BIIB104 / Biogen, Pfizer - LARVOL DELTA

Radiolabel uncovers nonintuitive metabolites of AMPAR potentiator BIIB104: Novel release of [14C]cyanide from 2-cyanothiophene and subsequent formation of [14C]thiocyanate. (PubMed, Drug Metab Dispos) - "BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an AMPAR potentiator investigated for the treatment of cognitive impairment associated with schizophrenia...Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with LC-MS following a chemical derivatization, so to be informed early during drug discovery Significance Statement Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate."

Journal • Alzheimer's Disease • Cholangiocarcinoma • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • Solid Tumor

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of BIIB104 in Cognitive Impairment Associated With Schizophrenia (CIAS): The Tally Study (ACNP 2022) - P2 | "BIIB104 (formerly PF-04958242), a potent and highly selective high-impact AMPA receptor (AMPAR) positive allosteric modulator (PAM), has potential to enhance AMPAR activation and hence augment NMDAR-induced synaptic potentiation... BIIB104 did not show statistically significant efficacy in the treatment of CIAS at either tested dose. The hypothesis that the high-impact AMPAR PAM BIIB104 would demonstrate clinically meaningful efficacy in the treatment of CIAS was not supported."

Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

TALLY: A Study to Evaluate the Safety and Efficacy of BIIB104 in Participants With Cognitive Impairment Associated With Schizophrenia (CIAS) (clinicaltrials.gov) - P2 | N=195 | Completed | Sponsor: Biogen | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

A Study to Evaluate Safety and Pharmacokinetics of BIIB104 in Healthy Japanese and Non-Japanese Participants (clinicaltrials.gov) - P1 | N=31 | Completed | Sponsor: Biogen | Recruiting ➔ Completed

Trial completion

A Study to Evaluate the Relative Bioavailability of Two Formulations of BIIB104 and Assess the Effect of Food on the Pharmacokinetics of BIIB104 Following Administration of a Single, Fixed, Oral Dose of BIIB104 in Healthy Participants (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Biogen | Enrolling by invitation ➔ Completed

Trial completion

A Study to Evaluate the Relative Bioavailability of Two Formulations of BIIB104 and Assess the Effect of Food on the Pharmacokinetics of BIIB104 Following Administration of a Single, Fixed, Oral Dose of BIIB104 in Healthy Participants (clinicaltrials.gov) - P1; N=36; Enrolling by invitation; Sponsor: Biogen; Not yet recruiting ➔ Enrolling by invitation

Enrollment open

TALLY: A Study to Evaluate the Safety and Efficacy of BIIB104 in Participants With Cognitive Impairment Associated With Schizophrenia (CIAS) (clinicaltrials.gov) - P2; N=196; Active, not recruiting; Sponsor: Biogen; Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

A Study to Evaluate the Relative Bioavailability of Two Formulations of BIIB104 and Assess the Effect of Food on the Pharmacokinetics of BIIB104 Following Administration of a Single, Fixed, Oral Dose of BIIB104 in Healthy Participants (clinicaltrials.gov) - P1; N=36; Not yet recruiting; Sponsor: Biogen

Clinical • New P1 trial

A Study to Evaluate Safety and Pharmacokinetics of BIIB104 in Healthy Japanese and Non-Japanese Participants (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: Biogen

Clinical • New P1 trial

TALLY: A Study to Evaluate the Safety and Efficacy of BIIB104 in Participants With Cognitive Impairment Associated With Schizophrenia (CIAS) (clinicaltrials.gov) - P2; N=219; Recruiting; Sponsor: Biogen; Trial completion date: Jun 2021 ➔ Feb 2022; Trial primary completion date: May 2021 ➔ Jan 2022

Clinical • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

[VIRTUAL] Preclinical and Clinical Characterization of the AMPAR Potentiator BIIB104 for the Treatment of Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2 | "Based on these concepts, the high-impact AMPAR positive allosteric modulator (“potentiator”) BIIB104 (previously PF-04958242) has been characterized preclinically and in multiple Ph1 trials where it demonstrated safety, tolerability, low-variability pharmacokinetics, and translational pharmacodynamics (both safety and working memory-specific efficacy) in both healthy volunteers (HV) and individuals with SCZ on stable doses of antipsychotics and other psychotropic medications. Most notable is that BIIB104 tempered ketamine-induced cognitive deficits in humans at similar BIIB104 exposures (and ketamine-dependent NMDAR occupancy) to those observed in ketamine-impairment preclinical WM models, strongly suggesting a translatable pharmacokinetic-pharmacodynamic effect for this mechanistic interaction (Shaffer, Clin Pharmacol Therapeut, 2018). A combination of this ketamine-disrupted HV study and the observed statistically significant improvement in the MCCB Working Memory..."

Preclinical • CNS Disorders • Schizophrenia

[VIRTUAL] Preclinical and Clinical Characterization of the AMPAR Potentiator BIIB104 for the Treatment of Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2 | "Based on these concepts, the high-impact AMPAR positive allosteric modulator (“potentiator”) BIIB104 (previously PF-04958242) has been characterized preclinically and in multiple Ph1 trials where it demonstrated safety, tolerability, low-variability pharmacokinetics, and translational pharmacodynamics (both safety and working memory-specific efficacy) in both healthy volunteers (HV) and individuals with SCZ on stable doses of antipsychotics and other psychotropic medications. Most notable is that BIIB104 tempered ketamine-induced cognitive deficits in humans at similar BIIB104 exposures (and ketamine-dependent NMDAR occupancy) to those observed in ketamine-impairment preclinical WM models, strongly suggesting a translatable pharmacokinetic-pharmacodynamic effect for this mechanistic interaction (Shaffer, Clin Pharmacol Therapeut, 2018). A combination of this ketamine-disrupted HV study and the observed statistically significant improvement in the MCCB Working Memory..."

Preclinical • CNS Disorders • Schizophrenia

[VIRTUAL] Preclinical and Clinical Characterization of the AMPAR Potentiator BIIB104 for the Treatment of Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2 | "Based on these concepts, the high-impact AMPAR positive allosteric modulator (“potentiator”) BIIB104 (previously PF-04958242) has been characterized preclinically and in multiple Ph1 trials where it demonstrated safety, tolerability, low-variability pharmacokinetics, and translational pharmacodynamics (both safety and working memory-specific efficacy) in both healthy volunteers (HV) and individuals with SCZ on stable doses of antipsychotics and other psychotropic medications. Most notable is that BIIB104 tempered ketamine-induced cognitive deficits in humans at similar BIIB104 exposures (and ketamine-dependent NMDAR occupancy) to those observed in ketamine-impairment preclinical WM models, strongly suggesting a translatable pharmacokinetic-pharmacodynamic effect for this mechanistic interaction (Shaffer, Clin Pharmacol Therapeut, 2018). A combination of this ketamine-disrupted HV study and the observed statistically significant improvement in the MCCB Working Memory..."

Preclinical • CNS Disorders • Schizophrenia

A Study to Explore Pharmacodynamic Effects of BIIB104 on Brain Circuitry in Healthy Participants (clinicaltrials.gov) - P1; N=29; Completed; Sponsor: Biogen; Recruiting ➔ Completed

Clinical • Trial completion • MRI

A Study to Explore Pharmacodynamic Effects of BIIB104 on Brain Circuitry in Healthy Participants (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: Biogen; Suspended ➔ Recruiting; Trial completion date: Jul 2020 ➔ Nov 2020; Trial primary completion date: Jul 2020 ➔ Nov 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date • MRI

A Study to Evaluate the Safety and Efficacy of BIIB104 in Participants with Cognitive Impairment Associated with Schizophrenia (CIAS) (clinicaltrialsregister.eu) - P2; N=219; Ongoing; Sponsor: Biogen Idec Research Limited

Clinical • New P2 trial • CNS Disorders • Schizophrenia

Multiple Ascending Doses of PF-04958242 in Subjects With Stable Schizophrenia (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Pfizer; Not yet recruiting -> Recruiting ; Trial primary completion date: Jun 2015 ->Mar 2015

Enrollment open • Trial primary completion date • Biosimilar • Schizophrenia

A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of PF-04958242 in Healthy Subjects (clinicaltrials.gov) - P1; N=13; Completed; Sponsor: Pfizer; Recruiting -> Completed

Trial completion • Biosimilar

A Study to Explore Pharmacodynamic Effects of BIIB104 on Brain Circuitry in Healthy Participants (clinicaltrials.gov) - P1; N=30; Suspended; Sponsor: Biogen; Recruiting ➔ Suspended

Clinical • Trial suspension

Auxiliary proteins are the predominant determinants of differential efficacy of clinical candidates acting as AMPA receptor positive allosteric modulators. (PubMed, Mol Pharmacol) - "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)...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 candidates PAMs. These data will inform both clinical outcomes as well as future rational development of new modulators."

Clinical • Journal

Preclinical and Clinical Characterization of the AMPAR Potentiator BIIB104 for the Treatment of Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2020) - P2 | "Based on these concepts, the high-impact AMPAR positive allosteric modulator (“potentiator”) BIIB104 (previously PF-04958242) has been characterized preclinically and in multiple Ph1 trials where it demonstrated safety, tolerability, low-variability pharmacokinetics, and translational pharmacodynamics (both safety and working memory-specific efficacy) in both healthy volunteers (HV) and individuals with SCZ on stable doses of antipsychotics and other psychotropic medications...Most notable is that BIIB104 tempered ketamine-induced cognitive deficits in humans at similar BIIB104 exposures (and ketamine-dependent NMDA receptor occupancy) to those observed in ketamine-impairment preclinical WM models, strongly suggesting a translatable pharmacokinetic-pharmacodynamic effect for this mechanistic interaction (Shaffer, Clin Pharmacol Therapeut, 2018). A combination of this ketamine-disrupted HV study and the observed statistically significant improvement in the MCCB Working..."

CNS Disorders • Schizophrenia

Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB104 in Healthy Japanese and Non-Japanese Participants (clinicaltrials.gov) - P1; N=31; Completed; Sponsor: Biogen; Recruiting ➔ Completed

Clinical • Trial completion

Biogen Inc (BIIB) Q4 2019 earnings call transcript (The Motley Fool) - "And in neurocognitive disorders, we continue to advance a Phase II study of BIIB104, an AMPA receptor potentiator for cognitive impairment associated with schizophrenia. We now expect data from this study in the second half of this year -- of next year."

P2 data

A Study to Evaluate the Safety and Efficacy of BIIB104 in Participants With Cognitive Impairment Associated With Schizophrenia (CIAS) (clinicaltrials.gov) - P2; N=219; Recruiting; Sponsor: Biogen; Trial completion date: Apr 2020 ➔ Apr 2021; Trial primary completion date: Apr 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date

A Study to Explore Pharmacodynamic Effects of BIIB104 on Brain Circuitry in Healthy Participants (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: Biogen; Not yet recruiting ➔ Recruiting; Trial completion date: Mar 2020 ➔ Jul 2020; Trial primary completion date: Feb 2020 ➔ Jul 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date • MRI