Buntanetap Improves Motor, Nonmotor and Cognitive Symptoms of Parkinson Disease in Phase 3 Study

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Over the 3-year treatment period, buntanetap resulted in improvements in motor and nonmotor functions in patients with postural instability and gait difficulty, a group with faster disease progression.

Maria Maccecchini, PhD, founder, president, and chief executive officer at Annovis

Maria Maccecchini, PhD

Newly announced data from a phase 3 study (NCT05357989) of patients with Parkinson disease (PD) showed that treatment with investigational buntanetap was safe and well tolerated, with noted improvements in motor and nonmotor activities, as well as cognitive function. Buntanetap, formerly known as Posiphen or ANVS401, targets neurodegeneration by inhibiting amyloid-ß, tau, alpha-synuclein, and TDP-43.1

In patients diagnosed with PD for longer than 3 years, use of buntanetap resulted in measurable declines in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II, III, and II+III, as well as Total scores compared with placebo and baseline. Those with diagnosis of less than 3 years had minimal or no deficits in MDS-UPDRS Part 2, for which the authors claimed it was a challenge to measure improvement and treatment effectiveness.

The study featured 450 individuals with PD, aged 40-85 years, who were assigned to either low- or high-dose buntanetap or placebo, for a 3-year period. Overall, more pronounced effects were observed in the higher, 20-mg dose cohort of the therapy. On MDS-UPDRS Part II+III, the 20 mg group with at least 3 years since diagnosis demonstrated changes of nearly –4 points of improvement whereas those in the 10 mg group showed minimal change and those on placebo worsened. Notably, both the 10 mg buntanetap and placebo groups showed worsened scores on MDS-UPDRS Part II while those in the higher dose buntanetap group experienced improvements of nearly –1 point from baseline.

"We are very pleased to see improvements in many of our patients over such a short course of treatment," Maria Maccecchini, PhD, founder, president, and chief executive officer at Annovis, said in a statement.1 "These compelling data reinforce our commitment to advancing buntanetap into a longer study, which will allow us not only to verify observed symptomatic improvements but also to explore buntanetap’s disease-modifying properties."

Patients included in the study had Mini-Mental State Exam (MMSE) scores between 20-30, with a small subgroup (12%) considered to have mild dementia, defined by scores between 20-26. In the entire enrolled population, those on placebo showed cognitive worsening throughout the trial in comparison with the buntanetap dosed groups, which maintained baseline levels, indicating a statistically significant effect in stopping cognitive decline.

In the subgroup of patients with mild dementia, cognition deteriorated at a faster pace in the placebo group compared with those on 10 mg buntanetap. Moreover, the 20 mg buntanetap group showed significant improvement in cognition compared with placebo.

Results also revealed that buntanetap resulted in improved motor and nonmotor PD-related functions in patients with postural instability and gait difficulty (PIGD), a phenotype of PD considered to have faster disease progression. Overall, those treated with the active agent demonstrated significant enhancements in MDS-UPDRS Part II, Part III, Part II+III, and Total scores. In addition, the therapy showed a safety profile that was consistent with prior data, including a previously completed study of patients with Alzheimer disease.

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In its announcement, Annovis provided clarification on the primary and secondary end points of the study, noting that MDS-UPDRS Part II alone was deemed sufficient for reflecting clinical relevant changes by the FDA. Consequently, the company adjusted its primary end point to MDS-UPDRS Part II, with MDS-UPDRS Part III as a secondary end point after originally choosing MDS-UPDRS Part II+III as the primary end point. All told, the therapy met both its primary and secondary end points in specified subgroups.

The study was actually completed in late 2023 with an original plan for data announcement in Q1 of this year; however, Annovis faced a delay in the process of data cleaning beyond the original prognosis. In a company announcement in May, Maccecchini stated that "too many samples showed no presence of buntanetap. We were expecting 33% blank samples from the placebo group, but we saw over 50% blank samples. We were afraid that we had mixed up bottles and that patients weren’t given what they were supposed to. If that had happened, the study would have been worthless."2

She added, "We promptly started searching for a possible explanation at every step of the way. We checked the content of the bottles – correct. We checked the distribution of the bottles – correct. We checked the labeling of the plasma samples – correct. We checked the distribution of the plasma samples – correct. So, we were left with the pharmacokinetic (PK) measurements. PK is measured by LC-MS/MS with a very expensive set of equipment under GLP, GCP, GMP, and is regulated by very strict FDA rules. It turns out that the group, which was evaluating the PK, modified the method, unfortunately affecting the measurements. We repeated the PK of the same samples and obtained an expected 33% of blank samples accounting for placebo."

Buntanetap was previously assessed in a phase 2/3, dose-ranging study (NCT05686044) of patients with mild to moderate AD who had MMSE scores between 14 and 24. At the end of 3 months of treatment, all 3 buntanetap treatment groups showed statistically significant improvement in ADAS-Cog11, the primary end point, from their corresponding baseline (7.5 mg: improved 2.19 [SE, 0.87]; P = .013; 15 mg: 2.79 [SE, 0.81]; P = .001; 30 mg: 3.32 [SE, 0.82]; P <.001). Both the 15 mg and 30 mg treatment groups also showed a statistically significant improvement relative to placebo (P = .042 and 0.015, respectively). Notably, there was a 3-fold difference in the proportion of participants to who improved in the 30 mg group relative to placebo.3

In accordance with the mechanism of action of buntanetap, the investigators observed a reduction in plasma total tau after treatment, providing further credence to the agent’s efficacy and mechanism of action. At the time of the data announcement, the company noted it will report back to the FDA and ask for an end-of-phase 2 meeting. Encouraged by the results, Annovis is planning an 18-month phase 3 trial focusing on biomarker-positive patients with early AD to further validate the therapy’s efficacy and safety profile.

REFERENCES
1. Annovis Bio Announces New Data from Phase III Parkinson’s Study Highlighting Improvements in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Cognition after Treatment with Buntanetap. News release. Annovis Bio. July 2, 2024. Accessed July 2, 2024. https://finance.yahoo.com/news/annovis-bio-announces-data-phase-120000626.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAALLdejMT0pyJypredPI7ZZagv285BLnCp1-g-bqv0l7gWvqgw_db9mrVwGFPDOv0Lwu8w7MTx_2yjwV7ewkzMiHNv0I7XhVM0uAwBDDcsZl4NthGbvOL_BUY1TgYVao4EGlGKDo9MluShAKHRbLDrK_6u4ckEK8vA6h_Vgomvo26
2. Annovis announces unblinding of the buntanetap phase 3 data in Parkinson’s disease. News release. Annovis Bio. May 9, 2024, Accessed July 2, 2024. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=2e909c76-e081-4e80-ac65-848183a83a9d
3. Annovis Bio announces statistically significant phase 2/3 data in patients with early Alzheimer’s disease. April 29, 2024. Accessed July 2, 2024. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=7f4c17db-2a47-4e91-8059-8d07dae9de11
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