The FDA published a summary pdf of Lecanemab the day before the accelerated approval day.
https://www.accessdata.fda.gov/drugsatf ... dacted.pdf
The 3 OLE Clarity fatalities that have been widely reported in the media were described in this pdf. Of interest, none of these patients on first reading would seem to have been directly related to Lecanemab treatment: None of these patients appeared to demonstrate ARIA on presentation to the hospital before treatment was started.
I was not clear what to make of these three fatalities reported for Lecanemab in the OLE.
It seemed that perhaps some newly emerging pattern related to Lecanemab treatment was unfolding. However from the below patient descriptions below this does not appear to be true.
The background for patient
[1]'s trajectory does not clearly indicate a connection to Lecanemab treatment.
There are so many other comorbidities that arose that it would be very difficult to ascribe a cause to the fatality.
Patient
[2] which has been discussed on forum is also not obviously caused by treatment. The imaging before tPA did not find the macrohemorrhages that occurred after tPA was administered.
The big surprise for me was the write-up for patient
[3]. On arrival to the hospital : "an MRI with and without contrast was reported as showing “no mass, no definite bleeding or edema or stroke”. This patient did not have
ARIA either?
None of these patients presented to the hospital with evidence of ARIA consistent with a side effect from Lecanemab?
pdf p. 32
301 Core and OLE ...
"12/1899 deaths (0.6%), none of which was preceded by documented ARIA, although 1 was an
intracranial hemorrhage (subject ) confirmed to be a
patient receiving placebo in a
December 14, 2022, response to an information request. There were no deaths reported in
studies 101, 104, 004, or ongoing study 303. One additional death in ongoing 301 OLE was
reported to the Agency on December 20, 2022 and reported in the journal, Science, on
December 21, 2022, and is described below.
... the Agency became aware of two additional deaths due to
intracerebral hemorrhage greater than 1 cm in the 301 OLE.
[1]
One event occurred in an 87-year-old male with a past medical history including atrial fibrillation, hyperlipidemia,
coronary artery disease, lacunar stroke, and cerebral microhemorrhage, with current
medications of donepezil, apixaban, and atorvastatin, as well as tamsulosin. The patient
sustained a fall on Day 77 after 6 doses of study drug, followed by pneumonia, COVID, and an
ulnar pseudoaneurysm treated with thrombin, and another fall from bed. A subsequent MRI
on Day 116 showed a left occipital intracerebral hemorrhage (> 1 cm). Apixaban was
stopped. This was followed by a myocardial infarction on Day 122 and TIA-like events on Day
126. The patient died on Day 144 due to the cardiopulmonary causes. ...
[2]
The second event occurred in a 65-year-old woman with MCI, homozygous for ApoE ε4, who
completed 301 Core on placebo and enrolled in 301 OLE. This case has been recently
published.23 Four days after the third dose of lecanemab, the participant was noted to have
garbled speech, and was taken to an emergency room. A CT of the head diagnosed a leftsided
ischemic stroke due to an LM3 occlusion. Tissue plasminogen activator (tPA) was
administered. Within 8 minutes after tPA she experienced a headache, and within 40 minutes
she became agitated. Repeat imaging showed bilateral intracerebral hemorrhage with
subarachnoid hemorrhage. The tPA was stopped and cryoprecipitate and tranexamic acid
were given for reversal of tPA. She was treated with Haldol for agitation and lorazepam and
Keppra for seizures. Her blood pressure was greater than 200 mmHg, for which she was
started on nicardipine infusion. Her encephalopathy worsened and she was intubated. MRI
performed 3 days after the CT scan showed extensive multicompartmental ICHs, innumerable
hematomas, SAH and right intraventricular hemorrhage with 5 mm leftward midline shift and
bilateral uncal herniation. At the patient’s directive, she was extubated and died eight days
after the last dose of study drug. A subsequent autopsy was reported to show extensive,
multi-focal intraparenchymal hemorrhage by gross pathology examination with microscopic
examination demonstrating AD neuropathologic change and widespread necrotizing
vasculitis involving blood vessels with cerebral amyloid angiopathy. Dr. Erten-Lyons notes
that a large vessel stroke, thrombolysis and cerebral amyloid angiopathy are all associated
with an increased risk of intracerebral hemorrhage which confound the ability to draw any
conclusions on causality.
[3]
An additional notable report of death in the 301 OLE (Mfr. Control No. :EC-2022-123944(0),
subject ), was submitted to FDA on December 20, 2022, and reported in the
journal, Science, on December 21, 2022.4 This was a 79 year old female with early
Alzheimer’s disease who completed 301 Core on placebo and was enrolled in the OLE in
. The patient was homozygous for ApoE ε4. The patient received 3 doses of
lecanemab 10 mg/kg every two weeks in the OLE. The last dose of study drug was
administered on . According to the CIOMS report, 1 week after the last
dose the subject experienced a sudden onset of difficulty speaking, staring into space, and
left side weakness, reported as a “possible CVA (cerebrovascular accident)” and “possible
seizure”. The subject was taken to an emergency department and was intubated and
hospitalized. An MRI with and without contrast was reported as showing “no mass, no
definite bleeding or edema or stroke”. A prior MRI from , was notable only for a
“a previously noted left parietal < 1 cm meningioma”. A seizure was suspected but no
definite seizure activity was noted. It was reported that the subject had never been on
anticoagulation during the study or in the hospital. The subject was extubated and 5 days
after the original event, developed respiratory distress and passed away. According to the
CIOMS report, the subject had risk factors for seizures, including underlying Alzheimer’s
disease, and for cerebrovascular disease, including advanced age, hyperlipidemia, aortic
atherosclerosis, chronic kidney disease, and prediabetes. According to the CIOMS form, an
autopsy was performed but results had not been reported to the investigator site.
Descriptions of brain bleeding and swelling, treatment of the event with steroids, and
multiorgan failure noted in the Science description, are not noted in the CIOMS form and
have not been submitted to the Agency for review. The Agency has requested that the
applicant provide additional information on the case, including MRI images and the autopsy
report. The applicant has not been able to obtain additional information as of January 3,
2023. The confirmation of the events reported in the Science article and their relationship to
study drug cannot be determined at this time; however, the available information does not
change the risk-benefit assessment for this review."