fourth-generation TKI, to wild-type EGFR (EGFR^WT) and its double-mutant (L858R/T790M; EGFR^DM) and triple-mutant (L858R/T790M/C797S; EGFR^TM) forms. We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another fourth-generation TKI), and erlotinib (a first-generation TKI) using absolute binding free energy calculations. Our findings reveal that BLU-945 and CH7233163 exhibit binding affinities to both EGFR^DM and EGFR^TM stronger than those of erlotinib, corroborating experimental data. We identified K745 and T854 as the key residues in the binding of fourth-generation EGFR TKIs. Electrostatic forces were the predominant driving force for the binding of fourth-generation TKIs to EGFR mutants. Furthermore, we discovered that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding capacity to EGFR mutants. Our study offers valuable theoretical insights for optimizing fourth-generation EGFR TKIs.

28 Jul 2022·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer

Q1 · MEDICINE

Article

Author: Brown, Victoria ; Eno, Meredith S. ; Perola, Emanuele ; De Savi, Chris ; Kim, Joseph ; Zalutskaya, Alena ; Özen, Ayşegül ; Hsieh, John ; Wilson, Kevin ; Schalm, Stefanie ; Williams, Brett D. ; Brooijmans, Natasja ; Kinkema, Caitlin ; Stevison, Faith ; Lee, Christopher ; Timsit, Yoav ; Garner, Andrew ; Guzi, Timothy J. ; Singh, Jatinder ; Woessner, Rich ; Zhang, Zhuo ; Campbell, John E. ; Dineen, Thomas A. ; Brubaker, Jason D. ; Medendorp, Clare ; Albayya, Faris ; Wilson, Douglas ; Fetalvero, Kristina

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

News (Medical) associated with Tigozertinib

09 Jan 2024

·www.fiercebiotech.com

JPM24, Day 2: GSK, Eli Lilly, Blueprint, SR One and more

Merger Monday lived up to its name, but Day 2 is also seeing deals at JPM 24. Welcome to Day 2 of the J.P. Morgan Healthcare Conference 2024 in San Francisco. Yesterday "Merger Monday" lived up to its name with deals for Novartis, J&J and Merck, and today, we’re also starting Tuesday with an early deal. Check out that deal and all the updates from JPM below. Want more? Fierce Biotech’s conference's kickoff Day 1 is available here, and Fierce Pharma’s can be found here. Tuesday 6:43 p.m. ET Jan. 9 Eli Lilly CEO David Ricks, speaking to the slow and steady progress that brought tirzepitide to the world, says the Indianapolis pharma is now ready to open up the chocolate factory. “I know a number of biotechs are in the room at this conference so it's worth mentioning: we're open for business on external innovation,” Ricks said at the J.P. Morgan Healthcare Conference Tuesday. Story Tuesday 6:10 p.m. ET Jan. 9 SR One CEO and managing partner Simeon George, M.D., said the firm was eyeing some investments in psychedelic-focused biotechs but is waiting on formally financing one to see how the space matures. He specifically pointed to the rollout of J&J's Spravato, an esketamine spray used to treat major depression. The treatment is currently one of J&J's fastest-growing products and is a pillar in the company's neuroscience portfolio. "We've been watching, obviously, how that has gone in terms of the launch and again, that product looks like it's starting to be on a nice ramp there," George said in an interview with Fierce Biotech on Tuesday. "My sense is there's going to be more than a couple of companies that will be interesting to look at from a fundraising perspective." George said there are probably "one or two" companies on the firm's shortlist, though he wouldn't specify which. Tuesday 3:45 p.m. ET Jan. 9 "We're seeing companies make investments in traditional pharma assets that are a little further along in the development pipeline," Sharon Flanagan, managing partner for global law firm Sidley's San Francisco office, told Fierce Biotech on the conference sidelines. "ADCs (antibody drug conjugates) are really interesting," she continued, citing Johnson & Johnson's $2 billion acquisition of ADC-focused Ambrx Biopharma. "So that's a way to do something that's still pharma, but with something novel and interesting, that has a spin to it. I do think in markets that are a little uncertain, sometimes the more truly novel types of products might get less interest." Tuesday 9:45 a.m. ET Jan. 9 Blueprint Medicines is pulling back from a core focus area, cutting two non-small lung cancer programs after getting a peak of early data. It was just a year ago that CEO Kate Haviland touted the EGFR tyrosine kinase inhibitors as the company's path to first-line treatment. The biotech says it will explore possible out-licensing deals to find a home for BLU-945 and BLU-451. Story Tuesday 3 a.m. ET Jan. 9 GSK is getting in on the M&A action as it snaps up respiratory biotech Aiolos Bio for $1 billion upfront and $400 million in biobucks. The deal sees GSK nab Aiolos’ leading asset AIO-001, a phase 2-ready mAb, with plans for the drug to also treat chronic rhinosinusitis with nasal polyps. Story.

09 Jan 2024

·www.fiercebiotech.com

Blueprint tears up plans, dropping 2 lung cancer programs after seeing early clinical data

Blueprint disclosed the news alongside an update on its plans for Gavreto. Blueprint Medicines is pulling back from one of its three areas of focus, dropping two non-small cell lung cancer (NSCLC) programs in response to early clinical data on the EGFR tyrosine kinase inhibitors. One year ago, Blueprint CEO Kate Haviland used a presentation at the J.P. Morgan Healthcare Conference to explain how the company designed a phase 1 EGFR-driven lung cancer study to give “the confidence that we can win in first line.” The decision to spend 2023 gathering data to inform a go/no-go decision reflected Haviland’s recognition that lung cancer was an ambitious and potentially “expensive endeavor.” Now, Blueprint has early evidence of whether its two drug candidates, BLU-945 and BLU-451, can deliver on its aim to develop best-in-class molecules capable of replacing the standard of care in frontline, EGFR lung cancer. Haviland pulled investment in the programs after getting a look at the data. “Combining this emerging data, from both the BLU-945 and the BLU-451 programs, with the evolving EGFR landscape, we have decided to deprioritize continued investment in EGFR-driven non-small cell lung cancer and to focus our R&D investments in the most compelling and highest value programs,” the CEO said at a JPM presentation this week. Blueprint’s interest in EGFR-driven lung cancer was built on evidence that the first three generations of TKIs had failed to address the need for a molecule that maintains activity against sensitizing mutations, notably L858R. The L858R mutation is associated with worse outcomes on the current standard of care. Blueprint believed a combination with AstraZeneca’s Tagrisso could provide more durable benefits. While the biotech has opted against spending its own cash to pursue that belief, it will “explore strategic options, including potential out-licensing” to support further development of BLU-945 and BLU-451. Blueprint disclosed the news alongside an update on its plans for Gavreto, the approved RET inhibitor that Roche decided to drop 11 months ago. Lacking global infrastructure in lung and thyroid cancer, the approved indications for Gavreto, Blueprint is stopping global development and marketing of the drug outside of the U.S. and China. CStone Pharmaceuticals owns the rights to Gavreto in China. In the U.S., Blueprint has found “a potential alternate partner” and “is continuing to work with the involved parties to define a scenario that enables continued availability of Gavreto.” Winding down work on Gavreto outside of those markets will reduce operating expenses without affecting the $175 million Blueprint received from Royalty Pharma in 2022.

Phase 1License out/inDrug Approval

09 Jan 2024

·firstwordpharma.com

Blueprint guts lung cancer portfolio, pulling Gavreto in certain markets

Blueprint Medicines is deprioritising some lung cancer programmes, citing an "evolving external landscape, emerging clinical data and partnering considerations." In an update at the ongoing JP Morgan healthcare conference, Blueprint said it would be scaling back Gavreto (pralsetinib) in certain markets, and culling a pair of early-stage assets.Last year, Roche terminated a collaboration between the companies due to strategic considerations and handed back global commercialisation and development rights for Gavreto, which is approved in the US to treat RET fusion-positive populations of non-small-cell lung cancer (NSCLC) and thyroid cancer. Gavreto had also received FDA accelerated approval for RET-mutant medullary thyroid cancer, but the partners withdrew the oral RET inhibitor for the indication last summer.Another partner to the rescue?Citing a lack of global infrastructure in lung and thyroid cancer, Blueprint now says it has decided to discontinue global development and marketing of Gavreto in territories excluding the US and China. It expects to begin winding down activities in the first quarter of 2024. An alternate partner for Gavreto in the US may be waiting in the wings, however; Blueprint said it is working with the parties involved to define a scenario that would allow the drug to continue to be available in the country.The move won't affect the $175-million upfront payment Blueprint received under a 2022 financing agreement with Royalty Pharma.Meanwhile, Blueprint also hinted that "emerging clinical data" spurred a decision to discontinue investing in the early-stage therapies BLU-945 and BLU-451 for EGFR-mutant NSCLC. The company got hold of BLU-451 via its purchase of Lengo Therapeutics in 2021 for up to $465 million, elbowing its way into an increasingly crowded niche within lung cancer.It is now considering different options for the assets, including potential out-licensing. That leaves BLU-525, another EGFR inhibitor, as Blueprint's sole pipeline candidate for lung cancer, according to its website.

AcquisitionAccelerated ApprovalDrug ApprovalLicense out/in

100 Deals associated with Tigozertinib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
EGFR positive non-small cell lung cancer	Phase 2	US	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	JP	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	CA	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	FR	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	NL	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	SG	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	KR	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	ES	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	TW	Blueprint Medicines Corp.	29 Jun 2021
EGFR positive non-small cell lung cancer	Phase 2	GB	Blueprint Medicines Corp.	29 Jun 2021

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04862780 (SYMPHONY, ASCO2023) Manual	Phase 1/2	Non-Small Cell Lung Cancer EGFR Mutation	133	BLU-945	xoybrnzxmw(zmnsrmffhr) = BLU-945 mono group: nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%); BLU-945+OSI group: fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%) cnnjaxzyvu (mbqlyfysbi ) View more	Positive	26 May 2023
				BLU-945+Osimertinib

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