Anti-drug antibodies can stop drugs from working and can cause infusion reactions. They are rare to common occurrances due to the target the drug, the person, the assay, the reporting levels and the route. The subcutaneous route is under the skin and can induce more antibody responses than the intravenous (Infusion) route. However we have seen the opposite and this is seen here. With ocrelizumab infusion the rate of ADA is reported to be low and is below 1% and in the real world it is low. In this study they do not exist so “they are unimportant and not to be considered” Now the detection depends on the assay but it can depend on the drug. Is 0% too low perhaps. They do inject more under the skin i.e 920mg vs 600mg and as some people were already treated i.e. and were B cell depleted already they wouldn’t make a good antibody response anyway. There were a couple of people that did make an ADA response but that was to stuff in the formulation.
With natalizumab under the skin we have seen the same conclusion that there are no ADA…and here it is too good to be true because here they inject the same amount in the skin as in the infusion and in the main study they switched people from infusion to subcutaneous and then reported no ADA. But if you use the infusion if you look in the label details it says 10% of people make ADA. If you use a different assay it is 80% but the point is with time it drops and so the people with the infusion first make and loose the ADA with time, but th time ADA starts people are tolerant. In the studies where they started people straigtht on to subcuatneous natalizumab it was only reported that there was one person with ADA at the 300mg dose. That is 1 of 26 people (4%) (Plavina et al. J Clin Pharmacol. 2016;56:1254-62 But that is persistant positives so similar to the i.v. route but in the summary of product characteristics (pg 33) it is not this. They did not mention 5 people that had non-persistent antibodies so the real result is 5/26 (19%) which is double the rate from the infusion trails (9%). We now understand that the rate of ADA is artifically low because they only reported functionally important levels allowing one to ignore people that had lower levels. Will this be the case of ocrelizumab, there has been a real world report using a different ADA assay and the level after infusion is still low at about 6%, but I think they are special as anti-=CD20 inhibit antibody cell formation and are self-protective and is re-assuring that ADA remain low over 2 years. ProfAngry has looked and they are indeed rare in people getting an infusion
Week 96 Analysis of the OCARINA II Study Characterizing Subcutaneous Ocrelizumab in Patients With Relapsing or Primary Progressive Multiple Sclerosis
Scott D. Newsome et al.
Objective: To further characterize the benefit-risk profile of ocrelizumab subcutaneous based on the Week (W) 96 analysis of efficacy, safety and patient-reported outcome data from OCARINA II (NCT05232825).
Background:OCARINA II showed ocrelizumab subcutaneous 920 mg (coformulated with recombinant human hyaluronidase PH20 [rHuPH20]) was noninferior to ocrelizumab intravenous 600 mg regarding drug exposure and had a similar benefit-risk profile in patients with relapsing or primary progressive multiple sclerosis (pwRMS/pwPPMS) up to W72.
Design/Methods:Ocrelizumab-naive pwRMS/pwPPMS (18-65 years; Expanded Disability Status Scale score [EDSS]: 0-6.5) were randomized 1:1 to ocrelizumab intravenous 600 mg or ocrelizumab subcutaneous 920 mg. At W24, all patients (ocrelizumab intravenous/subcutaneous and ocrelizumab subcutaneous/subcutaneous) could enter the treatment phase with ocrelizumab subcutaneous up to W96. Safety was evaluated in all patients who received ≥1 dose of ocrelizumab subcutaneous (all-exposure group).
Results:Ocrelizumab subcutaneous resulted in near-complete suppression of MRI and relapse activity up to W96, with 96.7% of patients being relapse free. Up to W96, annualized relapse rate was 0.02 and 0.03 for ocrelizumab intravenous/subcutaneous and subcutaneous/subcutaneous, respectively. EDSS remained stable up to W96, with a mean (SD) change from baseline of −0.12 (0.66) in the ocrelizumab intravenous/subcutaneous arm vs −0.16 (0.81) in the ocrelizumab subcutaneous/subcutaneous arm. In the ocrelizumab subcutaneous all-exposure group, 86.3% of patients had an adverse event (AE), 5.2% had a serious AE and 58.4% had an injection reaction (IR; local IR, 55.4%; systemic IR, 13.3%). All IRs were nonserious and mild/moderate in intensity, most resolved, and the incidence and severity decreased with subsequent injections. No treatment-emergent antidrug antibodies (ADA) to ocrelizumab were reported; 2 patients had treatment-emergent ADA to rHuPH20. Patient-reported outcomes data will be presented.
Conclusions:Ocrelizumab subcutaneous continues to show a favorable benefit-risk profile, similar to that of the well-established intravenous route of administration, and provides flexibility and convenience of administration for pwRMS/pwPPMS.
COI: Multiple …As every this post is about our work and we are using this paper to make a point about our work
Source: multiple-sclerosis-research.org