Therapeutics

Crenezumab

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Overview

Name: Crenezumab
Synonyms: MABT5102A , RG7412
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: AC Immune SA, Genentech, Hoffmann-La Roche
Approved for: None

Background

Crenezumab is a passive immunotherapy approach in which patients are treated with monoclonal antibodies that specifically recognize Aβ peptides. Crenezumab recognizes multiple forms of aggregated Aβ, including oligomeric and fibrillar species and amyloid plaques with high affinity, and monomeric Aβ with low affinity. This humanized antibody uses an IgG4 backbone. It was engineered to clear excess Aβ while exerting reduced subsequent effector function on microglia; the rationale is to stimulate amyloid phagocytosis while limiting release of inflammatory cytokines as a way to avoid side effects such as vasogenic edema (see Adolfsson et al., 2012). In terms of its binding specificity, crenezumab is similar to solanezumab (May 2015 news).

Crenezumab was confirmed to bind Aβ oligomers in vivo. In the PS2APP mouse model of amyloidosis, the antibody localized to brain regions rich in Aβ oligomers, including the periphery of plaques, and hippocampal mossy fibers. It did not bind to the dense core region of plaques, or vascular amyloid (Meilandt et al., 2019).

Findings

Two Phase 1 safety trials in healthy volunteers and people with Alzheimer's disease produced no evidence of vasogenic edema and a low incidence of asymptomatic cerebral microhemorrhage (Guthrie et al., 2020). This allowed Phase 2 to use higher doses and achieve higher brain exposure than was possible with previous immunotherapy approaches.

ABBY was a Phase 2 trial evaluating up to 15 mg/kg per month of subcutaneous crenezumab injections, conducted at more than 90 sites in North America and Europe in 450 people with mild to moderate AD. ABBY, and a 91-patient biomarker study called BLAZE, were completed in spring 2014; both continued into an open-label extension trial of 361 patients that ran until May 2016. ABBY missed its primary endpoints of change on ADAS-cog and CDR-SOB. Further analysis suggested a possible efficacy signal in mild AD, similar to solanezumab's EXPEDITION 1 and 2 results (Jul 2014 conference news; Cummings et al., 2018). BLAZE reported no separation between treatment and placebo groups on the primary endpoint of PET amyloid imaging, but did report a separation on the secondary endpoint of CSF Aβ (Dec 2014 conference news; Salloway et al., 2018Yoshida et al., 2020). Among 104 participants of both ABBY and BLAZE, crenezumab reduced CSF Aβ oligomers in treated participants (Yang et al., 2019). An ultrasensitive immunoassay for oligomers detected a median 43 percent to 48 percent decline after treatment, compared to 13 percent in the placebo group. More than 80 percent of treated people had lower oligomeric Aβ, whereas in the placebo group, CSF oligomeric Aβ declined in half and increased in the other half.

Crenezumab is also being tested in a prevention paradigm. In a landmark, adaptive, five-year study that started in 2013, crenezumab is the first immunotherapy to be evaluated as part of the Alzheimer Prevention Initiative (API, see May 2012 conference news). Bimonthly, subcutaneous injection of crenezumab is being compared to placebo for its ability to stave off cognitive decline and affect Alzheimer's biomarkers in presymptomatic carriers of the autosomal-dominant PSEN1 E280A mutation. Most trial participants live in and near Medellin, Colombia; some U.S. participants with similarly predisposing gene mutations also were to be recruited. The participants in this trial did not meet criteria for mild cognitive impairment at the time of enrollment. The trial uses a composite consisting of five separate cognitive tests as its primary outcome (Feb 2013 webinar). It also uses an extensive list of secondary outcomes, including safety, time to progression to MCI, as well as clinical outcomes and fluid and imaging biomarkers (see Tariot et al., 2018).This Phase 2 trial was expected to recruit 300 participants, but ultimately randomized 252 (Aug 2019 conference news; Rios-Romanets et al., 2020). This trial enrolled 150 participants into a tau PET substudy to evaluate the effect of crenezumab treatment on the change in tau burden over time in carriers of this mutation.

Following results of ABBY and of solanezumab's EXPEDITION, discussion centered on increasing the dose in subsequent crenezumab trials. In February 2015, Genentech started a Phase 1b study in 72 people with mild to moderate AD to compare three doses of intravenous crenezumab to placebo. Doses were not disclosed, but a three-month, double-blind course of monthly infusions was followed by a 12-month option of open-label dosing.

In July 2015, crenezumab was advanced into Phase 3, initially with a single study in prodromal AD. In January 2016, a study of 750 people with MCI or prodromal AD with biomarker evidence of Aβ pathology started enrolling. Called CREAD, this trial used change on the CDR-SB as its primary outcome and a range of cognitive and functional measures as secondary outcomes. CREAD used 233 study locations globally and was expected to run until 2020 (see also Blaettler, 2016).

At the 2016 CTAD conference, crenezumab's sponsors announced results of the 72-patient Phase 1 trial, as well as of exposure-response modeling done in a disease-progression simulation model. Company scientists claimed that both datasets predicted a stronger treatment benefit from the higher dose of 60 mg/kg of crenezumab infused once a month for the CREAD Phase 3 study, also confirming that this was the dose being evaluated in this trial.  

On February 28, 2017, AC Immune announced that Genentech had decided to start a second Phase 3 trial of 750 participants with prodromal to mild AD, to be called CREAD2 (press release).

In January 2019, Roche terminated both Phase 3 CREAD trials (Jan 2019 news). Initial results for CREAD1, presented in March at the AD/PD conference in Lisbon, Portugal, were wholly negative (May 2019 news). The data available by that time covered 13 percent of the 813 enrollees who had completed the treatment period of the trial as of January 2019; 14 percent had dropped out. Treatment and placebo groups were identical on the primary and secondary outcomes. Subgroup analyses by prodromal versus mild disease stage at baseline, by MMSE greater or less than 24, or by ApoE status yielded no treatment signal. The high dose used in this trial produced numerically more side effects than placebo, but the differences were small and raised no new safety concerns. According to more data presented at CTAD in 2019, treatment did not significantly affect amyloid PET, brain volume, or CSF tau measures. Other CSF markers—Aβ, neurogranin, NfL, α-synuclein, YKL-40, and GFAP—moved in the desired direction with treatment, indicating target engagement (Dec 2019 conference news). Full results for both trials were published after peer review (Ostrowitzki et al., 2022). Together, the trials enrolled 1,619 participants, with 173 completing two years of treatment in CREAD1. In CREAD2, no one reached two years of treatment before the trials were terminated. As previously reported, crenezumab was well-tolerated, but did not change the rate of decline on the CDR-SB or affect disease biomarkers.

From 2014 to 2019, Genentech ran two Phase 1 studies evaluating high-volume, high-flow subcutaneous infusion of crenezumab. The placebo-controlled studies enrolled 140 healthy people and compared different doses, volumes, and flow rates, with or without the permeation enhancer hyaluronidase. This enzyme transiently disrupts the extracellular matrix of the skin to accommodate larger infusion volumes and enhance bioavailability. According to published results, subcutaneous infusions of 6,800 mg antibody in up to 40 ml, at flow rates up to 4 ml/minute, were well-tolerated, with or without recombinant human hyaluronidase. Participants reported low pain scores during the abdominal infusions, and no serious or dose-limiting adverse events. Transient mild skin redness (erythema) was the most common infusion site reaction and occurred in most people, with larger areas involved at higher infusion volumes. Swelling at the infusion site was also common, and lessened when hyaluronidase was included. Pharmacokinetics were dose-proportional, and 6,800 mg infused in 40 ml over 10 minutes gave the same blood levels as the 60 mg/kg intravenous infusion used in the CREAD trial (Dolton et al., 2021).

On June 15 2022, Roche released topline results of the API Colombian prevention trial (June 2022 news). The trial was negative on its original primary, the API ADAD composite, and the coprimary of the Free and Cued Selective Reminding Test. The latter was added after the trial had started. Trends on both primaries and multiple secondary and exploratory endpoints favored crenezumab. After two upward dose adjustments during the trial, participants received 60 mg/kg antibody per month, a sevenfold increase over the beginning dose. Most participants were on the high dose for about two years, with no new safety issues. Ninety-four percent completed the trial. According to data presented at the August 2022 AAIC, treatment slowed declines by about 20 percent on both primary outcomes, but with large variability within treatment groups. Other measures showed a slowing that did not reach statistical significance; they were the CDR-SB and CDR, RBANS, progression to MCI or dementia, FDG-PET, brain shrinkage, tau PET, and CSF p-tau181, total tau and NfL. The only significant changes were a stabilization of Aβ42 and a rise in Aβ40 in the treated group compared to placebo (Aug 2022 conference news). The trial is expected to be completed by the end of the year.

As of February 2022, only the API primary prevention trial is continuing, to be completed by the end of the year.

This antibody is listed in clinicaltrials.gov under both crenezumab and MABT5102A.

Clinical Trial Timeline

  • Phase 2
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032
Genentech NCT01343966
N=372
Genentech NCT01397578
N=72
Genentech NCT01723826
N=400
Genentech NCT01998841
N=300
Hoffmann-La Roche NCT02670083
N=750

Last Updated: 23 Sep 2022

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References

News Citations

  1. Crenezumab Disappoints in Phase 2, Researchers Remain Hopeful
  2. Immunotherapy I: Baby Steps, but No Breakthroughs
  3. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  4. Crenezumab Update: Baseline Data from Colombian Prevention Trial
  5. Roche Pulls Plug on Two Phase 3 Trials of Crenezumab
  6. Keep Your Enthusiasm? Scientists Process Brutal Trial Data
  7. Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
  8. API Colombian Trial of Crenezumab Missed Primary Endpoints
  9. Crenezumab Secondaries Negative; Gantenerumab OLE Hints at Efficacy
  10. Shape of a Hug: How the Embrace of a Therapeutic Aβ Antibody Really Matters

Webinar Citations

  1. New Frontier: Developing Outcome Measures for Pre-dementia Trials

Therapeutics Citations

  1. Solanezumab

Paper Citations

  1. . Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks. J Alzheimers Dis. 2020;76(3):967-979. PubMed.
  2. . ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018 May 22;90(21):e1889-e1897. Epub 2018 Apr 25 PubMed.
  3. . Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (BLAZE). Alzheimers Res Ther. 2018 Sep 19;10(1):96. PubMed.
  4. . Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease. Alzheimers Res Ther. 2020 Jan 22;12(1):16. PubMed.
  5. . Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann Neurol. 2019 Aug;86(2):215-224. Epub 2019 Jun 22 PubMed.
  6. . The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's dise. Alzheimers Dement (N Y). 2018;4:150-160. Epub 2018 Mar 8 PubMed.
  7. . Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease Colombia Trial. Alzheimers Dement. 2020 Jul;16(7):1023-1030. Epub 2020 May 17 PubMed.
  8. . Clinical trial design of CREAD: a randomized, double-blind, placebo-controlled, parallel-group Phase-3 study to evaluate crenezumab treatment in patients with prodromal-to-mild Alzheimer’s disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 12.7 (2016): P609.
  9. . Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurol. 2022 Sep 19; PubMed.
  10. . Safety, Tolerability, and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers. Clin Pharmacol Ther. 2021 Nov;110(5):1337-1348. Epub 2021 Aug 27 PubMed.
  11. . An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci. 2012 Jul 11;32(28):9677-89. PubMed.
  12. . Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ. Alzheimers Res Ther. 2019 Dec 1;11(1):97. PubMed.

Other Citations

  1. PSEN1 E280A

External Citations

  1. press release
  2. crenezumab
  3. MABT5102A

Further Reading

Papers

  1. . Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies. Acta Neuropathol. 2015 Nov;130(5):699-711. Epub 2015 Oct 3 PubMed.
  2. . Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin. Sci Rep. 2016 Dec 20;6:39374. PubMed.
  3. . Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N‑truncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol. 2015 Nov;130(5):713-29. PubMed.
  4. . Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity. J Biol Chem. 2021 Jan-Jun;296:100508. Epub 2021 Mar 4 PubMed.
  5. . Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev. 2021 Jul;68:101339. Epub 2021 Apr 5 PubMed.
  6. . Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer's disease. Alzheimers Dement. 2021 Sep;17(9):1487-1498. Epub 2021 May 2 PubMed.
  7. . Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39. PubMed.
  8. . Can Anti-β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?. Neurol Genet. 2021 Feb;7(1):e535. Epub 2020 Dec 17 PubMed.