Dosing Underway for PIERRE Pivotal Study of ThecaFlex DRx System and Nusinersen

David Bauer, MD, MPH

Alcyone Therapeutics recently announced that the first patient has been dosed in the pivotal PIERRE study (NCT05866419) assessing its ThecaFlex DRx System, an implantable intrathecal catheter, as a way to ease the administration of nusinersen (Spinraza; Biogen) in patients with spinal muscular atrophy (SMA). The first patient was implanted by study investigator David Bauer, MD, MPH, at Texas Children’s Hospital in Houston, Texas.¹

PIERRE is a multicenter, multi-national, prospective, non-randomized, single-arm study that assesses the safety and performance of the ThecaFlex DRx System in a cohort of 90 patients aged at least 3 years old with SMA. The study is split into 2 stages, the first of which will include 10 patients across a limited number of sites while the second will expand to another 80 patients in a broader number of sites across the US and Europe.

"The ThecaFlex device has the potential to provide a significant benefit for patients with SMA who are being treated with SPINRAZA and are resistant to lumbar punctures. It may reduce the need for serial lumbar punctures under sedation and improve the overall administration experience of SPINRAZA," Bauer, a professor of pediatric neurosurgery at Baylor College of Medicine, said in a statement.¹

Alcyone believes ThecaFlex has the capabilities to be the first implantable device to enable subcutaneous access for delivery of antisense oligonucleotide therapies. Designed within Alcyone’s Falcon Delivery Platform, the ThecaFlex is built as an implantable intrathecal catheter, catheter fixation device, and subcutaneous port system to allow infusion therapies access to the cerebrospinal fluid (CSF). It is geared to be an alternative to lumbar puncture (LP), which is currently the standard of care approach to delivering therapeutics to CSF.

PIERRE will also assess a number of secondary outcomes, including the reduced anesthesia and radiation exposure compared with repeated LP, as well as the incidence of device-related adverse events (AEs) with ThecaFlex. In addition, investigators will evaluate incidence of procedural complications, number of nusinersen-related AEs and mean duration of radiation exposure.

"Currently, most of my SMA patients treated with SPINRAZA are dosed in the interventional radiology suite due to complex spines, and many of these visits require extended time and radiation, as well as the potential need for sedation,” Timothy Lotze, MD, lead neurologist for the PIERRE study and professor of pediatric neurology at Baylor, said in a statement.¹ "With ThecaFlex, these patients may be able to have their therapy administered through a sub-cutaneous injection into the port in the neurology clinic, reducing the need for anesthesia or radiation."

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Nusinersen, an antisense oligonucleotide that targets the root cause of SMA, has been available since 2016, when it became the first approved drug for the disease. Since then, nusinersen has demonstrated sustained efficacy across ages and SMA types with a well-established safety profile based on data in patients treated up to 8 years, combined with real-world experience.

In late 2023, new data from the NURTURE study (NCT023866553), an ongoing trial of infants likely to develop SMA type 1 or 2, highlighted the effects of nusinersen in this subgroup. Published in Muscle & Nerve, results showed continued benefit of nusinersen for up to 5 years of treatment. At the end of the analysis, all children, which included 15 with 2 SMN2 copies and 10 with 3 SMN2 copies, were alive, with none discontinuing the trial or treatment. No additional children utilized respiratory intervention since the prior data cut at 3 years. All 2-copy children achieved sitting without support, and most (14 of 15) achieved walking with assistance or walking alone (13 of 15).²

At the time of the results, lead investigator Thomas Crawford, MD, a pediatric neurologist at Johns Hopkins Medicine, told NeurologyLive® that, "This proves that this [nusinersen] is a disease modifying therapy, and not a transient therapy. Number two, because it's a disease modifying therapy, we must get this therapy into people as quickly as possible. It's essential that—especially with the most severely affected babies, the ones with two copies of SMN2—damage has been done at the time of birth. The longer we take until we get it, the more damage can be done. It produces a substantial difference in their outcome time."

REFERENCES
1. Alcyone Therapeutics announces first patient implanted in PIERRE IDE clinical study of the ThecaFlex DRx System for administration of Spinraza (nusinersen). News release. Alcyone Therapeutics. January 3, 2024. Accessed January 9, 2024. https://www.prnewswire.com/news-releases/alcyone-therapeutics-announces-first-patient-implanted-in-pierre-ide-clinical-study-of-the-thecaflex-drx-system-for-administration-of-spinraza-nusinersen-302024897.html
2. Crawford TO, Swoboda KJ, De Vivo D, et al. Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle & Nerve. 2023;68(2):157-170. doi:10.1002/mus.27853