Author: Rachael Hansford

First patient dosed in Phase 3 study of oral cladribine in gMG

Posted on September 3, 2024 by - Myasthenia Gravis

  • MyClad is a global Phase III study evaluating the efficacy and safety of cladribine capsules for the treatment of generalized Myasthenia Gravis (gMG)
  • Cladribine capsules have the potential to be the first oral treatment for gMG patients
  • gMG is a rare, chronic autoimmune neuromuscular disorder that results in muscle weakness in the eyes, mouth, throat, and limbs

29 August, 2024: Merck has announced the first patient has been dosed in the Phase III MyClad trial (NCT06463587) evaluating the efficacy and safety of oral cladribine for the treatment of generalized Myasthenia Gravis (gMG).  Cladribine capsules have the potential to be the first oral treatment for gMG patients. gMG is a rare, neuromuscular disorder causing muscle weakness that can be severe and have a significant impact on patients’ lives.

Cladribine is expected to selectively target B and T lymphocytes. These cells are thought to be the root cause of gMG through the production of the harmful autoantibodies that drive inflammation at the connection points between nerves and muscles. This mechanism of action coupled with a short course oral dosing taken at home may ultimately slow the progression of the disease by targeting its underlying cause while diminishing treatment burden.

“Given our extensive experience in addressing patients’ needs in immune-driven neurological conditions, we believe that cladribine capsules represent a highly differentiated potential therapeutic option for gMG,” said Jan Klatt, Head of Development Unit Neurology & Immunology for the Healthcare business of Merck KGaA, Darmstadt, Germany. “This treatment approach holds the promise of achieving a high degree of disease activity control, offering greatly improved convenience, and ultimately enabling patients to live their lives as normally as possible.”

MyClad is a global Phase III, randomised, double-blind and placebo controlled study designed to assess the efficacy and safety of cladribine capsules in 240 patients with gMG. 

Tolebrutinib meets primary endpoint in HERCULES phase 3 study

Posted on September 2, 2024 by - Multiple Sclerosis

First and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis

  • In the HERCULES study, tolebrutinib met the primary endpoint in delaying time to onset of confirmed disability progression in people with nrSPMS, a population for which there are currently no approved therapies and significant unmet medical need
  • The GEMINI 1 and 2 studies evaluating tolebrutinib in people with relapsing MS (RMS) did not show significance in the primary endpoint of reducing annualised relapse rate over Aubagio (teriflunomide). Analysis of the key secondary endpoint of pooled 6-month confirmed disability worsening (CDW) data showed a considerable delay in time to onset
  • Phase 3 study results will form the basis for future discussions with global regulatory authorities
  • Study results will be presented at the ECTRIMS medical meeting, September 20

2 September 2024: Positive results from the HERCULES phase 3 study showed that tolebrutinib, Sanofi’s oral brain-penetrant BTK inhibitor, met the primary endpoint of improvement over placebo in delaying time to onset of confirmed disability progression (CDP) in people with non-relapsing secondary progressive MS (nrSPMS). In the HERCULES study, nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Preliminary analysis of liver safety was consistent with previous tolebrutinib studies.

Results from the GEMINI 1 and 2 phase 3 studies evaluating tolebrutinib did not meet the primary endpoint of reducing annualised relapse rate (ARR), compared to teriflunomide, in people with relapsing forms of multiple sclerosis. However, analysis of the key secondary endpoint of pooled 6-month CDW data showed a considerable delay in time to onset, which supports the CDP data observed in HERCULES.

The PERSEUS phase 3 study in primary progressive MS, evaluating time to onset of CDP, is currently ongoing with study results anticipated in 2025.

Study results for HERCULES and GEMINI 1 and 2 will be presented at the upcoming European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) medical meeting in Copenhagen, Denmark, September 20, 2024. Tolebrutinib is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority.

About GEMINI 1 & 2
GEMINI 1 (clinical study identifier: NCT04410978) and GEMINI 2 (NCT04410991) were randomised, double-blind phase 3 clinical studies evaluating the efficacy and safety of tolebrutinib compared to teriflunomide in participants with relapsing forms of MS. Participants were randomised in both studies (1:1) to receive either tolebrutinib and placebo daily or 14mg teriflunomide and placebo.

The primary endpoint for both studies was the annualised relapse rate for up to approximately 36 months defined as the number of confirmed adjudicated protocol defined relapses. Secondary endpoints included time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as an increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0, an increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5 or an increase of ≥0.5 point from the baseline EDSS score when the baseline score was >5.5 in addition to the total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from baseline through the end of study, the total number of Gd-enhancing T1 hyperintense lesions as detected by MRI from baseline through the end of study and the safety and tolerability of tolebrutinib.

About HERCULES
HERCULES (NCT04411641) was a randomised, double-blind phase 3 clinical study evaluating the efficacy and safety of tolebrutinib in participants with non-relapsing secondary progressive MS compared to placebo. nrSPMS was defined at baseline as having a SPMS diagnosis with an EDSS between 3.0 and 6.5, no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Participants were randomised (1:1) to receive either an oral daily dose of tolebrutinib or matching placebo for up to approximately 48 months.

The primary endpoint was 6-month CDP defined as the increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.0, or the increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included 3-month change in 9 hole peg test and T25-FW test, time to onset of 3-month CDP as assessed by EDSS score, total number of new or enlarging T2 hyperintense lesions as detected by MRI, change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test and by the California Verbal Learning Test as well as the safety and tolerability of tolebrutinib.

About tolebrutinib
Tolebrutinib is an investigational, oral, brain-penetrant, and bioactive Bruton’s tyrosine kinase (BTK) inhibitor that achieves CSF concentrations predicted to modulate B lymphocytes and disease-associated microglia. Tolebrutinib is being evaluated in phase 3 clinical studies for the treatment of various forms of multiple sclerosis and its safety and efficacy have not been evaluated by any regulatory authority worldwide. For more information on tolebrutinib clinical studies, please visit http://www.clinicaltrials.gov.

Ubrelvy can prevent migraines when used early

Posted on August 30, 2024 by - Headache

AbbVie’s Ubrelvy (ubrogepant) — which is approved to treat migraines – can also help to prevent them when used before the onset of headache pain, according to a recent study from Neurology journal. The phase 3 PRODROME Trial suggests that Ubrelvy was 73% more effective in preventing a migraine attack than a placebo.

In the trial, 518 patients who have had 2 to 8 migraine headaches per month for at least a year were instructed to take their medicine after receiving warning signals that an attack was on its way. The symptoms in the prodrome stage of migraine include fatigue, dizziness, visual aura, neck pain and sensitivity to light and sound.

In the first round of treatment—which included two migraine episodes over a period of two months—patients received a 100 mg dose of Ubrelvy or placebo. In a second round of testing, patients were provided with the treatment that they did not receive in the initial round.

After 24 hours, 65% of those who received Ubrelvy reported that they were either “not at all limited” or were “a little limited,” compared to 48% of placebo recipients who reported the same. Additionally, within two hours of dosing, patients who had taken Ubrelvy were 73% more likely to report “no disability, able to function,” than those on placebo.   

“Based on our findings, treatment with ubrogepant may allow people with migraine who experience early warning signs before a migraine occurs to quickly treat migraine attacks in their earliest stages and go about their daily lives with little discomfort and disruption,”

Richard Lipton, M.D., vice chair of neurology at the Albert Einstein College of Medicine in Bronx, N.Y.

Read headache articles in ACNR’s Headache Archives

Leqembi® (lecanemab) authorised for early Alzheimer’s disease in Great Britain

Posted on August 22, 2024 by - Alzheimer's Disease, Dementia

In Great Britain, lecanemab is indicated for the treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease (AD) in adult patients that are apolipoprotein E ε4 (ApoE ε4)* heterozygotes or non-carriers1

Great Britain becomes the first country in Europe to authorise the medicine, which targets an underlying cause of AD1

Authorisation based on data from the global Phase 3 trial, Clarity AD, which demonstrated that lecanemab slowed disease progression vs placebo at 18 months1,2

Eisai is working collaboratively with health technology assessment bodies and the National Health Service to support access for eligible patients

22 August, 2024 – Eisai Europe Ltd. and Biogen International GmbH have announced today that Leqembi® (lecanemab) has been granted a Marketing Authorisation (MA) by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain. Lecanemab is indicated for the treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease (AD) in adult patients that are apolipoprotein E ε4 (ApoE ε4)* heterozygotes or non-carriers.1 Great Britain is the eighth country in the world to grant MA, making lecanemab the first monoclonal antibody therapy for early AD (MCI and mild dementia due to AD)2 that targets amyloid-beta (Aβ) to be authorised in a country in Europe.1

The medicine was awarded an Innovative Licensing and Access Pathway (ILAP) passport by the MHRA in February 2023,3 as there is a significant unmet patient need for treatments that alter an underlying cause of the disease for people living with early AD.4 Lecanemab is a humanised Aβ monoclonal antibody that selectively binds to Aβ aggregate species with preferential activity for toxic Aβ protofibrils** (as well as fibrils, which are a major component of Aβ plaques).1,2,5,6 It binds to these aggregate Aβ species to neutralise and clear them from the brain.1,2,5,6

The approval was primarily based on Phase 3 data from Eisai’s global, placebo-controlled, double-blind, parallel-group, randomised Clarity AD clinical trial, in which the medicine met its primary endpoint (change from baseline in the Clinical Dementia Rating Sum of Boxes [CDR-SB]† at 18 months) and all key secondary endpoints with statistically significant results.2 In the indicated population in Great Britain, the most common adverse reactions were infusion-related reaction, amyloid-related imaging abnormalities with haemorrhage (small spots of bleeding) (ARIA-H)‡, fall, headache and amyloid-related imaging abnormalities with cerebral oedema (build-up of fluid) (ARIA-E)‡‡.1,2

“Today signals a significant moment for the AD community. We are now one step closer to eligible people in Great Britain receiving a much-needed new treatment option that can slow disease progression, as demonstrated through clinical trials, by targeting an underlying cause of Alzheimer’s disease for the first time,” said Gary Hendler, Regional Chairman and CEO, Eisai EMEA, Senior Vice President & Global Corporate Officer, Eisai Co. Ltd, Tokyo. “This could mean maintaining independence and the ability to continue daily activities and hobbies for as long as possible. We are proud that 40 years of AD research has led to this important milestone.”

“The authorisation of lecanemab in Great Britain marks a significant step forward in the pursuit of innovation for AD,” said Wolfram Schmidt, President, Head of Europe, Biogen. “We remain steadfast in our mission to further AD research and bring treatment options to patients.”

In the UK, it is estimated that 982,000 people are living with dementia,7  and AD is the cause in 60-70% of people with dementia.8 These numbers are expected to rise, as the population ages.7,8 People living with AD can experience loss of cognition, memory and independence, as well as psychological symptoms such as depression and anxiety.9 For care partners, witnessing the changes in their loved ones can be difficult and providing round-the-clock care can impact their own emotional well-being, employment and finances.7,9

Eisai is working collaboratively with the National Institute for Health and Care Excellence, the Scottish Medicines Consortium and the National Health Service (NHS) to make this medicine available to eligible people living with early AD in Great Britain as soon as possible.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercialising and co-promoting the product and Eisai having final decision-making authority. In Great Britain, Eisai and Biogen will co-promote the medicine, with Eisai distributing the product as the MA Holder.

*Apolipoprotein E is a protein involved in the metabolism of fats in humans. It is implicated in AD.

**Protofibrils are thought to be the most toxic Aβ species that contribute to brain damage in AD and play a major role in the cognitive decline of this progressive and devastating disease. Protofibrils can cause neuronal damage in the brain, which can subsequently adversely affect cognitive function through multiple mechanisms.10 The mechanism by which this occurs has been reported not only by increasing the formation of insoluble Aβ plaques, but also by directly damaging signalling between neurons and other cells. It is believed that reducing protofibrils may reduce neuronal damage and cognitive impairment, potentially preventing the progression of AD.11

†CDR-SB is a commonly used diagnostic tool, which can help to stage dementia due to AD.12 It is a global cognitive and functional scale that measures six domains of functioning, including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.12

‡ARIA-H: amyloid-related imaging abnormalities with haemorrhage (cerebral microhaemorrhages and superficial siderosis).

‡‡ARIA-E: amyloid-related imaging abnormalities with oedema (oedema/effusion).

References

  1. Lecanemab Great Britain Summary of Product Characteristics.
  2. van Dyck, H., et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2023;388:9-21. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948.
  3. Eisai. Internal correspondence with MHRA. 17 February 2023.
  4. Gov.UK. 2023. Guidance: Innovative Licensing and Access Pathway. Available at: https://www.gov.uk/guidance/innovative-licensing-and-access-pathway. Last accessed: August 2024.
  5. Johannesson, M., et al. Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer’s disease brains. Molecular and Cellular Neuroscience. 2024;130:103949. https://doi.org/10.1016/j.mcn.2024.103949.
  6. Sehlin, D., et al. Large aggregates are the major soluble Aβ species in AD brain fractionated with density gradient ultracentrifugation. PLoS One. 2012;7(2):e32014. https://doi.org/10.1371/journal.pone.0032014.
  7. Alzheimer’s Society. 2024. The economic impact of dementia. Available at: https://www.alzheimers.org.uk/about-us/policy-and-influencing/dementia-scale-impact-numbers. Last accessed: August 2024. 
  8. World Health Organization. 2023. Dementia. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia. Last accessed: August 2024.
  9. Koca, E., Taşkapilioğlu, Ö., Bakar, M. Caregiver Burden in Different Stages of Alzheimer’s Disease. Archives of Neuropsychiatry. 2017;54(1):82-86.
  10. Amin, L., Harris, D.A. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nature Communications. 2021;12:3451. doi:10.1038/s41467-021-23507-z.
  11. Ono, K., Tsuji, M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease. International Journal of Molecular Sciences. 2020;21(3):952. doi: 10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706.
  12. Morris, J.C. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412-2414.
  13. U.S. Food and Drug Administration. 2023. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Last accessed: August 2024.
  14. Reuters. 2023. Japan approves Alzheimer’s treatment Leqembi by Eisai and Biogen. Last accessed: August 2024.
  15. The Pharma Letter. 2024. Brief – Alzheimer drug Leqembi now approved in China. Last accessed: August 2024.
  16. Pharmaceutical Technology. 2024. South Korea’s MFDS approves Eisai-Biogen’s LEQEMBI for Alzheimer’s. Last accessed: August 2024.
  17. Pharmaceutical Technology. 2024. Hong Kong approves Leqembi for Alzheimer’s treatment. Last accessed: August 2024.
  18. BioSpace. 2024. Leqembi approved for the treatment of Alzheimer’s disease in Israel. Last accessed: August 2024.
  19. United Arab Emirates Ministry of Health & Prevention. 2024. Registered Medical Product Directory. Leqembi. Last accessed: August 2024.

CREXONT for Parkinson’s disease – Amneal’s capsules gain FDA approval

Posted on August 9, 2024 by - Parkinson’s Disease

August 8th 2024: The US Food and Drug Administration (FDA) has granted approval to Amneal Pharmaceuticals‘ CREXONT (carbidopa/levodopa) extended-release capsules for the treatment of Parkinson’s disease. This novel oral formulation combines immediate-release granules and extended-release pellets, meaning that therapeutic levels of levodopa and carbidopa may be maintained with less frequent dosing to maximise “good on” time, defined as time without troublesome dyskinesia.

Clinical Efficacy

In the pivotal RISE-PD phase III clinical trial, CREXONT demonstrated statistically significant improvements in “Good On” time compared to immediate-release CD/LD. Specifically:

  • Patients experienced an additional 0.5 hours of “Good On” time per day
  • CREXONT required only three daily doses versus five for immediate-release CD/LD
  • Post-hoc analysis revealed 1.6 hours of additional “Good On” time per dose of CREXONT

Pharmacological Profile

CREXONT’s formulation differs from RYTARY, another extended-release CD/LD product. The innovative combination of immediate-release granules and extended-release pellets aims to provide:

  • Rapid onset of action
  • Prolonged duration of effect
  • More consistent plasma levodopa levels

Safety and Tolerability

The safety profile of CREXONT was consistent with that of immediate-release CD/LD formulations. The most commonly reported adverse events were nausea and anxiety.

Clinical Implications

CREXONT represents a potential paradigm shift in PD management, offering:

  • Reduced dosing frequency (three times daily)
  • Extended “Good On” time
  • Potential for improved patient compliance and quality of life

Valiltramiprosate -oral Aβ-targeting therapy for Alzheimer’s disease

Posted on August 8, 2024 by - Alzheimer's Disease, Dementia

American clinical-stage biopharmaceutical company Alzheon has recently presented promising interim results from its Phase II Biomarker Trial (NCT04693520) of its oral, brain-penetrant, amyloid-oligomer inhibitor ALZ-801 (valiltramiprosate) at the American Academy of Neurology 2024 annual meeting. ALZ-801 has the potential to be the first oral Aβ-targeting therapy to be approved in the US and EU in early AD, according to GlobalData, a data and analytics company.

Erela Dana, Director of Neurology at GlobalData, comments: “Amyloid beta (Aβ)-targeting therapies hold promise, with this mechanism of action (MOA) recently seeing some success with the FDA’s approval of Biogen’s anti-Aβ monoclonal antibody (mAb) Aduhelm (aducanumab) in 2021, followed by Eisai/Biogen’s anti-Aβ mAb Leqembi (lecanemab) in January 2023.”

ALZ-801 is currently in Phase III, being evaluated for the treatment of apolipoprotein E 4 (APOE4) carrier patients with early AD.

Key opinion leaders (KOLs) previously interviewed by GlobalData highlight that the ALZ-801 target population of early AD patients, who are homozygous for the APOE4 allele, represent a subgroup that has a strong unmet need for novel disease-modifying approaches.

So far, the results over two years of treatment with ALZ-801 have been presented of the four-year open-label biomarker study. Overall, ALZ-801 treatment demonstrated sustained improvement over two years in plasma biomarkers, hippocampal volume, and cognitive effects in the target population. 

Dana comments: “There is a strong correlation between the biomarker outcomes and ALZ-801’s cognitive benefits. The presented biomarker results support the disease-modifying effects of ALZ-801 in APOE4 carriers with early AD with promising clinical efficacy and favorable safety, with no observed cases of amyloid-related imaging abnormalities related to underlying vasogenic edema (ARIA-E), a known side effect of the anti-Aβ mAbs, to date.”

Further to its Phase II biomarker study, Alzheon plans to announce the topline results of its APOLLOE4 (NCT04770220) Phase III trial in Q3 2024, with a potential NDA submission to the US FDA later this year.

Dana concludes: “Should Phase III outcomes follow the positive outcomes from the two-year Phase II biomarker data and support the hypotheses that by acting upstream of anti-Aβ mAbs, ALZ-801 could provide significantly improved amyloid clearance, it would pave the way for Alzheon to launch its AD asset in 2025 as the first oral anti-Aβ DMT in the US.”

First-in-class therapy Cebranopadol for treatment of pain

Posted on August 7, 2024 by - Pain

Results shared at International Association for the Study of Pain (IASP) 2024 World Congress on Pain demonstrate that cebranopadol produces potent and prolonged pain relief with 25% less respiratory depression and significantly slower onset of effect with fewer respiratory adverse effects compared to oxycodone

Findings highlight therapeutic potential of cebranopadol, an investigational treatment with a promising, new mechanism of action designed to fill treatment gaps as a novel alternative to opioids for moderate-to-severe pain

August 6th, 2024; Tris Pharma, Inc. (Tris), a commercial-stage biopharmaceutical company focused on attention deficit hyperactivity disorder (ADHD), pain, addiction and neurological disorders, has announced new clinical data demonstrating that cebranopadol, a dual nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonist, produces significantly less respiratory depression than oxycodone. The findings are highlighted in a poster session on August 7, 2024, at the International Association for the Study of Pain (IASP) 2024 World Congress on Pain in Amsterdam.

“The study findings offer clinically meaningful evidence that cebranopadol can provide effective and equal pain management with reduced potential of respiratory depression as compared to oxycodone,” said James Hackworth, Ph.D., president, brand division at Tris Pharma. “As a first-in-class, dual-NMR agonist in development to treat moderate-to-severe pain, cebranopadol has the potential to significantly reduce side effects associated with MOP-related agonism while simultaneously lessening MOP-related abuse potential and dependence. These new respiratory data add to the growing body of evidence that supports cebranopadol’s potential as a safer alternative to opioids, and we plan to initiate Phase 3 studies very soon.”

Mediated by activation of the MOP receptor, respiratory depression is a life-threatening complication that can occur following opioid administration. The clinical study being presented at IASP compared cebranopadol to oxycodone at supratherapeutic doses (i.e., doses that are greater than the therapeutic concentration). The trial specifically evaluated both cebranopadol’s and oxycodone’s impact on respiratory depression, ability to produce analgaesia, the potential presence of a ceiling effect for cebranopadol at higher doses, and the evaluation of significant respiratory depression using a model for testing ventilatory response to hypercapnia. In the double-blind, placebo-controlled study, investigators randomised 30 healthy volunteers over a four-week treatment period to receive cebranopadol, oxycodone or placebo.

Summary of key findings presented at IASP 2024

Findings shared in the IASP 2024 poster presentation titled “Cebranopadol effects on ventilatory drive, central nervous system, and pain,” demonstrate that NOP receptor activation with cebranopadol effectively attenuates respiratory depression and that its dual-NMR agonism produces potent, long-lasting analgaesia. Key study results include:

  • At equianalgesic doses, cebranopadol produces 25% less respiratory depression compared to oxycodone.
  • Treatment with cebranopadol presents a longer time to impact on respiratory parameters compared to oxycodone, allowing for the gradual accumulation of arterial CO2 and mitigating the full manifestation of respiratory depression.
  • Cebranopadol achieved prolonged analgesic effects with gradual onset and offset.
  • Despite having a longer duration of effect, cebranopadol produces fewer respiratory adverse events over 24 hours, including apnea, respiratory depression and oxygen saturation decrease, compared to oxycodone.

“The delayed onset of respiratory effects as evidenced in this study highlights the differentiating characteristic of cebranopadol to significantly reduce MOP-related side effects frequently experienced with opioids,” said study author Albert Dahan, M.D., Professor of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. “These results reinforce the safety profile of cebranopadol by demonstrating that it gives the body time to adjust its breathing, which in turn may aid in delivering both a safe and effective pain management solution to patients. Combined with data from previous clinical and preclinical studies of cebranopadol, these findings also suggest a ceiling of respiratory depression may exist in humans and bring us closer to offering a better therapeutic for acute and chronic pain.”

Alzheimer’s drug lecanemab rejected by EMA

Posted on July 30, 2024 by - Alzheimer's Disease, Dementia

On 25 July 2024 the European Medicines Agency (EMA) rejected a licence for lecanemab to treat Alzheimer’s disease.

The EMA said the benefits did not counterbalance the risk of serious side effects, especially bleeding and swelling in the brain.

The MHRA in the UK is still considering whether to grant a licence, and a decision is expected soon. The drug was approved in the United States earlier this year and has already been approved by regulatory authorities in China, Hong Kong, Israel, Japan and South Korea.

In trials, lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months.

Alzheimer’s researchers called the trial results “historic” because no previous drug had convincingly shown that the underlying mechanism of the disease could be slowed.

What were the main reasons for refusing the application?

The main study showed that after 18 months of treatment, the CDR-SB score in patients treated with Leqembi increased by 1.21 compared with 1.66 in those who received placebo. Although patients given Leqembi had lower CDR-SB scores than those given placebo, the difference between the two groups was small. EMA’s human medicines committee, the CHMP, considered that the observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious adverse events associated with the medicine.

The most important safety concern with Leqembi is the frequent occurrence of amyloid-related imaging abnormalities (ARIA), a side effect, seen in brain imaging, that involves swelling and potential bleedings in the brain. Although most cases of ARIA in the main study were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain which required hospitalisation. The seriousness of this side effect should be considered in the context of the small effect seen with the medicine.

In addition, the CHMP was concerned by the fact that the risk of ARIA is more pronounced in people who have a certain form of the gene for the protein apolipoprotein E called ApoE4. The risk is highest in people with 2 copies of the ApoE4 gene, who are known to be at risk of developing Alzheimer’s disease and would therefore be likely to become eligible for treatment with Leqembi.

In reaching its opinion, the CHMP also considered the views of a scientific advisory group on neurology, which included experts such as neurologists and people living with the disease.

Overall, the CHMP considered that the benefits of treatment are not large enough to outweigh the risks associated with Leqembi. Therefore, it recommended refusing marketing authorisation in the EU.

You might like this article: Imaging presymptomatic Alzheimer’s disease

Pridopidine for ALS – promising results

Posted on July 24, 2024 by - Amyotrophic Lateral Sclerosis (ALS)

At the 10th Congress of the European Academy of Neurology (EAN) 2024, Prilenia Therapeutics presented promising results from the additional analyses of Phase II Healey ALS Platform Trial evaluating pridopidine in ALS patients. The positive results will pave the way for the Phase III trial of pridopidine.

Developing disease-modifying treatments for amyotrophic lateral sclerosis (ALS) has proved challenging. The high failure rate in ALS clinical trials is often attributed to the disease’s unclear aetiology and complex pathophysiology.

Erela Dana, Director of Neurology at GlobalData, comments: “The Healey ALS Platform Trial aims to accelerate the path to approval for ALS drugs by testing drugs simultaneously and adoptively. Given the challenges in developing treatments for this disease, the platform trial is anticipated to find an effective therapy more quickly, with fewer total participants and fewer participants on placebo.”

Pridopidine is an oral sigma-1 receptor (S1R) activator currently in Phase III for the treatment of ALS. Key opinion leaders (KOLs) previously interviewed by GlobalData highlight that pridopidine is likely to be positioned as the potential add-on drug of choice for bulbar onset ALS patients due to the potential positive effects of the mechanism on speech and bulbar function.

Dana comments: “The results presented at EAN showed significant benefits in definite, probable, and early (<18mo) ALS patients at 24 weeks follow-up for ALSFRS-R Total, ALSFRS-R respiratory, bulbar, quality of life, and quantitative speech characteristics.”

Beyond the Healey trial, Prilenia also enrolled its first patient in the National Institutes of Health (NIH)-sponsored Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) expanded access protocol (EAP2) at the end of March 2024. Prilenia is planning to use the pre-specified and additional analysis data from the Healey Platform Trial to inform its pivotal Phase III trial to further evaluate the efficacy and safety of pridopidine beyond the ongoing EAP.

If the Phase III outcomes follow the positive outcomes from the Healey study, they will pave the way for pridopidine to become a key part of the treatment landscape for ALS patients with the bulbar onset form of the disease. – Erela Dana, Director of Neurology, GlobalData