Date: 2012-06-25
Type of information: Results
phase: 2
Announcement: results
Company: Pfizer (USA - NY) Ablynx (Belgium)
Product: ozoralizumab
Action
mechanism: Ozoralizumab is a trivalent, bi-specific Nanobody (Nanobodies® are therapeutic proteins based on single-domain antibody fragments) that potently neutralises TNF alpha and binds to human serum albumin to increase its in vivo half-life. The Nanobody format has a number of significant advantages over the currently available TNF alpha inhibitors. It does not have an Fc domain (‘antibody tail’), and hence is not expected to engage the patient’s immune system. Its smaller size and the fact that ozoralizumab binds to human serum albumin could lead to an improved tissue penetration, for instance to inflamed joints. Its physicochemical properties allow for high concentration of the final drug product and for alternative routes of administration other than just injection.
Disease: rheumatoid arthritis
Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases
Country:
Trial
details: In February 2010, Pfizer started a long-term safety study for ATN-103, which is an open-label extension study of the Phase II trials. A total of 266 patients (85%) from these previous two Phase II studies rolled-over into the open-label extension study (OLE) (which was fully funded by Pfizer) and were treated with ozoralizumab by a subcutaneous (sc) injection every four weeks (Q4W) for an additional 48 weeks on top of methotrexate. Following a washout period of eight to twelve weeks during which no study-drug was administered, all patients started with a dose of 10 mg Q4W and subsequent doses could be escalated, dependent on their physician’s assessment, to 30 mg and then 80 mg Q4W.
A total of 86% of patients completed the study: 56% of the patients completed the study at 80 mg Q4W, 29% of the patients completed the study after a single dose escalation step to 30 mg Q4W, and 15% of the patients stayed at their starting dose of 10 mg Q4W.
Latest
news: * On June 25, 2012, Ablynx has announced that its anti-TNF alpha Nanobody, ozoralizumab (ATN-103), for the treatment of inflammatory diseases, showed excellent safety and efficacy results in the 48-week open-label extension study of the worldwide and Japanese Phase II trials in the treatment of patients with rheumatoid arthritis who have an insufficient response to methotrexate alone.
The following results refer to the study population that completed the study treatment and results are pooled for all patients who started at 10 mg and either stayed at 10 mg or subsequently received monthly injections of 30 mg and 80 mg.
Efficacy parameter Week 48 (N=230)
ACR20 84%
ACR50 63%
ACR70 32%
Clinical remission (DAS28<2.6) 38%
(DAS28 is an RA disease activity score based on C-reactive protein (CRP), tender and swollen joint counts of 28 defined joints and physician’s global health assessment; a total score of >5.1 is associated with high disease activity, moderate from 3.2 to 5.1, low disease activity from 2.6, and remission of disease if <2.6)
The ACR6 scores were highly comparable to reported OLE Phase II data from other TNF? blockers. Moreover, for patients who responded well on ozoralizumab in the proof-of-concept trial and entered the open-label extension study with low or no disease activity, doses starting as low as 10 mg monthly were sufficient to improve or maintain the patient’s response throughout the 48 weeks study period, suggesting the possibility of individualised dosing based on a patient’s disease activity and weight, which could offer important health economic and patient safety benefits.
With a mean improvement of 3.11 in the overall DAS287 score, a large proportion (38%) of patients achieved the criteria for disease remission (i.e. no signs of disease activity), the ultimate treatment goal.
These additional Phase II data (ACR20 84%; DAS28 remission 38%) demonstrates that ozoralizumab could have an important competitive and differentiated position in the $24 billion TNF alpha market. These data suggest that ozoralizumab enables individualised treatment, a real breakthrough in TNF? therapy, which could prove beneficial to patients and minimise the treatment cost. Moreover immunogenicity did not affect the efficacy of ozoralizumab. Only 2.6% of patients (7/266) tested positive for neutralising anti-drug antibodies (nADAs) at any time during the 48 week study and all of them completed the trial, with 57% (4/7) of these patients achieving DAS28 remission. Moreover, only 0.75% of patients remained positive for nADAs at the end of the treatment period. Humira® (adalimumab), the leading commercialised anti-TNF? product states on its label that it may produce neutralising antibodies in 1-12% of patients within one year of treatment, though recent data suggest that this number may be considerably higher and up to 35% (Ann Rheum Dis (2007) 66: 921-926, Rheumatol Int (2007) 27: 269-274, JAMA 305(14):1460; EULAR 2012 AB0055). In addition the label states that formation of anti-adalimumab antibodies is associated with reduced efficacy, which is confirmed in a recent publication to result in a diminished treatment response (only 4% of patients with nADAs achieved DAS28 remission), hence the need to switch to another drug regimen over time.
The most common adverse events associated with ozoralizumab treatment were infections. Of these, only 3 events per 100 patient years were serious, which is comparable to those seen with other TNF? drugs, indicating that ozoralizumab has a promising safety profile. An average reported number of 4.7 events per 100 patient years is reported for all currently marketed TNF? blockers.
Last November, Ablynx announced that it has regained worldwide rights from Pfizer to develop and commercialise Nanobodies targeting TNF-alpha. These rights include the product ozoralizumab (ATN-103) and the product PF-05230905, which is in Phase I trials.
Ablynx is now in partnership discussion for ozoralizumab.
* On May 17, 2011, Ablynx has announced top-line results from the recently completed POC Phase II clinical trial of ozoralizumab (ATN-103), an anti-TNF-alpha Nanobody® licensed to Pfizer, in patients with active rheumatoid arthritis. The study evaluated five different dosing groups plus placebo, and preliminary analysis of the data indicates that the study met its pre-defined primary efficacy endpoint with the highest dose of ozoralizumab (80 mg every 4 weeks) resulting in a statistically significant improvement of ACR20 responses compared with placebo at week 16. In addition, an improvement over placebo was also observed for secondary endpoints such as improvements of clinical scores, DAS28, ACR50, ACR70 and EULAR response at this dose level at week 16. No dose limiting toxicities were observed, and the adverse events and serious adverse events that did occur, did not show a clinically significant increase on increased dosing.
Pfizer have now confirmed that clinical proof-of-concept has been achieved and they are now engaged in a full technical, clinical and commercial evaluation to determine whether and how to take ATN-103 forward. Pfizer successfully completed Phase I studies with ATN-103 in the summer of 2009, and then initiated two randomized, double-blind Phase II trials in Japan, US and Rest of the World in September 2009, which finished recruitment of a total of 312 patients in September 2010.
