CME INDIA Presentation by Dr. K. Mugundhan, MD, DM (Neuro), FRCP (Glasg, Lond, Edin & Ire), FACP, FICP, Professor of Neurology and Head, Stanley Medical college, Chennai.

Based on a presentation at IANCON 2023, September, 16 and 17, 2023.

What is hot in neurology?

1. Efficacy of Omaveloxolone in Friedreich’s Ataxia: Delayed-Start Analysis of the MOXIe Extension.
2. Focused ultrasound thalamotomy for tremor treatment impacts the cerebello-thalamo-cortical network.
3. Trial of Deferiprone in Parkinson’s Disease.
4. Levodopa Dose Equivalency in Parkinson’s Disease: Updated Systematic Review and Proposals.

Pathogenesis of FA and Potential Role of Nrf2 Activator

• Nrf2 is a transcription factor which promotes the resolution of inflammation and restores mitochondrial function.
• Mutations in frataxin gene in FA result in vicious cycle of mitochondrial dysfunction and paradoxically reduced Nrf2.
• Nrf2 suppression further contributes to oxidative stress, mitochondrial dysfunction and reduced ATP production.
• Omaveloxolone (Omav) restores Nrf2 activity in FA cellular models and improves mitochondrial function.

MOXIe trials

• Part 1- dose ranging, safety, pharmacodynamic and pharmacokinetic activity of OMAV.
• Part 2- safety and efficacy.
• Extension-long term outcomes.

MOXIe – Part 1

• Randomized, placebo-controlled, dose-ranging trial (n=69).
• 69 Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks.
• Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day.
• Omaveloxolone was well tolerated, and adverse events were generally mild.
• Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day.
• No significant changes were observed in the primary outcome, peak work load in maximal exercise testing.
• At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06).
• Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus).
• In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day.

MOXIe – Part 2

• Multicenter, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of omaveloxolone 150mg per day in patients with FA.
• 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52).
• Omav significantly improved mFARS by -2.40 points relative to placebo at Week 48 (n=82; p=0.014).
• Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury.
•  Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.
• Interpretation: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA.
• Cardiac safety- Omaveloxolone did not increase blood pressure and was not associated with adverse effects on ECG or Echo parameters, including ventricular heart rate, QTc, wall thicknesses, or ejection fraction in patient with cardiomyopathy.
• Treatment with omaveloxolone was associated with asymptomatic, transient, reversible increases in aminotransferases without liver injury. Such changes could represent a consequence of reactivation of hepatic function in FA.
• Activation of Nrf2 induces aminotransferase genes and serum activity of ALT and AST.
• Omaveloxolone also increases ALT and AST protein levels in cell lines derived from nonhepatic tissues, such as colon, skeletal muscle, and kidney, indicating that omaveloxolone regulates transcription of ALT and AST genes in multiple organs.
• Changes in aminotransferase levels may reflect physiological adaptations to restoration of Nrf2 levels in FA.

MOXIe extension

• Open label extension study.
• compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo.
• Difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 points) was preserved after 72 weeks in the extension (-2.91 points).
•  In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.
• Conclusions: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich’s ataxia.

Focused ultrasound thalamotomy for tremor treatment

• Tremor is a prominent symptom in movement disorders. It is usually observed at rest in tremor-dominant Parkinson’s disease (TDPD), while essential tremor (ET) typically involves kinetic or postural tremor.
• The first line of treatment for tremor is pharmacological. However, medications offer limited effectiveness, especially as the disorders progress, and can cause adverse effects.
• In patients for whom tremor causes a severe reduction in quality of life, invasive procedures are explored. These include deep brain stimulation (DBS) and radiofrequency surgery.
• The ventral intermediate nucleus (VIM) of the thalamus is currently the standard of care target for ET and a common target for TDPD. The VIM is a motor thalamic nucleus which acts as a relay between the motor cortex and cerebellum, and is part of a cerebello-thalamo-cortical tremor network.
• Tremor is a prominent symptom in movement disorders. It is usually observed at rest in tremor-dominant Parkinson’s disease (TDPD), while essential tremor (ET) typically involves kinetic or postural tremor.
• The first line of treatment for tremor is pharmacological. However, medications offer limited effectiveness, especially as the disorders progress, and can cause adverse effects.
• In patients for whom tremor causes a severe reduction in quality of life, invasive procedures are explored. These include deep brain stimulation (DBS) and radiofrequency surgery.
• The ventral intermediate nucleus (VIM) of the thalamus is currently the standard of care target for ET and a common target for TDPD. The VIM is a motor thalamic nucleus which acts as a relay between the motor cortex and cerebellum, and is part of a cerebello-thalamo-cortical tremor network.
• In this nonrandomized controlled trial, MRgFUS applied in a sample of TDPD and ET patients with substantial hand tremor.
• Patients underwent MRI scanning and tremor symptom assessment at baseline (one or two days before the intervention), one day after the intervention, as well as one month, six months, and 12 months later.

Results

• VIM lesioning through MRgFUS alleviates tremor.
• All patients demonstrated an alleviation of tremor in their target hand following the MRgFUS intervention assessed with the CRST (Fahn-Tolosa-Marin Clinical Rating Scale for Tremor) or Unified Parkinson’s Disease Rating Scale (UPDRS).
• Impact on mood and adverse effects.
  • Changes in depressive symptoms, as assessed with the Beck Depression Inventory (BDI). There was a significant decrease in BDI scores at 1 month and a marginally significant decrease at 12 months.
  • Adverse effects one month after treatment included gait disturbance in three patients (23%), and paresthesia or numbness in five patients (37%). At 6 months, one PD patient presented with inflexible movement and slow reaction in the target hand, and another exhibited slight limb shaking in the leg on the treated side. By 12 months, all of the adverse effects had resolved.

Conclusion

• High-intensity Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a recent, non-invasive line of treatment for medication-resistant tremor. We used MRgFUS to produce small lesions in the thalamic ventral intermediate nucleus (VIM), an important node in the cerebello-thalamo-cortical tremor network, in 13 patients with tremor-dominant Parkinson’s disease or essential tremor.
• Significant tremor alleviation in the target hand ensued (t(12) = 7.21, p < 0.001, two-tailed)
• Our results indicate that MRgFUS is a highly efficient treatment for tremor, and that lesioning the VIM may result in the reorganization of the cerebello-thalamo-cortical tremor network.

Deferiprone in Parkinsonism

Results

• Efficacy: From baseline to week 36, the mean MDS- UPDRS total score increased (worsened) more in the deferiprone group than in the placebo group.
• Safety: Serious adverse events occurred more frequently in the deferiprone group, as did progression of Parkinson’s disease.

Conclusions

• In participants with newly diagnosed Parkinson’s disease who had never received dopaminergic therapy, deferiprone did not slow disease progression and was associated with worsening of symptoms and adverse events. This unexpected outcome may have been due to interference with dopaminergic synthesis by deferiprone.

Levodopa Dose Equivalency in Parkinson’s Disease

Background

To compare drug regimens across clinical trials in Parkinson’s disease, conversion formulae between antiparkinsonian drugs have been developed.

These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as ‘levodopa equivalent dose’ (LED).

Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used.

However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010.

Therefore, there is a need for revised and updated LED conversion formulae based on a fresh systematic review of the current literature.

This was done to update LED conversion formulae based on a systematic review by The Medline, Central, and Embase databases, searched from January 2010 to July 2021.

Results:

• The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review.
• Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon.

Conclusions:

• The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD.

References:

1. Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O’Grady M, Meyer CJ. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb;89(2):212-225. doi: 10.1002/ana.25934. Epub 2020 Nov 5. PMID: 33068037; PMCID: PMC7894504.
2. Trial of Deferiprone in Parkinson’s Disease D. Devos, J. Labreuche, O. Rascol, J.-C. CorvoN Engl J Med 2022;387:2045-55. DOI: 10.1056/NEJMoa2209254.
3. Jost ST, Kaldenbach MA, Antonini A, Martinez-Martin P, Timmermann L, Odin P, Katzenschlager R, Borgohain R, Fasano A, Stocchi F, Hattori N, Kukkle PL, Rodríguez-Violante M, Falup-Pecurariu C, Schade S, Petry-Schmelzer JN, Metta V, Weintraub D, Deuschl G, Espay AJ, Tan EK, Bhidayasiri R, Fung VSC, Cardoso F, Trenkwalder C, Jenner P, Ray Chaudhuri K, Dafsari HS; International Parkinson and Movement Disorders Society Non-Motor Parkinson Disease Study Group. Levodopa Dose Equivalency in Parkinson’s Disease: Updated Systematic Review and Proposals. Mov Disord. 2023 Jul;38(7):1236-1252. doi: 10.1002/mds.29410. Epub 2023 May 5. PMID: 37147135.

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