Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year

The goal of this clinical trial is to assess the safety and efficacy of GS010, a gene therapy, in improving the retina functional & structural outcomes in subjects with LHON due to the G11778A ND4 mitochondrial mutation when vision loss duration is present up to one year.

Start Date12 Mar 2018

Sponsor / Collaborator

Gensight Biologics SA

NCT02652780 / CompletedPhase 3

Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for More Than 6 Months and To 12 Months by LHON Due to the G11778A Mutation in the ND4 Gene

The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year.

Start Date01 Jan 2016

Sponsor / Collaborator

Gensight Biologics SA

NCT02064569 / CompletedPhase 1/2

An Open Label Dose Escalation Clinical Trial to Evaluate the Safety and the Tolerability of GS010 (rAAV2/2-ND4) in Patients With Leber Hereditary Optic Neuropathy Due to Mutations in the Mitochondrial NADH Dehydrogenase 4 Gene

The purpose of this study is to evaluate the safety and tolerability profile of ascending doses of GS010 in Leber Hereditary Optic Neuropathy (LHON) patients.

Start Date13 Feb 2014

Sponsor / Collaborator

Gensight Biologics SA

100 Clinical Results associated with Lenadogene nolparvovec

100 Translational Medicine associated with Lenadogene nolparvovec

100 Patents (Medical) associated with Lenadogene nolparvovec

132

Literatures (Medical) associated with Lenadogene nolparvovec

01 Sep 2024·Ophthalmology Science

Dose-Dependent Progression of Chorioretinal Atrophy at the Injection Site After Subretinal Injection of rAAV2/8 in Nonhuman Primates

Article

Author: Seitz, Immanuel P ; Ochakovski, G Alex ; Wozar, Fabian ; Reichel, Felix F ; Fischer, M Dominik ; Peters, Tobias ; Gelisken, Faik ; Bartz-Schmidt, K Ulrich

ObjectiveProgressive retinal atrophy has been described after subretinal gene therapy utilizing the adeno-associated virus (AAV) vector platform. To elucidate whether this atrophy is a consequence of inherent properties of AAV, or if it is related to the surgical trauma of subretinal delivery, we analyzed data from an Investigational New Drug-enabling study for PDE6A gene therapy in nonhuman primates.DesignAnimal study (nonhuman primates), retrospective data analysis.SubjectsForty eyes of 30 healthy nonhuman primates (macaca fascicularis) were included in the analysis. Two AAV dose levels (low: 1x10E11, high: 1x10E12) were compared with sham injection (balanced saline solution; BSS). Twenty untreated eyes were not analyzed.MethodsAnimals were treated with a sutureless 23G vitrectomy and single subretinal injections of AAV.PDE6A and/or BSS. The follow-up period was 12 weeks. Atrophy development was followed using fundus autofluorescence (AF), OCT, fluorescence angiography, and indocyanine green angiography.Main Outcome MeasuresArea [mm²] of retinal pigment epithelium atrophy on AF. Presence of outer retinal atrophy on optical coherence tomography. Area [mm²] of hyperfluorescence in fluorescence angiography and hypofluorescence in indocyanine green angiography.ResultsProgressive atrophy at the injection site developed in 54% of high-dose-treated, 27% of low-dose-treated, and 0% of sham-treated eyes. At the end of observation, the mean ± SD area of atrophy in AF was 1.19 ± 1.75 mm², 0.25 ± 0.50 mm², and 0.0 ± 0.0 mm², respectively (sham × high dose: P = 0.01). Atrophic lesions in AF (P = 0.01) and fluorescence angiography (P = 0.02) were significantly larger in high-dose-treated eyes, compared with sham-treated eyes. Rate of progression in high-dose-treated eyes was 4.1× higher compared with low-dose-treated eyes.ConclusionSubretinal injection of AAV.PDE6A induced dose-dependent, progressive retinal atrophy at the site of injection. Findings from multimodal imaging were in line with focal, transient inflammation within the retina and choroid and secondary atrophy. Atrophic changes after gene therapy with AAV-based vector systems are not primarily due to surgical trauma and increase with the dose given.Financial DisclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

01 Jan 2024·Biomedicine & Pharmacotherapy

Adeno-associated virus vector hydrogel formulations for brain cancer gene therapy applications

Article

Author: Barszcz, Sławomir ; Gawrychowski, Krzysztof ; Słyk, Żaneta ; Wrzesień, Robert ; Małecki, Maciej

Gelatin-based formulations are utilized in neurosurgical procedures, with Medisponge® serving as an illustration of a secure and biocompatible hemostatic formulation. Noteworthy are combined hemostatic products that integrate pharmacological agents with gelatin. Gelatin matrices, which host biologically active substances, provide a platform for a variety of molecules. Biopolymers function as carriers for chemicals and genes, a facet particularly pertinent in brain cancer therapy, as gene therapy complement conventional approaches. The registration of Zolgensma underscores the efficacy of rAAV vectors in therapeutic gene delivery to the CNS. rAAVs, renowned for their safety, stability, and neuron-targeting capabilities, predominate in CNS gene therapy studies. The effectiveness of rAAV vector therapy varies based on the serotype and administration route. Local gene therapy employing hydrogel (e.g., post-tumor resection) enables the circumvention of the blood-brain barrier and restricts formulation diffusion. This study formulates gelatin rAAV gene formulations and evaluates vector transduction potential. Transduction efficiency was assessed using ex vivo mouse brains and in vitro cancer cell lines. In vitro, the transduction of rAAV vectors in gelatin matrices was quantified through qPCR, measuring the itr and Gfp expression. rAAVDJ and rAAV2 demonstrated superior transduction in ex vivo and in vitro models. Among the cell lines tested (Hs683, B16-F10, NIH:OVCAR-3), gelatin matrix F1 exhibited selective transduction, particularly with Hs683 human glioma cells, surpassing the performance Medisponge®. This research highlights the exploration of local brain cancer therapy, emphasizing the potential of gelatin as an rAAV vector carrier for gene therapy. The functional transduction activity of gelatin rAAV formulations is demonstrated.

01 Jan 2024·Journal of Inherited Metabolic Disease

Gene therapy for mitochondrial disorders

Review

Author: Viscomi, Carlo ; Minczuk, Michal ; Keshavan, Nandaki ; Rahman, Shamima

AbstractIn this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno‐associated virus‐based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator‐like effector nucleases, zinc‐finger nucleases, and meganucleases (mitoARCUS). rAAV‐based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR‐Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR‐free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.

News (Medical) associated with Lenadogene nolparvovec

23 Jul 2024

·www.businesswire.com

GenSight Biologics Reports Cash Position as of June 30, 2024, and Provides Business Update

PARIS--( BUSINESS WIRE )--Regulatory News: GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today reported its cash position as of June 30, 2024, and provided a business update. “ As a result of our continuing financial discipline, GenSight Biologics is well-positioned to continue to advance towards our objectives,” commented Laurence Rodriguez , Chief Executive Officer of GenSight Biologics . “Our recent capital increase and the renegotiation of the terms of our short-term obligations demonstrate investor confidence in our strategy and plan of action.” Cash position as of June 30, 2024 As of June 30, 2024, the Company’s cash position amounted to €6.9 million, compared to €2.1 million as of December 31, 2023. The Company completed a successful offering in May 2024, which yielded gross proceeds of €9.2 million. Alongside this capital increase, the Company engaged in discussions with its creditors and, in particular, renegotiated the terms and conditions of its state-guaranteed loans as well as the terms of its convertible bonds with Heights Capital. On June 28, 2024, the Company resumed the quarterly amortization payments of the 2022 Convertible Bonds (OCA) through the issuance of new shares of the Company. Working Capital Statement The Company confirms that it has sufficient net working capital to meet its obligations until the beginning of the fourth quarter of 2024, as a result of its stringent cost-control policy and the renegotiation of its debts. With potential revenues generated by the resumption of the early access (AAC) program, which is targeted for the end of Q3 2024 based on the ability of the planned LUMEVOQ ® drug product batch to supply the AAC program, the Company expects to have sufficient net working capital to meet its obligations until the third quarter of 2025, after which the mandated rebates for the AAC will be paid. Business update The manufacture of LUMEVOQ ® drug product, which required an additional blending step to optimize the number of vials available for the early access program, was successfully performed in July as scheduled. Vials from the batch are now being tested for conformity to the required quality control standards. After accounting for testing requirements, over 100 vials could be available for patients. The full set of quality control results are expected in early September. If the quality control criteria are met, the Company expects to be ready to resume the AAC program in late September 2024. In parallel, the Company has been engaging with the French medicines safety agency ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé) and working with the Quinze-Vingts Hospital in Paris, France, to prepare for the resumption of the AAC program, as long anticipated by patients. About GenSight Biologics GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery. GenSight Biologics’ lead product candidate, LUMEVOQ® (GS010; lenadogene nolparvovec), an investigational compound that has not been registered in any country at this stage, was developed for the treatment of Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. The company is also developing an optogenetics product candidate, GS030, for the treatment of rare inherited diseases, such as Retinitis Pigmentosa, that cause degeneration of photoreceptors. Forward-Looking Statements This press release contains forward-looking statements, including statements regarding product development prospects and financial projections. These statements do not constitute guarantees of future performance and involve risks and uncertainties. A further list and description of risks and uncertainties that could cause actual results to differ materially from those set forth in the forward-looking statements in this press release can be found in GenSight Biologics’ regulatory filings with the French Autorité des Marchés Financiers (“AMF”). Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements and estimates, which speak only as of the date hereof. Other than as required by applicable law, GenSight Biologics undertakes no obligation to update or revise the information contained in this press release.

Financial StatementGene Therapy

11 Jul 2024

·www.businesswire.com

GenSight Biologics Launches Newsletter for Retail Investors

Gene Therapy

20 Jun 2024

·www.biospace.com

GenSight Biologics Renegotiates Financial Obligations and Provides Operational Updates

PARIS--(BUSINESS WIRE)-- Regulatory News: GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced the renegotiation of certain financial obligations, securing its financial position and improving short-term flexibility. The Company also provided operational updates. In connection with its two recent successful capital increases in February 2024 and May 2024, the Company initiated discussions with its creditors. As a result of these discussions, the Company and its creditors have renegotiated the terms and conditions of certain financial obligations. “We continue to make progress in optimizing financial management to support our objectives, and we are grateful to our banking partners and creditors for their continued collaboration in our journey,” commented Laurence Rodriguez, Chief Executive Officer of GenSight Biologics. “The renegotiated terms will give GenSight additional operating flexibility as it works on its priorities.” Renegotiation of the terms of state-guaranteed loans The Company and its creditor banks (BNP Paribas, CIC and Bpifrance) (the "Banks"), previously agreed to suspend the payment of the principal, subject to certain conditions. The parties have now agreed to extend the maturity of the loans until December 2024 and to adopt a new payment schedule for the outstanding principal and interest, featuring 6 monthly instalments with gradual amortization (5% of outstanding principal per month over July, August and September 2024, and then 28.3% over October, November and December 2024). Renegotiation of the terms for the convertible bonds with Heights Capital As previously announced, an additional amendment to the price limit set forth in the terms and conditions of the convertible bonds issued on December 28, 2022, to Heights Capital (the "2022 OCA”) was presented to the shareholders at the annual shareholders’ general meeting ("AGM") held on May 29, 2024, and was approved as the 30th resolution of the AGM. This new price limit equals to €0.3272 (the "Price Limit"1). The Company and Heights Capital previously decided to suspend the quarterly amortization payments for the redemption of the 2022 OCAs. In recently concluded discussions, the Company and Heights Capital have agreed that (i) the frozen quarterly amortization payments will be paid in accordance with the additional amortization rights mechanism contained in the terms and conditions of the 2022 OCAs and (ii) the quarterly amortization payment of the 2022 OCAs will resume through the issue of new shares by the Company starting from the amortization payment for June 28, 2024. Ongoing renegotiation of the terms for loan tranche from the European Investment Bank (EIB) As previously announced, the withdrawal of the GS010 (LUMEVOQ®) marketing authorization application in 2023 and the revision of the Company’s manufacturing plans invalidated the conditions for drawing down the €12 million Tranche B of the EIB loan from November 2022. The EIB and the Company have agreed to continue negotiating new drawdown conditions for Tranche B. Working Capital Statement The Company confirms that it has sufficient net working capital to meet its obligations until the second part of the third quarter of 2024. With the potential revenues generated by the resumption of AAC program, assuming the manufacture of the drug product batch for the AAC program is completed as planned, the Company anticipates that it would have sufficient net working capital to meet its obligations until the second quarter of 2025. Operational Updates The Company remains on track to resume the early access program (AAC) for GS010 (LUMEVOQ®) in France in Q3 2024. The blending of the two drug substance batches produced in 2023 is on track, and the Company has been in contact with the French medicines safety agency (ANSM) and Paris’ Quinze-Vingts Hospital (the reference medical center where initial treatments for the AAC will take place) to secure operational readiness as soon as product becomes available in Q3 2024. “The team is very much focused on having everything in place, so that patients, who we know have been waiting to be treated, can have access to the drug as soon as possible,” said Magali Taiel, Chief Medical Officer of GenSight Biologics. “Their urgency is ours.” As the company prepares for the release of five-year data from the REFLECT Phase III study of LUMEVOQ®, it has also conducted feasibility studies for the upcoming global RECOVER Phase III study, which is expected to start enrolling patients in H2 2025. Work continues on finalizing the protocol to address all comments received from regulatory authorities. Follow-up of GS030 (an optogenetic treatment candidate for Retinitis Pigmentosa) patients treated in the PIONEER Phase I/II trial is ongoing, with intermediate results from PIONEER expected in 2025. In parallel, the Company is advancing on a number of discussions with potential partners on strategic opportunities, including a possible merger, acquisition or licensing deal, assessed as one of the relevant options to move forward. About GenSight Biologics GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery. GenSight Biologics’ lead product candidate, LUMEVOQ® (GS010; lenadogene nolparvovec), an investigational compound that has not been registered in any country at this stage, was developed for the treatment of Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. The company is also developing an optogenetics product candidate, GS030, for the treatment of rare inherited diseases, such as Retinitis Pigmentosa, that cause degeneration of photoreceptors. _______________________ 1 The price corresponds to the volume-weighted average of the Company's share price on the regulated market of Euronext in Paris over the last eight (8) trading days preceding the date which is three (3) business days prior to publication of the notice of the AGM in the Bulletin d'Annonce Légale Obligatoire, less a 20% discount. View source version on businesswire.com: Contacts GenSight Biologics Chief Financial Officer Ivan Tortet itortet@gensight-biologics.com LifeSci Advisors Investor Relations Guillaume van Renterghem gvanrenterghem@lifesciadvisors.com +41 (0)76 735 01 31 Source: GenSight Biologics S.A. View this news release online at:

Phase 3Gene Therapy

100 Deals associated with Lenadogene nolparvovec

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Optic Atrophy, Hereditary, Leber	NDA/BLA	EU	Gensight Biologics SA	05 Sep 2020
ND4 mutant Leber Hereditary Optic Atrophy	Phase 3	GB	Gensight Biologics SA	12 Mar 2018
ND4 mutant Leber Hereditary Optic Atrophy	Phase 3	US	Gensight Biologics SA	12 Mar 2018
ND4 mutant Leber Hereditary Optic Atrophy	Phase 3	TW	Gensight Biologics SA	12 Mar 2018
Optic Atrophy, Hereditary, Leber	Preclinical	EU	Gensight Biologics SA	05 Sep 2020
Blindness	Preclinical	FR	Gensight Biologics SA	01 Jan 2016
Blindness	Preclinical	DE	Gensight Biologics SA	01 Jan 2016
Blindness	Preclinical	US	Gensight Biologics SA	01 Jan 2016
Blindness	Preclinical	IT	Gensight Biologics SA	01 Jan 2016
Blindness	Preclinical	GB	Gensight Biologics SA	01 Jan 2016

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03293524 (REFLECT, Biospace) Manual	Phase 3	Optic Atrophy, Hereditary, Leber	98	LUMEVOQ®	(lrczehnsjz) = beyond the +15 letter threshold that conventionally defines clinically meaningful improvement. cyefwhmpdz (iffudwdnbc )	Positive	20 Mar 2024
				Placebo
BusinessWire Manual	Not Applicable	ND4 mutant Leber Hereditary Optic Atrophy ND4 mutation	-	LUMEVOQ	(dyxveohamb) = azfwtzpqpf zmjmayheqq (kyuazgzcos ) View more	Positive	12 Mar 2024
				idebenone	(dyxveohamb) = velvijimfe zmjmayheqq (kyuazgzcos ) View more
REFLECT (ASGCT2023)	Phase 3	Optic Atrophy, Hereditary, Leber	-	Lenadogene nolparvovec	(ymolfkuwpn) = hwzwuwcwzz lgnywanalg (srpfclrpxz, 0.39 - 0.22)	Positive	01 May 2023
RESTORE (AAN2023)	Phase 3	-	72	Lenadogene nolparvovec-treated eyes	(gzvziworca) = vokmtvkbro tbjawfygnw (zrfczllowb )	Positive	25 Apr 2023
NCT03406104 (RESTORE, Corporate Publications) Manual	Phase 3	Optic Atrophy, Hereditary, Leber	55	Lenadogene nolparvovec	(gonaxolftt) = fnfxffwzbw bctikbhcxx (zxjraztold )	Positive	20 Jul 2022
				sham	(gonaxolftt) = icgvmwcxup bctikbhcxx (zxjraztold )
NCT03406104 (RESTORE, Pubmed) Manual	Phase 3	Optic Atrophy, Hereditary, Leber	61	Lenadogene nolparvovec	dpdwmlyhsm(danlccdezk) = hgrxmxstrh gptxbumrus (wyutuhnrtp ) View more	Positive	01 Sep 2021
NCT03406104 \| NCT03295071 (ARVO2021)	Phase 3	Optic Atrophy, Hereditary, Leber	-	rAAV2/2- ND4 gene therapy	(nrpltfqopp) = uemxrdsjuo rqcldwqucv (owkpgaqkgn )	-	01 Jun 2021
NCT02652767 (RESCUE, Pubmed) Manual	Phase 3	Optic Atrophy, Hereditary, Leber	38	rAAV2/2-ND4 (rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl))	(hrrjdmmtkk) = odszgoalhk bgvjonmpib (edqkznimnn, 0.52)	Negative	01 May 2021
				rAAV2/2-ND4 (sham injection)	(hrrjdmmtkk) = expkkyrcei bgvjonmpib (edqkznimnn, 0.62)
NCT02652780 (REVERS, Pubmed \| Sci Transl Med) Manual	Phase 3	Optic Atrophy, Hereditary, Leber	37	Lenadogene nolparvovec (rAAV2/2-ND4 (GS010) group)	(tqndednfca): P-Value = 0.894 View more	Negative	09 Dec 2020
				Lenadogene nolparvovec (sham injection group)
NCT02652767, NCT02652780 (RESCUE, REVERSE, AAN2020)	Phase 3	Optic Atrophy, Hereditary, Leber	-	rAAV2/2-ND4	hwfzlgjmze(xjqfpjwvie) = vlmgzsfodd xlcpyldnix (ewlpifqaln )	-	14 Apr 2020
				rAAV2/2-ND4	hwfzlgjmze(xjqfpjwvie) = scwuzggjbt xlcpyldnix (ewlpifqaln )

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Lenadogene nolparvovec

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation