GenSight Biologics Announces Five-Year Efficacy and Safety Results for LUMEVOQ® Gene Therapy at the Conclusion of the REFLECT Study

PARIS--(BUSINESS WIRE)--Feb 12, 2025--

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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 final efficacy and safety results at the conclusion of the REFLECT Phase III clinical trial with LUMEVOQ ® (GS010; lenadogene nolparvovec). The results show that five years after a one-time administration of the gene therapy, the visual acuity improvement among patients with LHON (Leber Hereditary Optic Neuropathy) was sustained while maintaining a favorable safety profile. Bilateral injections provided an additional effect compared to unilateral treatment, demonstrated in some of the responder rate analyses.

“ The latest REFLECT data confirms that the improvement seen with lenadogene nolparvovec is sustained 5 years after treatment has been given, including the additional benefit observed in participants receiving a bilateral intravitreal injection of the gene therapy,” said Prof. Patrick Yu-Wai-Man, MD, PhD, Professor of Ophthalmology and Honorary Consultant Neuro-ophthalmologist at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, United Kingdom, and International Principal Investigator of REFLECT. “ Importantly, REFLECT participants receiving a bilateral injection had a comparable safety profile to those treated unilaterally. ”

The findings reinforce the results observed at 4 years post-treatment administration, which were reported in March 2024.

Sustained and meaningful efficacy at Year 5

The evolution of the visual acuity over time shows that visual improvement after lenadogene nolparvovec treatment was maintained over 5 years in all subjects. The improvement of placebo eyes highlights the consistent contralateral treatment effect observed in all clinical trials (which was also documented in sham-treated eyes in the REVERSE 1 and RESCUE 2 trials).

(See Graph 1.)

Because of the severity of the acute phase in LHON, vision could still deteriorate to a low point or nadir in the initial period of the trial. This characteristic of the disease makes the observed nadir (i.e., the worst BCVA recorded from baseline to Year 5) a better reference point to assess the effect of the therapy than baseline vision, which varies greatly depending on the disease stage at the time of enrollment in the study. Relative to the observed nadirs, average visual acuity for all LUMEVOQ-treated eyes increased beyond the +15-letter threshold (-0.3 LogMAR change) that conventionally defines clinically meaningful improvement. (See Table 1.)

Responder analyses reinforce the finding of improved outcomes for patients, for whom natural history typically results in greatly impaired vision with a very low likelihood of spontaneous recovery 3. Five years after injection, patients who were bilaterally treated experienced a higher rate of clinically relevant recovery* from their nadir, compared to patients who had unilateral treatment (75% vs. 60%). 79% of bilaterally treated patients were able to read letters on a screen (on-chart vision), compared to 72% of patients treated in only one eye.

Table 1: Change in Best-Corrected Visual Acuity (BCVA) versus Nadir 5 Years after Injection

Database lock: Dec 31, 2024. Subjects bilaterally treated: 1st affected eyes: n=48; 2 nd affected eyes: n=48; subjects unilaterally treated: 1 st affected eyes: n=50; 2 nd affected eyes: n=50. p<0.0001 for all eye groups using linear mixed model.

Favorable safety profile

The favorable safety profile of LUMEVOQ ® continued to be confirmed, with the safety profile of the drug being demonstrated as comparable in bilaterally and unilaterally treated subjects. There was no study discontinuation related to systemic or ocular adverse events, and there were no serious ocular adverse events. The main ocular adverse event was intraocular inflammation, which was mostly mild and responsive to conventional treatment.

REFLECT was a randomized, double-masked, placebo-controlled Phase III trial involving 98 subjects with vision loss due to LHON caused by a mutated ND4 mitochondrial gene; enrolled ND4 subjects had vision loss up to one year from onset. All subjects received an intravitreal injection (IVT) of lenadogene nolparvovec in their first affected eye. The second affected eye was randomized to either a second IVT of LUMEVOQ ® or a placebo IVT, which was administered on the same day or the following day. 48 subjects were randomized to LUMEVOQ ® bilateral treatment, and 50 to lenadogene nolparvovec unilateral treatment (first-affected eye treated with LUMEVOQ ®, second-affected eye treated with placebo). REFLECT patients were followed up to 5 years post-injection.

* “Clinically Relevant Recovery”, or CRR, refers to an improvement in Best-Corrected Visual Acuity (BCVA) that satisfies one of two conditions: (1) A 10-letter (≥0.2 LogMAR) improvement for an on-chart starting visual acuity. (2) Improvement from “off-chart” to “on-chart” (≤1.6 LogMAR).

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About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on discovering and developing 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. GenSight Biologics’ lead product candidate, GS010, is in Phase III trials in Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease that leads to irreversible blindness in teens and young adults. 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.

About Leber Hereditary Optic Neuropathy (LHON)

Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1 st eye, with the 2 nd eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. 97% of subjects have bilateral involvement at less than one year of onset of vision loss, and in 25% of cases, vision loss occurs in both eyes simultaneously.

About LUMEVOQ ® (GS010; lenadogene nolparvovec)

LUMEVOQ ® (GS010; lenadogene nolparvovec) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. “LUMEVOQ” was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018. LUMEVOQ® (GS010; lenadogene nolparvovec) has not been registered in any country at this stage.

About REFLECT

REFLECT was a multi-center, randomized, double-masked, placebo-controlled study to evaluate the safety and efficacy of bilateral injections of GS010 in subjects with LHON due to the NADH dehydrogenase 4 ( ND4 ) mutation. In the active arm, GS010 was administered as a single intravitreal injection in each eye of each subject. In the placebo arm, GS010 was administered as a single intravitreal injection to the first affected eye, while the fellow eye received a placebo injection.

The primary endpoint for the REFLECT trial was the BCVA reported in LogMAR at 1.5 years (78 weeks) post-treatment in the second‑affected/not‑yet‑affected eye. The change from baseline in second‑affected/not‑yet‑affected eyes receiving GS010 and placebo was the primary response of interest. The secondary efficacy endpoints included: change from baseline in BCVA reported in LogMAR at 2, 3, 4 and 5 years post-treatment in the second‑affected/not‑yet‑affected eye compared to both placebo and the first‑affected eye receiving GS010, change from baseline in OCT and contrast sensitivity as well as quality of life scales.

The trial was conducted in multiple centers across Europe/UK (1 each in France, Spain, Italy and the UK), the US (6 centers) and Taiwan (1 center). The trial planned to enroll 90 subjects with vision loss up to 1 year in duration; 98 subjects were successfully screened and treated. The first subject was treated in March 2018 and the last one in July 2019. Long-term follow-up of the last patient was completed on July 23, 2024.

ClinicalTrials.gov Identifiers:
REFLECT: NCT03293524

Evolution of Visual Acuity in the REFLECT Phase III Study (Graphic: Business Wire)

PARIS (AP) — Bernadette Chirac, the steel-willed former first lady of France who spent 12 years at the Élysée Palace from 1995 to 2007 beside President Jacques Chirac — weathering his notorious infidelities with dry humor while building her own political power base in rural France — has died. She was 93.

President Emmanuel Macron confirmed her death Saturday, saying he and his wife Brigitte had learned with “great sadness” of the passing of a woman who marked French history, and changed the lives of millions through her charity work.

“A great lady of the heart has departed,” Macron said.

For more than half a century, Chirac was the fixed point in her late husband’s restless climb — through Parliament, two terms as prime minister, 18 years as mayor of Paris and, in 1995, the presidency.

Beyond the ceremonial role of first lady, Chirac became a political presence in her own right, closely watched for her influence around her husband, who died in 2019, and for the dry discipline with which she handled his reputation as a womanizer, a subject she later addressed with unusual frankness.

Swarmed by photographers in Corrèze in 1998 — after rumors that Jacques Chirac had been unreachable the night Princess Diana died because he was with an actress — she stepped from her car and deadpanned: “Calm down. I’m not Claudia Cardinale. Or Lollobrigida.”

She appears in the official photographs with her chin lifted, blond hair lacquered into place, a small handbag on her arm, looking less like a spouse than like an institution.

But the caricature never quite contained her.

The Chanel suits, dark glasses, nasal voice and withering judgments became part of the national image.

Beneath them was a relentless worker and a cold-eyed political operator who, almost alone among the wives of French presidents, built a base of power that was her own.

She was born Bernadette Thérèse Marie Chodron de Courcel on May 18, 1933, in Paris, into money, lineage and Catholic duty.

Her father’s family included soldiers, industrialists and diplomats; an uncle had served as an aide to Charles de Gaulle in wartime London.

But her life would be most marked by her time at the prestigious Sciences Po university in Paris, where she met Jacques Chirac, a handsome and much-courted young man whose appetite for politics would come to define them both.

They married in March 1956. The union lasted 63 years and was, by her own account, a long lesson in endurance.

Jacques Chirac was famous for his warmth, appetite and instinctive connection with crowds. Bernadette’s gifts were different, observers said.

She was controlled, socially formidable, devout, exacting and sometimes devastatingly funny.

The Catholic philosopher Jean Guitton called her the last queen of France, and she did little to discourage the idea.

Her husband’s reputation as a womanizer was an open secret she chose, after much pain, to meet with dry humor.

“At first, it was hard. I was very heartbroken, and then I got used to it,” she said years later in a television documentary. “I told myself that was how things were and that I had to accept it with as much dignity as possible.”

Sent to tend her husband’s rural stronghold in Corrèze while he pursued power in Paris, she did far more than tend it. In 1971, she was elected municipal councilor in Sarran. In 1979, she became a general councilor in Corrèze and held the seat until 2015.

Her influence grew after Jacques Chirac became president in 1995. The role of first lady in France has no constitutional power, but she made the Élysée a place where her approval mattered.

She could be loyal, cutting and unforgiving, and understood that campaigns are made not only of speeches and polls but of debts, slights and resentments.

Yet she also carved out a space for female authority inside a male political culture that had little interest in sharing power — making it quietly clear that she would not be reduced to “the wife of.”

By 2023, her severe glamour and political instincts had become familiar enough for Catherine Deneuve to play her in “Bernadette,” a comic movie about her years at the Élysée.

Her deepest grief stayed mostly private.

The Chiracs’ elder daughter, Laurence, developed severe anorexia after meningitis in adolescence and attempted suicide more than once. She never fully recovered and died in 2016 at 58.

That ordeal pushed Chirac toward the charitable work that reshaped her public image.

In 1994, she took over a medical charity that collected coins to support children in hospitals. To millions of French viewers, the woman once mocked for hauteur became the face of hospitalized children and families living around hospital beds.

She continued running it until 2019, when she handed it to Brigitte Macron, the wife of France's current president, and became honorary president.

By then, she had long since become a political force in her own name.

“My husband no longer does politics, but I do,” she said to journalists, after Jacques Chirac left office in 2007.

She famously nicknamed Dominique de Villepin, the Élysée official she distrusted, “Nero,” yet also reportedly helped engineer her husband’s reconciliation with Nicolas Sarkozy, the former protégé who had betrayed him politically.

Her 2001 memoir, “Conversation,” written with journalist Patrick de Carolis, sold hundreds of thousands of copies and introduced the French to a franker, funnier and more independent woman than many had assumed.

After Jacques Chirac left the Élysée, his health declined and his public voice faded. Hers remained sharper for longer. Asked how he was, according to French media, she answered in her flat, unmistakable voice: “He keeps the dog.”

Age and grief eventually drew her out of public view.

By the time Jacques Chirac died in 2019, she was too fragile to take part in the public farewell where France and foreign leaders honored him.

The Élysée said Saturday that Macron was inviting the public to pay tribute to Bernadette Chirac opposite the presidential palace.

FILE - Former French President Nicolas Sarkozy speaks with former first lady Bernadette Chirac during the inauguration of the Foundation Claude Pompidou, Centre teaching and research on Alzheimer's disease, Monday, March 10, 2014, in Nice, southeastern France. (AP Photo/Lionel Cironneau, File)

FILE - French President Jacques Chirac and his wife Bernadette arrive at the airport in Hanover, Germany on Sunday, June 25, 2000. (AP Photo/Jens Meyer, File)

FILE - From left: Cherie Blair, wife of British Prime Minister Tony Blair Bernadette Chirac, wife of French President Jacques Chirac, Lyudmila Putina, wife of Russian President Vladimir Putin, and First Lady Laura Bush, converse as they walk to a press conference site at the G-8 Summit on Sea Island, Ga., Wednesday, June 9, 2004. (AP Photo/Ric Feld, File)

FILE - French President Jacques Chirac, center left, and his wife First Lady Bernadette Chirac are surrounded by the crowd after addressing New Year wishes to the inhabitants of the region of Correze, in Tulle, southwestern France, Saturday, Jan. 14, 2006. (AP Photo/Bob Edme, File)

FILE - Bernadette Chirac, wife of former French President Jacques Chirac attends a ceremony to pay tribute to Simone Veil in the courtyard of the Invalides in Paris, France, Wednesday, July 5, 2017. (AP Photo/Michel Euler, File)