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Neflamapimod Shows Promising Phase 2b Extension Data in Dementia With Lewy Bodies
Key Takeaways
- Newly formulated neflamapimod capsules showed significant clinical benefits in DLB patients, improving CDR-SB and CGIC scores compared to old capsules and placebo.
- The new formulation achieved higher plasma drug concentrations, attributed to improved dissolution kinetics, and demonstrated a lower incidence of falls.
Participants who received the new batch of capsules during the extension phase experienced a lower incidence of falls compared with those taking the old capsules or placebo.
James E. Galvin, MD, MPH
(Credit: Miami Miller School of Medicine)
According to a recent company update from CervoMed, positive results from the first 16 weeks of the extension phase of the phase 2b RewinD-LB study (NCT05869669) of neflamapimod showed that treatment with newly formulated neflamapimod capsules demonstrated significant clinical benefits in patients with dementia with Lewy bodies (DLB) compared with an old batch and placebo.1 Presented at the 8th International Lewy Body Dementia Conference, these results suggest that neflamapimod has the potential to positively impact the course of DLB, particularly with its new formulation.2.3
To analyze the change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB), the primary end point of the initial phase, the study employed a linear mixed-effects model for repeated measures. From the end of the initial phase through week 16, the change in CDR-SB was shown to be significantly lower in the new capsule group compared with the old capsule group (difference = -0.73; 95% CI, -1.14 to -0.32; P <.001).
When analyzed from the overall baseline through week 16 of the extension, the new capsules showed a positive effect compared with placebo (difference = -0.45; 95% CI, -0.78 to -0.15; P = .003). This effect was more pronounced in participants with plasma ptau181 levels below 2.2 pg/mL, a threshold linked to Alzheimer disease-related copathology identified in the phase 2a study.
"I was very pleased to review the findings of the 16-week timepoint for the open-label extension. While it was disappointing to see that the double-blind phase of the trial failed to meet its outcomes, further analyses of the trial suggested that the measured plasma drug levels did not reach sufficient concentrations to see an effect. It is believed that this was due to the age of the capsules used in the double-blind phase,"coprincipal investigator James E. Galvin, MD, MPH, professor of neurology at the Miller School of Medicine in Miami, told NeurologyLive in a recent interview.
"In the open-label extension a new capsule formulation was used and reached the targeted mean trough plasma concentration," Galvin added. "As the open-label extension contained 55 people on the old formulation and 94 people on the new formulation, differences in primary outcomes were able to be detected comparing new vs old capsules on the CDR-SB supporting slowed progression. This was even more prominent in individuals that had plasma ptau181 levels below 2.2 pg/ml. A similar result was also seen in the global impression of change (ADCS-CGIC)."
Of the 159 participants originally enrolled in the first 16-week double-blind, placebo-controlled phase of the study, 152 completed this initial phase, and 149 participants continued on to the extension phase, where all received neflamapimod. Although participants and site staff knew that everyone in the extension phase received the same treatment, they were unaware of which batch of capsules was given during the first 16 weeks of the extension.
Among the 149 who transitioned to the extension, 55 participants received the same batch of capsules used in the initial phase, and 94 received a new batch, either throughout the extension or starting at different points: 46 from day 1, 22 from week 4, and 26 from week 8. Completion rates for the first 16 weeks of the extension were 87.3% for the old capsule group and 91.5% for the new capsule group.
"There are currently no approved therapies in the US for DLB and for the more than 1.5 million patients living with the disease, this is a great unmet need. The results of the Phase 2b open-label extension help explain the lack of findings from the Phase 2b double-blind phase, and replicate the positive findings from the Phase 2a study. This gives great hope for a Phase 3 study that if positive could provide a route for a potential disease-modifying treatment for DLB," Galvin told NeurologyLive.
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At week 8 of the extension, the new capsules led to a significantly improved Clinical Global Impression of Change (CGIC) score (4.02 vs. 4.46 with old capsules; P = .035), indicating a lesser degree of clinical worsening. A larger difference was observed in participants with lower plasma ptau181 (< 2.2 pg/mL)(3.90 with new capsules vs. 4.45 with old capsules; P = .011). Furthermore, a within-subject analysis revealed that participants who switched from placebo in the initial phase to new capsules in the extension had a reduced CGIC score compared with those who had been on placebo throughout (3.94 vs. 4.46; P = .035).
John Alam, MD
(Credit: CervoMed)
“We, along with our clinical investigators, were certainly very excited by these findings. DLB is a devastating disease for which there are no approved therapies, and we believe these findings demonstrate the potential neflamapimod could offer these patients, their caregivers and their families. At the same time, we are not surprised," coprincipal investigator John Alam, MD, CEO at CervoMed, told NeurologyLive in a recent interview. "The consistency and magnitude of these results are in line with the results observed in our earlier Phase 2a study, and from that perspective re-affirms the confidence we’ve had in neflamapimod as a potential treatment from DLB for some time now."
Both old and new capsules had similar tolerability profiles, with no new safety concerns raised during the extension phase. The rate of falls was lower in the new capsule group compared with the old capsule group during the extension (7.4% vs. 14.5% for all participants; 4.0% vs. 15.4%; P = .025, for participants with plasma ptau181 < 2.2 pg/mL). Additionally, participants who received new capsules had a lower incidence of falls compared with those who had received placebo in the initial phase (7.4% vs. 18.8% for all participants, P = .04; 4.0% vs. 19.7%; P = .007, for participants with plasma ptau181 < 2.2 pg/mL).
As previously reported, a within-subject comparison (n = 13) found that plasma drug concentrations were significantly higher with the new capsules (5.1 ng/mL vs. 4.0 ng/mL; P = .03) than with the old capsules. Analysis suggests the lower bioavailability of the old capsules was because of the aging of the capsules, which led to suboptimal dissolution kinetics, rather than chemical degradation.
“To date, there is not a single drug approved in the U.S. or E.U. for the management of DLB which creates an enormous unmet medical need, and the comments in our initial announcement from Drs. James Galvin and John-Paul Taylor – two of the preeminent thought leaders in the DLB space – underscore the degree to which an effective treatment would be a game-changer for DLB patients and their families," Alam said. "We look forward to completing the extension phase of the RewinD-LB study later this year and are excited to finalize our Phase 3 plans and move neflamapimod forward into the next phase of development."
