High-Dose Aβ and Tau Immunotherapies Complete Initial Safety Tests
Part 3 of a three-part story.
Since Aβ passive immunotherapy emerged as a potential treatment for Alzheimer’s disease, drug developers have struggled with a major challenge—how to get enough antibody into the brain to have the desired effect without unleashing potentially dangerous inflammatory responses. Many antibodies tested in AD trials have caused amyloid-related imaging abnormalities on MRI scans. ARIAs reflect blood vessel damage, likely caused by microglial responses to the therapy. Reducing effector function, or the antibody’s ability to activate microglia, has emerged as a viable strategy, as was evident by two presentations at this year’s Alzheimer’s Association International Conference, held July 16–20 in London. Two other talks outlined safety data from two novel tau immunotherapies, which have also been tested at much higher doses than some of the early Aβ antibodies, such as gantenerumab.
Genentech’s Helen Lin reviewed long-term safety data from crenezumab, which is currently undergoing two Phase 3 trials called CREAD1 and CREAD2. Lin reviewed a Phase 1 trial designed to test the safety and tolerability of up to 120 mg/Kg crenezumab given intravenously. That’s higher than the 15 mg/Kg intravenous doses used in a prior Phase 2. This Phase 1 trial was a bridging study, said Lin, to help the researchers to determine how high they can dose in Phase 3 trials. Being an IgG4, a class of antibody with reduced effector function, crenezumab was expected to elicit less ARIA.
This high-dose Phase 1 recruited 50- to 90-year-old people with a diagnosis of mild to moderate AD. They had an MMSE of 18 to 28 or a CDR of 0.5 or 1.0., and a positive amyloid PET scan to ascertain AD was the reason for the cognitive symptoms. The volunteers were split into three cohorts, each of whom received placebo or drug once a week for four weeks. Crenezumab doses of 30 or 45 mg/Kg were given to 26 people in cohort 1. The 26 and 23 patients in the second and third cohorts each received either 60 or 120 mg/Kg, respectively, if on drug. At week 13, patients had the option of rolling over into an active extension trial at the same dose, except for those originally taking 120 mg/Kg, who continued with 60 mg/Kg. The high dose works out to 7,800 mg/week for a 65 Kg patient, or much higher than the 225 mg per month of gantenerumab given to patients in the failed Scarlet Road trials (Dec 2014 news).
The cohort studies are completed, and the active extension has begun, said Lin. Genentech designed the trial to test the lowest dose first. If no safety or toxicity concerns emerged, the next cohort was enrolled, and so on until the highest dose was tested. Lin said the majority of adverse events recorded during the 13-week blinded phase were unrelated to the drug. So far in the active extension there have been five adverse events that turned up in three or more individuals, but seem unrelated to drug dose, said Lin. These included anxiety, falls, and headache. Out of the 75 patients there have been nine serious adverse events. In general, the SAEs were consistent with those in the Phase 2 clinical trials, said Lin. One patient in each of cohorts 2 and 3 developed pneumonia, were treated, and continued in the trial. Some patients developed infusion site reaction, but these were mild and tended not to recur, said Lin. Again, these appeared unrelated to dose.
On MRI there were no cases of imaging abnormalities due to leaky blood vessels, called ARIA-E. ARIA-H, which are due to microhemorrhages, occurred in patients in cohorts 1 and 2, but they were asymptomatic and required no treatment said Lin.
Lin concluded that no dose-limiting toxicity was apparent from this trial. “This Phase 1 supports this idea at doses four times greater than used in the Phase 2 trial,” she said.
Thor Ostenfeld, AstraZeneca, Cambridge, U.K., outlined data from a Phase 1 trial of MEDI1814. This monoclonal antibody developed at MedImmune, which is now part of AstraZeneca, was designed to target Aβ42 and not Aβ40. An IgG1, its effector function has been reduced with a triple mutation in its Fc tail. In rats and monkeys, MEDI1814 increased total Aβ42 and decreased free Aβ42 in the CSF, without changing Aβ40 levels, said Ostenfeld.
The two-part Phase 1 trial tested the antibody in single and multiple ascending doses in patients with probable AD and an MMSE of 16 to 26. An MRI scan during screening had to be consistent with an AD diagnosis. In the first part, 45 volunteers received placebo or 25, 100, 300, 900, and 1,800 mg of MEDI1814 intravenously, or 100 mg subcutaneously, and were then followed for 16 weeks. In the multiple ascending dose part, 32 volunteers received either placebo, 300, 900, or 1,800 mg IV or 200 mg subcutaneously. Three doses were given at four-week intervals. Safety evaluations included an MRI at day 36 for the single dose, and day 92 for those on multiple doses.
Ostenfeld reported no serious adverse events. None of the 57 people on drug in either the SAD or MAD part of the trial had signs of either ARIA-H or ARIA-E. Ditto for changes in vital signs. About half the people on drug and 40 percent of those on placebo had adverse events, which included headache, dizziness, and diarrhea. “The overwhelming majority of adverse events were mild and resolved during the trial,” said Ostenfeld.
The plasma concentration of the antibody increased with dose in both the single and multiple dosing regimens, said Ostenfeld. The antibody reduced free Aβ42 in the CSF, to the point of almost completely eliminating this peptide at higher antibody doses. Total CSF Aβ42 increased, but there was no change in levels of Aβ40 in the CSF, in keeping with the drug’s proposed mechanism of action. Ostenfeld showed that subcutaneous administration also reduced free Aβ42 in the CSF.
Tau Antibodies Look Promising
Researchers from AbbVie/C2N and from Genentech outlined results from their Phase 1 trials tau antibodies. AbbVie 8E12 recognizes extracellular, aggregated tau; Genentech humanized RO7105705, a mouse monoclonal antibody, to also target tau in the extracellular space, hoping to block the spread of toxic forms.
The mouse version of AbbVie 8E12 reduced disease progression in tauopathy models, slowed brain volume loss, and improved performance in behavioral tests, noted Kumar Budur from AbbVie in North Chicago. He reviewed Phase 1 results in people with progressive supranuclear palsy and gave a brief overview of a Phase 2 AD trial.
AbbVie conducted the PSP study at 12 clinical centers in the United States. Single doses of 2.5 to 50 mg/Kg were injected intravenously and volunteers were tracked for three months for signs of clinical change. Volunteers had to have a diagnosis of possible or probable PSP with a PSP rating scale score between 20 and 50. They had to have an MRI scan consistent with the disease, and be able to walk at least five steps with minimal assistance, said Budur. People who had had symptoms for more than five years, or signs of another neurodegenerative disorder, were excluded. Of 38 patients screened, 30 enrolled and were randomized three to one drug to placebo, which worked out to seven on placebo and 23 on drug. Sixteen were men, the average age was 69, and PSP ratings score was 36. Nine people received 50 mg, while three received each of the other doses.
Adverse events occurred in 21 volunteers, including seven people on placebo. Five people each had dermatitis or a fall, and three each had headache or skin abrasions. Other AEs included fatigue and bacteria in the urine, which was asymptomatic. Budur described three serious adverse events. A patient on 15 mg/Kg suffered a subdural hematoma following a fall; however, this person had a history of falls, which are common in PSP patients, and this patient’s latest fall was likely unrelated to the treatment, Budur said. One person on 50 mg/Kg developed cardiovascular disease due to high blood pressure, which was also deemed unrelated to the drug. The third SAE, a case of increased agitation, was in a person who got 25 mg/Kg. Investigators thought this might be related to the treatment, though this person, too, had a history of anxiety and agitation during times of stress, including while undergoing medical procedures.
The antibody’s plasma half-life is 27 to 37 days, said Budur. Its maximal blood concentration increased with dose, and the CSF-to-plasma ratio was .18 to .35, said Budur.
In the ongoing Phase 2 trial for AD, Budur reported no evidence of dose-related adverse events. He said the pharmacokinetics and were similar to other antibodies. This trial is testing three doses of AbbVie 8E12, each in 100 people who have mild or probable AD against placebo in another 100 patients. Patients will be treated over 96 weeks with a 16-week follow-up period. Budur also said that AbbVie is recruiting for a Phase 2 trial in PSP. This multiple dose trial will recruit 180 people to evaluate safety and efficacy over 52 weeks, he said. Primary outcome measure will be change in PSP rating scale.
Geoffrey Kerchner from Genentech, South San Francisco, reviewed data from a Phase 1 trial of RO7105705. He said no adverse events had been detected in rats or monkeys in preclinical testing. The Phase 1 trial recruited healthy volunteers between ages 18 and 80, and patients with mild to moderate AD who were between 50 and 80. The AD patients had an MMSE of 16 to 28 and a positive brain amyloid scan. The trial tested escalating single doses in seven cohorts of healthy volunteers, then four weekly doses in healthy volunteers and AD patients. The single doses in healthy volunteers went from 225 to a whopping 16,800 mg. Kerchner noted a 15-day window between doses for safety evaluations. The drug was given intravenously or subcutaneously.
The last patient has completed the final clinic visit, said Kerchner, but as of his talk in London, results were still blinded. All Kerchner could say was that the antibody had generated no serious adverse events, and minor AEs unrelated to the drug included headache, respiratory tract infection, nausea, and vomiting. Nine volunteers experienced AEs attributed to the drug, including bruising and pain at the injection site.
Kerchner said the antibody’s half-life in plasma was 32 days, which is on par with other antibodies. Both plasma and CSF concentration increased with dose.—Tom Fagan
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