Phase 2 extension trial shows sustained benefits of Anavex 2-73

Drugmaker Anavex Life Sciences says data indicates treatment is disease modifying

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term treatment with Anavex 2-73 (blarcamesine) provided sustained reductions in disease severity and progression for adult Rett syndrome patients, according to findings from the open-label extension (OLE) part of a Phase 2 trial.

The reductions were significantly greater in patients who were initially assigned to Anavex 2-73 in the Phase 2 trial (NCT03758924) compared with those who started the treatment seven weeks later in the OLE part.

The experimental treatment’s developer, Anavex Life Sciences, believes the data indicate  Anavex 2-73 does not just ease symptoms, but can modify the course of the disease.

“We believe these promising long-term clinical results in adult patients with Rett syndrome provides further support of the beneficial effect of Anavex 2-73 … for patients with Rett syndrome,” Christopher U. Missling, PhD, president and CEO of Anavex, said in a company press release.

In Rett syndrome, changes in brain development lead to severe and progressive neurological symptoms, including declines in verbal abilities, a loss of motor skills, behavioral challenges, and seizures.

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Restoring brain signaling in Rett patients

Anavex 2-73 is a small molecule designed to activate a protein called sigma-1 receptor (SIGMAR1), which is believed to be important for maintaining a proper balance of nerve cell signaling and promoting neuroplasticity, the process by which the brain adapts and rewires itself in response to new experiences.

By activating SIGMAR1, Anavex believes Anavex 2-73 will help to restore more normal brain signaling in Rett patients. The company hopes that rather than just reducing symptom severity, the experimental therapy will be disease-modifying, meaning it will slow disease progression in the long-term.

Anavex 2-73 has earned fast track, rare pediatric disease, and orphan drug designations in the U.S., all of which are intended to provide incentives to help speed the development of a treatment toward regulatory approval.

The Phase 2 study was designed to evaluate the investigational therapy’s safety, tolerability, and efficacy among 25 women with Rett, ages 18-45, enrolled at sites in the U.S. All participants were given Anavex 2-73 (5 mg) or a placebo, taken as an oral liquid daily for seven weeks.

Top-line trial data showed Anavex 2-73 was well tolerated and led to statistically significant and clinically meaningful reductions in symptom severity after seven weeks of treatment.

Specifically, 66.7% of treated patients experienced significant reductions in scores on the Rett Syndrome Behavior Questionnaire (RSBQ), a caregiver-reported measure of disease severity, compared with 10% of the placebo group.

Scores on the Clinical Global Impression Improvement Scale (CGI-I), a clinician-rated measure of disease severity, also indicated more patients on the experimental treatment (86.7%) saw sustained improvements compared with those on a placebo (40%).

After completing the trial, 24 participants opted to enter a 12-week OLE, in which all received Anavex 2-73. The OLE was later extended to 36 weeks, or about eight months.

Results now show that the benefits of Anavex 2-73 observed in the main trial were maintained through the 12-week OLE, according to Anavex.

Participants originally assigned to Anavex 2-73 in the main trial continued to see reductions in RSBQ scores until the end of the OLE. Patients previously on a placebo who switched to the treatment in the OLE also began to see improvements.

Yet, patients who were always on Anavex 2-73 experienced statistically significant reductions in disease severity compared with those who started off on placebo and later transitioned to the active treatment.

Moreover, the reduction in annual rate of disease progression among the longer-term treatment group was more than three times greater than in patients who started the treatment seven weeks later.

Classifying a treatment as disease-modifying therapy

Such observations are key criteria for classifying a therapy as disease modifying, according to the company, which noted the benefits of Anavex 2-73 observed among patients using it since the start of the main trial were greater than what could be explained by a treatment that only eases symptoms.

As such, Anavex believes the experimental treatment likely has combined symptomatic and disease-modifying effects.

Data from the Phase 3 AVATAR clinical trial (NCT03941444), conducted in Australia and the U.K., similarly indicated that Anavex 2-73 could safely ease symptom severity in women with Rett.

The company plans to submit the findings for publication in a peer-reviewed medical journal.

It also is conducting a Phase 2/3 clinical trial to test the safety and efficacy of Anavex 2-73 in children and adolescents. The EXCELLENCE trial (NCT04304482), which has now completed dosing, enrolled 92 girls with Rett syndrome, ages 5-17, who had lost spoken language or motor skills.

The trial’s main goals are to determine Anavex 2-73’s safety in this patient population, as well as its ability to ease symptom severity in the RSBQ scale. Top-line data are expected in the coming months.

“We are looking forward to the upcoming read-out of the Anavex 2-73 … EXCELLENCE Phase 2/3 Rett syndrome clinical trial in pediatric patients with Rett syndrome,” Missling said.