# data[].attributes.body
We believe that treatment should include early detection and intervention screening through:

DNA tests for individuals considering children

Test fetus during pregnancy

Screen newborns for genetic issues

Treatments for genetic disorders

# data[].attributes.body
Overall, preclinical trial data demonstrated promising results for future scAAV9-SMN1 gene therapies and sparked the development of clinical trials for Zolgensma discussed below

# data[].attributes.body
Introduction

Alonso, T. (2022). How Novartis became a multinational pharmaceutical giant. Study Factory. https://www.cascade.app/studies/novartis-strategy-study

Baker, S. (2021). Why Texas Added Spinal Muscular Atrophy To Required Screenings For Newborns [Electronic Image]. KERA News. https://www.keranews.org/health-wellness/2021-06-14/why-texas-added-spinal-muscular-atrophy-to-required-screenings-for-newborns

Britannica, T. Editors of Encyclopaedia (2023). Novartis AG. Encyclopedia Britannica. https://www.britannica.com/topic/Novartis-AG

Buntz, B. (2023). Novartis Acquisitions (Past 3 Years) [Electronic Image]. Pharmaceutical Processing World. Cleveland, Ohio. https://www.pharmaceuticalprocessingworld.com/2023-06-novartis-continues-ma-trend-chinook-acquisition/

Gatlin, A., & Carson, A. C. E. (2023). Novartis Breaks Out After Putting Up Its Best Profit Growth In Two Years. Investor’s Business Daily. https://www.investors.com/news/technology/novartis-stock-novartis-earnings-q2-2023/

Liu, A. (2020). Pandemic hits Novartis sales with eye meds, Cosentyx suffering from slowdown. Fierce Pharma. https://www.fiercepharma.com/pharma/novartis-hit-by-eye-drugs-covid-19-slowdown-pushes-back-zolgensma-new-formulation-filing

Novartis AG - 27 year Stock Price History | NVS. (n.d.). MacroTrends. https://www.macrotrends.net/stocks/charts/NVS/novartis-ag/stock-price-history

Novartis. (2019). Novartis stands behind Zolgensma® (onasemnogene Abeparvovec-xioi) for the treatment of children less than 2 years of age with spinal muscular atrophy. Novartis. https://www.novartis.com/news/media-releases/novartis-stands-behind-zolgensma-onasemnogene-abeparvovec-xioi-treatment-children-less-2-years-age-spinal-muscular-atrophy#:~:text=Zolgensma%20is%20designed%20to%20address,time%20intravenous%20(IV)%20infusion.

Novartis. (n.d.). Product sales [Electronic Image]. Novartis. https://www.novartis.com/investors/financial-data/product-sales

# data[].attributes.body
Barbier, I., Hadiastri Kusumawardhani, Chauhan, L., Pradyumna Harlapur, Mohit Kumar Jolly, & Schaerli, Y. (2023). Synthetic Gene Circuits Combining CRISPR Interference and CRISPR Activation in E. coli: Importance of Equal Guide RNA Binding Affinities to Avoid Context-Dependent Effects. ACS Synthetic Biology, 12(10), 3064–3071. https://doi.org/10.1021/acssynbio.3c00375

Cayman Chemical. (2023). Lipid Nanoparticle (LNP-0315) Exploration Kit. Caymanchem.com; Cayman. https://www.caymanchem.com/product/35426.

Curran, K. (2020, May 16). Guide to genetic information and DNA testing. Rising Tide Biology. https://www.risingtidebio.com/review-dna-genetic-testing/

Day, J. W., Mendell, J. R., Mercuri, E., Finkel, R. S., Strauss, K. A., Kleyn, A., Tauscher-Wisniewski, S., Tukov, F. F., Reyna, S. P., & Chand, D. H. (2021). Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Safety, 44(10), 1109–1119. https://doi.org/10.1007/s40264-021-01107-6

Gardner, J. (2022, May 21). Roche SMA drug approved in youngest infants, challenging Novartis and Biogen. BioPharma Dive. https://www.google.com/url?q=https://www.biopharmadive.com/news/roche-evrysdi-sma-fda-approval-infants-zolgensma/624608/&sa=D&source=docs&ust=1701226959600040&usg=AOvVaw3Bi8q8rqL_NRSlRHCfpTwl

Novartis. (2019, May 24). AveXis Announces Innovative Zolgensma® Gene Therapy Access Programs for US Payers and Families. Novartis. https://www.novartis.com/news/media-releases/avexis-announces-innovative-zolgensma-gene-therapy-access-programs-us-payers-and-families

Novartis. (2021, March 15). New Zolgensma data demonstrate age-appropriate development when used early, real-world benefit in older children and durability 5+ years post-treatment. Novartis. https://www.novartis.com/news/media-releases/new-zolgensma-data-demonstrate-age-appropriate-development-when-used-early-real-world-benefit-older-children-and-durability-5-years-post-treatment

Novartis. (2023, July 27). Redirect Notice. Www.google.com. https://www.google.com/url?q=https://clinicaltrials.gov/study/NCT05335876&sa=D&source=docs&ust=1701141361931830&usg=AOvVaw0XCeIuc0gUqK8qrcu0IbTQ

Sethi, B., Kumar, V., Mahato, K., Coulter, D. W., & Mahato, R. I. (2022). Recent advances in drug delivery and targeting to the brain. Journal of Controlled Release, 350, 668–687. https://doi.org/10.1016/j.jconrel.2022.08.051

Stewart, J., & BPharm. (2019, July 1). Zolgensma (onasemnogene abeparvovec-xioi) FDA Approval History. Drugs.com. https://www.drugs.com/history/zolgensma.html.

Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., Li, Y., & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. https://doi.org/10.3390/pharmaceutics14122682

# data[].attributes.body
Day, J. W., Howell, K., Place, A., Long, K., Rossello, J., Kertesz, N., & Nomikos, G. (2022). Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatrics, 22(1), 632. https://doi.org/10.1186/s12887-022-03671-x

Devi, M., Kanimozhi, L., Ruth, J. E., & Chandralekha, K. (2022). Review on Zolgensma: Milestone in spinal muscular atrophy. International Journal of Health Sciences, 6(S2), 5502-5510. https://doi.org/10.53730/ijhs.v6nS2.6393

Mendell, J. R., Al-Zaidy, S., Shell, R., Arnold, W. D., Rodino-Klapac, L. R., Prior, T. W., ... & Kaspar, B. K. (2017). Single-dose gene-replacement therapy for spinal muscular atrophy. New England Journal of Medicine, 377(18), 1713-1722. https://doi.org/10.1056/NEJMoa1706198

Mendell, J. R., Al-Zaidy, S. A., Lehman, K. J., McColly, M., Lowes, L. P., Alfano, L. N., ... & Shell, R. (2021). Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA neurology, 78(7), 834-841. https://doi.org/10.1001/jamaneurol.2021.1272

Novartis. (2023a). Efficacy: START trial. Zolgensma® (onasemnogene abeparvovec-xioi). https://www.zolgensma-hcp.com/clinical-experiences/start-trial-efficacy/

Novartis. (2023b). Efficacy: STR1VE trial. Zolgensma® (onasemnogene abeparvovec-xioi).

https://www.zolgensma-hcp.com/clinical-experiences/str1ve-trial-efficacy/

Novartis. (2023c). Efficacy: LTFU. Zolgensma® (onasemnogene abeparvovec-xioi). https://www.zolgensma-hcp.com/clinical-experiences/start-long-term-follow-up-study-efficacy/

Stolte, B., Schreiber-Katz, O., Günther, R., Wurster, C. D., Petri, S., Osmanovic, A., ... & Hagenacker, T. (2022). Prevalence of anti-adeno-associated virus serotype 9 antibodies in adult patients with spinal muscular atrophy. Human gene therapy, 33(17-18), 968-976.

# data[].attributes.body
Chaytow, H., Faller, K. M., Huang, Y. T., & Gillingwater, T. H. (2021). Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine. Cell Reports Medicine, 2(7), 100346. https://doi.org/10.1016/j.xcrm.2021.100346

Duque, S. I., Arnold, W. D., Odermatt, P., Li, X., Porensky, P. N., Schmelzer, L., Meyer, K., Kolb, S. J., Schümperli, D., Kaspar, B. K., & Burghes, A. H. M. (2015). A large animal model of spinal muscular atrophy and correction of phenotype. Annals of Neurology, 77(3), 399–414. https://doi.org/10.1002/ana.24332

Jones, K. (2019). Mutations in SMN1 contribute to SMA [Electronic Image]. Thermofisher Scientific, Waltham, MA, United States. https://www.thermofisher.com/blog/wp-content/uploads/sites/9/2019/03/figure201.jpg

McCarty, D. M. (2008). Self-complementary AAV Vectors; Advances and Applications. Molecular Therapy, 16(10), 1648–1656. https://doi.org/10.1038/mt.2008.171

Novartis (2023). How ZOLGENSMA works [Electronic Image]. Novartis Gene Therapies, Bannockburn, IL, United States. https://www.zolgensma-hcp.com/about-zolgensma/moa/

Ogbonmide, T., Rathore, R., Rangrej, S. B., Hutchinson, S., Lewis, M., Ojilere, S., Carvalho, V., & Kelly, I. (2023). Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma). Cureus, 15(3), e36197. https://doi-org.myaccess.library.utoronto.ca/10.7759/cureus.36197

Thomsen, G., Burghes, A. H. M., Hsieh, C., Do, J., Chu, B. T. T., Perry, S., Barkho, B., Kaufmann, P., Sproule, D. M., Feltner, D. E., Chung, W. K., McGovern, V. L., Hevner, R. F., Conces, M., Pierson, C. R., Scoto, M., Muntoni, F., Mendell, J. R., & Foust, K. D. (2021). Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue. Nature Medicine, 27(10), 1701–1711. https://doi.org/10.1038/s41591-021-01483-7

Valori, C. F., Ning, K., Wyles, M., Mead, R. J., Grierson, A. J., Shaw, P. J., & Azzouz, M. (2010). Systemic Delivery of scAAV9 Expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy. Science Translational Medicine, 2(35), 35ra42-35ra42. https://doi.org/10.1126/scitranslmed.3000830

ZOLGENSMA [prescribing information]. Bannockburn, IL: Novartis Gene Therapies, Inc; 2023.

# data[].attributes.body
85% pf patients gained head control, 59% could roll from back to side, 64% could sit without support for ≥30 seconds, 5% could stand alone and walk alone, as opposed to the 0% in natural history.

# data[].attributes.body
START + START LTFU:

The range of ethnicities represented was limited.

The rationale behind why the low-dose cohort had 3 patients and the high-dose cohort had 12 was left unaddressed.

⅓ of patients in START LTFU received add-on therapy. As such, gain and maintenance of motor milestones for these patients may not solely be attributed to Zolgensma.

STR1VE:

Traditionally, Phase III compares treatment of interest with standard current drug therapy (or placebo). However, that was not the case for STR1VE.

A larger sample size would also improve statistical significance.

# data[].attributes.attachment_caption
Fig. 3.2.1. Zolgensma demonstrated a prolonged improvement to CHOP INTEND scores up to 12 months post infusion (Novartis, 2023b).

# data[].attributes.body
Rapid mean score improvements from baseline of 6.9 points and 16.4 points were exhibited at 1- and 12-months post-treatment respectively.

# data[].attributes.attachment_caption
Fig. 3.2.2. Zolgensma aided in the ability to thrive (defined by swallowing function, nutritional support, and weight maintenance) (Novartis, 2023b).  

# data[].attributes.body
At 18-months of age, 41% of patients fulfilled all three criteria for the ability to thrive in comparison to none in the control group.

# data[].attributes.body
Almost all patients (95%) achieved CHOP INTEND scores ≥40, indicative of better motor function.

# data[].attributes.body
Results:

Aligning with results from START, 91% (20/22) of patients surpassed the 18-month age mark.

Patients were alive and free of permanent ventilation.

** 1 patient withdrew from the study and another passed away due to respiratory failure unrelated STR1VE-US.

# data[].attributes.body
Results:

As of the May 2022 data cut, all patients were alive and free of permanent ventilation.

With 100% of patients maintaining motor milestones achieved at the end of START, Zolgensma was found to exhibit durability of effect up to 7.5 years post-treatment.

30% of patients even gained an additional motor milestone of standing with assistance.

Add-on SMA therapy was not needed for ⅔ of the patients.

# data[].attributes.body
d) According to the immunohistochemistry assay, it is evident that scAAV9 is efficient at entering motor neuron cells (see the scAAV9-GFP). When visualizing SMN, the same properties of the scAAV9-GFP hold true as SMN is widely expressed throughout the motor neurons in red fluoresence (Valori et al., 2010).

# data[].attributes.attachment_caption
d) Immunohistochemistry assay demonstrating the effectiveness of the scAAV9 at expressing SMN (Valori et al., 2010).

# data[].attributes.body
c) Western blot analysis reveals that the scAAV9-coSMN lead to significant increases in the amount of SMN expressed at the lumbar spinal cord, the gastrocnemius and liver in comparison to the other two models. The liver is of particular interest as this increase in liver SMN expression may play a role in Zolgensma's hepatotoxicity side effect (Valori et al., 2010).

# data[].attributes.attachment_caption
c) Western blot analysis of SMN expression within various tissues (Valori et al., 2010)

# data[].attributes.body
Zolgensma was found to sustain bulbar function, enabling 92% of patients to speak, swallow, and feed orally.

It also supported the maintenance of nutritional and respiratory status - majority of patients who did not require support prior to gene therapy continued without it.

# data[].attributes.attachment_caption
Fig. 3.1.3. Zolgensma significantly enhanced motor function as assessed by CHOP INTEND (Novartis, 2023a). 

# data[].attributes.body
92% of patients achieved unprecedented CHOP INTEND scores of ≥40 (from initial mean score of 28).

Improvement could be observed as early as 1 month post-infusion.

# data[].attributes.attachment_caption
Fig. 3.1.2. Zolgensma helped patients achieve and maintain motor milestones (Novartis, 2023a).

# data[].attributes.body
Patients gained head control (92%), could roll from back to side (75%), sit without support for ≥30 seconds (75%), stand alone (17%) and walk alone (17%), all of which in natural history, no untreated SMA1 patients could do.

# data[].attributes.body
c) The amount of estimated motor units following treatment is increased in pre-symptomatic and symptomatic groups. Interestingly the difference between pre-symptomatic vs SMN knockout is significantly different but the difference between treated at symptom onset vs SMN knockout is not significantly different. Perhaps implying that timing of treatment is important (Duque et al., 2015).

# data[].attributes.attachment_caption
d)  Bar graph representing the estimated number of motor units amongst control, SMA, treated pre-symptomatic, and treated at symptom onset groups.

# data[].attributes.body
(Duque et al., 2015)

# data[].attributes.body
a) Following the knockdown of the SMN gene there was a decrease in SMN protein levels relative to beta actin amounts (Figure a). In comparison to the control, it was observed that scAAV9-shSMN treated mice displayed less SMN protein expression (Duque et al., 2015).

# data[].attributes.attachment_caption
c) Choline acetyltransferase (ChAT) in blue represents motor neurons, GFP in green indicating successful scAAV9 + shSMN treatment (gene silencing), SMN in red.

# data[].attributes.body
(Duque et al., 2015)

# data[].attributes.attachment_caption
Fig. 3.1.1. Zolgensma greatly increased event-free survival (Novartis, 2023a). 

# data[].attributes.body
Results (High-Dose Cohort):

100% of patients surpassed the 20-month age mark where traditionally only 8% survived without permanent ventilation.

# data[].attributes.body
c) Within the three treatment groups, it is evident that when treated with scAAV9 + SMN prior to or upon symptom onset that there is a significant improvement in the amount of SMN protein (red fluorescence). This can be visualized through the purple fluorescence in the image as ChAT (blue fluorescence) is present in all motor neurons (Duque et al., 2015).

# data[].attributes.body
b) Knockdown of the pig SMN gene led to development of SMA phenotypes expressed in the treated pigs. Some common phenotypic representations being unable to stand and pronounced muscle weakness (Duque et al. 2015).

# data[].attributes.body
b) When SMN expression levels were normalized, it is further supported that the optimized SMN codon led to a significantly larger increase in the amount of SMN expression. This increase was significantly larger in comparison to controls and the old SMN codon (Valori et al., 2010).

# data[].attributes.body
a) When testing the new codon optimized SMN gene, there was a larger amount of SMN expression, indicated by the red fluorescence. This new codon optimized SMN was more effective than previous models at inducing SMN expression (Valori et al., 2010).

# data[].attributes.attachment_caption
b) Graphical representation of the amount of normalized SMN expression between control, LV-coSMN and LV-wtSMN

# data[].attributes.body
In 2010, this preclinical trial presented a scAAV9 encoding SMN protein that was more effective than previous literature at inducing SMN protein expression via lentiviral vectors. The goal of this study was to optimize SMN expression and enhance overall SMN distribution in mice SMA models (Valori et al., 2010) They treated SMA phenotype mice with their new optimized SMN encoding scAAV9 and presented the following results:

# data[].attributes.attachment_caption
a) Fluorescent imaging of SMN expression when using the old SMN lentivirus in comparison to the optimized codon (coSMN) lentivirus (Valori et al. 2010)

# data[].attributes.attachment_caption
b) Pigs demonstrating SMA phenotype following shSMN treatment (Duque et al., 2015).

# data[].attributes.attachment_caption
a) SMN protein expression following shSMN knockout (Duque et al., 2015).

# data[].attributes.headline
2. scAAV9 + human SMN was successful at increasing SMN protein and motor units

# data[].attributes.subject
2. scAAV9 + human SMN was successful at increasing SMN protein and motor units

# data[].attributes.headline
1. Knockdown of the SMN gene resulted in successful SMA phenotype generation

# data[].attributes.subject
1. Knockdown of the SMN gene resulted in successful SMA phenotype generation

# data[].attributes.body
Researchers wanted to observe if the effects of scAAV9, encoding human SMN, in mice could be translated to a large animal model. In order to do this, researchers created the first pig model of SMA by knocking out pig SMN1 using a scAAV9 containing shRNA (Duque et al., 2015). They then treated the pig models with scAAV9 encoding human SMN1 and found the following key findings and results:

# data[].attributes.body
In accordance with the outcomes of START, Zolgensma helped maintain respiratory status.

A large majority of patients did not require ventilatory support at any point throughout the duration of STR1VE-US.

# data[].attributes.headline
2. Systemic scAAV9-coSMN injection into the facial vein -> efficient transfer to various tissues and extensive expression

# data[].attributes.subject
2. Systemic scAAV9-coSMN injection into the facial vein -> efficient transfer to various tissues and extensive expression

# data[].attributes.headline
1. The new codon optimized SMN (coSMN) resulted in greater SMN expression

# data[].attributes.subject
1. The new codon optimized SMN (coSMN) resulted in greater SMN expression

# data[].attributes.body
(Novartis, 2023c; Mendell et al., 2021)

# data[].attributes.body
The molecular mechanism of the Zolgensma treatment can be divided into five different steps:

1. Intravenous injection of the scAAV9 containing human SMN1 gene (Novartis, 2023)

2. Injected scAAV9 crosses the blood brain barrier into motor neuron cells (Novartis, 2023)

3. The scAAV9 then enters the motor neuron nucleus and transducts the human SMN1 gene into the nucleus (Novartis, 2023)

4. The self complementary DNA encoding the human SMN1 gene forms a circular episome structure under the control of the strong promoter -> continuous SMN protein production (Thomsen et al., 2021)

5. SMN protein quantities increase to counteract SMA phenotype (Novartis, 2023)

# data[].attributes.attachment_caption
Image obtained from the Zolgensma website

# data[].attributes.body
Zolgensma is composed of several components:

1. Self complementary adeno-associated virus 9 (scAAV9)

Forms an intramolecular dsDNA template (McCarty, 2008)

Bypasses the initial DNA duplication step in the transcription process (McCarty, 2008)

2. Hybrid promoter

Allows for continuous expression of the SMN1 gene (Thomsen et al., 2021)

3. Functional SMN1 gene

Encodes human SMN1 gene

# data[].attributes.attachment_caption
Graphical representation from ThermoFisher differentiating SMN2 and SMN1 gene protein products.

# data[].attributes.body
Prior to Zolgensma’s FDA approval, the only treatment available was Nusinersin which targeted SMN2. SMN2, although similar to SMN1, produces a non functional version of the SMN protein as a result of an exclusion of exon 7 in the dysfunctional protein product. Nusinersin is a treatment using antisense oligonucleotides that modifies the SMN2 protein product so that it includes exon 7 by targeting an intronic splicing silencer N1 (ISS-N1). Removal of ISS-N1 led to functional exon 7 including proteins (Chaytow et al., 2021).

# data[].attributes.body
SMN proteins have been implicated in various cellular activities (Ogbomide et al., 2023). Some major activities of importance are pictured above.

# data[].attributes.body
Here is a heartwarming example of a child with SMA treated with Zolgensma. From the Zolgensma Youtube Channel.

# data[].attributes.attachment_link.title
Gene Therapy for SMA Type 1: Evelyn's Story

# data[].attributes.body
SMA can be categorized into 4 different types based on the intensity, age of onset and motor capability. SMA I is the most severe categorized by inability to sit. SMA II is categorized by requiring support to walk, SMA III ability to achieve some walking abilities, SMA IV is the onset of SMA in adulthood (Ogbomide et al., 2023).

# data[].attributes.body
What is SMA?

Spinal muscular atrophy (SMA), is an autosomal recessive disease in individuals who are born without a functioning survival motor neuron one (SMN1) gene. The autosomal recessive mutation in the SMN1 gene leads to dysfunctional SMN1 proteins and decreases the total amount of functional SMN protein available (Duque et al., 2015).

SMA patients experience loss of muscle strength and paralysis because of...

Loss of alpha motor neurons (AMNs) in the lower brainstem and spinal cord -> impaired skeletal muscle-spinal cord communication (Ogbomide et al., 2023).

# data[].attributes.body
The development and approval of Zolgensma involved collaboration with researchers, partners, and families who participated in the clinical trials. Additionally, the OneGene ProgramTM by AveXis, a Novartis company, provides comprehensive patient support, offering a dedicated, personalized support team to assist families throughout the Zolgensma treatment journey (Novartis, 2019).

# data[].attributes.body
Safety Profile:

LNPs are considered safer compared to viral vectors, including scAAV, as they typically exhibit lower immunogenicity and reduced risk of immune responses against the delivery system itself (Yang et al., 2022).

Reduced Toxicity:

The study suggests that LNPs can exhibit favourable pharmacokinetic and toxicological behaviours, indicating a lower likelihood of adverse effects compared to some other nonviral vectors (Yang et al., 2022).

Improved Pharmacokinetics:

LNPs can be engineered to enhance pharmacokinetic properties, such as stability in circulation, targeted delivery to specific tissues, and controlled release of genetic material. This can contribute to improved efficacy(Yang et al., 2022).

Gene Therapy for Tumors and Diseases:

The study highlights the use of lipidic vectors for gene therapy in tumours and other diseases. This suggests that LNPs have been explored as effective carriers for delivering genetic material to target tissues (Yang et al., 2022).

Transfection Efficacy:

While the study acknowledges that nonviral vectors, including LNPs, may have lower transfection efficacy compared to viral vectors, ongoing research aims to optimize and improve the delivery efficiency of LNPs (Yang et al., 2022).

# data[].attributes.body
One study done in 2023, introduces a CRISPR-based gene expression control system known as CRISPR-Toggle, utilizing both CRISPR interference (CRISPRi) and SoxS-based CRISPR activation (CRISPRa) in Escherichia coli. The study reveals that the use of the same scaffold guide RNA structure for both CRISPRi and CRISPRa complexes mitigates these effects, ensuring predictable behaviour and providing a robust platform for synthetic gene circuits (Barbier et al). In the context of Zolgensma, the CRISPR-Toggle system could offer better control over gene expression, reducing side effects by fine-tuning the modulation of the SMN1 gene with increased precision and predictability.

# data[].attributes.headline
Navigating Advancements: Unveiling Potential Innovations for Zolgensma's Safety and Delivery

# data[].attributes.subject
Navigating Advancements: Unveiling Potential Innovations for Zolgensma's Safety and Delivery

# data[].attributes.headline
Enduring Impact: Novartis Unveils Ongoing Long-Term Assessment of Zolgensma, estimated completion in 2039

# data[].attributes.subject
Enduring Impact: Novartis Unveils Ongoing Long-Term Assessment of Zolgensma, estimated completion in 2039

# data[].attributes.body
Treatment-Emergent Serious Adverse Events (SAEs):

Number of participants experiencing adverse events meeting criteria such as

--> fatality, life-threatening conditions, persistent or significant disability, congenital anomalies, hospitalization, or events requiring medical intervention.

Adverse Events of Special Interest (AESI):

Number of participants with identified and potential risks associated with OAV101

--> hepatotoxicity, thrombocytopenia, cardiac adverse events, sensory abnormalities suggestive of ganglionopathy, and thrombotic microangiopathy. Assessment conducted by the investigator (Novartis, 2023).

# data[].attributes.body
Karan -- Introduction

Jeffrey Wong -- Drug development & Preclinical trial

Yvonne Hew -- Clinical trials

Xinyan -- Analysis & Future outlook

# data[].attributes.headline
Crucial Role of Early Detection and Intervention in Managing Neuronal Disorders

# data[].attributes.subject
Crucial Role of Early Detection and Intervention in Managing Neuronal Disorders

# data[].attributes.headline
Into the Future: Mapping the Long-Term Course and Potential Innovations of Zolgensma

# data[].attributes.subject
Into the Future: Mapping the Long-Term Course and Potential Innovations of Zolgensma

# data[].attributes.body
·      One-Time Intravenous Infusion: Zolgensma stands out as the only one-time intravenous (IV) injection treatment for SMA. Unlike competitors that require ongoing administration, Zolgensma's single-dose gene therapy is designed to provide long-lasting effects.

·      Clinical Trial Results: The approval of Zolgensma was based on data from the ongoing Phase 3 STR1VE trial and the completed Phase 1 START trial. The clinical trials demonstrated unprecedented rates of survival, rapid motor function improvement, and durable milestone achievements. Patients in the trials showed the ability to sit without support, a milestone rarely achieved in untreated SMA patients (Day et al., 2021).

# data[].attributes.attachment_caption
The table was made based on information provided by a review (Gardner, 2022).

# data[].attributes.headline
Comparison of Cost with Other SMA Treatments

# data[].attributes.subject
Comparison of Cost with Other SMA Treatments

# data[].attributes.headline
Zolgensma vs. the Rest: Why it Stands Out Among SMA Treatment Alternative

# data[].attributes.subject
Zolgensma vs. the Rest: Why it Stands Out Among SMA Treatment Alternative

# data[].attributes.attachment_caption
Figure 3. Enhanced Delivery Efficiency with Zolgensma IV Injection in Children Under 2 Years Old. Biorender-generated.

# data[].attributes.headline
Strategic Precision: How Restricting Treatment to Under 2 Years Maximizes Gene Delivery Efficiency

# data[].attributes.subject
Strategic Precision: How Restricting Treatment to Under 2 Years Maximizes Gene Delivery Efficiency

# data[].attributes.body
The drug, Zolgensma, demonstrates its remarkable capability to cross the Blood-Brain Barrier (BBB) in patients under 2 years-old, a pivotal aspect that underscores the critical mechanism by which Zolgensma exerts its therapeutic effects (Sethi et al., 2022).

# data[].attributes.headline
From Infancy to Independence: Zolgensma's Role in Transforming Live

# data[].attributes.subject
From Infancy to Independence: Zolgensma's Role in Transforming Live

# data[].attributes.body
Post-treatment results, where children under 2 years old can:

walk independently

permanently free of ventilation if treated pre-symptom (Novartis, 2021).

# data[].attributes.body
The company’s stock value remained somewhat consistent excluding the market crash at the start of the pandemic due to restrictions on therapies that required hospital stays (Liu, 2020). The price quickly recovered and remained consistent. The recent spike occurred from a record high in sales (Gatlin, 2023).

# data[].attributes.body
Cosentyx is by far the highest-earning product by Novartis this past year. This drug is used for the treatment of skin disorders such as psoriasis. Even though Zolgensma is not the most profitable, the drug's mechanism of action piqued our interest for further analysis (Novartis, 2019).

# data[].attributes.attachment_caption
Figure 2. Zolgensma-Mediated Rescue of SMA Patients. Representation generated using Biorender, illustrating the replacement of the functional SMN1 gene.

# data[].attributes.headline
Targeting the Root Cause: Zolgensma's Precision in Addressing Genetic Defect 

# data[].attributes.subject
Targeting the Root Cause: Zolgensma's Precision in Addressing Genetic Defect 

# data[].attributes.body
Unique Targeting:

Zolgensma exclusively targets the SMN1 gene, addressing the root cause of SMA.

Comprehensive Impact:

Directly addressing the genetic basis, Zolgensma has transformative potential for SMA.

Innovative Approach:

Zolgensma pioneers an innovative approach, addressing a genetic disorder where traditional treatments may lack efficacy.

Reshaping Treatment Landscape:

Zolgensma's unique SMN1 gene targeting positions it as a frontrunner, reshaping the SMA treatment landscape.

# data[].attributes.body
Novartis is traded on both the Swiss Exchange and NYSE and nearly half of the company’s annual revenue is earned in the United States (Alonso, 2022).

# data[].attributes.headline
Strengths, Successes and Future Challenges

# data[].attributes.subject
Strengths, Successes and Future Challenges

# data[].attributes.body
Novartis is a big pharmaceutical company that focuses on building trust with the public through industry-leading ethical standards and working towards making the world a better place. It was formed in 1997 from the merger of two major Swiss drug companies, Ciba-Geigy and Sandoz. Novartis has affiliates in about 140 countries and is engaged in the development, manufacture, and marketing of pharmaceuticals. The companies that were involved in the establishment of Novartis formed a special cartel to help compete against foreign firms. This reduced competition within Switzerland and allowed the companies to expand together with little to no domestic competition. Over the years, Novartis has acquired nearly 30 companies along with the expansion into different industries like eye care and gene therapies (Britannica, 2023). However, it may prove difficult to match supply with demand, especially with the required increase in manufacturing rate (Gatlin, 2023).

# data[].attributes.body
START + START LTFU:

The use of both a low-dose and high-dose cohort was beneficial, given the appropriate therapeutic dose has yet to be determined.

STR1VE:

STR1VE was conducted in US, EU and AP - respective genetic differences amongst populations can be accounted.

# data[].attributes.body
Vomiting.

Elevated levels of aminotransferases (may result in acute serious liver injury or failure).

Treated with oral prednisolone (corticosteroid) before and after infusion with Zolgensma.

(Devi et al., 2022)

# data[].attributes.body
About: An open-label, single-arm, single-dose clinical trial that aimed to demonstrate the efficacy of Zolgensma. STR1VE-US was conducted at 12 hospitals and universities in the USA and uses a historical cohort as a control (n=23).

Procedure:

Symptomatic patients (n=22) <6 months of age were enrolled.

A single IV infusion of Zolgensma (1·1×10¹⁴ vg/kg of body weight - built on findings from START) was administered.

Weekly follow-ups were conducted for 4 weeks, followed by subsequent monthly assessments until patients reached 18 months of age.

# data[].attributes.body
About: An ongoing, observational follow-up study that aimed to monitor the long-term safety of Zolgensma. START LTFU began after the completion of START and is set to last 15 years.

Procedure:

START participants (n=13) from the high-dose cohort (n=10) and low-dose cohort (n=3) were enrolled and studied.

2 patients’ families declined participation.

# data[].attributes.attachment_caption
Figure 1. The FDA approval milestones for Zolgensma (Stewart, 2019). 

# data[].attributes.headline
Zolgensma's Green Light: How FDA Fast Track Approval Shaped its Path to Success

# data[].attributes.subject
Zolgensma's Green Light: How FDA Fast Track Approval Shaped its Path to Success

# data[].attributes.body
Accelerated timelines for drug development.

Increased opportunities for ongoing dialogue with the FDA.

Eligibility for accelerated approval based on surrogate endpoints.

Shortened FDA review period to 6 months.

Submissions of completed sections for ongoing review.

Enhanced guidance and insights from FDA experts.

Fast Track designation may extend to multiple indications.

Enhanced market positioning and attractiveness for investment.

# data[].attributes.headline
Path to Progress: Understanding the Factors Behind Zolgensma's Phenomenal Success

# data[].attributes.subject
Path to Progress: Understanding the Factors Behind Zolgensma's Phenomenal Success

# data[].attributes.body
About: An open-label, single-arm, dose-escalation clinical trial that aimed to study the efficacy of Zolgensma. START lasted 24-months and used a historical cohort as control (n=23).

Procedure:

Symptomatic patients (n=15) <9 months of age were divided into 2 cohorts—a low-dose cohort (n=3) and a high-dose cohort (n=12).

A single IV infusion of Zolgensma was administered.

The low-dose (6.7 × 10¹³ vg/kg of body weight) cohort received approximately ¹⁄₃ the dosage received by the high-dose (2.0 × 10¹⁴ vg per/kg of body weight) cohort.

# data[].attributes.body
Zolgensma is a one-time gene therapy treatment for spinal muscular atrophy in patients less than 2 years of age. From being developed in 2019, it has already generated more than $1.3 billion in annual sales just last year (Alonso, 2022). Zolgensma is expected to eventually earn between $1.5 to $2 billion annually. Being the most expensive drug upon release at $2.1 million, it is currently the only approved gene therapy for SMA targeting the SMN1 gene. Zolgensma has treated over 3000 patients and continues to be further improved to change more lives (Novartis, 2019).

# data[].attributes.body
(Novartis, 2023b; Day et al., 2021)

# data[].attributes.body
(Novartis, 2023a; Mendell et al., 2017)

# data[].attributes.body
Endpoints:

Event-free survival.

Change from baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores.

Motor milestone and developmental achievements.

** Event defined as death or need for ≥14 days of permanent ventilatory support.

** CHOP INTEND is an assessment tool designed to evaluate motor function in infants with SMA. It comprises a 0-64 scale with higher scores indicating better function.

Inclusion criteria:

Genetically confirmed SMA1 diagnosis.

** Bi-allelic SMN1 mutations and one or two copies of SMN2.

Exclusions criteria:

Genetic modifier c.859G>C in SMN2 exon 7.

Anti-AAV9 antibody titers >1:50.

Use of other investigational or commercial products intended for the treatment of SMA

** This genetic modifier predicts a milder phenotype.

** Ratio excluded to prevent potential impact on therapy efficacy and risk of adverse events due to preexisting antibodies.

(Novartis, 2023a; Novartis, 2023b; Novartis, 2023c; Stolte et al., 2022)