A Novel PEGylated Interferon Beta‐1a for Multiple Sclerosis: Safety, Pharmacology, and Biology

Hu, Xiheng; Miller, Larisa; Richman, Sandra; Hitchman, Stacy; Glick, Gabrielle; Liu, Shifang; Zhu, Ying; Crossman, Mary; Nestorov, Ivan; Gronke, Robert S.; Baker, Darren P.; Rogge, Mark; Subramanyam, Meena; Davar, Gudarz

doi:10.1177/0091270011407068

Cited by 106 publications

(107 citation statements)

References 24 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…However, the immunogenicity of PEG-IFN ␤-1a in monkeys is not predictive of the human response. When PEG-IFN ␤-1a was tested in humans, no subject developed NAbs after single-or multipledose PEG-IFN ␤-1a treatment (Baker et al, 2010;Hu et al, 2011). This observation is consistent with IFN ␤-1a, of which the immunogenicity rate was 2 to 5% in a study in patients with MS (Panitch et al, 2002; http://www.accessdata.…”

Section: Discussionsupporting

confidence: 64%

“…It is noteworthy that these observations in Rhesus monkeys are in contrast to those in humans, where neopterin elevation was of longer duration after PEG-IFN ␤-1a treatment than that after IFN ␤-1a treatment at comparable doses (Hu et al, 2011). Furthermore, preliminary PK/PD modeling did not indicate reduction of the stimulatory effect in humans over a 1-week exposure (data not shown).…”

Section: Discussionmentioning

confidence: 81%

“…administered once weekly for 5 weeks, and the no-observed-adverse-effect level was determined to be 100 g/kg. These studies were used to successfully enable two phase 1 clinical trials of PEG-IFN ␤-1a in healthy subjects (Hu et al, 2011); data from which in turn enabled a phase 3 study in patients with relapsing MS.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Human interferon (IFN) ␤ has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN ␤-1a (PEG-IFN ␤-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN ␤-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN ␤-1a and PEG-IFN ␤-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN ␤-1ashowed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN ␤-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN ␤-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN ␤-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 g/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 g/kg (11 MIU/kg), the highest dose tested.

show abstract

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overall, the prevalence and impact of the anti-PEG preAbs varies with specific products and study populations (16,(62)(63)(64)(65)(66) (Table II). High incidences of treatment induced anti-PEG antibodies have been documented only for the large conjugates of highly immunogenic proteins, such as Pegloticase ™ (Table II).…”

Section: Pegylated Biologic Proteinsmentioning

confidence: 99%

Pre-existing Antibody: Biotherapeutic Modality-Based Review

Gorovits

Clements-Egan

Birchler

et al. 2016

AAPS J

View full text Add to dashboard Cite

Abstract. Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.

show abstract

“…Hu et al studied the differences in absorption kinetics of PEG-IFN β-1a, following IM versus SC administration to rhesus monkeys (49). PEG-IFN β-1a is a second-generation IFN β-1a-20-kDa PEG conjugate and is currently in phase III studies for the treatment of MS, with the goal of decreasing the frequency of administration compared to the approved unconjugated IFN β-1a (Anovex, Table I).…”

Section: Pegylationmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

Vugmeyster

Harrold

2012

AAPS J

View full text Add to dashboard Cite

Abstract. Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.

show abstract

A Novel PEGylated Interferon Beta‐1a for Multiple Sclerosis: Safety, Pharmacology, and Biology

Cited by 106 publications

References 24 publications

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Pre-existing Antibody: Biotherapeutic Modality-Based Review

Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

Contact Info

Product

Resources

About