Injectable non-immunogenic PEG-like conjugate that forms a subcutaneous depot and enables sustained delivery of a peptide drug

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. Unfortunately, PEG is immunogenic and forms vacuoles, and improvement in PEGylated drugs' half-life is at an asymptote. Here, we developed a PEG-like, non-immunogenic, and injectable conjugate technology for sustained delivery of biologics. An optimal poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) depot of exendin, a peptide drug used in the clinic in treating type 2 diabetes, outperformed PEG, non-depot-forming POEGMA, and a clinical sustained-release exendin-4 formulation in efficacy and pharmacokinetics. Notably, POEGMA was non-immunoreactive, while PEG induced a persistent anti-PEG immune response, leading to its subsequent doses' early clearance and loss of efficacy. POEGMA did not induce vacuolization. Solving these problems of PEG and improving upon its half-life benefits by creating injectable POEGMA conjugates that form a drug depot under the skin and provide sustained efficacy breathe new life into an established and valuable drug delivery technology that is facing an impasse.

An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.

Long-Term Efficacy and Safety of Erenumab

ObjectiveTo report the efficacy and safety of erenumab among episodic migraine (EM) patients who were unsuccessful on 2–4 preventive treatments observed at week 64 of Open-Label Extension Phase (OLEP) of the LIBERTY study (ClinicalTrials.govNCT03096834).MethodsThe OLEP evaluating monthly erenumab 140 mg for 3 years, enrolled 240 patients who completed the double-blind treatment phase (DBTP) of 12 weeks during which they received placebo or erenumab 140 mg subcutaneous injections every 4 weeks as monotherapy. Efficacy outcomes were evaluated through the initial 52 weeks of OLEP (from DBTP baseline to total 64 weeks) in the overall population, patients receiving erenumab in DBTP, and patients from DBTP placebo arm who switched to erenumab in OLEP. Endpoints included reduction of ≥50% in monthly migraine days (MMD) from DBTP baseline and change in MMD from DBTP baseline, Headache Impact Test, and Migraine Physical Function Impact Diary (Physical Impairment and Everyday Activities) scores.ResultsAltogether, the week 52 visit of the OLEP was completed by 204/240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increase from 29.9% at weeks 9%–12% to 44.3% at week 61–64. The 50% responder rate in patients who initiated erenumab in the OLEP remained higher in the OLEP (50.0% at week 61–64) than during DBTP (14.2% at weeks 9–12) compared to patients in continuous erenumab arm. In the OLEP, the 50% responder rate for the overall population increased from weeks 13–16 until weeks 37–40 and then remained stable through weeks 61–64. Patients treated with erenumab in DBTP showed sustained effects on all efficacy outcomes; those initiating erenumab in the OLEP demonstrated continued improvement from week 13 onward. Adverse events (AEs) were reported, considering both treatment groups, by ∼80.8% (serious AEs [SAEs] by 6.7%); 76.3% (5.9%) in the continuing erenumab arm; and 85.2% (7.4%) in those starting erenumab in OLEP. No deaths were reported.ConclusionsIn patients with EM who were unsuccessful on 2–4 prior preventive treatments, the LIBERTY study demonstrated sustained efficacy on erenumab monotherapy treatment through 64 weeks in both treatment arms. Safety of erenumab was consistent with that observed in previous clinical trials.Classification of evidenceThe current study provides Class IV evidence on data from patients with episodic migraine, that erenumab is safe and provides sustained efficacy at 52 weeks.Clinicaltrials.gov identifierNCT03096834.