Conference Coverage

Bryostatin Is Safe in Patients With Moderate to Severe Alzheimer’s Disease

Preliminary trial data suggest that the drug may provide sustained cognitive improvement.


LONDON—Bryostatin is safe and tolerable in patients with moderate to severe Alzheimer’s disease, according to the results of a phase II study presented at the 2017 Alzheimer’s Association International Conference. The drug also may provide sustained improvements in cognition and activities of daily living. The study results provide grounds for future trials with longer treatment durations to assess bryostatin’s efficacy, said Martin R. Farlow, MD, Vice-Chairman for Research in the Department of Neurology at Indiana University School of Medicine in Indianapolis.

Martin R. Farlow, MD

Bryostatin activates protein kinase C ε (PKCε), an enzyme that promotes synaptogenesis and learning. Preclinical studies indicate that bryostatin enhances synaptogenesis, inhibits apoptosis, reduces amyloid plaque formation, and inhibits tau phosphorylation. In transgenic mouse models of Alzheimer’s disease, bryostatin improved learning and memory retention. The drug has a novel, potentially regenerative mechanism of action, compared with other therapies for Alzheimer’s disease.

An Improvement Over Standard of Care?

Dr. Farlow and colleagues conducted a phase II trial to assess the safety and tolerability of bryostatin. Eligible patients had advanced Alzheimer’s disease with a Mini-Mental State Exam (MMSE) score of between 4 and 15. Participants were receiving stable standard-of-care therapy with cholinesterase inhibitors, memantine, or both. In the double-blind study, the researchers randomized participants to 20 mg of bryostatin, 40 mg of bryostatin, or placebo. Participants received IV treatment every other week for 12 weeks. Investigators evaluated patients at weeks 5, 9, and 13.

The trial’s secondary objectives were to assess drug dosing and to evaluate bryostatin’s efficacy at week 13. The primary efficacy measure was the Severe Impairment Battery (SIB), and the secondary efficacy measure was the Alzheimer’s Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV).

In all, 49 participants received 20 mg of bryostatin, 48 received 40 mg of bryostatin, and 50 received placebo. Participants’ mean age was 71.6, and mean MMSE score was 10.2. Approximately 52% of participants were women, and the study arms were well balanced. Eight patients in the 20-mg group, 18 patients in the 40-mg group, and nine controls withdrew from the study. Withdrawal of consent in the 40-mg group accounted for the majority of study withdrawals.

Lower Dose Had Greater Tolerability

The rate of treatment-emergent adverse events was 65% in the 20-mg group, 83% in the 40-mg group, and 58% among controls. Myalgia was more common in the 20-mg group (2%) and the 40-mg group (9%) than among controls (0%). Infusion-site reactions occurred in 6% of controls, 17% of the 20-mg group, and 15% of the 40-mg group. The rates of decreased appetite, decreased weight, and falls were similar in the 20-mg group and controls, but higher in the 40-mg group.

In the modified intention-to-treat (mITT) analysis, the difference from controls in SIB at week 13 was 1.9 in the 20-mg group and 0.8 in the 40-mg group. Among participants who completed the study, the difference from controls in SIB at week 13 was 2.6 in the 20-mg group and 1.5 in the 40-mg group. Improvement in SIB for the 20-mg group, compared with controls, was apparent by week 5. This improvement persisted through week 13.

In the mITT analysis, the difference from controls in ADCS-ADL-SIV at week 13 was 1.4 in the 20-mg group and 0.8 in the 40-mg group. Among participants who completed the study, the difference from controls in ADCS-ADL-SIV at week 13 was 1.6 in the 20-mg group and 1.1 in the 40-mg group.

Daniel Alkon, MD

The drug’s biochemistry explains these results, according to Daniel Alkon, MD, President and Chief Scientific Officer of Neurotrope Bioscience, the company that is developing bryostatin. Upon administration, bryostatin first triggers a brief period of activation of PKCε, followed by downregulation of PKCε, and finally de novo synthesis of PKCε. “If you give a high enough dose, you can actually trigger so much downregulation that it overwhelms the activation,” said Dr. Alkon. The 40-mg dose appeared to trigger more downregulation in humans than it had in animals, thus establishing a maximum dosing limit. Previous biochemical studies have shown that bryostatin’s synaptogenic benefits can outlast brief periods of PKCε activation by hours.

The number of patients studied was suitable for assessing safety, but the length of the trial was insufficient for assessing efficacy, said Dr. Farlow. “IV administration obviously is not ideal,” and subcutaneous injection or oral administration could improve the compound’s clinical utility, he said.

“With a safe dose that did show evidence of a sustained benefit for these patients, we are encouraged to optimize dosing further in our next trials,” said Dr. Alkon. “We are hoping that we get not only a larger improvement with further optimization and with fewer drugs already on board (that could interfere with bryostatin efficacy), but a much more prolonged improvement.”

Erik Greb

Suggested Reading

Hongpaisan J, Sun MK, Alkon DL. PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci. 2011;31(2):630-643.

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