Secukinumab immunogenicity was low, as shown by TE-ADA detection in only 11 of 2842 (0·4%) patients with moderate-to-severe plaque psoriasis treated with secukinumab. All but one of the patients with TE-ADAs were biologic naive. Neither TE-ADAs nor neutralizing antibodies were associated with loss of secukinumab efficacy or issues of clinical concern.

Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli. The payload is delivered upon inflation of a balloon folded within the RP, which deflates immediately after drug delivery. Here we present results from two clinical studies demonstrating the safety, tolerability and performance of the RP in healthy humans. In the first study, three versions of the RP (A, B and C) were evaluated, which were identical in all respects except for the diameter of the balloon. The RP successfully delivered a biotherapeutic (octreotide) in 3 out of 12 subjects in group A, 10 out of 20 subjects in group B and 16 out of 20 subjects in group C, with a mean bioavailability of 65 ± 9% (based on successful drug deliveries in groups A and B). Thus,  reliability of drug delivery with the RP ranged from 25 to 80%, with success rate directly related to balloon size. In a separate study, the deployment of the RP was unaffected by fed or fasting conditions suggesting that the RP may be taken with or without food. These promising clinical data suggest that biotherapeutics currently administered parenterally may be safely and reliably delivered via this versatile, orally ingestible drug delivery platform. Graphical abstract

Background Monoclonal antibodies (mAbs) comprise a large and important class of therapeutic biologicals with the potential for treatment of a wide range of clinical indications. Secukinumab (AIN457) is a new fully human mAb targeting IL-17A for the treatment of inflammatory diseases. Administration of mAbs can be associated with immunogenicity via the induction of anti-drug antibodies (ADAs). ADAs can lead to unwanted clinical consequences, such as loss of exposure, loss of efficacy due to altered pharmacokinetics and/or functional neutralization and, in the worst case, anaphylactic reaction and immune complex diseases. The assessment of ADA formation is therefore a critical component in the assessment of biotherapeutic safety. Methods The immunogenicity assessment strategy for secukinumab follows a three-tiered approach. First, samples are analyzed for presence of ADA in a screening assay which takes a 5% false-positive rate into account. In a second step, screening assay positive samples are tested in a confirmatory assay (competition with excess drug) that identifies true positive responses. Finally, true immunogenicity-positive samples are quasi-quantified via titration. In addition, pharmacokinetics and clinical efficacy/safety data are also evaluated. A Biacore-based assay was used during the early stages of the secukinumab program (up to phase 2B), and an MSD-based bridging assay was applied during the later stages of the program (proof-of-concept, phase 2B, phase 3). The MSD assay is able to detect 4 ng/mL of a positive control anti-secukinumab antibody and can detect 500 ng/mL of this positive control in the presence of 14.7 µg/mL secukinumab, consistent with current regulatory guidelines. Samples to assess immunogenicity were obtained from individual subjects encompassing 18 clinical studies in different indications during treatment and during follow-up. So far, 1582 subjects have been tested for ADAs, of which 486 have been tested with the MSD assay. Dosing regimens included single doses such as 25 mg subcutaneously in psoriasis patients as well as multiple 7 x 10 mg/kg doses intravenously in MS patients over a six-month period. Results None of the subjects tested for immunogenicity developed sustained ADAs. In total, 4 subjects met the definition of treatment-related, transient positive immunogenicity showing low ADA titers. None of these subjects had evidence of loss of efficacy, deviating PK behavior, or reported anaphylactic reaction or immune complex disease. Conclusions Based on the available data, secukinumab appears to carry a low risk of immunogenicity. In the very few transient immunogenicity-positive patients identified so far, there has been no indication of altered pharmacokinetics or loss of efficacy, and no adverse event that could be linked to immunogenicity has been detected. More data from the ongoing phase 3 studies are required to strengthen this encouraging finding in a larger patient population. Disclosure of Interest U. Klein Employee of: Novartis, E. Liang Employee of: ...

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Aim: We developed a platform to painlessly deliver by mouth drugs that cannot be administered orally. This ingestible, capsule-like device deploys inside the small intestine and injects into its wall a biotherapeutic payload sealed inside a dissolvable microneedle. Results: We tested the delivery and examined the pharmacokinetics of several biopharmaceuticals, including recombinant human insulin, human immunoglobulin G, octreotide and teriparatide in anesthetized and conscious pigs and dogs. The bioavailability of these compounds delivered by the capsules was similar to that after subcutaneous delivery. For instance, the mean peak serum concentration of insulin after capsule delivery in 8 anesthetized pigs was 517 ± 109 pmol/l, versus 342 ± 50 pmol/l after subcutaneous injection in 9 other, sham-operated pigs. In vivo safety studies were conducted in 23 conscious beagles, which received between 2 and 18 capsules. All devices transited painlessly through the GI tract and were excreted within 96 h. The mean gastric residence time (GRT) of the capsules was 93 min, and subsequent intestinal deployment time (IDT) was 28 minutes. A pilot study in 10 fasting and 10 postprandial human volunteers examined the tolerability and safety of the capsule devoid of microneedle and payload. The mean GRT of the capsule was 217 ± 36 min in the postprandial and 100 ± 79 min in the fasting state, while the IDT were closely similar (100 ± 40 vs. 97 ± 30 min) in both groups. No subject perceived the device transit, deployment or excretion. Conclusions: The studies completed thus far in anesthetized or conscious animals have confirmed that this ingestible device can deliver drugs in sufficient amounts and rate to obtain therapeutic blood concentrations. Its oral administration was well tolerated by the human subjects. First-in-man studies are being planned to test the ability of this ingestible device to deliver pharmaceuticals in healthy human volunteers and patients. Disclosure R. Ruffy: Employee; Self; RANI Therapeutics. M. Hashim: Board Member; Self; Rani Therapeutics. Employee; Self; InCube Labs LLC. A. Dhalla: Employee; Self; Rani Therapeutics, LLC. R. Korupolu: None. P. Karamchedu: Employee; Self; Incube labaoratories, Rani Therapeutics. B. Syed: None. R. Abdul Wahab: Employee; Self; Rani Therapeutics. S. Beraki: Employee; Self; InCube Laboratories, RANI Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. L. Fusaro: None. A. Garapaty: None. A. Dasari: None. L. Fung: Employee; Self; Rani Therapeutics. Z.T. Al-Shamsie: Employee; Spouse/Partner; Google. Employee; Self; Rani Therapeutics, InCube Labs LLC. A. Toledo: Employee; Self; InCube Labs LLC, Rani Therapeutics. V. Salgotra: Employee; Self; Incubelabs, Rani Therapeutics. S. Sharma: None. E. Liang: None. D. Gratta: Employee; Self; InCube Labs, Rani Theraputics. M. Imran: Other Relationship; Self; InCube Labs, InCube Ventures, Rani Therapeutics.