The development of CFTR (cystic fibrosis conductance transmembrane regulator) modulators for people with cystic fibrosis (pwCF) and eligible for these treatments is a true therapeutic revolution. The major beneficial effect of CFTR modulators (CFTRm) on pulmonary function and the reduction of pulmonary exacerbations should have a considerable impact on the quality of life and patient's life expectancy. Data on the impact of CFTRm on glucose tolerance abnormalities are still very fragmentary. The investigators can think that their use, earlier and earlier in the history of the disease, will transform the evolutionary trajectories of patients on the respiratory, nutritional and metabolic levels.
Diabetes represents a major challenge in the management of pwCF because it is a factor in morbidity and mortality at all stages of the disease, from children to patients with terminal respiratory failure requiring lung transplantation. Early abnormalities in glucose tolerance observed in childhood, before the stage of diabetes, are also associated with poor pulmonary and nutritional outcomes. Experimental data suggest a positive effect of CFTRm on insulin secretion. However, investigators do not currently know the impact of CFTRm in patients with very early glucose disorders or at the stage of diabetes treated with insulin. Recently continuous glucose measurement (CGM) devices represent very effective tools for assessing abnormalities in glucose tolerance before the stage of diabetes and for monitoring patients treated with insulin.

Start Date01 Mar 2024

Sponsor / Collaborator

Les Hopitaux Universitaires de Strasbourg

ACTRN12624000146594 / Not yet recruitingNot Applicable

Assessment of regional lung ventilation via X-ray velocimetry (XV) imaging following thecommencement of ETI (elexacaftor/tezacaftor/ivacaftor) treatment in children with cystic fibrosis

Start Date01 Mar 2024

Sponsor / Collaborator

WomenS & ChildrenS Hospital

[+1]

ACTRN12623001136695 / RecruitingPhase 4IIT

Organoid Guided N-of-1 (ORIGIN-1) Trial: A phase 4 study to investigate whether people with CF with rare CFTR mutations who have an in vitro response to Trikafta will also have a clinically meaningful response to Trikafta versus placebo

Start Date13 Nov 2023

Sponsor / Collaborator

The University of Newcastle

100 Clinical Results associated with Elexacaftor/Ivacaftor/Tezacaftor

100 Translational Medicine associated with Elexacaftor/Ivacaftor/Tezacaftor

100 Patents (Medical) associated with Elexacaftor/Ivacaftor/Tezacaftor

Literatures (Medical) associated with Elexacaftor/Ivacaftor/Tezacaftor

01 Feb 2024·American Journal of Respiratory and Critical Care Medicine

Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related Events

Review

Author: Tian, Simon ; Volkova, Nataliya ; Tullis, Elizabeth ; Ramsey, Bonnie ; Correll, Christoph U ; Ahluwalia, Neil ; McKone, Edward ; Mall, Marcus A ; Waltz, David ; Chu, Chenghao ; Taylor-Cousar, Jennifer L ; DeMaso, David R

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (pwCF) aged 2 years and older with at least one F508del-CFTR allele or more. After U.S. approval in 2019, reports emerged of depression-related adverse events in pwCF treated with ELX/TEZ/IVA. Objectives: To review available evidence on depression-related events in pwCF treated with ELX/TEZ/IVA in the context of background epidemiology in pwCF. Methods: Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CF transmembrane conductance regulator (CFTR) modulators in which placebo was administered, along with data from CF registries in the United States and Germany and cumulative postmarketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA after initial approval in the United States (October 2019) through October 2022, were reviewed and used to calculate exposure-adjusted rates of depression-related adverse events and prevalence of depression. In addition, a scientific literature review was conducted to identify ELX/TEZ/IVA publications reporting depression-related events or changes in depressive symptoms after treatment initiation. Measurements and Main Results: In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32/100 person years (PY) in the pooled ELX/TEZ/IVA group (n = 1,711) and 3.24/100 PY in the pooled placebo group (n = 1,369). The exposure-adjusted rates of suicidal ideation and suicide attempt were also similar between the pooled ELX/TEZ/IVA group and pooled placebo group (ideation: 0.23/100 PY vs. 0.28/100 PY; attempt: 0.08/100 PY vs. 0.14/100 PY). In the postmarketing setting, the exposure-adjusted reporting rates of depression-related events were low in context of the background prevalence in pwCF (all depression-related events: 1.29/PY; suicidal ideation: 0.12/100 PY; and suicide attempt: 0.05/100 PY). Assessments of individual case reports were confounded by preexisting mental health conditions, intercurrent psychosocial stressors (including coronavirus disease [COVID-19] lockdowns), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the United States and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change after treatment initiation. Published studies utilizing the nine-item Patient Health Questionnaire did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA. Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.

01 Feb 2024·Molecular Biology of the Cell

Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states

Article

Author: Wąchalska, Magda ; Deol, Kirandeep K ; Riepe, Celeste ; Kopito, Ron R ; Olzmann, James A ; Porteus, Matthew H ; Amaya, Anais K

Over 80% of people with cystic fibrosis (CF) carry the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel at the apical plasma membrane (PM) of epithelial cells. F508del impairs CFTR folding causing it to be destroyed by endoplasmic reticulum associated degradation (ERAD). Small-molecule correctors, which act as pharmacological chaperones to divert CFTR-F508del from ERAD, are the primary strategy for treating CF, yet corrector development continues with only a rudimentary understanding of how ERAD targets CFTR-F508del. We conducted genome-wide CRISPR/Cas9 knockout screens to systematically identify the molecular machinery that underlies CFTR-F508del ERAD. Although the ER-resident ubiquitin ligase, RNF5 was the top E3 hit, knocking out RNF5 only modestly reduced CFTR-F508del degradation. Sublibrary screens in an RNF5 knockout background identified RNF185 as a redundant ligase and demonstrated that CFTR-F508del ERAD is robust. Gene-drug interaction experiments illustrated that correctors tezacaftor (VX-661) and elexacaftor (VX-445) stabilize sequential, RNF5-resistant folding states. We propose that binding of correctors to nascent CFTR-F508del alters its folding landscape by stabilizing folding states that are not substrates for RNF5-mediated ubiquitylation.

01 Jan 2024·SAGE Open Medicine

Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with Phe508del mutation: Evidence from randomized controlled trials

Article

Author: He, Rong ; Deng, Zehui ; Yu, Bin ; Lin, Fei

Objective::

This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of elexacaftor–tezacaftor–ivacaftor (ELX-TEZ-IVA) on patients with cystic fibrosis (CF).

Methods::

A systematic search was performed in PubMed, Embase, and the Cochrane Library from inception to August 1, 2022. Meta-analysis was conducted using Review Manager 5.3 software.

Results::

Six studies comprising seven reports involving a total of 1125 CF patients were included. The meta-analyses indicated that ELX-TEZ-IVA significantly improved the percentage predicted forced expiratory volume in 1 s (ppFEV1) by 10.29% (95% confidence interval (CI) (6.44, 14.14), p < 0.00001) and the CF questionnaire-revised respiratory domain (CFQ-R RD) by 14.59 points (95% CI (9.25, 19.94), p < 0.00001) compared to placebo, ivacaftor (IVA), or tezacaftor–ivacaftor (TEZ-IVA). In addition, the ELX-TEZ-IVA group showed significantly lower sweat chloride concentrations by 40.30 mmol/L (95% CI (−49.85, −30.74), p < 0.00001). However, the incidence of adverse events in the ELX-TEZ-IVA group was slightly higher than that in the placebo, IVA, or TEZ-IVA groups.

Conclusion::

ELX-TEZ-IVA demonstrated efficacy in improving ppFEV1, CFQ-R RD, and sweat chloride concentrations in patients with CF. However, caution should be exercised regarding the incidence of AEs, particularly mild and moderate ones.

News (Medical) associated with Elexacaftor/Ivacaftor/Tezacaftor

13 May 2024

·www.biospace.com

Data from the first human study demonstrate excellent performance of Zerion Pharma’s Dispersome® technology

May 13, 2024 (COPENHAGEN, Denmark). Zerion Pharma A/S (“ZERION”) today announces positive results from the first human clinical study of a Dispersome® formulation of the drug Ivacaftor, a pharmaceutical used to treat cystic fibrosis. The study was conducted by ZERION’s Spanish partner Insud Pharma, a global leader in generic and branded pharmaceuticals. The clinical study was a comparative oral bioavailability pilot study designed to assess the pharmacokinetic parameters of two different Ivacaftor Dispersome® formulations relative to the approved product Kalydeco® 150 mg film-coated tablets (Ivacaftor). Ivacaftor is formulated as a polymeric amorphous solid dispersion in Kalydeco®. The study was conducted as a crossover study with the participation of 18 subjects (healthy volunteers). One of the Ivacaftor Dispersome® formulations showed improved bioavailability compared to the reference product, while the pharmacokinetic parameters for the second formulation were equivalent to Kalydeco®. Both Ivacaftor Dispersome® formulations carried high content (drug load) of Ivacaftor and were designed to increase the solubility of this poorly soluble compound. “We are extremely pleased with the results of this study that mark the conclusion of years of efforts to demonstrate the benefit of our Dispersome® technology for patients. The study results are just spot on and confirm the good performance that we had predicted from in-vitro studies in our laboratory as well as multiple animal studies on many other drugs. The results represent the biggest milestone for ZERION so far, and prove that Dispersome® will bring benefits to patients in the form of completely new or better drug products”, says Ole Wiborg, CEO of ZERION, adding: ”Without the efforts of our partner Insud Pharma, we would not have accomplished this. Thus, we are truly grateful to Insud Pharma that early on showed trust in our technology and has been performing excellent in their planning and carrying out the clinical study”. ZERION announced its collaboration with Insud Pharma in August 2022. The Ivacaftor Dispersome® product is the first product originating from the collaboration that has been investigated in a human clinical trial. Ivacaftor is used to treat cystic fibrosis in patients with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is also used in combination with other drugs such as tezacaftor and elexacaftor to treat people with cystic fibrosis. About Zerion Pharma A/S ZERION develops its own proprietary drug formulations and offers its Dispersome® technology platform to established pharma companies as a means to solve their challenging drug solubility problems. By applying ZERION’s technology, the solubility of poorly soluble compounds may be greatly enhanced, which improves their oral bioavailability and thereby therapeutic outcomes for the patients. ZERION was established in 2019 as a spin-out from the University of Copenhagen based on almost a decade of research. About Insud Pharma Insud Pharma operates throughout the entire pharmaceutical value chain, delivering specialist expertise in scientific research, development, manufacturing, sales and marketing for a wide range of active pharmaceutical ingredients (APls), finished dosage forms (FDFs), branded pharmaceuticals for human and animal care and biopharmaceutical products to treat and prevent diseases across different therapeutic areas. With over 45 years' experience, Insud Pharma is well-positioned in the global pharmaceutical sector and is committed to continuous growth and diversification. Insud Pharma is present at every level of the chemical and pharmaceutical industry through its business units including, among others, Chemo, Exeltis and Xiromed. Insud Pharma has 9,000 employees and operates in more than 50 countries. For more information, please visit or contact: Ole Wiborg, CEO Mobile: +45 40 96 80 18 E-mail: info@zerion.eu Follow us on: LinkedIn

Clinical Result

07 May 2024

·www.fiercebiotech.com

Vertex files FDA approval ask for next-gen cystic fibrosis candidate, resumes diabetes cell therapy trial

Vertex's next-gen cystic fibrosis treatment is a once-daily triple CFTR modulator regime. Vertex Pharmaceuticals is ahead of schedule, filing a new drug application for its next-gen cystic fibrosis (CF) treatment dubbed vanza triple. Vertex completed the regulatory submission a month before its goal of mid-2024, CEO Reshma Kewalramani, M.D., said on a first-quarter earnings call May 6. The investigational treatment is a once-daily triple CFTR modulator regimen made up of vanzacaftor, tezacaftor and deutivacaftor. Earlier this year, vanza triple achieved the main goals across several phase 3 programs, demonstrating noninferiority against Vertex’s own twice-daily Trikafta for improving lung function and superiority to Trikafta in lowering levels of sweat chloride. Now, Vertex is asking for the FDA to approve vanza triple for people with CF aged 6 years and older. The Boston-based company also completed a submission in Europe for the same indication and is on track to complete submissions in the U.K., Canada, Australia, New Zealand and Switzerland, Kewalramani said. In the U.S., Vertex intends to use its FDA priority review voucher, which guarantees an expedited six-month review process. Other big updates from the biotech include resumed enrollment in a phase 1/2 diabetes trial, which is evaluating an allogeneic, stem cell-derived insulin-producing islet cell therapy dubbed VX-880. Vertex implemented a voluntary hold on the trial back in January after two deaths deemed unrelated to treatment occurred. After an independent data monitoring committee reviewed data from the trial, Vertex has resumed dosing and completed enrollment of 17 patients who have Type 1 diabetes with impaired hypoglycemic awareness and severe hypoglycemia. The company expects to finish dosing soon. Vertex plans to share updated data on the cell therapy—which has previously shown promise in eliminating the need for insulin in a small group of patients—at the American Diabetes Association Scientific Sessions conference in June. The two updates come a few weeks after Vertex announced plans to sell autoimmune and inflammatory disease-focused Alpine Immune Sciences for $4.9 billion. The transaction is expected to close in the second quarter of this year.

Phase 3Cell TherapyClinical ResultPriority Review

07 May 2024

·firstwordpharma.com

Vertex upbeat on Casgevy launch as cell collections outdo bluebird’s Lyfgenia

Vertex Pharmaceuticals said that since gaining the first approvals late last year for Casgevy (exagamglogene autotemcel), five patients have had stem cells collected as of mid-April in preparation for manufacturing of the gene therapy. Stuart Arbuckle, chief operating officer, called the progress “excellent,” noting that “many patients have [also] begun the treatment journey” in the markets where Casgevy is approved, which include the US, Europe and the Middle East.The therapy, which utilises CRISPR/Cas9 gene-editing technology and carries a list price of $2.2 million in the US, is authorised for use in patients with sickle-cell disease (SCD) and transfusion-dependent beta thalassaemia. Arbuckle, speaking on the company’s first-quarter earnings call, explained that the cell collections have occurred across all regions where Casgevy is available.Meanwhile, bluebird bio recently said it completed the first commercial cell collection for its cell-based gene therapy Lyfgenia (lovotibeglogene autotemcel). The product is approved in the US, where it has a list price of $3.1 million and is used to treat SCD patients with a history of vaso-occlusive events. Both Casgevy and Lyfgenia gained clearance from the FDA last December.Casgevy ‘ramping more quickly’Mizhuo analysts noted that Casgevy “seems to be ramping more quickly” than Lyfgenia, particularly in the US, in terms of cell collections-to-treatment centres. According to the analysts, Vertex and co-development partner CRISPR Therapeutics have 18 active collection sites in the US, while bluebird has over 60 centres.Globally, Vertex says it has activated more than 25 authorised treatment centres (ATCs) for Casgevy, with a target of bringing 75 priority centres online. Analysts at Morgan Stanley forecast that a total of 80 patients will receive Casgevy in 2024, including 54 in the US.Revenue in second halfArbuckle indicated that the drugmaker continues to “make great progress with payers,” although he reiterated that it will only “recognise revenue…near the end of the patient journey at infusion.” Vertex is including Casgevy revenue in its overall annual sales forecast of $10.55 billion to $10.75 billion, with the gene therapy contributing in the second half of the year. However, the company’s cystic fibrosis (CF) products are still set to generate the majority of sales.In the first quarter, the drugmaker’s product revenue increased 13% to $2.7 billion, topping estimates of $2.6 billion, led by $2.5 billion in sales of the CF treatments Trikafta and Kaftrio. Meanwhile, net income reached $1.1 billion, up from around $700 million in the prior year.Pipeline in focusDavid Song of Tema ETFs remarked "over the next 12 to 18 months, investors are evaluating whether Vertex can sustain its CF franchise for several years and expand upon it through internal pipeline development, as well as business development." The company recently agreed to buy Alpine Immune Sciences for $4.9 billion, gaining the experimental drug povetacicept for IgA nephropathy.Vertex is also hoping to bring a non-opioid pain drug to market, having initiated an FDA rolling submission for suzetrigine, while its other pipeline bets include inaxaplin in autosomal dominant polycystic kidney disease and VX-880 in type 1 diabetes. For related analysis, see Vital Signs: Dissecting dealmaking at Vertex and its Alpine takeout.

AcquisitionGene TherapyDrug ApprovalCell Therapy

100 Deals associated with Elexacaftor/Ivacaftor/Tezacaftor

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KEGG	Wiki	ATC	Drug Bank
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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Cystic Fibrosis	US	Vertex Pharmaceuticals, Inc.	21 Oct 2019

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cough	Phase 3	AU	Vertex Pharmaceuticals, Inc.	12 Oct 2021
Cough	Phase 3	BE	Vertex Pharmaceuticals, Inc.	12 Oct 2021
Cough	Phase 3	CA	Vertex Pharmaceuticals, Inc.	12 Oct 2021
Cough	Phase 3	ES	Vertex Pharmaceuticals, Inc.	12 Oct 2021
Glucose Metabolism Disorders	Phase 3	AU	Vertex Pharmaceuticals, Inc.	15 Jan 2021
Glucose Metabolism Disorders	Phase 3	BE	Vertex Pharmaceuticals, Inc.	15 Jan 2021
Glucose Metabolism Disorders	Phase 3	CZ	Vertex Pharmaceuticals, Inc.	15 Jan 2021
Glucose Metabolism Disorders	Phase 3	FR	Vertex Pharmaceuticals, Inc.	15 Jan 2021
Glucose Metabolism Disorders	Phase 3	IT	Vertex Pharmaceuticals, Inc.	15 Jan 2021
Glucose Metabolism Disorders	Phase 3	NL	Vertex Pharmaceuticals, Inc.	15 Jan 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04545515 (CTgov)	Phase 3	Cystic Fibrosis	120	IVA+ELX/TEZ/IVA	jypgcaivrl(roehdpzcog) = zjpdyurinu szusdsrljn (vwadpaggkh, nhxpwuofrm - fhovkdrhlc) View more	-	08 May 2024
NCT03525574 (CTgov)	Phase 3	Cystic Fibrosis	507	IVA+ELX/TEZ/IVA	blcdgesrpu(oltjsuwtbp) = tqamanfofg lpupsxackf (caabvhpezt, kncvazbepl - vppeeatmqj) View more	-	08 May 2024
NCT04058366 (CTgov)	Phase 3	Cystic Fibrosis	251	IVA+ELX/TEZ/IVA	qtkzlxwlny(hodgnkceji) = eigixsikod otohuhkkgp (zteilijmnm, qqbjxjatuc - tiqvyvffgf) View more	-	16 Jan 2024
AASLD2023	Not Applicable	Cystic Fibrosis	154	Elexacaftor/tezacaftor/ivacaftor	mvpqyzwjcc(hlzdsbpkmp) = wjfyjhaida zbxhjuxmhn (bixufexexa ) View more	-	10 Nov 2023
NCT04969224 (CTgov)	Phase 3	Cystic Fibrosis \| Cough	82	IVA+ELX/TEZ/IVA	jmhafdcygo(ouijzvmzqo) = lvkwkuxdke agidohszgm (jbcszptrlr, hhyrwwriur - uuegtjrdwj) View more	-	03 Oct 2023
NCT04599465 (CTgov)	Phase 3	Cystic Fibrosis \| Glucose Metabolism Disorders	69	IVA+ELX/TEZ/IVA	ntookrmtli(drsxqfokex) = rypgokjyhy ukopdcisgm (avcgsskjyt, oazfcxxavr - ziqiltatiq) View more	-	03 Aug 2023
NCT04043806 (CTgov)	Phase 3	Cystic Fibrosis	458	IVA+ELX/TEZ/IVA	bmrlqmbbmh(rgmqhifasv) = fagrfsxeop dpajcfyxjn (tremtmauda, mxxsgjwram - xjjgklpgfq) View more	-	06 Jul 2023
ADA2023	Not Applicable	Cystic fibrosis related diabetes	24	Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy	tsqrwkhqqa(ohijfdcieb) = dfkskocvwz mazdanxnpo (miudpcewyh ) View more	-	20 Jun 2023
FDA Manual	Not Applicable	Cystic Fibrosis F508del Mutation	107	TRIKAFTA	vlbuyqlory(airfhemaup): Difference = 10.0 (95% CI, 7.4 - 12.6), P-Value = <0.0001 View more	Positive	26 Apr 2023
FDA Manual	Not Applicable	Cystic Fibrosis F508del Mutation	107	Tezacaftor/Ivacaftor		Positive	26 Apr 2023
FDA Manual	Not Applicable	Cystic Fibrosis F508del Mutation	403	TRIKAFTA	cgiiekluks(yozesdejse): Difference = 13.8 (95% CI, 12.1 - 15.4), P-Value = <0.0001 View more	Positive	26 Apr 2023
FDA Manual	Not Applicable	Cystic Fibrosis F508del Mutation	403	Placebo		Positive	26 Apr 2023

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