Results and evaluation of a first‐in‐human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods

Sturm, Stefan; Delporte, Marie‐Laure; Hadi, Salah; Schobel, Scott; Lindemann, Lothar; Weikert, Robert J.; Jaeschke, Georg; Derks, Michael; Palermo, Giuseppe

doi:10.1111/bcp.13466

Cited by 11 publications

(25 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The modified CRM (mCRM) with control for the probability of over‐dosing was used for the assessment of safety/tolerability. This part of the Bayesian framework has been described in detail previously . In addition, the mCRM was further modified to allow for the estimation of PD parameters by means of the following maximum effect (E max ) model with an additive error:

y_{i} = \frac{E_{\max} \times {dose}_{i}^{v}}{{ED}_{50}^{v} + {dose}_{i}^{v}} + ε_{i}

where ν denotes the Hill parameter, the residual errors ε i are normally distributed around 0 with variance of σ 2 s .…”

Section: Methodsmentioning

confidence: 99%

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

Sturm

Günther

Jaber

et al. 2018

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Aims Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry‐into‐human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. Methods Part 1 had a randomized, double‐blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6–18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two‐period cross‐over design (n = 8). Results Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi‐phasic decline with a mean terminal half‐life of 40–69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27–55%) of the estimated maximum increase in SMN2 mRNA. Conclusions Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full‐length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing.

show abstract

y_{i} = \frac{E_{\max} \times {dose}_{i}^{v}}{{ED}_{50}^{v} + {dose}_{i}^{v}} + ε_{i}

where ν denotes the Hill parameter, the residual errors ε i are normally distributed around 0 with variance of σ 2 s .…”

Section: Methodsmentioning

confidence: 99%

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

Sturm

Günther

Jaber

et al. 2018

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…As for mGlu 5 agonists, a PAM of mGlu 5 , VU0409551, has shown robust cognitive and behavioral effects in several animal models of schizophrenia . Another Phase II trial has recently been initiated …”

Section: Treatment Based On Glutamate Hypothesismentioning

confidence: 99%

Glutamate hypothesis in schizophrenia

Uno

Coyle

2019

Psychiatry Clin Neurosci

287

172

View full text Add to dashboard Cite

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.

show abstract

“…wherein d * is an arbitrary fixed reference dose to improve numerical stability, and log denotes the natural logarithm . Assuming a distribution for the parameters α and β as being bivariate normal with mean μ and covariance matrix Σ will define a typically wide range of a priori possible relationships between the human dose and the EA rate as illustrated in Figure .…”

Section: The Continual Reassessment Methodsmentioning

confidence: 99%

“…Under these assumptions, we chose a logistic regression model for the relationship between a dose d and the likelihood p for an individual to experience an EA at dose d via the equation wherein d* is an arbitrary fixed reference dose to improve numerical stability, and log denotes the natural logarithm. 32 Assuming a distribution for the parameters α and β as being bivariate normal log (p∕(1 − p)) = α+β ⋅ log (d∕d * ), Derived from the minimally informative prior distribution curve; for doses of 450 mg and 1,750mg, a p(EA > 5%) of 45.3% and 91.8%, respectively, was estimated. c p(EA > 5%) for 225 mg includes the scenario that 12 subjects were enrolled into the preceding 150 mg dose step and no EAs had been noted.…”

Section: Mathematical Conceptmentioning

confidence: 99%

A Framework Proposal to Follow‐Up on Preclinical Convulsive Signals of a New Molecular Entity in First‐in‐Human Studies Using Electroencephalographic Monitoring

Abt

Dinklo

Rothfuß

et al. 2019

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Traditionally, in dose‐escalating first‐in‐human (FiH) studies, a dose cap with a 10‐fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in animals. However, the convulsive risk seen in animals does not generally translate to humans. Several lines of evidence are summarized indicating that in a dose‐escalating setting, electroencephalographic epileptiform abnormalities occur at lower doses than clinical convulsive events. Therefore, we propose to consider the occurrence of epileptiform abnormalities in toxicology studies as premonitory signals for convulsions in dose‐escalating FiH studies. Compared with the traditional dose‐cap approach, this may allow the exploration of higher doses in FiH and, subsequently, phase II studies without compromising human safety. Similarly, the presence or absence of electroencephalographic epileptiform abnormalities may also aid the assessment of proconvulsive risk in situations of increased perpetrator burden as potentially present in pharmacokinetic and/or pharmacodynamic drug–drug interactions.

show abstract

Results and evaluation of a first‐in‐human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods

Cited by 11 publications

References 16 publications

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

Glutamate hypothesis in schizophrenia

A Framework Proposal to Follow‐Up on Preclinical Convulsive Signals of a New Molecular Entity in First‐in‐Human Studies Using Electroencephalographic Monitoring

Contact Info

Product

Resources

About