Novel therapy for the Long QT Syndrome based on the mechanism of action of the disease-causing mutations
Long QT syndrome type 2 (LQT2) accounts for
35% of all LQTS cases and is difficult to manage, as beta-blockers frequently fail to provide full protection. Most LQT2 patients (pts) have a Class 2 mutation, which implies defective "trafficking".
Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic fibrosis (CF) in patients homozygous for the F508del mutation in the CFTR gene. LUM corrects protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring their cell surface expression. The investigators recently demonstrated that LUM can rescue in vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from pts with LQT2 Class 2 mutations (PMID: 29020304) and in these same two patients Orkambi administrated for 7 days at the same dosage approved for cystic fibrosis showed to reduce their QTc (PMID: 30753398).
With the present phase II clinical trial (MAST2) the investigators will enroll 20 LQT2 patients (see inclusion and exclusion criteria) and they will test in vivo the efficacy of Orkambi in shortening their QTc. Patients will be admitted to hospital for a maximum of 7 days (minimum in-hospital stay based on evidence of QTc shortening). Orkambi will be administered at the dose approved for cystic fibrosis and during the entire period continuous ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed and QTc length and morphology will be analyzed.

Start Date15 Jun 2021

Sponsor / Collaborator

Istituto Auxologico Italiano

NCT04235140 / CompletedPhase 3

A Phase 3, Open-label, and Rollover Study to Evaluate the Long-term Safety and Tolerability of Lumacaftor/Ivacaftor Treatment in Subjects With Cystic Fibrosis Who Are Homozygous for F508del and 12 to <24 Months of Age at Treatment Initiation

This is a Phase 3, multicenter, open-label and roll-over study in subjects who are 12 to <24 months of age at initiation of Lumacaftor/Ivacaftor (LUM/IVA) treatment.

Start Date24 Feb 2020

Sponsor / Collaborator

Vertex Pharmaceuticals, Inc.

NCT03894657 / CompletedNot Applicable

Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. Pathway to Personalized Therapy in Cystic Fibrosis

The purpose of the study is to investigate whether the correction of CFTR function by Lumacaftor/Ivacaftor in a patient-derived primary nasal cell model is a surrogate biomarker for respiratory improvement in Orkambi® treated patients.

Start Date18 Dec 2019

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

100 Clinical Results associated with Ivacaftor/Lumacaftor

100 Translational Medicine associated with Ivacaftor/Lumacaftor

100 Patents (Medical) associated with Ivacaftor/Lumacaftor

109

Literatures (Medical) associated with Ivacaftor/Lumacaftor

01 Jan 2024·Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

Elexacaftor/tezacaftor/ivacaftor improves chronic rhinosinusitis detected by magnetic resonance imaging in children with cystic fibrosis on long-term therapy with lumacaftor/ivacaftor

Article

Author: Zhao, Shengkai ; Schenk, Jens-Peter ; Wuennemann, Felix ; Sommerburg, Olaf ; Becker, Johanna K Z ; Graeber, Simon Y ; Alrajab, Abdulsattar ; Baumann, Ingo ; Eichinger, Monika ; Kauczor, Hans-Ulrich ; Chung, Jaehi ; Mall, Marcus A ; Stahl, Mirjam ; Wielpütz, Mark O ; Wucherpfennig, Lena ; Seitz, Angelika

INTRODUCTION:

Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied.

METHODS:

30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6-16y). MRI were evaluated using the CRS-MRI score.

RESULTS:

After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275-0.999).

CONCLUSIONS:

ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.

01 Jan 2024·Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor

Article

Author: van der Sijs, H ; Ruijgrok, E J ; Smeets, T J L ; de Winter, B C M ; Janssens, H M

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.

12 Oct 2023·ACS medicinal chemistry letters

A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis.

Article

Author: Kolykhalov, Alexander A ; Hong, Jeong S ; Davies, Huw M L ; Fu, Haian ; Rab, Andras ; Sorscher, Eric J ; Du, Yuhong ; Yang, Xun ; Ponnaluri, Sadhana S ; Tracy, William F ; Manfredi, Candela ; Qui, Min ; Joshi, Disha

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

News (Medical) associated with Ivacaftor/Lumacaftor

21 Jun 2024

·www.fiercepharma.com

Vertex clinches Trikafta and other cystic fibrosis drug reimbursement deal in England

Last November, NICE acknowledged in draft guidance the effectiveness of Vertex’s CF cocktails, but the agency stopped short of dubbing the medicines cost-effective. Cystic fibrosis (CF) patients and their families in England can rest a little easier this week, thanks to an extended long-term reimbursement deal inked by Vertex Pharmaceuticals and the country’s National Health Service (NHS). The accord comes after years of back-and-forth in the United Kingdom over the cost of Vertex’s life-saving—yet expensive—CF drugs. Vertex announced the updated reimbursement deal with the NHS on Thursday, which ensures access to the drugmaker’s CF meds Trikafta (known as Kaftrio in the U.K.), Symkevi and Orkambi for all existing and future eligible cystic fibrosis patients in England. It’s expected that similar deals will soon materialize in Wales, Scotland and Northern Ireland, according to the British Broadcasting Corporation (BBC). The agreement comes after the U.K.’s drug cost gatekeeper, the National Institute for Health and Care Excellence (NICE), issued a positive recommendation for Vertex’s roster of CFTR modulators in June. In November 2023, NICE acknowledged in draft guidance the effectiveness of Vertex’s CF cocktails, but the agency stopped short of dubbing the medicines cost-effective. “Even when considering the condition’s severity … the most likely cost-effectiveness estimates for [Trikafta], [Symkevi] and [Orkambi] are above the range that NICE considers an acceptable use of NHS resources,” the government agency said at the time. The situation mirrored a yearslong standoff between Vertex and the NHS over the pricing of Orkambi and other CF drugs that was resolved in 2019 with a four-year government reimbursement deal. Trikafta was added to the scheme in 2020. At the time of NICE’s decision last fall, David Ramsden, CEO of the Cystic Fibrosis Trust, argued that Vertex, NICE and the NHS must “urgently work together to find a solution to make these treatments available for all those who could potentially benefit.” Under the latest deal, patients will also receive access to any future license extensions on Vertex’s CF meds, the company explained in its release. Moreover, Vertex, NICE and the NHS are working on a path towards “rapid access” for Vertex’s next investigational cocktail for CF, which combines vanzacaftor, tezecaftor and deutivacaftor, should the combo therapy pass muster with England’s drug regulator. CF is a genetic condition in which a faulty protein affects the body’s cells, tissues and mucus- and sweat-producing glands. Patients with the disease make thick, sticky mucus that can build up and cause damage or infection to organs like the lungs and pancreas. The most serious and common complications of CF are respiratory in nature, including serious lung infections. Vertex’s flagship drug Trikafta is a combination of elexacaftor, ivacaftor and tezacaftor. It works by helping defective CF transmembrane conductance regulator proteins work more effectively. Vertex’s roster of CF medicines is currently “broadly available” in more than 60 countries, including Australia, France, Italy, Germany, the Republic of Ireland, the Netherlands, Spain and the U.S., the company explained. Meanwhile, another pricing standoff could be brewing between NICE and Vertex on the drugmaker’s CRISPR Therapeutics-partnered gene therapy for sickle cell disease, Casgevy. In draft guidance unveiled in March, the cost watchdog did not endorse Casgevy—which gained its U.K. approval in November 2023—but caveated that it was “exploring further data collection” on the therapy’s effectiveness and a potential commercial arrangement.

Gene Therapy

21 Jun 2024

·www.biospace.com

Vertex Finally Reaches Pricing Deal With England’s NHS for Cystic Fibrosis Drugs

Pictured: Vertex Pharmaceuticals' headquarters in Boston, Massachusetts/iStock, hapabapa Vertex Pharmaceuticals on Thursday announced that it has entered into an extended, long-term reimbursement agreement with England’s National Health Service, granting access to its cystic fibrosis treatments Kaftrio (ivacaftor/tezacaftor/elexacaftor), Symkevi (ezacaftor/ivacaftor) and Orkambi (lumacaftor/ivacaftor). The biotech did not disclose specific details of the deal, only revealing that it would also apply to future license extensions of these drugs. Vertex is working on similar deals in Scotland, Wales and Northern Ireland. Ludovic Fenaux, senior vice president of Vertex International, said in a statement that the company is “delighted” to have reached a deal with the National Health Service (NHS), adding that the reimbursement agreement will ensure “long-term access” to Kaftrio, Symkevi and Orkambi for cystic fibrosis (CF) patients in England. Vertex is currently in talks with NHS England as well as the drug pricing watchdog National Institute for Health and Care Excellence (NICE) to ensure rapid access to the biotech’s next-generation triple combination CF treatment. In a Phase III readout posted in February 2024, the investigational therapy, dubbed vanza triple, matched Kaftrio in terms of improving patients’ lung function, and outperformed the approved treatment in terms of sweat chloride levels. Thursday’s reimbursement deal comes after the NICE in October 2023 declined to recommend Kaftrio, Symkevi and Orkambi for use in CF patients. At the time, the watchdog said that while the drugs’ efficacy data support their clinical benefit, they were too expensive to be covered. “The most likely cost-effectiveness estimates for [Kaftrio, Orkambi and Symkevi] are above the range that NICE considers an acceptable use of NHS resources,” the agency wrote. However, earlier this week, NICE reversed its recommendation. In its final draft guidance, the watchdog said that given the severity of CF and its effects of quality and length of life, the cost-effectiveness estimates for Kaftrio, Symkevi and Orkambi now fell within its threshold of acceptable use of NHS resources. While NICE’s recommendation and the NHS deal names three of Vertex’s CF drugs, the centerpiece is Kaftrio, which the watchdog said yielded better short- and long-term improvements than Symkevi and Orkambi. Kaftrio is also known as Trikafta in the U.S. and is a three-drug combo that first won the FDA’s approval in October 2019, allowing its use in patients aged 12 years and older bearing at least one copy of the F508del mutation in the CTFR gene. Trikafta works by increasing the number and improving the function of F508del-CFTR proteins at the cell surface. Trikafta won additional approvals in 2021, for use in CF patients ages 6 to 11 years, and in 2023, for patients 2 through 5 years. 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.

Phase 3Drug Approval

18 Jun 2024

·www.biospace.com

Enlaza Therapeutics Appoints Jeffrey Leiden, M.D., Ph.D., as a Key Advisor

Executive Chairperson and former CEO of Vertex Pharmaceuticals to help guide the development of a high-value pipeline of first-in-class covalent protein drugs from Enlaza’s War-Lock™ platform LA JOLLA, Calif.--(BUSINESS WIRE)-- Enlaza Therapeutics, the first covalent biologic platform company, today announced the appointment of Dr. Jeffrey Leiden, Executive Chairperson of Vertex Pharmaceuticals, as a key advisor to the company. Dr. Leiden has more than 40 years of experience in the biopharma industry developing life-improving medicines and building companies that transform the industry. “Jeff is one of the most accomplished and admired leaders in our industry. He has dedicated his career to developing important first-in-class medicines from novel breakthrough technologies that have helped millions of people with serious diseases,” said Sergio Duron, Ph.D., CEO of Enlaza Therapeutics. “With our War-Lock platform, we can create covalent protein drugs with the potential to improve treatments for many diseases. Jeff’s guidance will be invaluable as we establish a diverse pipeline and advance our lead assets toward clinical development.” "While covalency has been a long-standing strategy in small molecule drug development, Enlaza is the first to incorporate covalency into biologics, unlocking a new class of protein therapeutics," said Dr. Leiden. "I look forward to working closely with the Enlaza team to realize the full potential of this exciting new drug discovery and development platform and help create meaningful new medicines for patients.” As CEO and President of Vertex from 2012 through 2020, Dr. Leiden built a robust pipeline of drug candidates, with a particular focus on therapies that cure or modify the course of disease. Under his leadership, Vertex delivered the first and only medicines to treat the underlying cause of cystic fibrosis for patients with certain forms of the disease, including KALYDECO®, ORKAMBI®, SYMDEKO® and TRIKAFTA®. In 2015, he established a collaboration with CRISPR Therapeutics to develop transformative therapies for sickle cell disease (SCD), beta thalassemia (TDT) and other diseases; and in 2023, CASGEVY™ was approved as the first gene-editing therapy in the world for SCD and TDT. In 2019, he led the Vertex acquisition of Semma Therapeutics to develop a clinical program to investigate what may be the first potentially curative stem cell-based therapy for type 1 diabetes. Prior to joining Vertex, Dr. Leiden was a managing director at Clarus Ventures, a life sciences venture capital firm, from 2006 through 2012. Dr. Leiden was President, Chief Operating Officer and Chief Scientific Officer of Abbott Laboratories, Pharmaceuticals Products Group, and a member of the board of directors of Abbott Laboratories from 2000 to 2006. At Abbott he led the development and commercialization of HUMIRA®. From 1987 to 2000, Dr. Leiden held several academic appointments, including the Rawson Professor of Medicine and Pathology and Chief of Cardiology and Director of the Cardiovascular Research Institute at the University of Chicago, the Elkan R. Blout Professor of Biological Sciences at the Harvard School of Public Health, and Professor of Medicine at Harvard Medical School. He is an elected member of both the American Academy of Arts and Sciences and the National Academy of Medicine. About the War-Lock™ Platform Enlaza’s covalent biologic platform, called War-Lock, creates highly specific therapeutic warheads that covalently bind to drug targets of interest. This white-space technology enables, for the first time, a covalent-acting protein drug that retains the selectivity of small-format biologics. Protein drugs produced by the platform can be modified to incorporate various payloads and achieve specific delivery to target tissues with high fidelity. About Enlaza Therapeutics Enlaza Therapeutics is pioneering the field of covalent biologics. This novel class of protein therapeutics has the potential to delivers more efficacious and safer treatments for patients. The company's proprietary War-Lock™ platform leverages leading synthetic biology technology for site-specific covalent coupling driven by drug binding. Enlaza is building a pipeline of first-in-class covalent biologics. For more information, please visit .

Executive Change

100 Deals associated with Ivacaftor/Lumacaftor

External Link

KEGG	Wiki	ATC	Drug Bank
-	Ivacaftor/Lumacaftor	R07AX30	-

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Cystic Fibrosis	US	Vertex Pharmaceuticals, Inc.	02 Jul 2015

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ERS2022	Not Applicable	Cystic Fibrosis F508del	-	LUM/IVA cohort (US)	-	-	04 Sep 2022
				LUM/IVA cohort (UK)
NCT03601637 (Pubmed) Manual	Phase 3	Cystic Fibrosis F508del mutation	60	Lumacaftor+Ivacaftor (18 to <24 months)	-	Positive	30 Jun 2022
				Lumacaftor+Ivacaftor (12 to <18 months)	imjlpihair(fazpkppcdg) = btexpuovxl onptquymxc (vhdnpzeuzf ) View more
NCT03625466 (CTgov)	Phase 2	Cystic Fibrosis	51	placebo (Part 1: Placebo)	rdalxyspsi(ikwwoqohad) = cmddraswpz dlzzorfwsm (oidjqnlcqp, rnvilhjgra - rjdnsopwvl) View more	-	08 Dec 2021
				LUM/IVA (Part 1: LUM/IVA)	rdalxyspsi(ikwwoqohad) = jpdirouopl dlzzorfwsm (oidjqnlcqp, lpvfhlxxej - xqvkzmdszj) View more
ERS2021	Not Applicable	Cystic Fibrosis F508del	-	LUM/IVA	qdkjdgboex(qgaxfnjlfd): OR = 0.16 (95% CI, 0.07 - 0.38) View more	-	05 Sep 2021
				lumacaftor/ivacaftor (LUM/IVA)
NCT03061331 (Pubmed \| J Cyst Fibros) Manual	Phase 2	Cystic Fibrosis A455E-CFTR Mutation	20	Placebo+Ivacaftor+Lumacaftor	htkxjvlxmg(foquavggfm) = dfdxipyxuy pxvsaoyjho (tjcokrbuee )	Negative	01 Sep 2021
				Placebo+Ivacaftor+Lumacaftor	htkxjvlxmg(foquavggfm) = quxomttepa pxvsaoyjho (tjcokrbuee )
NCT03125395 (VX16-809-116, Pubmed \| Lancet Respir Med) Manual	Phase 3	Cystic Fibrosis F508del mutation	57	Ivacaftor/Lumacaftor	yesjvdklbo(ldxcodvnvi) = simbjsuwmq zchjvkgwjw (lofxxaxhhn ) View more	Positive	01 Sep 2021
NCT02807415 (Pubmed)	Not Applicable	Cystic Fibrosis	30	Lumacaftor-Ivacaftor	zeiowlrgsk(jfpejsjqus) = zgocmxjhcs smmywucgeg (gdbplbldqw, -938.7 to 290.4)	-	18 Feb 2021
ERS2020	Not Applicable	Cystic Fibrosis Phe508del mutation	5	Lumacaftor/Ivacaftor therapy	etmovcccrh(aonrskiyon) = jsxnztksus lczkaqxwtn (wacxcvwncf, 24.9 - 38.4)	-	07 Sep 2020
NCT03125395 (VX16-809-116, CTgov)	Phase 3	Cystic Fibrosis	57	LUM/IVA	pymtsmcvro(cpniztitgc) = adsedzwjwe whpneebfug (lyqwxrbnef, knasivpere - lwnkrlwucf) View more	-	07 Aug 2020
Pubmed	Not Applicable	Cystic Fibrosis	193	Lumacaftor/Ivacaftor	vxtgxfdsxm(jytuceolye) = chmziiwxwx iyaxretlcc (ocqskpyugh ) View more	Positive	09 Jul 2020

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