 joined the MJH Life Sciences team in October 2020, originally writing for 

Victoria Johnson

This content is courtesy of GeneTherapyLive, a sister publication. To view the original post, 

According to a recent announcement, Novartis' intrathecal (IT) gene therapy OAV-101 (formerly AVXS-101; onasemnogene abeparvovec) had its partial clinical hold lifted by the FDA and may proceed with the phase 1 STRONG trial (NCT03381729). The decision comes after the company presented data from a comprehensive nonclinical toxicology study that addressed toxicity issues observed in preclinical studies. 

The therapy is the IT version of Zolgensma, its intravenous gene therapy which received approval for the treatment of SMA in pediatric patients less than 2 years of age in March 2019. Questions about inflammatory responses and dorsal root ganglia (DRG) following IT administration of OAV-101 observed in animal studies prompted the hold of the study.  

"We are very pleased that our comprehensive nonclinical data package has addressed all issues identified related to DRG toxicity and the FDA has reached the decision that we may proceed with our OAV-101 IT clinical trial program and initiate the STEER trial," said Shephard Mpofu, MD, senior vice president and chief medical officer, Novartis Gene Therapies, in a statement.

 "We believe that all patients diagnosed with SMA should be able to benefit from the transformative impact of gene therapy and we remain confident that investigational OAV-101 IT is a viable potential treatment path for older patients who often have ongoing unmet needs, and for whom a one-time treatment could be especially compelling."

The company also announced plans to initiate the phase 3 STEER trial which will evaluate efficacy, safety, and tolerability of OAV-101 IT in treatment-naïve patients with SMA type 2 who are aged 2 to 18 years and are able to sit but have never walked. The company plans for the trial to build on the results of the STRONG trial, which, before its hold, demonstrated significant increases in Hammersmith Functional Motor Scale Expanded (HFMSE) for SMA scores and clinically meaningful responses in patients aged 2 to 5 years. 

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The randomized, double-blind, sham-controlled study will compare OAV-101 to sham treatment over a 52-week period. Primary end points will be the change in HFMSE score and safety, and the secondary end point will evaluate change on the Revised Upper Limb Module (RULM) scale. The trial plans to enroll more than 100 patients, all of whom will receive OAV-101 after the blinded treatment period.

"We are very pleased to see that a plan has been reached from Novartis, the FDA, and EMA working together to move this IT approach forward," said Kenneth Hobby, president, Cure SMA. "This route of administration has the potential to open up access for older patients to all the benefits of gene therapy. We have seen the interest among our symptomatic patients and their families in gene therapy, and this study is an important step in understanding its potential to address unmet needs that remain in the SMA community."

Novartis previously announced plans to initiate the phase 3b global SMART (NCT04851873) study of IV Zolgensma.2 The study will evaluate the safety and efficacy of Zolgensma in children with SMA weighing between 8.5 kg and 21 kg following a 1-time IV infusion. The company hopes the study will supplement real-world evidence of the treatment’s merits.

The study plans to enroll 24 symptomatic children with SMA across Europe, North America, Australia, and Taiwan, with follow-up through 12 months. The primary end point consists of key safety assessments including the evaluation of adverse events, laboratory data, vital signs, and cardiac safety monitoring. Secondary efficacy end points will assess motor milestone achievements according to the World Health Organization-Multicentre Growth Reference Study (WHO-MGRS), Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) criteria, HFMSE scores, and the Revised Upper Limb Module (RULM).

"SMART is a study designed to expand the clinical evidence for Zolgensma in children up to 21 kg,” said Nicole Gusset, PhD, president, SMA Europe, in a statement.

 “We have seen the interest in Zolgensma among physicians and families across Europe and believe this additional safety and efficacy data will help the community better understand its potential and inform treatment decisions for young children with SMA.”

1. Novartis announces lift of partial clinical trial hold and plans to initiate a new, pivotal Phase 3 study of intrathecal OAV-101 in older patients with SMA. News release. Novartis. August 3, 2021. Accessed Augut 9, 2021. 

https://www.novartis.com/news/media-releases/novartis-announces-lift-partial-clinical-trial-hold-and-plans-initiate-new-pivotal-phase-3-study-intrathecal-oav-101-older-patients-sma


2. Novartis to initiate SMART Phase 3b global study of Zolgensma in children up to 21 kg, building on real-world experience. News release. Novartis. April 23, 2021. Accessed August 9, 2021. 

https://www.novartis.com/news/media-releases/novartis-initiate-smart-phase-3b-global-study-zolgensma-children-21-kg-building-real-world-experience

Articles

In addition to the uplifted phase 1 study, Novartis also initiated the phase 3 STEER study, which will evaluate OAV-101 in treatment-naive patients with SMA type 2 aged between 2 and 18 years old. 

SMA Gene Therapy Cleared to Proceed Following FDA Clinical Hold

Data from a recent study suggest that sleep profile may be able to 

predict the trajectory of cognitive function

 in patients with mild-to-moderate Alzheimer disease (AD).

Investigators found a significant difference of –1.51 (95% CI, 2.43 to –0.59) in the Mini-Mental State Examination (MMSE) after 12 months of follow-up between deep and light sleepers. Sleep depth and cognitive decline exhibited a dose-response relationship (

-trend = .02). A similar relationship was seen between sleep depth and processing speed as measured by the Stroop words test (SWT; 

 = .016) and executive function as measured by the verbal fluency test (VFT; 

“This is the first study to report an association between sleep and cognitive decline after the diagnosis of Alzheimer’s disease. Accordingly, the sleep profile may have a predictive role in relation to the cognitive function of mild-moderate Alzheimer’s disease patients after 12 months of follow-up,” first author Adriano D. S. Targa, MD, Centro de Investigación Biomédica, Red de Enfermedades Respiratorias, Spain, and colleagues wrote.

Targas and colleagues analyzed data from 125 patients with a median age of 75.0 years (interquartile range [IQR], 72.0-80.0) as part of an ancillary study of a prospective trial (NCT02814045) designed to evaluate the influence of obstructive sleep apnea (OSA) on the cognitive decline of patients with AD after 1 year of follow-up. The patients had a median MMSE score of 23.0 (IQR, 22.0-25.0). They were mostly women (57.6%). The most common comorbidities were hypertension (59.2%) and dyslipidemia (41.6%).

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The investigators confirmed the differences in MMSE between deep and light sleepers by performing a sensitivity analysis adjusted for confounding factors. This analysis yielded a significant difference of –1.20 (95% CI, –1.33 to –0.12). Further stratification into deep, moderate, and light sleepers yielded a mean change of –0.89 (95% CI, –2.10 to 0.30) in deep sleepers, –1.59 (95% CI, –2.84 to –0.34) among moderate sleepers and -2.35 (95% CI, –3.71 to –1.01) among light sleepers. A linear trend test demonstrated a significant change of –0.72 (95% CI, 1.33 to –0.12) after adjusting for confounding factors.

Further differences were found between deep and light sleepers after controlling for sex, age, and educational level, with a significant –1.3 (95% CI. –2.35 to –0.26) difference in SWT score and –1.04 (95% CI, –1.94 to –0.14) in VFT score. These remained significant after sensitivity analyses.

A –1.15 (95% CI, -2.29 to –0.01) difference on the Stroop color test and –1.23 (95% CI, –2.42 to –0.04) difference on trail-making test-A scores were also seen, but these were not significant after sensitivity analyses.

“Further studies will be necessary to investigate whether relationships of causality between the observed associations are present and to evaluate whether the predictive role of sleep is maintained after longer periods of follow-up. In case of a positive response, sleep-based interventions could be considered to prevent a marked cognitive decline,” Targas and colleagues wrote.

 previously spoke with Christian Agudelo, MD, Evelyn F. McKnight Neurocognitive Scholar, University of Miami Miller School of Medicine, about a study he served as lead investigator for that found a link between poor sleep patterns and cognitive decline.

While the effects of poor sleep have yet to be determined in different race or age populations, Agudelo noted that there could be neurodevelopmental issues that stem from poor sleep, but also that behavioral tendencies and the lack of prioritizing sleep may have an impact as well. He also stressed that these associations should additionally be observed in younger populations and that the need for diversifying study populations is crucial to further justify broader implications.

1. Targas ADS, Benitez ID, Dakterzada F, et al. Sleep profile predicts the cognitive decline of mild-moderate Alzheimer’s disease patients. 

 May 2021. zsab117. doi: 10.1093/sleep/zsab117
2. Agudelo C, Tarraf W, Wu Benson, et al. Actigraphic sleep patterns and cognitive decline in the Hispanic Community Health Study/Study of Latinos. 

While the relationship between sleep and cognition needs to be further studied, sleep-based interventions may be a future approach to help prevent cognitive decline. 

Sleep Profiles May Predict Cognitive Decline in Alzheimer Disease

 and efficacy in the phase 2b VISION-DMD study (NCT03439670) in the treatment of individuals with Duchenne muscular dystrophy (DMD).

Both the low (2 mg/kg/day) and high dosages (6 mg/kg/day) showed strong efficacy in the study’s primary and secondary end points. The primary end point was superiority in change of time to stand from supine positioning to standing (TTSTAND) velocity with the high dose of vamorolone compared to placebo. The treated group had a difference of 0.06 (95% CI, 0.02-0.10) rises per second from baseline (

 = .002). This is a clinically relevant improvement in TTSTAND from 6.0 to 4.6 seconds in the treated group and a corresponding deterioration in the placebo group from 5.4 to 5.5 seconds.

“Today’s news is a tremendous milestone for patients and Santhera as we further advance vamorolone as a foundational treatment option in DMD. The treatment effect translates into the potential to delay disease progression by about two years and indicates disease modifying potential of vamorolone,” Dario Eklund, chief executive officer, Santhera, said in the company’s announcement. “We now look forward to working with regulatory authorities to bring vamorolone to DMD patients, first in the US and subsequently in Europe.

The secondary end points were also met, including TTSTAND velocity in the low-dose group (

 = .02), 6-minute walk test in the high-dose (

 = .009), and time to run/walk 10 m test in the high-dose group (

 = .002). No statistically significant differences were observed between vamorolone high dose and prednisone on the secondary end points.

Pamrevlumab, Vamorolone, and Others Headline Robust Pipeline in Duchenne Muscular Dystrophy

“We are thrilled about the positive results of the VISION-DMD study as it represents a culmination over a decade of scientific research,” Eric Hoffman, PhD, president and CEO, ReveraGen BioPharma and professor, Pharmaceutical Sciences, Binghamton University–State University of New York, added to the statement. “We are grateful to have been able to gather such important data and would like to thank all VISION-DMD participants, their families and caregivers, as well as investigators and study personnel, for their commitment to this ongoing program.”

The investigational agent from Santhera and ReveraGen is a first-in-class dissociative steroid that aims to retain the anti-inflammatory activity of corticosteroids while decreasing the deleterious adverse events (AEs). If successful, vamorolone may be a promising alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD. The significant systemic AEs associated with high-dose corticosteroids diminish patient quality of life, so addressing these AEs is of high priority. Santhera noted that it plans to file a new drug application with the FDA in the first quarter of 2022, requesting priority review.

“The strength of evidence for both efficacy and safety of vamorolone over such a wide dose range from 2 to 6 mg/kg/day allows clinicians to individually tailor treatment of Duchenne patients by starting at the higher 6 mg/kg/day dose of vamorolone with equivalent efficacy to daily prednisone and titrate the dose according to how well the treatment is tolerated whilst maintaining optimal efficacy. I am enthusiastic that this approach may allow patients to avoid side effects that currently lead to discontinuing steroid treatment, meaning they are able stay on for longer,” Craig McDonald, MD, professor and chair, Department of Physical Medicine & Rehabilitation and Director of Neuromuscular Disease Clinics, UC Davis Health, said in the statement.

Vamorolone showed a favorable safety and tolerability profile over prednisone. The 24-week study was completed by 114 of 121 patients (94%). Both the high- and low-dosages showed favorable safety and tolerability profiles. No patients treated with vamorolone discontinued the study due to treatment-emergent AEs (TEAEs). The vamorolone-treated group had 96 TEAEs in the low-dose group and 91 TEAEs in the high-dose group compared to 120 TEAEs in the prednisone-treated group. Vamorolone high dose was found to be significantly superior to prednisone (

 = .02) in a prespecified analysis of clinically relevant AEs.

Vamorolone did not show stunting of growth as reported with conventional corticosteroids in previously published results of 2.5-year (113 patient years) open-label studies. These results were validated in the double-blind study in which high dose vamorolone showed a significant difference in growth velocity compared to 0.75 mg/kg/day prednisone (

“Stunting of growth is a major concern of families and patients treated with corticosteroids, and we are delighted to see this superiority of vamorolone proven in this double-blind study,” Paula Clemens, MD, study co-chair and vice chair, VA Affairs; and professor, Neurology, University of Pittsburgh School of Medicine, added to the statement.

Santhera and ReveraGen announce positive and statistically highly significant topline results with vamorolone in pivotal VISION-DMD study. News release. Santhera. June 1, 2021. https://www.globenewswire.com/news-release/2021/06/01/2239124/0/en/Santhera-and-ReveraGen-Announce-Positive-and-Statistically-Highly-Significant-Topline-Results-with-Vamorolone-in-Pivotal-VISION-DMD-Study.html

Santhera and ReveraGen announced findings of the phase 2b VISION DMD study of the investigational therapy. 

Vamorolone Efficacious in Treatment of DMD, Superior to Prednisone in Safety

This content originally appeared on our sister site, GeneTherapyLive. Read it 

The first patient has been dosed in BlueRock Therapeutics' phase 1 study (NCT04802733) of DA01 for the treatment of Parkinson disease (PD), Bayer, the holding company of BlueRock, recently announced. Asklepios BioPharmaceutical (AskBio), another subsidiary of Bayer, is also enrolling patients in its phase 1b clinical study (NCT04167540) of glial cell line-derived neurotrophic factor (GDNF) gene therapy for PD.

“The potential of BlueRock and AskBio’s clinical candidates to treat PD could be immense,” said Wolfram Carius, head, cell and gene therapy, Bayer, in a statement.

 “For the first time, it might be possible to stop and reverse this degenerative disease and truly help patients with their high unmet medical need. The start of clinical trials represents the beginning towards a truly breakthrough treatment option to dramatically improve the lives of patients.”

-derived dopaminergic neurons designed to innervate the putamen to reverse the regenerative process and potentially restore motor function in people with PD. Unlike standard-of-care symptomatic treatments like levodopa, whose effects diminish over time, BlueRock aims to target PD at its root cause with DA01.

The trial will enroll 10 patients at sites in the US and Canada who will undergo surgical implantation of the DA01 cells. The primary end points of the study are safety and tolerability at 1 year post-transplant. Secondary end points are transplanted cell survival and motor effects at 1- and 2-years post-transplant, as well as continued safety and tolerability and feasibility of transplantation.

Glial Cell Line-derived Neurotrophic Factor

The GDNF study, supported by the California Institute for Regenerative Medicine, dosed its first patient with an infusion of GDNF in August 2020. Ten patients have been enrolled since then into the study to assess safety and preliminary efficacy. The one-time treatment provides a continuous production of GDNF, an advantage over intermittent protein infusions. The therapy is designed to promote the survival and functioning of vulnerable brain cells that degenerate in PD.

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“I’ve been investigating therapeutic gene therapy approaches for PD for nearly 30 years, and [this trial] marks a significant milestone for the field and may lead to major therapeutic opportunities for those suffering with this devastating condition, along with their families,” said Krystof S. Bankiewicz, MD, PhD, chief executive officer, Brain Neurotherapy Bio, part of Asklepios Bio, in an earlier statement.

 “We thank the current and future participating patients and the Neurology and Neurosurgery teams conducting the clinical study at The Ohio State University, the University of California San Francisco and the University of California Irvine medical centers.”

Previous research has shown that GDNF, delivered via the adeno-associated virus serotype 2 (AAV2) vector, achieved sustained expression that can promote regeneration of midbrain neurons and significant motor recovery in mouse and nonhuman primate studies. AAV2-GDNF targets brain cells within the putamen to produce and release GDNF protein. The GDNF payload consists of a human GDNF DNA sequence attached to regulatory sequences to ensure long-term stability of the payload. The treatments is administered in an MRI-guided, convection-enhanced infusion into the brain.

“There is an urgent need in the clinic for a treatment that may alter course of disease progression for patients with PD,” said Amber Van Laar, MD, movement disorder neurologist and Senior Director for Clinical Affairs of BNB. “GDNF gene therapy, if proven safe, is one such therapeutic that may mitigate and possibly reverse such clinical features of Parkinson disease,” added Adrian Kells, PhD, BNB’s Chief Operating Officer.

1. Bayer to advance two first-of-its-kind cell and gene therapies for Parkinson’s disease. News release. Bayer. June 8, 2021. 

https://www.media.bayer.com/baynews/baynews.nsf/id/Bayer-to-advance-two-first-of-its-kind-cell-and-gene-therapies-for-Parkinsons-disease?Open&parent=news-overview-category-search-en&ccm=020


2. Brain Neurotherapy Bio, Inc. announces treatment of first patient in new GDNF gene therapy trial for Parkinson’s disease. News release. Brain Neurotherapy Bio. August 25, 2020. https://e674c233-41f6-46e5-a454-6ee455f25619.usrfiles.com/ugd/e674c2_4ee7cd0693a9413cbb10b0a666f48fe4.pdf

Bayer provided an update on their phase 1 and 1b studies of dopaminergic neurons and GDNF gene therapy, respectively, for the treatment of PD.

Victoria Johnson

Articles

SMA Gene Therapy Cleared to Proceed Following FDA Clinical Hold

Sleep Profiles May Predict Cognitive Decline in Alzheimer Disease

Vamorolone Efficacious in Treatment of DMD, Superior to Prednisone in Safety

Gene Therapy Studies Underway in Parkinson Disease