A phase I, single-dose, randomized, crossover, relative bioavailability and food-effect study and phase I, single-dose, fixed-sequence, crossover, pH-effect study of belvarafenib (GDC-5573) in healthy subjects

Start Date20 Sep 2022

Sponsor / Collaborator-

CTIS2022-503107-21-00

/ Not yet recruitingPhase 1

- GO42273

Start Date16 Dec 2021

Sponsor / Collaborator

Genentech, Inc.

CTR20210680

/ RecruitingPhase 2

泛瘤肿精准免疫及靶向治疗的II期平台试验（TAPISTRY）

[Translation] Phase II platform trial of pan-tumor precision immunotherapy and targeted therapy (TAPISTRY)

本研究通过NGS法鉴别体细胞突变和潜在预测生物标志物，对据此选择的多种疗法治疗实体瘤患者的有效性和安全性进行评价。

[Translation]

This study evaluated the efficacy and safety of multiple therapies selected by NGS to identify somatic mutations and potential predictive biomarkers in patients with solid tumors.

Start Date07 Sep 2021

Sponsor / Collaborator

F. Hoffmann-La Roche Ltd.

[+1]

100 Clinical Results associated with Belvarafenib

100 Translational Medicine associated with Belvarafenib

100 Patents (Medical) associated with Belvarafenib

Literatures (Medical) associated with Belvarafenib

20 Aug 2024·Journal of Virology

The Raf kinase inhibitors Dabrafenib and Regorafenib impair Zika virus replication via distinct mechanisms

Article

Author: Elbahesh, Husni ; Wilken, Lucas ; Rimmelzwaan, Guus F

ABSTRACTZika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that has been associated with congenital neurological defects in fetuses born to infected mothers. At present, no vaccine or antiviral therapy is available to combat this devastating disease. Repurposing drugs that target essential host factors exploited by viruses is an attractive therapeutic approach. Here, we screened a panel of clinically approved small-molecule kinase inhibitors for their antiviral effects against a clinical isolate of ZIKV and thoroughly characterized their mechanisms of action. We found that the Raf kinase inhibitors Dabrafenib and Regorafenib potently impair the replication of ZIKV, but not that of its close relative dengue virus. Time-of-addition experiments showed that both inhibitors target ZIKV infection at post-entry steps. We found that Dabrafenib, but not Regorafenib, interfered with ZIKV genome replication by impairing both negative- and positive-strand RNA synthesis. Regorafenib, on the other hand, altered steady-state viral protein levels, viral egress, and blocked NS1 secretion. We also observed Regorafenib-induced ER fragmentation in ZIKV-infected cells, which might contribute to its antiviral effects. Because these inhibitors target different steps of the ZIKV infection cycle, their use in combination therapy may amplify their antiviral effects which could be further explored for future therapeutic strategies against ZIKV and possibly other flaviviruses.IMPORTANCE There is an urgent need to develop effective therapeutics against re-emerging arboviruses associated with neurological disorders like Zika virus (ZIKV). We identified two FDA-approved kinase inhibitors, Dabrafenib and Regorafenib, as potent inhibitors of contemporary ZIKV strains at distinct stages of infection despite overlapping host targets. Both inhibitors reduced viral titers by ~1 to 2 log 10 (~10-fold to 100-fold) with minimal cytotoxicity. Furthermore, we show that Dabrafenib inhibits ZIKV RNA replication whereas Regorafenib inhibits ZIKV translation and egress. Regorafenib has the added benefit of limiting NS1 secretion, which contributes to the pathogenesis and disease progression of several flaviviruses. Because these inhibitors affect distinct post-entry steps of ZIKV infection, their therapeutic potential may be amplified by combination therapy and likely does not require prophylactic administration. This study provides further insight into ZIKV-host interactions and has implications for the development of novel antivirals against ZIKV and possibly other flaviviruses.

01 May 2023·Journal of Biological Chemistry

Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib

Article

Author: Tkacik, Emre ; Eck, Michael J ; Ha, Byung Hak ; Li, Kunhua ; Vinals, Javier ; Gonzalez-Del Pino, Gonzalo ; Beyett, Tyler S ; Park, Eunyoung

Upon activation by RAS, RAF family kinases initiate signaling through the MAP kinase cascade to control cell growth, proliferation, and differentiation. Among RAF isoforms (ARAF, BRAF, and CRAF), oncogenic mutations are by far most frequent in BRAF. The BRAF^V600E mutation drives more than half of all malignant melanoma and is also found in many other cancers. Selective inhibitors of BRAF^V600E (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. By contrast, a number of "type II" RAF inhibitors have been developed as potent inhibitors of RAF dimers. Here, we compare potency of type II inhibitors tovorafenib (TAK-580) and naporafenib (LHX254) in biochemical assays against the three RAF isoforms and describe crystal structures of both compounds in complex with BRAF. We find that tovorafenib and naporafenib are most potent against CRAF but markedly less potent against ARAF. Crystal structures of both compounds with BRAF^V600E or WT BRAF reveal the details of their molecular interactions, including the expected type II-binding mode, with full occupancy of both subunits of the BRAF dimer. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.

24 Apr 2023·Journal of chemical information and modeling

Analysis of the ERK Pathway Cysteinome for Targeted Covalent Inhibition of RAF and MEK Kinases.

Article

Author: Zhan, Shaoqi ; Liu, Ruibin ; Shen, Jana ; Romany, Aarion ; Clayton, Joseph

The ERK pathway is one of the most important signaling cascades involved in tumorigenesis. So far, eight noncovalent inhibitors of RAF and MEK kinases in the ERK pathway have been approved by the FDA for the treatment of cancers; however, their efficacies are limited due to various resistance mechanisms. There is an urgent need to develop novel targeted covalent inhibitors. Here we report a systematic study of the covalent ligandabilities of the ERK pathway kinases (ARAF, BRAF, CRAF, KSR1, KSR2, MEK1, MEK2, ERK1, and ERK2) using constant pH molecular dynamics titration and pocket analysis. Our data revealed that the hinge GK (gate keeper)+3 cysteine in RAF family kinases (ARAF, BRAF, CRAF, KSR1, and KSR2) and the back loop cysteine in MEK1 and MEK2 are reactive and ligandable. Structure analysis suggests that the type II inhibitors belvarafenib and GW5074 may be used as scaffolds for designing pan-RAF or CRAF-selective covalent inhibitors directed at the GK+3 cysteine, while the type III inhibitor cobimetinib may be modified to label the back loop cysteine in MEK1/2. The reactivities and ligandabilities of the remote cysteine in MEK1/2 and the DFG-1 cysteine in MEK1/2 and ERK1/2 are also discussed. Our work provides a starting point for medicinal chemists to design novel covalent inhibitors of the ERK pathway kinases. The computational protocol is general and can be applied to the systematic evaluation of covalent ligandabilities of the human cysteinome.

News (Medical) associated with Belvarafenib

24 Apr 2024

·www.fiercebiotech.com

Roche's pipeline rethink hits 20% of new molecules as cancer candidates join discard pile

Roche CEO Thomas Schinecker, Ph.D., said the cull has focused on assets that have a “lower likelihood” of success. Roche has performed a little light spring cleaning, sweeping (PDF) a pair of phase 1 solid tumor drugs and an early-stage psychiatric disorder prospect out of the door as part of its update for the first quarter. The culls are part of a broader refocusing that has removed 20% of new molecules from the pipeline in recent quarters. The spring cancer clearout affected belvarafenib and RG6286. Belvarafenib, also known as RG6185 and HM95573, is an oral RAF kinase inhibitor that Roche’s Genentech licensed from Hanmi Pharmaceutical for $80 million upfront in 2016. The candidate was in phase 1 at the time of the deal. Hanmi began a phase 1b study to test belvarafenib in combination with either cobimetinib or cetuximab in 2017. Hanmi, which retained the rights to the asset in South Korea, published data from the phase 1 trial and an expansion study in 2019 and continued to track patients in the phase 1b study to assess the effect of combining belvarafenib with a MEK or EGFR inhibitor. A Roche spokesperson said Genentech was “investigating belvarafenib in two clinical studies in various cancers” but has stopped enrollment in the trials and removed the asset from the portfolio. Genentech will continue to provide study treatment and monitor currently enrolled patients. The cut is part of a wider cull that has seen Roche terminate 20% of its new molecular entities since the third quarter of last year. Roche CEO Thomas Schinecker, Ph.D., said on a media call Wednesday that the cull has focused on assets that have a “lower likelihood” of success. The drugmaker needs to terminate some programs to free up cash to invest in accelerating “a number of projects that have a high likelihood to succeed and have a huge patient impact,” Schinecker said. Roche has split programs into three categories: highly promising prospects it wants to accelerate; assets that don’t warrant further investment because they are unlikely to be first or best in class; and molecules that need to generate more data to show whether they are a priority. Schinecker said the changes will continue in the second quarter, but the pipeline will settle down beyond that. The other newly culled oncology candidate, RG6286, is a bispecific antibody that binds to the colorectal cancer antigen LY6G6D and CD3 on T cells. Genentech began testing the candidate, which is also known as BLYG8824A, in colorectal cancer patients in 2020. The phase 1 clinical trial has an estimated primary completion date of early 2026. Roche also used the update to confirm the removal of camonsertib, also known as RG6526, from phase 1. The Swiss drugmaker told Repare Therapeutics it is returning the rights to the synthetic lethal drug candidate in February, days after the dosing of a phase 2 patient and triggering a $40 million payment. Finally, Roche removed one neuroscience candidate from its phase 1 pipeline and switched horses in an infectious disease. The neuroscience asset, RG6163, was in development psychiatric disorders, but Roche had said little publicly about the program. In complicated urinary tract infections, Roche dropped one LepB inhibitor, RG6319, and switched its focus to another molecule against the same target, RG6436.

Phase 1Phase 2PROTACsLicense out/in

24 Apr 2024

·firstwordpharma.com

Roche pipeline overhaul hits 20% of new molecules

Roche has cut 20% of new molecular entities from its pipeline since the third quarter of last year as it overhauls its portfolio to focus on “high-impact” projects. CEO Thomas Schinecker noted Wednesday alongside the company’s first quarter financial results that the terminated assets, which include three cancer drugs, were not innovative enough.The executive indicated that the gaps in its pipeline will be filled with external drugs. “We are open for M&A,” Schinecker said, with a focus on areas including cardiovascular and metabolism disorders, neuroscience and oncology. “Based on whether or not the deal makes sense, then we are also open to doing larger acquisitions,” he added.Oncology assets cut in the first quarter by Roche comprise Repare Therapeutics’ camonsertib – already announced in February – along with belvarafenib in solid tumours and RG6286 in colorectal cancer. The company has also recently backed away from a number of oncology collaborations, including one with HOOKIPA Pharma on arenaviral immunotherapy for KRAS-mutated cancers and another with Adaptimmune Therapeutics to develop T-cell therapies for cancer.Other drugs to face the chop in the first quarter include the LepB inhibitor RG6319 for urinary tract infections and RG6163 in psychiatric disorders. “Doubts around R&D productivity will take time to lift,” Jefferies analysts Peter Welford and Lucy Codrington noted.COVID impact overRoche’s first-quarter revenue slipped 6% to CHF 14.4 billion ($), with sales of prescription drugs falling by the same percentage to CHF 10.9 billion. Schinecker explained that “the appreciation of the Swiss franc versus most currencies impacted sales,” which would have risen by 2% on a constant exchange rate (CER) basis.The company reaffirmed that revenue and core earnings per share will both increase in the mid-single-digit range on a CER basis. Roche noted that for the remainder of the year, “there will be no further material impact of COVID-19 sales decline.”More to come.

ImmunotherapyBiosimilarAcquisitionFinancial Statement

24 Apr 2024

·www.biospace.com

Roche Trims Four Early Assets as Q1 Sales Slip 6% on Currency, COVID Headwinds

Pictured: Roche’s building in Shanghai, China iStock , Robert Way Despite being hit with a continuing decline in COVID-19 sales and a strong Swiss franc, Roche on Wednesday reported first-quarter sales were up 2% at constant exchange rates. Roche released its first-quarter 2024 earnings results on Wednesday posting a 6% decline in sales compared to the same prior year period, as the company continued to be weighed down by weak demand for COVID-19 products and currency headwinds while narrowly beating analysts’ expectations. In the first quarter of 2024, the pharma group’s sales brought in around $15.79 billion, down from its Q1 2023 earnings of approximately $16.78 billion. The performance of Roche’s pharmaceuticals division likewise slowed by 6% in the quarter, with its sales falling to $11.96 billion from $12.71 billion in the same period last year. CEO Thomas Schinecker in a statement attributed the decline to the ongoing contraction of the COVID-19 market and to the “appreciation of the Swiss franc versus most currencies,” which in turn had a significant adverse impact on the group’s sales reported in Swiss francs. At constant exchange rates, Roche’s earnings grew by 2%. Excluding pandemic-related products, sales increased by 7%. “After this quarter, the COVID-19-related impact on sales is largely behind us,” Schinecker added. The eye treatment Vabysmo (faricimab-svoa) emerged as Roche’s strongest growth driver, bringing in $927.4 million in Q1, a 108% increase compared with the same period in 2023 while beating the analyst consensus. Vabysmo was first approved in February 2022 for wet age-related macular degeneration and diabetic macular edema. The drug picked up another approval in October 2023 for retinal vein occlusion. The blood cancer therapy Polivy (polatuzumab vedotin-piiq) and breast cancer medicine Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzfx) were also strong growth contributors in Q1. These assets brought in $424 million and $273 million, respectively, representing sales increases of 70% and 81%. Roche’s top-performing asset was Ocrevus which secured $1.82 billion in Q1, representing 8% growth from the same time period in 2023. As for its pipeline, the pharma group disclosed in Wednesday’s earnings presentation that it had discontinued the development of four early-stage assets including camonsertinib—which was being trialed in solid tumors—and belvarafenib, which was likewise being assessed for solid tumors in combination with Genentech’s Cotellic (cobimetinib). Roche also terminated two new molecular candidates—one for colorectal cancer and one for psychiatric disorders. Looking forward to the rest of the year, Roche reaffirmed its 2024 outlook and noted in its statement that the company expects a sales increase in the mid-single digit range at constant exchange rates. To meet its forecast, Roche has several milestones lined up including a potential U.S. and European Union approval for crovalimab in paroxysmal nocturnal hemoglobinuria and for subcutaneous Ocrevus in relapsing or primary progressive multiple sclerosis. The pharma group is also preparing for key readouts for the Phase III VERONA study of Venclexta plus azacitidine in first-line myelodysplastic syndrome, as well as the Phase IIb PADOVA trial of prasinezumab in Parkinson’s disease. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com .

Drug ApprovalPhase 2Phase 3Financial StatementPhase 1

100 Deals associated with Belvarafenib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	South Korea	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	South Africa	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Belgium	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Taiwan Province	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Italy	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	United States	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Hong Kong	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Switzerland	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Portugal	Hoffmann-La Roche, Inc.	18 Jan 2021
Colorectal Cancer	Phase 2	Japan	Hoffmann-La Roche, Inc.	18 Jan 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04589845 (TAPISTRY, ESMO2024)	Phase 2	Metastatic Solid Tumor \| Solid tumor \| Non-Small Cell Lung Cancer \| Colorectal Cancer BRAF class II	-	Belvarafenib 400 mg	(rsvcedngiq) = 30 (100.0) vs 23 (95.8) of pts experienced at least one adverse event with Belvarafenib 400 mg vs Placebo azxeavrlbc (mlifnpmdqb ) View more	Negative	14 Sep 2024
NCT04589845 (TAPISTRY, ESMO2024)	Phase 2		-	Placebo		Negative	14 Sep 2024
NCT03284502 (HM-RAFI-103, ESMO 12023 \| ESMO 22023) Manual	Phase 1	BRAF mutation Solid Tumors BRAF mutation	133	Belvarafenib 300mg PO BID + Cobimetinib 20mg PO TIW	-	Positive	23 Oct 2023
NCT03284502 (HM-RAFI-103, ESMO 12023 \| ESMO 22023) Manual	Phase 1	BRAF mutation Solid Tumors BRAF mutation	133	Belvarafenib 300mg PO BID + Cobimetinib 20mg PO TIW (SC-A: BRAF fusion)	(uxzfohzcvu) = nywriulvnu lurecundho (gpemdweiig, 68.05 - 99.83) View more	Positive	23 Oct 2023
NCT03284502 (ESMO2021) Manual	Phase 1	RAS/RAF mutation Solid Tumors NRAS Mutation \| BRAF Mutation	118	cobimetinib+belvarafenib (NRASm melanoma)	(rczlcfghxe) = The most common treatment-emergent adverse events (TEAEs) were dermatitis acneiform (52.5%), diarrhea (28.0%), rash (27.1%), and increased CPK level (25.4%). ceirxhycxt (pzzqbdxieh )	Positive	16 Sep 2021
NCT03284502 (ESMO2021) Manual	Phase 1	RAS/RAF mutation Solid Tumors NRAS Mutation \| BRAF Mutation	118	cobimetinib+belvarafenib (BRAFm melanoma)		Positive	16 Sep 2021
NCT03284502 (ASCO2021)	Phase 1	NRAS Mutant Melanoma \| HR-positive/HER2-low Solid Tumors	32	Belvarafenib	(yqaoygfyut) = hztpbtckjk zbkpbtnrko (yqvyhelocx )	-	28 May 2021
NCT02405065 \| NCT03118817 (ASCO2019)	Phase 1	BRAF mutation Solid Tumors	-	Belvarafenib	nyxijimkqq(zhbtsgidtv) = The most common treatment-emergent adverse events that occurred in more than 20% of patients were dermatitis acneiform oyhdqskrqo (axedjhlrfo ) View more	Positive	26 May 2019
NCT02405065 (ASCO 12016 \| ASCO 22016) Manual	Phase 1	Solid tumor	31	Belvarafenib	(lfcjlvqnrs) = One patient at 200mg BID experienced grade 3 skin rash fkcutnmgke (miyqksdbci ) View more	Positive	05 Jun 2016
AACR2015	Phase 1	Melanoma	-	HM95573	nopakwpmxh(zfpgdlqsmy) = iifmcmwwyd nvvmawuebd (mrdsmxgctk ) View more	-	01 Aug 2015

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