The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss

Bednar, Martin M.; DeMartinis, Nicholas; Banerjee, Anindita; Bowditch, Stephen; Gaudreault, François; Zumpano, Laura; Lin, Frank R.

doi:10.1001/jamaoto.2015.0791

Cited by 11 publications

(6 citation statements)

References 22 publications

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“…The results of these early trials, even if unsuccessful at identifying an efficacious therapy, will be important in informing the design of future ARHL clinical trials. The first reported clinical trial designed to treat ARHL with a pharmacological agent was conducted by Pfizer and completed in 2013 using PF-04958242, a positive allosteric modulator of the AMPA receptor, an ionotropic glutamate receptor (Bednar et al 2015).…”

Section: Therapeutic Approaches To Treating or Preventing Arhlmentioning

confidence: 99%

Age-Related Hearing Loss

Bowl

Dawson

2018

Cold Spring Harb Perspect Med

244

160

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Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate agerelated auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL.

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Section: Therapeutic Approaches To Treating or Preventing Arhlmentioning

confidence: 99%

Age-Related Hearing Loss

Bowl

Dawson

2018

Cold Spring Harb Perspect Med

244

160

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“…A recent clinical trial demonstrated that AMPA receptor potentiator (PF-04958242) attenuated the schizophrenia-relevant ketamine-induced cognitive impairment in verbal learning and working memory 100 , suggesting the use of AMPA receptor potentiator for the treatment of cognitive impairments associated with schizophrenia. Additionally, PF-04958242 has been shown to improve auditory function significantly in age-related sensorineural hearing loss 101 . Another AMPA receptor potentiator, LY451395, which has been in Phase II development with possible use in Alzheimer’s disease whereas abnormalities of glutamatergic homeostasis also occur.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression

et al. 2022

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Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.

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“…The substantial prolongation of the cerebellar synaptic currents by both PAMs is consistent with the known motor side effects of high-impact PAMs at higher exposures (Zasadny et al, 2009;Shaffer et al, 2013Shaffer et al, , 2015 and could potentially precipitate Purkinje cell toxicity that occurs when AMPARs are overactivated (Garthwaite and Garthwaite, 1991;Brorson et al, 1995). Though BIIB104 exhibits a clear cross-species, dose-dependent engagement of cerebellar processes (i.e., increased cGMP, motor dysfunction, and FDG uptake), no evidence of Purkinje cell toxicity has been reported (Shaffer et al, 2015), and the drug has been safe and welltolerated in humans (Zasadny et al, 2009;Bednar et al, 2015). Procognitive activity occurs at nanomolar free drug concentrations (Shaffer et al, 2015;Ranganathan et al, 2017), with a projected therapeutic index of ∼37 for self-limiting tremors in humans (Shaffer et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators

Ishii

Stolz²,

Swanson³

2020

Molecular Pharmacology

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Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in preclinical and clinical studies. Their therapeutic window is narrow, however, and clinical application will likely only occur if greater discrimination in activity is achieved. Toward that end, we compared the modulatory activity of two PAMs recently considered as clinical candidates, LY451395 (mibampator) and PF-04958242/BIIB104, on recombinant and native AMPA receptors (AMPARs). We found that the principle molecular determinant that shaped modulatory activity of both PAMs on deactivation (recombinant) and decay (synaptic) of AMPARs was the auxiliary protein incorporated into the receptor complexes. AMPARs containing the stargazin/g2 transmembrane AMPAR regulatory protein (TARP) were slowed to a .10-fold degree by both PAMs as compared with those incorporating g8 TARP. Neither subunit composition nor flip/flop splice variation had substantive effect. Similarly, stargazin/g2-containing mossy fiber EPSCs in cerebellar granule neurons were slowed to a ∼5-fold greater degree than EPSCs in hippocampal CA1 pyramidal cell neurons, which express the g8 TARP. LY451395 exhibited greater efficacy than BIIB104 at both synapses. These studies provide insight into the receptor constituents that determine efficacy of sulfonamide PAMs. We conclude that compounds that discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/g2 efficacy such as BIIB104, could act as viable procognitive therapeutics. SIGNIFICANCE STATEMENTPositive allosteric modulators (PAMs) of AMPA receptors enhance cognitive function in a variety of preclinical models. A clearer understanding of the critical determinants of PAM activity could yield critical insight into pathways to maximize their therapeutic index. Here we show that auxiliary proteins for AMPARs play a major, but thus far underappreciated, role in shaping recombinant and neuronal AMPAR modulation by two clinical candidate PAMs. These data will inform both clinical outcomes as well as future rational development of new modulators.

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The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss

Abstract: clinicaltrials.gov Identifier: NCT01518920.

Cited by 11 publications

References 22 publications

Age-Related Hearing Loss

Age-Related Hearing Loss

Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression

Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators

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