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Zolgensma (onasemnogene abeparvovec-xioi), the newly approved gene therapy for the treatment of AMS in infants and children under 2 years of age, acts by directly providing motor neurons with a healthy copy of SMN1 gene damaged by mutations in these patients and unable to produce an essential protein.
Carried by a virus designed to be harmless – a subtype of adeno-badociated virus called AAV9 – that is infused into the blood or injected into the spinal cbad, the therapy enters the central nervous system to deliver an active gene to those cells. nerve specialized motor. which controls the muscular contraction.
An adeno-badociated virus, or AAV, was chosen because of its ability to cross blood vessels and enter the muscles. The specific type used, AAV9, comes from a preclinical work that has shown that it targets brain and spinal cord cells "at unprecedented levels, in an unprecedented way", said Brian Kaspar, chief scientist at AveXis, in February SMA News today.
AveXis developed this therapy and, largely because of its success, was acquired in 2018 by Novartis, which will market it.
Motor neurons are found mainly in the spinal cord and brainstem, which is connected to the spinal cord, and are dependent on the SMN protein produced by SMN1 for their health and survival. They send signals through the central nervous system that tell the skeletal muscles to contract or contract, making voluntary movements possible.
Zolgensma "has the ability to produce normal or even higher than normal levels of SMN1 gene that is so necessary for all these patients "said Kaspar, and to do it" immediately and continuously. "
Its nature of continuous work is one reason why therapy is considered by its developers as a punctual treatment, especially in patients treated at the time of diagnosis or early onset of the disease. Their thinking is based on data from a Phase 1 study (NCT02122952) that began in 2014 and none of the 15 type 1 patients treated as infants need to be included in the study. a second intravenous injection since, some up to five years.
The combination of efficiency and sustainability also explains why Novartis, in collaboration with AveXis, is testing Zolgensma in other types of ADMs. Various clinical trials are underway or planned.
Current studies are:
- STR1VE Phase 3 study (NCT03306277) on intravenous delivery in type 1 infants under 6 months of age; fully registered and its data also influenced the FDA's approval decision.
- STR1VE-EU (NCT03461289), the European Phase 3 equivalent of STR1VE, now welcomes infants under 6 months of age on sites across the continent.
- the STRIVE-AP phase 3 study, soon to be opened (NCT03837184), an equivalent study in three countries in the Asia-Pacific region; Registration information is available here.
- phase 3 SPR1NT (NCT03505099) in 44 pre-symptomatic infants <6 weeks old with SMN2 copies, that is, to recruit in the United States and elsewhere.
- phase 1 STRONG Trial (NCT03381729) in type 2 SMA children aged 6 months to 5 years and able to sit independently for 10 seconds or more; she is now recruiting patients from her US sites. This study will administer Zolgensma by intrathecal injection (spinal cord).
A separate trial, called REACH, for AMS patients aged 1 to 3 years and under 18 years is planned for patients who are not eligible for these studies. When he starts, he will also use an intrathecal injection to administer Zolgensma.
All current trials are open, which means that there is no placebo group and all registered patients are treated.
STRONG uses a single intrathecal injection (IT) because its developers consider that this more targeted pathway is preferable for older patients, while systemic IV infusions are better thought out in the treatment of infants. Computer administration also reduces the viral dose, reducing the risk of immune response against the AAV9 vector.
As of April 24, 151 patients had been treated with Zolgensma on the types of ADMs 1 and 2, as well as Novartis and AveXis, in a recent update for investors. Everyone is now part of "The largest single treatment population of any gene therapy studied so far in the world," said David Lennon, president of AveXis, in a previous update.
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