Lecanemab approved!

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J11
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Lecanemab approved!

Post by J11 »

Yeah!
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Re: Lecanemab approved!

Post by J11 »

FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment


Today, the U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease. Leqembi is the second of a new category of medications approved for Alzheimer’s disease that target the fundamental pathophysiology of the disease. These medications represent an important advancement in the ongoing fight to effectively treat Alzheimer’s disease.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Alzheimer’s disease is an irreversible, progressive brain disorder affecting more than 6.5 million Americans that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. While the specific causes of Alzheimer’s are not fully known, it is characterized by changes in the brain—including amyloid beta plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections. These changes affect a person’s ability to remember and think.

Leqembi was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The results of a Phase 3 randomized, controlled clinical trial to confirm the drug's clinical benefit have recently been reported and the agency anticipates receiving the data soon.

Researchers evaluated Leqembi’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. 

These results support the accelerated approval of Leqembi, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology. 

The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure. Another warning for Leqembi is for a risk of infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure. The most common side effects of Leqembi were infusion-related reactions, headache and ARIA.

As specified in the prescribing information, Leqembi is indicated for the treatment of Alzheimer’s disease. The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials. The labeling also states that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. 

The approval of Leqembi was granted to Eisai R&D Management Co., Ltd.
J11
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Re: Lecanemab approved!

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Hmm, Leqembi?

Shouldn't there always be a u after the letter q?
I know I know quibbling, even still.
Last edited by J11 on Fri Jan 06, 2023 3:19 pm, edited 1 time in total.
J11
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Re: Lecanemab approved!

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Lecanemab prescribing information
Prescribing Information.pdf
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broiler_x
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Re: Lecanemab approved!

Post by broiler_x »

I think this is another poor decision by the FDA, but not as bad as for Aduhelm. I also don't expect payers (insurers and Medicare, etc.) to pay for this drug due to it's very marginal efficacy data. I have been studying this antibody very extensively over the last few months and I've discussed these results with several AD experts. We all agree: like Adulhelm, the biomarker data looks impressive and unlike Adulhelm, there does appear to be a reduction in cognitive decline at the beginning of dosing. However, that benefit appears to go away after 6-9 months. After that, with continued repeated dosing there is no difference between the placebo and the drug in reducing cognitive decline. Keep in mind, this also does not stop or reverse cognitive decline, but just reduces it for a brief period. The paper with the clinical results is available freely here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768996/

The data I'm referring to is Fig. 9 which shows the cognitive efficacy graphs.

I would paste that data here, but I'm not sure what the rules are about inserting data from anther publication.

Now, you might be thinking: reducing decline for a few months is still great and better than nothing! I agree, however it comes at significant costs. First, there have been 3 treatment-related deaths in these trials. All three had to do with patients who had strokes and were given the standard of care for strokes (like blood thinners). The response from the drug companies and clinicians is to not use those drugs with anyone who is using Lecanumab. So, if you have a stroke and you're on Lecanumab, you're just out of luck?

The second big cost is actually that: the cost. Pricing has not been announced, but since it is an antibody it will be expensive and likely greater than $20K/year. And patients must start taking this years before showing any significant cognitive decline. And we won't even know if those patients will actually ever develop AD. So just start dosing anyone in their 60's or earlier who might have a family history of AD, or maybe displaying earlier MCI for the rest of their lives? Sounds awesome for Biogen. But that would financially devastate Medicare and insurance companies. So this would dramatically raise health care costs for everyone, for a drug that might slow cognitive decline for a few months? And treat people that we don't know will ever develop AD? I don't think payers will reimburse for that.

I actually understand why the FDA approved this, because they simply look at safety and efficacy and not economics and effects on health care costs. That's not their job. I also like how this has caused excitement in the AD research field which has been so dismal for so long. I'm definitely seeing a lot more interest from investors in this field which we haven't seen for years. So for that, I applaud this effort. But I don't see this as actually doing much to help people I'm afraid.
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Re: Lecanemab approved!

Post by circular »

I wonder how the results compare with Aricept, which also temporarily slows cognitive decline. We have the new “q without a u” drug slowing decline compared with placebo but not with the currently approved Aricept, which does the same thing but I think (?) with lower risk. This may be covered somewhere that I haven’t seen.

I also question how many doctors will genotype their patients for ApoE4 before prescribing it. I would bet that most won’t even bring that variable up with their patients, at least I don’t trust them to, putting our sisters and brothers at risk.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Lecanemab approved!

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Good one circ! Yea, "q without a u"!

It's one of times where you get everything right and then a kid goes: "Hey mister, you spelled it wrong!"
I suppose human perfection is when you get everything important right and there are still a few slipups.

They really should send things to J11 in beta.
These slips up could be caught before going to press.

I really do not see how a $50 saliva test that is widely accessible without prescription will be a barrier for a drug (such as lecanemab) that might have full present value costs over $100,000. There is fairly clear differences in risk between those with e33 and e44. I would not call it good clinical judgment to ignore such differences.
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Re: Lecanemab approved!

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broiler_x, this is already such a help to me.

Centuries of my family have been affected by Alzheimer's. Every generation has inherited our family's dominant form of AD from whenever the original mutation arose. In my experience, Alzheimer's has always been silently present in our life. For example, even 10 years ahead of an actual diagnosis our loved one was unrecognizable to close friends and family. Dementing illness has always been the central conversation in our life. There has never been a time in which dementia was not our truth. Before our loved one, our loved one's parent had AD. Alzheimer's is our life. Developing effective AD treatments will offer us a chance to become part of a shared mainstream perception of reality. As it is now the million mile stare wasn't only how our demented relatives looked at us as the illness progressed, but also how we stared out to the community while we tried to cope with the AD in our life.

The AD clinical trials only treated once patients had acquired an official dementia diagnosis. Yet, for us this is decades into illness progression. Dementia is when your entire cognitive ability has eroded to the point where you need almost constant care. The cognitive tests used such as MMSE ask whether you can remember 3 items, whether you know when and where you are. I thought I should get a trophy for a perfect score; though these tests are meant to assess very minimal performance. More realistic tests like clinical memory testing for those in the normal range might have stories with 25 information items.

Even when our loved one was progressing through the preMCI stage there was nothing that could be done. We just watched year after year after year while the decline occurred. There was nothing we could do. During this time the neurodegeneration would have been destroying the hippocampus and other brain regions. With the Lecanemab approval I do not see how it could be considered sound clinical judgment to ignore such progression. For many other people with e33 or even e34 AD it can be very unclear what is behind their cognitive decline; for many it would not be Alzheimer's. Many people can have silent amyloid without Alzheimer's. In our family context, cognitive impairment has always meant Alzheimer's and this would be clearly determinable by mere observation decades before a medical diagnosis.

With us as soon as we saw a memory decline we would know it was AD. We don't need a $5000 PET amyloid scan. When it's dominant illness, it isn't as if it it's going to be anything other than AD. Yet, our family doctor apparently was unaware of the diagnosis decades past the time it was obvious to family members. In modern anonymous society, one can pass for normal largely by not saying much. For our loved, the strategy was to always be happy and laughing and this was mostly effective.

Lecanemab gives us an option. We will no longer have to wait until our brain's deteriorated to the stage of frank dementia. It no longer is rational to say well we think you should wait another ten years with that neurotoxin in your brain, wait until you have firmly established CAA and irreversible clinical symptoms and probably a range of comorbidities and comedications and then we'll treat with gram scale mabs.

We are so fortunate. We have not even reached the memory decline stage of AD yet. We could take safe low dose mabs at ~1 mg/kg a few times a year for possibly $1000 per year, without MRIs/PETs and without risk of ARIA. That is possibly all we will ever need. This is such a breakthrough for us.

This isn't even some fantasy either. Those people who had low dose Aducanumab in their systems were slow progressors or never developed AD. It's already largely established that treating before progressing will effectively forestall cognitive decline.

Treating early could have very large preventative effects. Waiting until there is near global amyloid neuropathology means there will be extensive cognitive deficits to overcome. In this setting it isn't even really amyloid anymore -- amyloid has merely set the fire and activated tau. No amyloid to activate --> no downstream tau --> no AD. an ounce of prevention = 1 pound of cure.
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Re: Lecanemab approved!

Post by broiler_x »

J11,

You were the original poster and super proponent for the adulhelm "celebration" thread on this website. I was the Negative Nancy (or Debby Downer?) in that thread and said that the FDA approval was a major mistake and that the drug would never be reimbursed by payers. Turned out I was right. I wish I wasn't right, as I would love to embrace a truly excellent treatment that would change people's lives.

J11, are you part of the so-called amyloid mafia? (I did not make up this term, sorry if it is offensive, but everyone in AD research knows this term well) You are now back trumpeting yet another anti-amyloid treatment. I really hope I'm wrong - I hope it works!! But, I have a 20+ year career in antibody therapeutics, including 2 different projects for antibodies against ABeta (beta amyloid), and for one I was the leader of the project. So I know this field really well. Let's not forget the scandal from a few months ago that exposed fraud in the amyloid theory with doctored data from a seminal paper.

Anyway, I am not impressed with the efficacy data. In fact, it's a bit concerning as when they opened up the open label extension and allowed all trial patients to get the lecanumab, you actually saw a great increase in cognitive decline - far greater than seen in any previous part of the trial. Taken at face value, it appears that lecanumab slows cognitive decline for the first 6 months or so, but then in later dosing it accelerates cognitive decline. I'm not just making this up - look at the paper I referenced above. In the open label extension in Fig. 9 (labeled OLE) they gave the drug to anyone that wanted it and you see a very rapid increase in cognitive decline.

I find myself again working in AD antibody therapy, even though I said I never would again. However my company is working on a novel target. So we have been watching this development with lecanumab very closely. As I said earlier, we appreciate the excitement that this has generated, as we have new investors. But we also believe that we need to act quickly as we expect this drug to be another flop and eventually hurt the AD research field again.
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Re: Lecanemab approved!

Post by floramaria »

J11 wrote: Fri Jan 06, 2023 4:05 pm They really should send things to J11 in beta.
:lol:
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