Dr. Marwan Sabbagh: “It is exciting to see efficacy of potential new drugs for DLB, the most common dementia after Alzheimer’s. It is a huge area of unmet need.”
EIP Pharma, Inc. (www.eippharma.com), a CNS-focused therapeutics company, provided the full results of the Phase 2 AscenD-LB study in patients with mild-to-moderate dementia with Lewy bodies (DLB) during an oral presentation at the 13th Clinical Trials in Alzheimer’s Disease (CTAD) meeting.
The study met the primary endpoint with significant, clinically-relevant effect size improvement in cognition in patients receiving neflamapimod 40mg three times daily (TID) compared to those receiving either placebo or neflamapimod 40 mg twice daily (BID), as assessed by a Neuropsychological Test Battery (NTB) designed to evaluate attention and executive function.
Neflamapimod is an investigational drug that is a brain-penetrant, oral small molecule that inhibits the intra-cellular enzyme p38 MAP kinase alpha (p38α). P38α, which is expressed in neurons under conditions of stress and disease, plays a major role in inflammation-induced synaptic toxicity, leading to impairment of synaptic function.
Synaptic dysfunction is known to be a major drive of the deficits in cognitive function that are defining characteristics of many CNS diseases.
Results of a 161-patient, 24-week treatment double-blind placebo-controlled study of neflamapimod in early Alzheimer’s Disease (AD) were reported at the 12th CTAD meeting in December 2019, and further at the AAT-AD/PD™ Focus Meeting in April 2020.
In the early AD study, neflamapimod demonstrated target engagement, with significant reduction relative to placebo in CSF p-tau and tau; and suggested that cognition was improved in the patients with the highest quartile of plasma drug concentrations.
Significant improved outcomes
The positive effect of the neflamapimod as seen on the Neuropsychological Test Battery (NTB) was evident at week 4 and was maintained throughout the 16-week study period.
Multiple sensitivity analyses (with or without imputation of any missing data) support the primary analysis, demonstrating significantly improved outcomes on the NTB in the neflamapimod TID patients compared to those receiving placebo.
Analyses of secondary endpoints further support that the cognition effects of neflamapimod TID are clinically meaningful, with a statistically significant clinically relevant effect on the Timed Up and Go Test and encouraging positive trends on the 10-item Neuropsychiatric Inventory (NPI-10), particularly with respect to hallucinations, and on the Clinical Dementia Rating Sum-of-boxes (CDR-SB).
Throughout the study, neflamapimod was well tolerated.
May become first approved DLB therapy
“The demonstrated positive effects on the AscenD-LB study’s primary endpoint, cognition, and as well as on a number of secondary endpoints, establishes proof-of-concept for neflamapimod as a possible treatment for patients with Dementia with Lewy Bodies.
“If these findings are confirmed in Phase 3 clinical studies, neflamapimod could potentially become the first approved therapy for this devastating disease,” said Stephen Gomperts, MD, PhD, Director of the Lewy Body Dementia Unit and Assistant Professor of Neurology at Massachusetts General Hospital, and an investigator in the AscenD-LB study.
“DLB is not only the second most common neurodegenerative dementia but is also associated with substantial reduction of patient quality of life and high caregiver burden.”
Neflamapimod was very well tolerated with no treatment discontinuation due to study drug-related adverse events. There were ten early treatment discontinuations, four due to intercurrent medical illness (two each in placebo and neflamapimod BID recipients) and six due to withdrawal of consent and/or disease worsening (two in placebo and four in neflamapimod BID).
There were four serious adverse events (SAEs) reported in the placebo group and three in neflamapimod BID recipients, all of which were considered unrelated to study drug administration. There were no SAEs or early treatment discontinuations amongst neflamapimod TID recipients.
Treatment-emergent adverse events (TEAEs) considered possibly-related (“related”) to study drug were reported in 29 percent of placebo-recipients, 31 percent of neflamapimod BID and 35 percent of neflamapimod TID recipients.
All related TEAEs were mild or moderate in severity, with 73 percent being mild. Related TEAEs reported in more than one subject in the study were headache (placebo 1 subject, neflamapimod BID 1 subject, neflamapimod TID 3 subjects), diarrhea (3, 0, 1) and nausea (1, 2, 0).
Received Fast Track designation
“It is exciting to see efficacy of potential new drugs for Lewy Body Dementia,” said Marwan Sabbagh, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health. “It is a huge area of unmet need.”
“We are very grateful to the study participants in AscenD-LB and their caregivers for their persistence and commitment, especially through the restrictions imposed by Covid-19, and to study site staff and the clinical study operations team, who all together brought this important clinical trial to a successful completion,” said John Alam, MD, CEO of EIP Pharma, who presented the results at a late-breaker session during the meeting.
Neflamapimod as a treatment for DLB received Fast Track designation from the Division of Neurology Products at the U.S. Food and Drug Administration in November 2019.
About Dementia with Lewy Bodies
Dementia with Lewy Bodies (DLB) is a serious disease representing 15 to 20 percent of the dementia population, with an estimated 700,000 to 1 million affected individuals in the US.
DLB is characterized by progressive dementia and fluctuating cognition (particularly deficits in attention), visual hallucination, parkinsonism (tremor and gait disturbances) and sleep disturbances.
The quality of cognitive impairments seen in the early stages of DLB is different than that of other dementias such as AD. Memory recall remains intact until later stages, but attention, executive function, and visuospatial skills are prominent in mild-to-moderate DLB, and the first to decline.
Patients with DLB incur higher healthcare costs, have longer hospitalizations, report lower quality of life, and have caregivers with higher levels of distress when compared with patients with AD.
There are no treatments for DLB that have been approved by the US FDA or European Medicines Agency thus far.
Phase 2 AscenD-LB Study Results
AscenD-LB was a Phase 2 double-blind, placebo-controlled, 16-week treatment proof-of-concept study (“AscenD-LB”) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB) conducted at 22 centers in the United States and two centers in the Netherlands. 91 patients were enrolled between October 2019 and March 2020 and randomized to receive 40 mg neflamapimod capsules or matching placebo capsules (randomized 1:1) for 16 weeks.
The dosing regimen was based on weight, with study participants weighing less than 80 kg receiving capsules twice daily (BID) and those weighing greater than or equal to 80 kg receiving capsules three times daily (TID). All patients had to have already been receiving oral cholinesterase inhibitor therapy for at least 3 months (stable dose for greater than 6 weeks) and continued such therapy without dose modification during the study. The AscenD-LB study is registered at clinicaltrials.gov as study NCT04001517.
Primary Endpoint Results
The primary endpoint was a study-specific Neuropsychological Test Battery (NTB) that was designed to primarily evaluate attention and executive function. The NTB was comprised of four computerized tests from the Cogstate® battery (Detection, Identification, One Card Learning, One Back) and two tests recorded on paper (Letter Fluency, Category Fluency).
The NTB was assessed at baseline, week 4, week 8 and week 16. The NTB was analyzed as a composite in which the individual tests were equally weighted. Per the Statistical Analysis Plan, the primary statistical analysis approach was linear Mixed effects Model for Repeated Measures (MMRM) utilized with all available data for the modified ITT efficacy population (i.e. subject with at least one on-treatment NTB evaluation). The results of these analyses and secondary/sensitivity analyses are shown in the table below.
Due to pandemic-related restrictions imposed on the ability to see patients at many of the clinical sites from March to May 2020, approximately 25 percent of the site visits were conducted remotely via telephone or video chat. The majority of such remote visits occurred at week 8.
To assess the impact of missing tests due to remote monitoring, all primary endpoint analyses were performed both without imputation of that missing data (i.e. “observed data”) and with imputation by last observation carried forward (LOCF). The LOCF analysis, which for the pre-specified analysis was secondary, was considered applicable and relevant since the effect of the drug was seen as early as week 4 and because the missing data was not due to patient discontinuation but rather to the impossibility to perform all in person tests at each patient visit.
Exploratory analysis of the results from individual tests and alternative composites derived from the individual tests (e.g. attention composite, executive function composite) indicate that the positive effect on the primary endpoint was driven primarily by the effects of neflamapimod on attention (MMRM analysis of attention composite: p=0.023 for neflamapimod vs. placebo, MMRM effect size = 0.41).
Secondary Endpoint Analyses
Analyses of secondary endpoints are supportive and in line with the primary endpoint observations and suggest that the effect of neflamapimod TID on cognition has a clinically meaningful impact on function:
- Timed Up and Go (TUG) Test. Performed at baseline, weeks 8 and 16. At baseline, the mean time required for completing the TUG was approximately 13 seconds and balanced between placebo and neflamapimod recipients. MMRM analysis of the on-treatment results demonstrated significant improvement in neflamapimod TID recipients compared to placebo recipients (p=0.03, effect size = 0.50). From baseline to week 16, the mean time required to complete the tests decreased (i.e. improved) by 1.4 (+/- 1.0) seconds in the neflamapimod TID group and increased (i.e. worsened) by 1.5 (+/- 0.9) seconds amongst placebo recipients.
- 10-item NeuroPsychiatric Inventory (NPI-10). Performed at baseline, weeks 4, 8 and 16. The on-treatment results demonstrated encouraging trends in neflamapimod TID recipients compared to placebo recipients, with numerically greater mean improvement from baseline at each study visit in the neflamapimod recipients. Within the NPI sub-categories, hallucination scores were reported on at least one occasion in 36 patients. Within that group, an improvement on hallucination severity was seen in neflamapimod TID over neflamapimod BID and placebo (Jonckhere-Terpstra statistic improvement in neflamapimod TID > neflamapimod BID > placebo, p< 0.1 at each of week 4, 8 and 16).
- Clinical Dementia Rating Sum of Boxes (CDR-SB). Performed at baseline, weeks 8 and 16. Jonckheere-Terpstra trend analysis of improvement in neflamapimod TID > neflamapimod BID > placebo demonstrated positive trends at both week 8 (p=0.07) and week 16 (p=0.19). CDR-SB is a test that best measures differences in progression of the disease. In this 16-week study, patients in the placebo group did not measurably progress.
EIP Pharma, Inc. is a private, Boston, MA-based company advancing CNS-focused therapeutics to benefit patients with neurodegenerative diseases.