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Bayesian Frameworks for Rare Disease Clinical Development Programs
Published in Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger, Bayesian Methods in Pharmaceutical Research, 2020
Freda Cooner, Forrest Williamson, Bradley P. Carlin
As an example, Myozyme/Lumizyme (alglucosidase alfa) is an enzyme replacement therapy approved for Pompe disease. The original approval of Myozyme in 2006 was based on a historically controlled trial. The primary endpoint is time-to-death that starts from age 0 for both current trial subjects and the matching historical control cohort. Serving as the FDA statistical reviewer, Kammerman (2006) pointed out the decision was misleading, as the current trial subjects had to survive long enough to be enrolled into the trial, whereas all historical control subjects without any intervention were traced back to age 0. This is just one example where it is unachievable to mimic a randomized trial with a poorly matched historical control group. However, Bayesian statisticians could potentially build a simulator to generate a control group from the posterior distribution based on the whole historical group (inclusive of the matching cohort) and a noninformative prior. A second example is offered by Brineura (cerliponase alfa), the first treatment approved for a form of Batten disease. The approval in 2017 was also based on a single-arm historically-controlled study. The cohort was matched based on a physician rating, and the statistical reviewers (Min et al., 2017) spent much effort finding a suitable matching criteria to identify a “matching” historical control cohort. Through proper predictive modeling, Bayesian statistics may be introduced to provide a better estimate or distribution of the treatment effect through simulation. Unlike the Myozyme case, obtaining a consensus from clinical colleagues on the analysis model or acceptable treatment effect measurements may be challenging. Often, the so-called historical control is a simple literature review summary (e.g. Cholbam — cholic acid approval; U.S. Food and Drug Administration, 2015), and there is little statisticians can do to facilitate evaluation except design and produce simulations based on these summary data.
Metabolism of bioconjugate therapeutics: why, when, and how?
Published in Drug Metabolism Reviews, 2020
Hanlan Liu, Jayaprakasam Bolleddula, Andrew Nichols, Lei Tang, Zhiyang Zhao, Chandra Prakash
NeoGAA is an investigational second-generation alglucosidase alfa enzyme replacement therapy for the treatment of Pompe disease that has been specifically designed for enhanced receptor targeting and enzyme uptake through greater affinity for the M6P receptors on muscle cells, with the aim of enhancing glycogen clearance and improving on the clinical efficacy achieved with GAA (Figure 27). In preclinical studies, neoGAA showed approximately fivefold greater potency than alglucosidase alfa with respect to tissue glycogen reduction compared to alglucosidase alfa. In the Pompe mouse model, neoGAA reduced similar levels of substrate at one-fifth the dose of alglucosidase alfa (Zhu et al. 2009). The expected lower doses of neoGAA needed for the treatment of Pompe patients could also result in a decreased magnitude of the host immune response to the administered therapeutic, which in turn could positively impact the efficacy of treatment.
Enzyme replacement therapy for the treatment of Pompe disease
Published in Expert Opinion on Orphan Drugs, 2018
(2) ERT in combination with other drugs Alglucosidase alfa and miglustat (Federico II University of Naples, Italy)Amicus rhGAA (ATB200) and miglustat (AT2221) (Amicus Therapeutics)Alglucosidase alfa and albuterol (Duke University, United States). Albuterol was previously found effective with branched-chain aminoacids [62].Alglucosidase alfa and clenbuterol (Duke University, United States). Clenbuterol was found effective in murine Pompe disease [63].
Identification of approval conditions for orphan drugs for neurological disorders by the Japanese regulatory agency
Published in Expert Opinion on Orphan Drugs, 2018
Harumasa Nakamura, Shin’ichi Takeda, Masaru Iwasaki
Conducting confirmatory pivotal efficacy studies for orphan drugs is challenging due to the rarity of the diseases being targeted. In these situations, recruiting a sufficient number of patients for clinical trials is inherently difficult, and it would not be realistic for a regulatory agency to require an adequate number of patients for these clinical trials in order to prove efficacy based on statistical analysis. Further, placebo-controlled clinical trials may be unethical and unnecessary for drugs intended to treat rare diseases that are life-threatening and rapidly fatal. One example of such a rare disease is infantile Pompe disease, for which alglucosidase alfa was approved for treatment in Japan in the absence of any domestic trials.