Alzheimer's drugs · FDA record

FDA RECORD · THREADS

Where the agency held, and where it moved.

Origin
The first agency position on this thread in the record.
Consistent
Holds to the earlier position it is compared to.
Conditional
Holds to the earlier position only under a condition the agency states.
Departs
Moves away from the earlier position it is compared to.
Not addressed
The decision's loaded documents do not address this thread.
ThreadAduhelmAccelerated approvalLeqembiAccelerated approvaldonanemabComplete responseLeqembiTraditional approvalKisunlaTraditional approvalLeqembi IqlikSubcutaneous maintenance dosingLeqembi IqlikSubcutaneous initiation dosing
T1 SurrogateOrigin+1Consistent+1—Consistent———
T2 Effect sizeOrigin+1Conditional—ConsistentConsistent——
T3 ARIAOrigin+1Departs Consistent+1—Departs ConsistentConsistentConsistent+1Consistent
T4 DataOrigin+2Conditional ConsistentConsistent+1ConsistentConsistent+1——
T5 ConfirmatoryOrigin+1Consistent—Consistent———

T1 Surrogate

Is removing amyloid reasonably likely to predict benefit?

  1. ADU-T1-1 Aduhelm, accelerated approval Origin

    I concur with ON that the BLA has met the requirements for accelerated approval, including with ON’s conclusion that Biogen has provided substantial evidence of effectiveness on the surrogate endpoint of reduction in brain amyloid plaque and that the surrogate endpoint is reasonably likely to predict clinical benefit, for the reasons set forth in ON’s summary memorandum.

    Office Director memorandum · PDF p. 3 · action of · fda.gov ↗

    Origin: the first agency position on T1 in this record.

  2. ADU-T1-2 Aduhelm, accelerated approval Origin

    Finally, a surrogate outcome for which there is substantial evidence of effectiveness, reduction in amyloid beta plaques on PET imaging, has been assessed in the aducanumab development program, and is reasonably likely to predict clinical benefit, as demonstrated in the reviews discussing the relationship of amyloid plaque reduction to clinical outcome.

    Summary review · PDF p. 8 · action of · fda.gov ↗

    Origin: the first agency position on T1 in this record.

  3. LEQ-T1-1 Leqembi, accelerated approval Consistent

    The Agency has previously found with the accelerated approval of aducanumab that reduction of brain Aβ plaque on PET is reasonably likely to predict clinical benefit in Alzheimer’s disease.

    Summary review · PDF p. 4 · action of · fda.gov ↗

    Compared to ADU-T1-1, Aduhelm, accelerated approval, .

  4. LEQ-T1-2 Leqembi, accelerated approval Consistent

    There is substantial evidence that lecanemab reduces Aβ plaques, and this reduction is reasonably likely to result in clinical benefit for patients.

    Summary review · PDF p. 5 · action of · fda.gov ↗

    Compared to ADU-T1-2, Aduhelm, accelerated approval, .

  5. Donanemab, complete response letter

    [no position recorded on this thread]

  6. LQT-T1-1 Leqembi, traditional approval Consistent

    These approvals were based on a demonstration of reduction of amyloid beta on PET imaging, a surrogate endpoint that was determined to be reasonably likely to predict clinical benefit.

    Approval package (reviews) · PDF p. 50 · action of · fda.gov ↗

    Compared to LEQ-T1-1, Leqembi, accelerated approval, .

  7. Kisunla, traditional approval

    [no position recorded on this thread]

  8. Leqembi Iqlik, subcutaneous maintenance

    [no position recorded on this thread]

  9. Leqembi Iqlik, subcutaneous initiation

    [no position recorded on this thread]

T2 Effect size

Is the difference on the cognitive scale meaningful?

  1. ADU-T2-1 Aduhelm, accelerated approval Origin

    Study 302 provides the primary evidence of effectiveness as a robust and exceptionally persuasive study demonstrating a treatment effect on a clinically meaningful endpoint and reinforced by effects on secondary endpoints, biomarkers, and in relevant subgroups.

    Clinical review · PDF p. 14 · action of · fda.gov ↗

    Origin: the first agency position on T2 in this record.

  2. ADU-T2-2 Aduhelm, accelerated approval Origin

    A p-value < .05 doesn’t necessarily reflect a clinically meaningful effect especially if there would be connotations of disease modification but the actual evidence supporting that is lacking and there is a failed study calling that p-value into question.

    Statistical review · PDF p. 111 · action of · fda.gov ↗

    Origin: the first agency position on T2 in this record.

  3. LEQ-T2-1 Leqembi, accelerated approval Conditional

    Prespecified analyses of data at Week 79 suggested reduced decline on clinical endpoints by approximately 20% to 40%, as well as a reduced decline on other clinically meaningful outcome measures.

    Summary review · PDF p. 28 · action of · fda.gov ↗

    Compared to ADU-T2-1, Aduhelm, accelerated approval, .

  4. Donanemab, complete response letter

    [no position recorded on this thread]

  5. LQT-T2-1 Leqembi, traditional approval Consistent

    The effect on the primary endpoint represents a clinically meaningful reduction of clinical decline.

    Approval package (reviews) · PDF p. 51 · action of · fda.gov ↗

    Compared to LEQ-T2-1, Leqembi, accelerated approval, .

  6. KIS-T2-1 Kisunla, traditional approval Consistent

    The effect on the ADAS-cog, iADL, and CDR-SB endpoints in Study AACI represent a clinically meaningful reduction of clinical decline.

    Summary review · PDF p. 4 · action of · fda.gov ↗

    Compared to LQT-T2-1, Leqembi, traditional approval, .

  7. Leqembi Iqlik, subcutaneous maintenance

    [no position recorded on this thread]

  8. Leqembi Iqlik, subcutaneous initiation

    [no position recorded on this thread]

T3 ARIA

How is swelling and bleeding risk weighed, monitored and labeled, including for ApoE4 carriers?

  1. ADU-T3-1 Aduhelm, accelerated approval Origin

    The incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4) carriers than in ApoE ε4 non-carriers (42% and 20%, respectively).

    Prescribing information (label) · PDF p. 5 · action of · fda.gov ↗

    Origin: the first agency position on T3 in this record.

  2. ADU-T3-2 Aduhelm, accelerated approval Origin

    Obtain brain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth dose of 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA.

    Prescribing information (label) · PDF p. 6 · action of · fda.gov ↗

    Origin: the first agency position on T3 in this record.

  3. LEQ-T3-1 Leqembi, accelerated approval Consistent

    Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein E ε4 homozygotes compared to heterozygotes and noncarriers.

    Prescribing information (label) · PDF p. 1 · action of · fda.gov ↗

    Compared to ADU-T3-1, Aduhelm, accelerated approval, .

  4. LEQ-T3-2 Leqembi, accelerated approval Consistent

    Obtain an MRI prior to the 5th, 7th, and 14th infusions.

    Prescribing information (label) · PDF p. 2 · action of · fda.gov ↗

    Compared to ADU-T3-2, Aduhelm, accelerated approval, .

  5. LEQ-T3-3 Leqembi, accelerated approval Departs

    Consider testing for ApoE ε4 status to inform the risk of developing ARIA when deciding to initiate treatment with LEQEMBI.

    Prescribing information (label) · PDF p. 5 · action of · fda.gov ↗

    Compared to ADU-T3-1, Aduhelm, accelerated approval, .

  6. Donanemab, complete response letter

    [no position recorded on this thread]

  7. LQT-T3-1 Leqembi, traditional approval Consistent

    Since Leqembi was approved on January 6, 2023, we have become aware of clinical trial data showing an increased risk of symptomatic, serious, and severe radiographic amyloid related imaging abnormalities (ARIA) in ApoE ε4 homozygotes who are treated with Leqembi compared to heterozygotes and noncarriers.

    Supplement approval letter · PDF p. 10 · action of · fda.gov ↗

    Compared to LEQ-T3-1, Leqembi, accelerated approval, .

  8. LQT-T3-2 Leqembi, traditional approval Departs

    Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.

    Prescribing information (label) · PDF p. 2 · action of · fda.gov ↗

    Compared to LEQ-T3-3, Leqembi, accelerated approval, .

  9. KIS-T3-1 Kisunla, traditional approval Consistent

    The incidence of ARIA in AACI was higher in ApoE ε4 homozygotes (55% on donanemab vs. 22% on placebo) than in heterozygotes (36% on donanemab vs 13% on placebo) and noncarriers (25% on donanemab vs 12% on placebo).

    Summary review · PDF p. 6 · action of · fda.gov ↗

    Compared to LQT-T3-1, Leqembi, traditional approval, .

  10. IQM-T3-1 Leqembi Iqlik, subcutaneous maintenance Consistent

    Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to assess a known serious risk of amyloid related imaging abnormalities in patients who are homozygous for ApoE e4.

    Approval letter · PDF p. 5 · action of · fda.gov ↗

    Compared to LQT-T3-1, Leqembi, traditional approval, .

  11. IQM-T3-2 Leqembi Iqlik, subcutaneous maintenance Consistent

    Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers.

    Prescribing information (label) · PDF p. 3 · action of · fda.gov ↗

    Compared to KIS-T3-1, Kisunla, traditional approval, .

  12. IQI-T3-1 Leqembi Iqlik, subcutaneous initiation Consistent

    Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers.

    Prescribing information (label) · PDF p. 3 · action of · fda.gov ↗

    Compared to IQM-T3-2, Leqembi Iqlik, subcutaneous maintenance, .

T4 Data

Were the trials, analyses and exposure adequate?

  1. ADU-T4-1 Aduhelm, accelerated approval Origin

    The only valid analysis of Study 301 is the prespecified randomization supported analysis of study 301 which failed for the high dose (p=0.83) and this study outcome should not be discounted without an extremely compelling reason (which there is not).

    Statistical review · PDF p. 9 · action of · fda.gov ↗

    Origin: the first agency position on T4 in this record.

  2. ADU-T4-2 Aduhelm, accelerated approval Origin

    Based on the considerations above, the applicant has provided substantial evidence of effectiveness to support approval.

    Clinical review · PDF p. 133 · action of · fda.gov ↗

    Origin: the first agency position on T4 in this record.

  3. ADU-T4-3 Aduhelm, accelerated approval Origin

    Studies 301 and 302 meet ICH E1A guidelines for exposure of at least 300 subjects at 6 months and 100 subjects at 12 months at the proposed doses.

    Clinical review · PDF p. 240 · action of · fda.gov ↗

    Origin: the first agency position on T4 in this record.

  4. LEQ-T4-1 Leqembi, accelerated approval Consistent

    Given the robust, persuasive, and consistent effects of lecanemab on an acceptable surrogate endpoint, brain Aβ plaque on PET, Study 201 can be considered a single adequate and well-controlled trial that provides substantial evidence of effectiveness.

    Summary review · PDF p. 5 · action of · fda.gov ↗

    Compared to ADU-T4-2, Aduhelm, accelerated approval, .

  5. LEQ-T4-2 Leqembi, accelerated approval Conditional

    Although the 6- month exposure numbers did not meet the ICH E1 guideline, the Division considers that the number of 1 year exposures and the determination that Alzheimer’s disease is a serious and life-threatening disease offset those limitations.

    Summary review · PDF p. 5 · action of · fda.gov ↗

    Compared to ADU-T4-3, Aduhelm, accelerated approval, .

  6. DON-T4-1 Donanemab, complete response letter Consistent

    The safety database is insufficient to adequately characterize the long-term safety of Kisunla in the treatment of Alzheimer’s disease.

    Complete response letter · PDF p. 2 · action of · fda.gov ↗ · scanned page, OCR-checked

    Compared to ADU-T4-3, Aduhelm, accelerated approval, .

  7. DON-T4-2 Donanemab, complete response letter Consistent

    Your BLA submission contains data for only 49 patients who were exposed to Kisunla at the highest proposed dosage regimen (700 mg for 3 doses followed by 1400 mg thereafter) for 12 months.

    Complete response letter · PDF p. 2 · action of · fda.gov ↗ · scanned page, OCR-checked

    Compared to ADU-T4-3, Aduhelm, accelerated approval, .

  8. LQT-T4-1 Leqembi, traditional approval Consistent

    The collective evidence from Study 201 and 301 continue to demonstrate substantial evidence of effectiveness for lecanemab for the treatment of Alzheimer’s disease, and support the traditional approval of lecanemab in this population.

    Approval package (reviews) · PDF p. 51 · action of · fda.gov ↗

    Compared to LEQ-T4-1, Leqembi, accelerated approval, .

  9. KIS-T4-1 Kisunla, traditional approval Consistent

    The safety of donanemab was characterized in a safety database of adequate size.

    Summary review · PDF p. 5 · action of · fda.gov ↗

    Compared to DON-T4-1, Donanemab, complete response letter, .

  10. KIS-T4-2 Kisunla, traditional approval Consistent

    Together, the results of these two adequate and well-controlled studies, AACI and AACG, provide substantial evidence of effectiveness for donanemab for the treatment of Alzheimer’s disease.

    Summary review · PDF p. 4 · action of · fda.gov ↗

    Compared to LQT-T4-1, Leqembi, traditional approval, .

  11. Leqembi Iqlik, subcutaneous maintenance

    [no position recorded on this thread]

  12. Leqembi Iqlik, subcutaneous initiation

    [no position recorded on this thread]

T5 Confirmatory

What did approval require next, and was it delivered?

  1. ADU-T5-1 Aduhelm, accelerated approval Origin

    In order to verify the clinical benefit of aducanumab, conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of Alzheimer’s disease.

    Approval letter · PDF p. 6 · action of · fda.gov ↗

    Origin: the first agency position on T5 in this record.

  2. ADU-T5-2 Aduhelm, accelerated approval Origin

    When residual uncertainty exists about the clinical benefit of a drug, it is important to address that uncertainty, and accelerated approval provides an opportunity to address the uncertainty associated with a surrogate outcome that is reasonably likely to predict clinical benefit by requiring a post-approval study to verify the clinical benefit predicted by the effect on the surrogate.

    Summary review · PDF p. 8 · action of · fda.gov ↗

    Origin: the first agency position on T5 in this record.

  3. LEQ-T5-1 Leqembi, accelerated approval Consistent

    In order to verify the clinical benefit of lecanemab-irmb, conduct a randomized, controlled trial to evaluate the efficacy of lecanemab-irmb compared to an appropriate control for the treatment of Alzheimer’s disease.

    Approval letter · PDF p. 3 · action of · fda.gov ↗

    Compared to ADU-T5-1, Aduhelm, accelerated approval, .

  4. Donanemab, complete response letter

    [no position recorded on this thread]

  5. LQT-T5-1 Leqembi, traditional approval Consistent

    We have reviewed your submission and conclude that the above requirement was fulfilled.

    Supplement approval letter · PDF p. 10 · action of · fda.gov ↗

    Compared to LEQ-T5-1, Leqembi, accelerated approval, .

  6. Kisunla, traditional approval

    [no position recorded on this thread]

  7. Leqembi Iqlik, subcutaneous maintenance

    [no position recorded on this thread]

  8. Leqembi Iqlik, subcutaneous initiation

    [no position recorded on this thread]