AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
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According to an industry report today, AbbVie has called a halt to the Phase 2 trial of its anti-tau antibody ABBV-8E12 for progressive supranuclear palsy after it failed a futility analysis. AbbVie announced the termination during a quarterly earnings call. No other details were immediately available.
"While I and others were hopeful about the PSP trial, individuals in this and other PSP trials are already at a relatively advanced stage of clinical disease by the time they are diagnosed and able to enter these trials, so I am not overly surprised there was not a clear benefit," David Holtzman of Washington University, St. Louis, wrote to Alzforum.
According to David Freundel, a public affairs director at Abbvie, this is also the end for two extension studies evaluating ABBV-8E12 in patients with PSP. Ditto for Abbvie's pre-approval access program (PAA) to this antibody for primary tauopathies. "AbbVie recommends that patients in the ABBV-8E12 PSP studies, and the ABBV-8E12 PAA for primary tauopathies currently on treatment with ABBV-8E12, speak with their physician about the appropriate next steps regarding their treatment," Freundel wrote to Alzforum.
The antibody is also in a Phase 2 trial of 400 people with MCI and early dementia due to Alzheimer’s disease. This trial is continuing without changes. "I think prospects for AD are still good, as the stage of tauopathy in the AD trial is relatively early," Holtzman noted.
Different types of tau fibrils characterize PSP and AD, with the former containing only four-repeat (4R) tau, and the latter a mix of 3R and 4R tau.
ABBV-8E12 and some other anti-tau antibodies currently in trials, including Biogen’s BIIB092, target the N-terminus of tau. These antibodies have high affinity, though some reports indicate that they do not block propagation of misfolded tau in cellular assays. Antibodies against tau’s mid-region, which are in development at several companies, performed better in these assays (Apr 2018 conference news).
Biogen’s shares fell after news of the AbbVie trial termination, but recovered by end of day.—Madolyn Bowman Rogers
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We are aware of reports that AbbVie has discontinued the Phase 2 study for their anti-tau antibody (ABBV-8E12) in PSP.
Biogen’s development plans for gosuranemab (BIIB092) remain unchanged. Specifically, our Phase 2 study in PSP is advancing as planned. We completed enrollment last September and expect the data readout by the end of 2019. We are also continuing to progress the Phase 2 study in AD.
In addition, we continue to advance Phase 1 studies of both BIIB076, a distinct anti-tau antibody, and BIIB080, an antisense oligonucleotide targeting tau through a mechanism distinct from that of antibodies. It’s important to note that Alzheimer’s disease and PSP are distinct tauopathies, both pathologically and clinically.
Lille Neuroscience & Cognition
More than 20 years ago, Braak stages were defined in Alzheimer’s disease with a hierarchical pathway of tau-based neurodegeneration. Such observations are now explained by the prion-like propagation hypothesis (Mudher et al., 2017). In line with this hypothesis and with the identification of tau in the extracellular space, extracellular tau species are now considered by the scientific community as key drivers in the spread of tau pathology, making them attractive targets for immunotherapy approaches. Many clinical trials are currently ongoing.
Among them, AbbVie has stopped the Phase 2 trial for progressive supranuclear palsy (PSP) of the ABBV-8E12 antibody. There is no further information available but a few comments can be made about the selection of the antibody, the targeted population, and the future.
According to the Alzforum data sheet, ABBV-8E12 is related to the murine anti-tau antibodies HJ series and more precisely the HJ8.5 antibody (Kfoury et al., 2012; Yanamandra et al., 2013; Yanamandra et al., 2015). The ABBV-8E12 antibody targets the amino-terminal region of tau, as do BIIB092 and RO7105705 antibodies. In humans, secreted tau species often lack the amino-terminal region and thus, there is still a debate about the best region to target. Other antibodies currently in clinical trials such as BIIB076, JNJ63733657, and UCB0107 recognize different tau epitopes (Apr 2018 conference news; Corvol and Buée, 2019).
The ABBV-8E12 antibody has been selected through a screening of antibodies able to block seeding activity from brain extracts of P301S tau-transgenic mice using a FRET biosensor cell assay. In vivo, the antibody was able to reduce neurofibril-related degeneration, microglia-based inflammation, and behavioral deficits. It was predicted that antibodies that block tau uptake would create a ‘‘sink’’ in the extracellular space that would promote clearance by other mechanisms (Yanamandra et al., 2013). Thus, to better target extracellular tau, IgG4, a low Fc-receptor-binding isotype immunoglobulin, was chosen for clinical trials.
Tau immunotherapy is attractive because extracellular tau can be targeted in the context of the prion-like propagation hypothesis. If such a hypothesis, in regard to brain connectivity, is well supported in AD, it is not always evident in other tauopathies such as PSP (Cope et al., 2018). In fact, tau is increased in cerebrospinal fluid of AD patients but not PSP patients (Barthélemy et al., 2016). Experimental data suggested that amyloid may facilitate tau truncation and secretion in AD (Sato et al., 2018). Such tau secretion may not be found in PSP and thus, we have to be cautious extrapolating data obtained in AD research to other tauopathies such as PSP.
One may ask if PSP is not the best disease target for tau immunotherapy. That ABBV-8E12 is still ongoing in a Phase 2 clinical trial of MCI and early AD patients may be justified.
Some studies on transgenic models could also suggest that plasma tau is a potential biomarker for therapeutic monitoring. Indeed, the active immunization of the THY-tau22 mouse model by peptides containing a pathological phosphorylated epitope (pS422) reduced pathological tau species in the brain and delayed cognitive deficits but was associated with a significant increase in plasma tau concentrations (Troquier et al., 2012).
However, if plasma tau can be detected, it is not clear if its level reflects pathological processes in the brain. Some authors suggest that antibodies will create a ‘‘sink’’ in plasma, pulling pathological tau species out of the brain. Other studies indicate that antibodies may stabilize tau species in plasma through the formation of an antibody-(tau) antigen complex. In fact, peripheral administration of the anti-tau ABBV-8E12 antibody increased plasma tau by binding to it and extending its half-life in plasma in transgenic mice, and also in PSP patients (Yanamandra et al., 2017).
Such observations suggest a need to re-evaluate our priorities for basic and clinical research on tauopathies. For instance, in basic research, understanding the mechanisms of tau clearance in non-overexpressing experimental models must be a priority. Disease-specific experimental models, such as those for PSP, must be developed since tauopathies are very heterogeneous. Thus, observations made in one disease condition may not be applicable to other disorders.
With a number of clinical trials ongoing, the next challenge would be to validate target engagement and efficacy of drug candidates. Future clinical trials need to show target engagement as done for BIIB092 (Boxer et al., 2019). Drug target efficacy is also the next challenge. The development of tau PET imaging and tau quantification assays will be real assets in this regard (Leuzy et al., 2019; Schöll et al., 2019).
Finally, AD is a combination of pathological processes, including amyloid, tau, and inflammation. Targeting a single entity is likely to be insufficient. Amyloid immunotherapy has facilitated amyloid clearance without any improvement in cognition. Whether tau immunotherapy would lead to tau clearance without any cognition improvement because amyloid pathology and neuroinflammation remain, is still a question. The FDA and EMA have also to change their rules to facilitate clinical trials with combinations of drug candidates.
References:
Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Alavi Naini SM, Mandelkow EM, Mandelkow E, Buée L, Goedert M, Brion JP. What is the evidence that tau pathology spreads through prion-like propagation?. Acta Neuropathol Commun. 2017 Dec 19;5(1):99. PubMed.
Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem. 2012 Jun 1;287(23):19440-51. Epub 2012 Mar 29 PubMed.
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo. Neuron. 2013 Oct 16;80(2):402-14. PubMed.
Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015 Mar;2(3):278-88. Epub 2015 Jan 23 PubMed.
Corvol JC, Buée L. A new step towards targeting tau. Lancet Neurol. 2019 Jun;18(6):517-518. PubMed.
Cope TE, Rittman T, Borchert RJ, Jones PS, Vatansever D, Allinson K, Passamonti L, Vazquez Rodriguez P, Bevan-Jones WR, O'Brien JT, Rowe JB. Tau burden and the functional connectome in Alzheimer's disease and progressive supranuclear palsy. Brain. 2018 Feb 1;141(2):550-567. PubMed.
Barthélemy NR, Gabelle A, Hirtz C, Fenaille F, Sergeant N, Schraen-Maschke S, Vialaret J, Buée L, Junot C, Becher F, Lehmann S. Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. J Alzheimers Dis. 2016;51(4):1033-43. PubMed.
Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TL, Miller TM, Karch CM, Bateman RJ. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018 May 16;98(4):861-864. PubMed.
Troquier L, Caillierez M, Burnouf S, Fernandez-Gomez FJ, Grosjean MJ, Zommer N, Sergeant N, Schraen-Maschke S, Blum D, Buee L. Targeting phospho-Ser422 by active Tau immunotherapy in the THY-Tau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res. 2012 Jan 23; PubMed.
Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med. 2017 Apr 19;9(386) PubMed.
Boxer AL, Qureshi I, Ahlijanian M, Grundman M, Golbe LI, Litvan I, Honig LS, Tuite P, McFarland NR, O'Suilleabhain P, Xie T, Tirucherai GS, Bechtold C, Bordelon Y, Geldmacher DS, Grossman M, Isaacson S, Zesiewicz T, Olsson T, Muralidharan KK, Graham DL, O'Gorman J, Haeberlein SB, Dam T. Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial. Lancet Neurol. 2019 Jun;18(6):549-558. PubMed.
Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, Nordberg A. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry. 2019 Jan 11; PubMed.
Schöll M, Maass A, Mattsson N, Ashton NJ, Blennow K, Zetterberg H, Jagust W. Biomarkers for tau pathology. Mol Cell Neurosci. 2018 Dec 7; PubMed.
University of Alabama at Birmingham
While it is always disappointing when a clinical trial doesn’t deliver positive news, it is probably important not to over-generalize either to other diseases or other antibodies. PSP was chosen for many of the initial tau antibody trials because it is the most common “pure tauopathy” that can be confidently diagnosed clinically. But by the time a PSP diagnosis is clear enough to meet enrollment criteria for this kind of study, the disease is already in a fairly advanced stage, quite possibly past the point where halting tau propagation would be expected to help. We also know that there are differences in the types of tau and tau pathology between tauopathies (especially between Alzheimer’s disease and the 4R tauopathies like PSP), so tau antibodies will probably not have the same effects in all tauopathies. As far as other tau immunotherapy programs go, it is also important to remember that the antibodies in different programs are distinct, recognizing different epitopes, conformations, and aggregation states, with different avidity, and often with different Ig subclasses and effector function. I think they are unlikely to have “class effects,” i.e. the effects of one antibody are unlikely to predict effects of another.
That said, there are many reasons to be circumspect about the potential for tau immunotherapy. Extracellular tau is highly fragmented and post-translationally modified and we still have much to learn about the specific tau species responsible for spreading of tau pathology in various tauopathies. The problematic tau species may be present at very low concentrations, and in many cases we do not know if tau antibodies reach adequate concentrations in the interstitial fluid and have high enough avidity for these seeding species, which could be a small fraction of extracellular tau. And of course even if we were able to halt spreading of tau aggregates, there is evidence from various model systems dissociating tau aggregate pathology from neuronal dysfunction and death.
Tau remains an attractive therapeutic target for a variety of neurodegenerative diseases. We should maintain a broad view, as the potential of tau-directed therapies is not limited to tau immunotherapy.
University of California, San Diego
I have not seen the announcement, but my general comments relate to two questions: target and tools. For tau passive immunotherapy, the antibody would need to reach its target of a tau seed or a misfolded form of tau in sufficient amount to make a difference. Whether this antibody or another anti-tau antibody can encounter pathogenic forms of tau after peripheral administration is a key question, and it is not clear where this contact might potentially occur.
Regarding tools, tau PET imaging is an important tool that can help to assess progression of tau pathology, although there have been issues for some of the tau ligands for imaging brainstem. CSF and plasma neurofilament light both have potential as biomarkers that indirectly measure neurodegeneration in PSP. However, we do have not assays or tools currently available to be able to directly measure target engagement in humans.
University of Ulsan
Tau was previously thought to exist solely in the cytosol, but this has changed. Now we know that tau is also in the extracellular space. There may be a variety of tau species in the extracellular space. Some forms of extracellularly secreted tau may have physiological roles, and other forms of tau may have pathological effects.
If a tau antibody targets the physiological or total forms of tau, it could have adverse effects. Hence, the epitope choice should be carefully considered when a therapeutic tau antibody candidate is being developed.
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