Recapping Research From 2023 AAN Annual Meeting


As a recap from AAN 2023, get caught up on some of the latest news in neurology as the NeurologyLive® team shares some of our data updates.

In recent months, the NeurologyLive® team has been covering the news and conducting interviews with experts on the latest updates in the clinical care of patients with neurological diseases, such as dementia or Alzheimer, epilepsy, headache or migraine, movement disorders, multiple sclerosis, neuromuscular diseases, sleep medicine, and stroke.

To recap the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, the team has culminated some of the biggest pieces of news to offer updates on new developments in the literature about different neurological conditions to spread awareness on prevention and treatment approaches.

Click here for more coverage of AAN 2023.

Latest Literature

Pridopidine Shows Clinically Meaningful Results in Huntington Disease for Patients Not on Neuroleptics, Chorea Medications

Findings from the phase 3 PROOF-HD study (NCT04556656) showed that pridopidine (Prilenia), an investigational agent in development for Huntington disease (HD), did not meet its primary end point; however, investigators observed improved clinical outcomes among patients not taking neuroleptics and/or chorea medications.1 All told, pre-specified analyses that excluded patients on neuroleptics and/or chorea medications resulted in beneficial effects on multiple end points of overall progression, motor, and cognition.

The main study included a 6-week screening period, 2-week titration period, 53-week double-blind, full-dose treatment period, followed by a 2-week follow-up. A total of 500 individuals with HD were randomly assigned 1:1 to pridopidine, a highly selective and potent sigma-1 receptor (S1R) agonist, in doses of 45 mg BID, or placebo. Patients in the trial had CAG repeats of more than 36, Unified Huntington’s Disease Rating Scale (UHDRS)-IS levels of less than 90%, and were allowed antipsychotic, antidepressant, chorea, or other psychotropic medications.

In total, 458 (91.8%) patients completed 65 weeks of treatment. In the modified intend-to-treat population, pridopidine showed no favorable benefit over placebo in change of Total Functional Capacity (THC), a composite of the primary end point UHDRS. At 26 weeks, pridopidine showed a beneficial effect vs placebo on TFC (Δ 0.55; P = .058), but showed an even greater effect when excluding neuroleptics (Δ 0.86; P = .02).

In the whole sample, which included those taking neuroleptics and/or chorea medications, investigators observed mean difference of change of –44.4 ms (P = .03) on Q-Motor pronation supination inter-tap-interval (ITI) between pridopidine and placebo groups. When excluding neuroleptics, pridopidine showed a stronger effect, as demonstrated by differences of ­–69.3 ms (P = .02) at 52 weeks.

Serum Ravulizumab Concentrations Maintained Above Therapeutic Threshold in AQP4+ NMOSD

In a pharmacokinetics (PK) and pharmacodynamics (PD) analysis of the CHAMPION-NMOSD open-label, phase 3 study (NCT04201262), results showed that serum ravulizumab (Ultomiris; Alexion) concentrations were maintained above the therapeutics threshold in patients with antiaquaporin (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) through 50 weeks of treatment.2

In 60 minutes after dose administration in all patients, serum ravulizumab concentrations achieved the therapeutic threshold (175 μg/mL) or above it and were maintained from the first dose to week 50. Following week 50 with a maintenance ravulizumab dose, the mean (SD) Cmax and Ctrough were 1877.6 (413.61) and 754.1 (220.71) μg/mL, respectively (n = 52).

In the trial, researchers evaluated ravulizumab on efficacy and safety in 58 adult patients with anti-AQP4 NMOSD who experienced at least 1 attack or relapse in the 12 months prior to the screening visit. The participants also had Expanded Disability Status Scale scores of 7 or less, had a body weight of at least 40 kg at trial entry, and were allowed to stay on stable supportive immunosuppressive therapy for the duration of the study. The patients received a weight-based intravenous loading dose of ravulizumab (2400–3000 mg), then a maintenance dose on day 15 (3000–3600 mg) and every 8 weeks following.

In the PK, investigators analyzed the maximum observed concentration, Cmax assessed at the end of infusion, and concentration at the end of the dosage interval, Ctrough assessed at predose, for ravulizumab. As for the PD assessments, time-matched observed serum free complement 5 (C5) concentration up to 50 weeks was assessed. By the end of the first ravulizumab infusion, immediate and complete inhibition of serum free C5 (terminal complement) was observed (free C5 serum concentrations <0.5 μg/mL) and sustained throughout the treatment period in patients with NMOSD.

Leriglitazone Demonstrates Lesion Growth Deceleration in Pediatric Cerebral Adrenoleukodystrophy

New interim results from the phase 2 open-label NEXUS study NCT04528706) on leriglitazone (Minoryx Therapeutics), a peroxisome proliferator-activated receptor γ agonist for pediatric cerebral adrenoleukodystrophy (cALD), showed that all evaluable patients were clinically stable and radiologically displayed disease arrest or lesion growth stabilization after 24 weeks of treatment.3

Among the 11 evaluable patients that demonstrated lesion growth deceleration or disease arrest (95% confidence interval [CI]: 71.5, 100), 5 showed arrested disease (45.5%, 95% CI, 13.9–68.4%) and all had met the pre-defined continuation criteria for the trial. Notably, the median change from baseline was 0.0 (0.0–1.0) for the neurological function score (NFS) and 0.0 (0.0–3.0) for the Loes score (LS).

In the trial, 17 boys enrolled between the ages of 2–12 years old with cALD with or without gadolinium-enhancing lesions received a once-daily oral leriglitazone. The primary endpoint was the proportion of patients with clinically and radiologically arrested disease at week 96 with the success criteria as one-sided 95% CI greater than 10%. The analysis included the assessment of study continuation criteria (at least 4 out of 13 patients with arrested disease or lesion growth deceleration without clinical progression). As for the secondary endpoints, change from baseline in NFS and LS were assessed. Also as an exploratory endpoint, change from baseline in plasma biomarker concentrations was analyzed.

In radiological changes assessed by LS, results showed as similar to those attained with Hematopoietic Stem-Cell Transplantation (HSCT)-based therapies. Hence, there either was no change or minimal growth with plateauing observed at week 24. Additionally, plasma levels of neurofilament light stabilized and trended as paralleling the results of lesion volume. Neurofilament light chain concentrations stabilized in most patients following a parallel profile to lesion volume change.

Phase 3 NEURO-TTRansform Findings Signify Eplontersen as Promising Agent for hATTR Polyneuropathy

About a month after Ionis Pharmaceuticals announced positive results from its phase 3 NEURO-TTRansform study (NCT04136184) assessing its investigational agent eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), further details of the study were presented at the 2023 AAN Annual Meeting.4

All told, treatment with eplontersen resulted in clinically and statistically significant benefits seen through week 66 compared with placebo. Overall, 47.2% and 57.6% of patients treated with the agent showed improvements on modified Neuropathy Impairment Score +7 (mNIS +7) composite score and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, whereas 16.7% and 20.0% of those on placebo improved on these respective measures.

The multicenter, global trial enrolled 168 patients across 15 countries, with 144 who received eplontersen and 24 who received inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR. Patients in the study were between 18 and 82 years old and had ATTRv-PN defined by Coutinho Stage 1 or 2, documented genetic mutation in the TTR gene, and had signs/symptoms consistent with polyneuropathy. Patients on inotersen crossed over at 35 weeks, while those originally assigned to eplontersen remained on the drug through the final analysis at 66 weeks. The study also includes an open-label extension of up to 3 years or 20-week post-treatment evaluation.

In total, 136 of the 144 individuals on eplontersen completed 66 weeks of treatment, with reasons for discontinuation that included adverse events (AEs; n = 5), voluntary withdrawal (n = 1), investigator decision (n = 1), and ineligibility (n = 1). At week 65, eplontersen-treated individuals showed significant and sustained reductions in serum TTR concentration relative to placebo. Specifically, those on the active drug showed least square mean changes of –81.7% compared with placebo, which showed –11.2% (difference, ­–70.4%; 95% CI, –75.2 to –65.7; P <.0001).

Phase 3 PROGRESS Results Highlight Atogepant’s Benefit in Chronic Migraine

Weeks after the FDA expanded the indication for atogepant (Qulipta; AbbVie) to include the treatment of chronic migraine, findings presented at the 2023 AAN Annual Meeting further supported its efficacy.5

The data presented was from the phase 3 PROGRESS study (NCT03855137), a 12-week trial that was the basis for the expanded indication. PROGRESS included 778 individuals with chronic migraine who were randomly assigned to either atogepant 30 mg twice daily (BID), 60 mg once daily (QD), or placebo. Like many migraine studies, the primary end point was change from baseline in mean monthly migraine days (MMDs), with proportion of patients experiencing at least 50% reduction in 3-month average of MMDs as the secondary end point.

As baseline, the mean MMDs in the modified intent-to-treat (mITT) population (n = 755) were 18.6-19.2 across groups. At the end of the 12-week treatment period, patients on atogepant 30 mg BID and 60 mg QD experienced mean change in MMDs of ­–7.5 and –6.9 days, respectively, compared with changes of –5.1 for those on placebo (30 mg BID vs placebo: P <.0001; 60 mg BID vs placebo; P = .0009). Reduction of at least 50% in 3-month average of MMDs was achieved by 42.7% of participants in the atogepant 30 mg BID group, 41.0% in the atogepant 60 mg QD group, and 26.0% in the placebo group (30 mg BID vs placebo: P = .0003; 60 mg QD vs placebo; P = .0009).

1. Feign A, et al. PRidopine outcome on function in HD: preliminary topline results. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Clinical trials plenary session PL5.
2. Ortiz S, Pittock S, Berthele A, et al. Pharmacokinetics and Pharmacodynamics of Ravulizumab in Adults with Anti-Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder During the Phase 3 CHAMPION-NMOSD trial. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 004.
3. Mallack EJ, Garcia-Cazorla A, Constante JR, et al. Interim Results from the NEXUS Open-Label Registration Study on the Safety and Efficacy of Leriglitazone in the Treatment of Childhood Cerebral AdrenoleukodystrophyPresented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 002. Emerging Science Session 2.
4. Khella S, Marques W, Dasgupta NR, et al. Eplontersen in hereditary ATTR-polyneuropathy: week 66 final analysis of the phase 3 NEURO-TTRansform study. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. LB
5. Pozo-Rosich P, Ailani J, Ashina M, et al. Atogepant for the preventive treatment of chronic migraine: results from the PROGRESS phase 3 trial. Presented at: 2023 AAN Annual meeting; April 22-27; Boston, MA. Abstract 003980.
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