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Articles

The newly added cohort allows for greater opportunity to treat patients earlier, with the hope of impacting disease course and preserving muscle.

Phase 1/2 AFFINITY DUCHENNE Trial Expands to Include Younger Cohort of Duchenne Muscular Dystrophy

Videos

The associate professor of neurology at Mayo Clinic College of Medicine discussed findings from a post-hoc analysis of the phase 3 PREVAIL study presented at AHS 2024 assessing eptinezumab in patients with chronic migraine. [WATCH TIME: 4 minutes]

Assessing Long-Term Benefit of Eptinezumab for Chronic Migraine: Amaal Starling, MD, FAHS, FAAN

Suvecaltamide did not meet the primary endpoint in the phase 2b trial but showed numeric improvements and was well-tolerated.

Jazz’s Suvecaltamide Fails to Meet Primary End Point in Phase 2b Trial of Essential Tremor

Here's some of what is coming soon to NeurologyLive® this week. 

This Week on NeurologyLive® — July 1, 2024

, has been with the team since September 2022. Follow her on Twitter 

The Cleveland Clinic Foundation Parkinson's Inpatient Program is a proactive, multidisciplinary intervention aimed to enhance the quality and safety of care for hospitalized patients with Parkinson disease.

Cleveland Clinic's Parkinson Disease Inpatient Program Improves Patient Outcomes

The director of the OhioHealth ALS Clinic and vice chair of the ALS Association Care Services Committee discussed the upcoming ALS Nexus Conference and how themes of the event align with the direction of clinical care. [WATCH TIME: 3 minutes]

Previewing ALS Association’s Inaugural Nexus Conference: John Novak, MD, MS

As part of our monthly clinician spotlight, NeurologyLive® highlighted seizure disorder expert Danielle Andrade, MD, MSc, FRCPC, director of the Adult Genetic Epilepsy Program at the University of Toronto.
 

NeurologyLive® Clinician of the Month Spotlight: Danielle Andrade, MD, MSc, FRCPC

NeurologyLive is your direct connection to the latest neurology news and interviews with expert neurologists in multimedia formats.

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ATMRD 2024

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Video Series

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Authors

In this segment, Negroski comments on the realism behind wearing off effect of treatments, specifically ocrelizumab, and how clinicians may work around some of these issues.

Managing Wearing Off Effect in High-Efficacy Disease-Modifying Therapies

Negroski discussed some of the takeaways from an analysis of patients with stable MS who chose to switch from natalizumab to other, more moderate-efficacy oral disease-modifying therapies. 

Treatment Decisions With Stable MS

In this conversation, Negroski provides commentary on the role of lymphocyte counts and specifically a study evaluating changes in these counts for patients switching between dimethyl and diroximel fumarates.

Role of Lymphocyte Counts in MS

Donald Negroski, MD, shared thoughts on retrospective data assessing patients with multiple sclerosis who switched from S1P-modulating agents to ozanimod, another approved disease-modifying therapy. 

Switching From S1P-Modulating Therapies to Other DMTs

Agne Straukiene, MD, discussed how combining advanced therapies with lifestyle modifications can improve outcomes and slow disease progression in MS.. 

Integrating Advanced Therapies and Holistic Management in Multiple Sclerosis Care: Agne Straukiene, MD

"Promoting a brain-healthy and metabolically healthy lifestyle can slow disease progression and enhance the quality of life for [patients] living with multiple sclerosis."

Lifestyle and environmental factors can significantly influence the progression of neurological conditions such as multiple sclerosis (MS). Lack of exercise, poor diet, smoking, excessive alcohol intake, social determinants, medications, poor sleep, and comorbidities can even worsen MS by affecting patients’ brain health and depleting neurological reserves. Beyond disease-modifying therapies, clinicians believe that the approach to MS treatment should entail a "brain-healthy" and "metabolically-healthy" lifestyle to preserve neurological reserves and slow disease progression.

, a group of experts proposed recommendations for self-regulated lifestyle modifications to potentially enhance brain health, directly impact disease progression, and improve outcomes in patients with MS.

 Conducted by senior author Agne Straukiene, MD, and colleagues, the paper highlighted the importance of self-management and adopting a multidisciplinary, collaborative and person-centered care approach that comprises of the healthcare team, the patient’s family and support groups in the community.

, Straukiene, a consultant neurologist at Torbay and Southern Devon Healthcare NHS Foundation Trust, discussed how lifestyle and environmental factors impact the health and disease progression in patients with MS. She also talked about the key recommendations for lifestyle modifications for patients with MS from the recently published paper. Furthermore, she spoke about how advanced therapies can be integrated with holistic management strategies to preserve neurological reserves in patients living with MS.

REFERENCES
1. Giovannoni G, Ford HL, Schmierer K, et al. MS care: integrating advanced therapies and holistic management. Front Neurol. 2024;14:1286122. Published 2024 Jan 30. doi:10.3389/fneur.2023.1286122

The consultant neurologist at Torbay and Southern Devon Healthcare NHS Foundation Trust discussed how combining advanced therapies with lifestyle modifications can improve outcomes and slow disease progression in patients with multiple sclerosis. [WATCH TIME: 4 minutes]

Clinical

According to a recent announcement, the FDA has issued a complete response letter (CRL) to NeuroDerm for its submission of ND0612, a 24-hour/day subcutaneous infusion of liquid levodopa/carbidopa (LD/CD), as a potential treatment for ON time in Parkinson disease (PD). Mitsubishi Tanabe Pharma and its wholly owned subsidiary, NeuroDerm, noted that they are reviewing the CRL and will work closely with the FDA to address its comments to consider the future direction.

ND0612’s application was supported by data from the phase 3 BouNDless trial (NCT04006210), a double-blind, double-dummy, active-controlled trial that featured 259 patients with PD who experienced at least 2.5 h/day of OFF time. In the study, treatment with the investigational agent resulted in an additional 1.72 h (95% CI, 1.08-2.36) of ON time without troublesome dyskinesia compared with oral LD/CD (change, –0.48 h; 95% CI, –0.94 to –0.02; 

The study, published earlier this year in 

, met its primary end point and first 4 secondary end points as well. Of the 9 prespecified hierarchical outcomes, significant treatment differences favoring subcutaneous ND0612 included daily OFF time (–1.40; 95% CI, –1.99 to –0.80), Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)-II scores (–3.05; 95% CI, –4.28 to –1.81), Patients Global Impression of Change (OR, 5.31; 95% CI, 2.67-10.58), and Clinical Global Impression of Improvement (OR, 7.23; 95% CI, 3.57-14.64). Of note, hierarchical testing ended after the 4th secondary end point.

FDA Grants Regenerative Medicine Advanced Therapy Designation for AMT-130 Gene Therapy in Huntington Disease

Of those randomized, 94% (n = 243) completed the study, where they continued on into the open-label extension. Throughout the open-label optimization and double-blind phase, most patients experienced at least 1 adverse event (AE) while on ND0162. Infusion site reactions, most of which were mild, were the most commonly reported AE (open-label ND0612: 83%; ND0612 double-blind: 57%; oral LD/CD: 43%). There were 7 reported serious AEs found in 4 patients, which included infusion-site cellulitis (n = 2), infusion-site abscess and infusion-site ulcer (n = 1), and parasthesia and peripheral sensorimotor neuropathy (n = 1).

ND0612 is designed to improve the drugs’ pharmacokinetic profiles by avoiding gastric involvement and maintaining stable and continuous therapeutic levodopa plasma concentrations. The thought behind the drug is that it may provide sustained relief of motor fluctuations in patients with PD, backed by robust long-term safety data. To date, the therapy has a documented cumulative exposure exceeding 500 patient-years, with some patients already in their 7th year of treatment in the long-term safety trial.

During BouNDless, a relatively small number of patients discontinued therapy in both groups, 5.5% (n = 7) in the ND0612 and 3.1% (n = 4) in the immediate-release LD/CD group, The rates of AEs were similar, with 80.5% (n = 103) of those in the ND0612 group reporting AEs compared with 74% (n = 97) of those in the immediate-release LD/CD group.

REFERENCES
1. Mitsubishi Tanabe Pharma Corporation provides US regulatory update on ND0612. News release. June 11, 2024. Accessed June 19, 2024. 

https://neuroderm.com/our-company/news-and-events/fda-letter/


2. Espay AJ, Stocchi F, Pahwa R, et al. Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612 for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomized, double-blind, double-dummy, multicenter trial. The Lancet Neuro. Published online March 15, 2024. doi:10.1016/S1474-4422(24)00052-8

ND0612, an investigational agent, had supportive data from the pivotal phase 3 BouNDless trial, a large-scale, phase 3 study of patients with Parkinson disease.

Parkinson Therapy ND0612 Receives Complete Response Letter

Top stories in neurology, neurological disorders

Neurology News Network

Welcome to this special edition of Neurology News Network. I'm Marco Meglio.

FDA has issued a complete response letter

 (CRL) to NeuroDerm for its submission of ND0612, a 24-hour/day subcutaneous infusion of liquid levodopa/carbidopa (LD/CD), as a potential treatment for ON time in Parkinson disease (PD). Mitsubishi Tanabe Pharma and its wholly owned subsidiary, NeuroDerm, noted that they are reviewing the CRL and will work closely with the FDA to address its comments to consider the future direction. ND0612’s application was supported by data from the phase 3 BouNDless trial (NCT04006210), a double-blind, double-dummy, active-controlled trial that featured 259 patients with PD who experienced at least 2.5 h/day of OFF time. In the study, treatment with the investigational agent resulted in an additional 1.72 h (95% CI, 1.08-2.36) of ON time without troublesome dyskinesia compared with oral LD/CD.

According to a recent announcement, Otsuka Pharmaceutical 

 of the development of its novel compound AVP-786, a CYP2D6 inhibitor, for the treatment of patients with Alzheimer disease (AD) agitation. The company noted that it plans to continue its research and development efforts to meet the unmet needs of patients who experience agitation associated with AD. The termination of the development of this drug candidate was decided by the company after a detailed analysis of results from the completed phase 3 clinical trial (NCT03393520) assessing AVP-786 in patients with AD agitation. In February 2024, top-line results of the trial showed that the treatment failed to distinguish itself from placebo in this patient population, which consisted of 550 participants across 90 centers worldwide.

 from its pivotal phase 1/2 REVEAL studies assessing TSHA-102, an adeno-associated (AAV)-based gene therapy for patients with Rett syndrome. All told, treatment with the therapy resulted in durable improvements across clinical domains in a small group of both adult and pediatric patients, including motor skills, communication/socialization, autonomic function, and seizures, in addition to demonstrating a safe profile. Designed as a one-time lumbar intrathecal treatment, TSHA-102 aims to address the genetic root cause of Rett by delivering a functional form of MECP2 to cells in the central nervous system. Following an independent data monitoring committee review of safety data from the first high dose patient in the adolescent and adult trial, dosing for a high-dose cohort is expected to commence in Q3 2024.

For more direct access to expert insight, head to NeurologyLive.com. This has been Neurology News Network. Thanks for watching.

Neurology News Network. for the week ending June 22, 2024. [WATCH TIME: 4 minutes]

ND0612 Receives Complete Letter Response, Otsuka Terminates AVP-786, TSHA-102 Performs in Phase 1/2 REVEAL Studies

New preliminary findings in a responder-analysis from the ongoing open-label phase 2b BeyoND trial (NCT02726386) assessing ND0612 (NeuroDerm), a 24-hour/day subcutaneous infusion of liquid levodopa/carbidopa (LD/CD), showed a reduction in OFF time at 12 months among patients with Parkinson disease (PD) who experience motor fluctuations, supporting the efficacy of the treatment in this patient population.

In the analysis, investigators identified 44% of patients (n = 214) as treatment responders, using the last observation carried forward, and reported that this level of response was maintained over 12 months of follow-up. Notably, researchers also noted that at 12 months 63.5% of patients achieved at least a 25% reduction in OFF time from baseline and 26.9% of patients achieved at least a 75% reduction in OFF time.

These results were presented at the 3rd Annual 

Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress

 from June 22-25, 2024, in Washington, DC, by lead author Aaron L. Ellenbogen, DO, MPH, FACN, neurologist and movement disorder specialist at Michigan Institute for Neurological Disorders. Participants in the BeyoND trial were diagnosed with PD, had at least a Hoehn & Yahr score of 3 during ON, and experienced at least 2 hours of daily OFF time. In the performed analysis of daily OFF time, as recorded by patient home diaries, investigators defined a responder conservatively as a patient that achieved at least 50% reduction from baseline in adjusted mean daily OFF time.

Additional findings showed that 12.8% of patients achieved a 100% OFF time reduction with the treatment at 12 months. Using only observed cases, excluding the last observation carried forward, investigators reported that the rate of ND0612 treatment responders increased from 44.0% at month 1 (n = 150) to 53.3% at month 6 (n = 107), and 56.7% at month 12 (n = 90). Previous findings with ND0612 at 1 year revealed a favorable safety and tolerability profile. Further prior results showed that the adjusted mean daily ‘Good ON’ time, which is the sum of ON time without dyskinesia plus ON time with non-troublesome dyskinesia, increased from baseline by 2.3 hours at month 3 and maintained for at least 12 months.

Depression Linked With Worsened Non-Motor Symptoms in Parkinson Disease

 (CRL) to NeuroDerm for its submission of ND0612 as a potential treatment for ON time in PD. Mitsubishi Tanabe Pharma and its wholly owned subsidiary, NeuroDerm, noted that they are reviewing the CRL and will work closely with the FDA to address its comments to consider the future direction.

ND0612’s application was supported by data from the phase 3 BouNDless trial (NCT04006210), a double-blind, double-dummy, active-controlled trial that featured 259 patients with PD who experienced at least 2.5 h/day of OFF time. In the study, treatment with the investigational agent resulted in an additional 1.72 h (95% CI, 1.08-2.36) of ON time without troublesome dyskinesia compared with oral LD/CD (change, –0.48 h; 95% CI, –0.94 to –0.02; P <.0001).

Click here for more coverage of ATMRD 2024

REFERENCES
1. Ellenbogen AL, Espay AJ, Isaacson S, et al. Reductions in OFF time with ND0612 for patients with Parkinson's disease experiencing motor fluctuations: Responder-analysis from an open-label Phase 2b. Presented at: ATMRD; June 22-25, 2024; Washington, DC.
2. Mitisubishi Tanabe Pharma Corporation provides US regulatory update on ND0612. News release. June 11, 2024. Accessed June 22, 2024. https://neuroderm.com/our-company/news-and-events/fda-letter/
3. Espay AJ, Stocchi F, Pahwa R, et al. Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612 for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomized, double-blind, double-dummy, multicenter trial. The Lancet Neuro. Published online March 15, 2024. doi:10.1016/S1474-4422(24)00052-8

An open-label phase 2b trial assessing ND0612 showed that the rate of treatment responders increased over a 12-month period among patients with Parkinson disease who experienced motor fluctuation.

ND0612 Reduces OFF Time for Motor Fluctuations in Parkinson Disease at 12 Months

According to a new announcement, the FDA has approved a new generic version of deflazacort (Emflaza; PTC Therapeutics), a treatment indicated for patients 5 years of age and older with Duchenne muscular dystrophy (DMD). The new generic, which allows for greater access and improved cost-effectiveness, is from Cranbury Pharmaceuticals, a wholly-owned subsidiary of Tris Pharma.

"We were pleased to see a generic option for deflazacort, which has been available for much longer in Europe at generic prices. As corticosteroids like deflazacort represent standard-of-care for Duchenne, the wider availability of deflazacort will provide options for some families who may have previously had challenges getting the brand name version, Emflaza, approved," 

, executive vice president and chief research officer of the 

Deflazacort oral suspension, a corticosteroid indicated for DMD, has been on the market since 2017 under the name Emflaza and manufactured by PTC Therapeutics. It has several noted warnings and precautions, including alterations in endocrine function, immunosuppression and increased risk of infection, alterations in cardiovascular/renal function, gastrointestinal perforation, behavioral and mood disturbances, and effects on bones, among others. It is contraindicated in patients with known hypersensitivity to deflazacort or to any of the inactive ingredients.

"Duchenne muscular dystrophy is a devastating rare disease, and with limited treatment options available there is a critical need for the greater accessibility that a generic therapy can bring," Ketan Mehta, founder and chief executive officer at Tris Pharma, said in a statement.

 "This FDA approval is a significant milestone for the patients, caregivers and physicians who may depend on this medication to treat DMD. Our portfolio of differentiated, high-quality generic medications has always been core to our business at Tris, and I look forward to continuing to expand our generic offerings under our new subsidiary, Cranbury Pharmaceuticals."

Final Readout of FIREFISH Study Showcases Risdiplam’s Pronounced Effects in Spinal Muscular Atrophy

Since its approval, deflazacort has been recommended as a once-daily 0.9 mg/kg tablet administered orally. Dosage of the therapy must be decreased gradually if the drug has been administered for more than a few days. Patients are also to administer live attenuated or live vaccines at least 4 to 6 weeks prior to starting deflazacort. The therapy can be taken with or without food, and patients are prohibited from taking the therapy with grapefruit juice.

"Tris Pharma founded Cranbury as part of the company’s continued commitment to develop high-quality medicines and make them accessible to individuals who need them," Janet Penner, president at Cranbury, said in a statement.

 "The launch of deflazacort oral suspension aligns with this commitment, and we are proud to provide this critical therapy to those with DMD. As a tenured member of the Tris team, I am honored to take on the role of president of our new subsidiary and have the opportunity to provide important generic medicines to patients with a range of disorders and diseases."

This was the second approved generic for deflazacort, following Aurobindo Pharma’s approval in early February. Aurobindo, an Indian-based company, gained clearance to market deflazacort tablets in doses of 6 mg, 18 mg, 30 mg, and 36 mg, which was bioequivalent and therapeutically equivalent to the reference listed drug strengths in its original approval.

Deflazacort was originally approved in patients with DMD aged 5 and older but was later expanded in 2019 to include children age 2 to 5 years. At the time, it made deflazacort the only FDA-approved treatment for patients with DMD age 2 and older, regardless of disease-causing genetic mutation. The original approval was based on data from a phase 3 randomized, double-blind, placebo-controlled study of 196 patients with DMD aged 5 to 15 over a 52-week period that compared treatment with deflazacort with prednisone and placebo.

REFERENCES
1. Cranbury Pharmaceuticals receives US FDA approval for first generic version of Emflaza oral suspension (deflazacort) for Duchenne muscular dystrophy. News release. June 12, 2024. Accessed June 12, 2024. https://www.trispharma.com/cranbury-pharmaceuticals-receives-u-s-fda-approval-for-first-generic-version-of-emflaza-oral-suspension-deflazacort-for-duchenne-muscular-dystrophy/
2. Aurobindo Pharma receives USFDA approval for deflazacort tablets, 6 mg, 18 mg, 30 mg, and 36 mg. News release. Aurobindo Pharma. February 12, 2024. Accessed June 12, 2024. https://www.aurobindo.com/api/uploads/disclosureofeventsinformation/LetterToSEsPressReleaseUSFDAproductAproval12022024.pdf
3. PTC Therapeutics receives FDA approval for the expansion of the Emflaza® (deflazacort) labeling to include patients 2-5 years of age. News release. PTC Therapeutics. June 7, 2019. Accessed June 12, 2024. www.prnewswire.com/news-releases/ptc-therapeutics-receives-fda-approval-for-the-expansion-of-the-emflaza-deflazacort-labeling-to-include-patients-2-5-years-of-age-300863988.html.
4. Griggs RC, Miller JP, Greenberg CR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology. 2016;87(20):2123-2131.

Deflazacort, a corticosteroid approved for children with Duchenne muscular dystrophy, has been on the market since 2017 under the name Emflaza.

FDA Approves Cranbury’s Generic Version of Deflazacort to Treat Duchenne Muscular Dystrophy

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted that the data from the phase 3 TRAILBLAZER-ALZ-2 trial (NCT04437511) assessing donanemab (Eli Lilly), an investigational agent in development for Alzheimer disease (AD), was sufficient enough in demonstrating clinical benefit. In the coming weeks, the agency will give its final decision as to whether the therapy will be approved.

At the conclusion of the hearing, the committee voted 11-0 (11 Yes; 0 No; 0 Abstain) that the evidence presented showed that donanemab is effective for the treatment of AD in the population enrolled in clinical trials with mild cognitive impairment (MCI) and mild dementia. In determining the vote, the committee members also factored in whether there was efficacy across the entire population, or in just a subset of patients (e.g., those with low, medium, and high tau levels).

, a professor of neurology, psychiatry, and pharmacology at the 

 and director of the NYU Alzheimer Drug Trial Program, told NeurologyLive

 when asked to share his reaction. "The 11:0 vote of the advisory panel represents a solidifying consensus among neurologists that anti-Aß antibodies are a valid disease-modifying strategy for treating patients with AD."

If approved, donanemab, a humanized IgG monoclonal antibody, would be the third antiamyloid therapy to gain the FDA's greenlight, following the conditional approval of aducanumab (Aduhelm; Biogen) in 2021, and lecanemab (Leqembi; Eisai) in 2023—although aducanumab no longer remains on market after it was removed earlier this year. The proposed indication for donanemab would be for patients with MCI or mild dementia stages of disease, administered as a 700-mg intravenous infusion every 4 weeks, followed by 1400 mg every 4 weeks. In the presentation, Eli Lilly noted that its proposed dosing regimen may be stopped once brain amyloid plaque is cleared.

"Clearance of Aß deposits from the brain by aducanumab renders the ensuing course of the disease indolent, slowing clinical progression of the disease," Sadowski said when questioned on how donanemab would benefit patients with AD.  

"Provides more effective clearance of Aß than lecanemab. Complete Aß clearance can be achieved within 6 months and 12 months in 35% and 50% of individuals treated with donanemab, respectively," Sadowski said when asked how this treatment differs from others for AD. "This means lower health care costs and greater convenience for the patients. Dosing also is more convenient every 4 weeks versus every 2 weeks but causes more adverse events."

Toward the end of the meeting, the committee resoundingly agreed that the data supported the effectiveness of donanemab. Members of the committee brought up concerns with the idea of requiring tau imaging and were aligned that this is not feasible currently, considering the sophisticated nature of tau testing and practical concerns that may come with it at this time. During the discussion, panelists noted they felt as though the evidence was strong, noting the effects donanemab may have on delaying staging for patients, especially at earlier stages. Some felt discomfort extending the treatment to no- or low-tau–level groups, considering patients with this status were not included in the major phase 3 study.

Throughout the meeting, questions were raised about the safety of donanemab, including its impact on amyloid-related imaging abnormalities (ARIA), for which was found in nearly one-fourth of patients in the phase 3 trial. Across the study and its open-label extension, there were 5 ARIA-related deaths in patients on donanemab, none of which were apolipoprotein (

)e4 homozygotes. ARIA-E risk was consistently driven by APOE e4 genotype, number of baseline microhemorrhages, presence of superficial siderosis at baseline, and +/– baseline amyloid.

In donanemab’s defense, the manufacturers noted that symptoms of ARIA can mimic ischemic stroke. They considered offering several recommendations if the drug were to be approved, including having patients carry a medical information card indicating that they are being treated with donanemab. Additionally, they recommended healthcare providers be aware that ARIA can present with focal neurologic symptoms that can mimic stroke, and should considered the potential for ARIA and potential benefits and risks when considering the use of a thrombolytic agent in a donanemab-treated patient with symptoms of stroke.

TRAILBLAZER-ALZ-2 was a large-scale, phase 3, double-blind, placebo-controlled trial that featured 1736 patients with early-stage AD who received either donanemab (n = 860) or placebo (n = 876) every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-square mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. The study comprised of patients with either low/medium tau pathology (68.1%; n = 1182) or high tau pathology (31.8%; n = 552). Of note, it excluded those with no/very low tau.

In the low/medium tau population, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, ­–7.01 to –5.03) in the donanemab group and ­–9.27 (95% CI, –10.23 to ­–8.31) in the placebo group, otherwise a 35.1% (95% CI, 19.90-50.23) slowing of disease progression. The impacts were less pronounced in the overall population, with between-group score differences of 2.92 (95% CI, 1.51-4.33; P <.001), representing a 22.3% (95% CI, 11.38-33.15) slowing of disease progression.

TRAILBLAZER-ALZ-2 was a follow-up to the phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the original biologics license application of donanemab. The FDA responded to Eli Lilly’s application with 

, noting that the company needed to provide data from at least 100 patients who received a minimum of 12 months of continuous treatment with donanemab.

 At the time, the agency indicated that the data to meet the exposure expectation would likely need to include unblinded safety data from TRAILBLAZER-ALZ-2 upon completion.

TRAILBLAZER-ALZ, which began in 2017, met its primary end point, with donanemab slowing decline on the iADRS by 32% compared with placebo at 18 months. The company claimed improvement on all secondary end points of cognition and function, although not all were statistically significant. In addition, amyloid-related imaging abnormalities (ARIA), a concern for antiamyloid therapies, were found in 27% of treated patients, with 6% becoming symptomatic. The study included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance.

TRAILBLAZER-ALZ-2 originally began as a phase 2 study but was enlarged to a phase 3 registrational study. The primary outcome, change in iADRS, was judged using a disease-progression model, rather than solely on change at the final time point. Within the low/medium tau population, investigators observed between-group differences of –0.67 (95% CI, –0.95 to –0.40; 36.0% slowing of clinical progression) for CDR-SB, 1.83 (95% CI, 0.91-2.75; 39.9% slowing of clinical progression) for ADCS-iADL, and –1.52 (95% CI, –2.25 to –0.79; 32.4% slowing of clinical progression) for ADAS-Cog13, at week 76. In this same cohort, donanemab-treated patients had a 38.6% (HR, 0.614; 95% CI, 0.471-0.800; P <.001) lower risk of progression to the next clinical stage on CDR-Global over the 76-week treatment time frame.

2023 Alzheimer’s Association International Conference (AAIC)

, further highlighted the therapy’s impact on relevant AD progression. At 76 weeks, brain amyloid plaque levels decreased by 88.0 centiloids (95% CI, –90.20 to –85.87) with donanemab treatment and increased by 0.2 centiloids (95% CI, –1.91 to 2.26) in the placebo group in the low/medium tau population. In this group, 80.1% (95% CI, 76.12-83.62) of donanemab-treated patients achieved amyloid clearance by week 76 whereas no patients on placebo achieved the same. In terms of plasma phosphorylated tau (p-tau)217, an exploratory outcome, investigators observed differences of –0.25 (95% CI, –0.28 to –0.22; P <.001) tau standardized uptake value ratio (SUVR) in the low/medium tau population relative to placebo and –0.22 (95% CI, –0.24 to –0.20; P <.001) in the combined population at 76 weeks.

In TRAILBLAZER-ALZ-2, donanemab demonstrated a safety profile that was similar to phase 2 findings and consistent with class effects observed with amyloid plaque-lowering therapies. In total, 24% of patients experienced ARIA-E, with most ARIA-E events found to be largely mild to moderate radiographically. In terms of timing, ARIA-E first occurred after receiving up to 3 donanemab infusions in most cases (58%). First ARIA-E events radiographically resolved in 98% of participants, with a mean resolution time of around 10 weeks. Of note, 6% of patients on active treatment experienced recurrent ARIA-E.

The therapy was also assessed in TRAILBLAZER-ALZ-4, a randomized trial comparing treatment effects to aducanumab (Aduhelm; Biogen), the first approved antiamyloid therapy that was recently discontinued from market. After 6 months of treatment, 37.9% of donanemab-treated patients (n = 71) achieved amyloid clearance vs 1.6% of those on aducanumab (n = 69; 

<.001). In the intermediate tau subpopulation, 38.5% of donanemab-treated patients vs 3.8% of aducanumab-treated patients achieved amyloid clearance (

REFERENCES
1. FDA Peripheral and Central Nervous System Drugs Advisory Committee (PCNS). 

. June 10, 2024. Accessed June 10, 2024.
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239
3. US Food and Drug Administration Issues Complete Response Letter for Acceleterated APproval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed January 19, 2022. prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
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5. Mintun M, Solomon P, Sims JR, Salloway S. Donanemab in early symptomatic Alzheiemr’s disease: efficacy and safety in TRAILBLAZER-ALZ 2, a phase 3 randomized clinical trial.

In a pivotal, large-scale, phase 3 trial, donanemab met its primary end point, demonstrating more pronounced effects in patients with early-stage Alzheimer disease who had low/medium tau status.

Donald Negroski, MD

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