produced in a recombinant Chinese hamster ovary ( CHO ) cell line . Because the glycosylation pattern varies between ch14.18 / CHO and ch14.18 / SP2 / 0 ( Unituxin ® ) due to the different production cell lines , which might influence pharmacokinetics , efficacy and safety of the antibody , the two products are not considered biosimilars . However , no direct clinical comparison between the two products has been conducted .
Dinutuximab beta was developed by the Vienna-based biotech company , Apeiron Biologics AG , as a result of a collaborative effort between academic institutions ( the SIOPEN group ), Austrian private investors , and public and private research initiatives . EUSA Pharma ( UK Limited ) acquired the exclusive global commercialisation rights of dinutuximab beta from Apeiron Biologics AG in September 2016 . On 8 May 2017 , the European Commission granted marketing authorisation for ‘ dinutuximab beta Apeiron ’.
The EMA evaluated the clinical efficacy of dinutuximab beta in three studies : APN311-202 ; 302 ; and 303 . Study 202 was a Phase I / II dose schedule finding study of ch14.18 / CHO continuous infusion combined with subcutaneous aldesleukin ( IL-2 ) in patients with primary refractory or relapsed neuroblastoma . Ch14.18 / CHO was administered as a ten-day continuous infusion for a total of five cycles , combined with IL-2 and 13-cis RA . A total of 44 patients from Spain , France , Italy , UK , Germany , Israel , and Austria with relapsed / refractory neuroblastoma were enrolled . 18 At the end of treatment , response was observed in 14 / 33 patients ( 42 %) with measurable disease . The treatment response was higher in refractory disease ( 48 %; 10 / 21 ) than in relapsed disease ( 33 %; 4 / 12 ) and the range for the duration of response was from five weeks to three years , median 2.3 years . Study 303 was a ‘ Retrospective analysis of data collected during the administration of ch14.18 / CHO continuous infusion combined with subcutaneous aldesleukin ( IL-2 ) in patients with HR-NB under a compassionate use program ’. Ch14.18 / CHO was given in combination with fixed doses of subcutaneous IL-2 , and cis-retinoic acid . Between November 2009 and August 2013 , 54 patients were treated . Half of the patients had relapsed NB ; 15 ( 28 %) had refractory disease ; and 9 ( 17 %) had received first-line neuroblastoma treatment with either complete response or at MRD . At the end of treatment ( 5 – 6 cycles ) a response ( CR + PR ) was observed in 12 / 39 patients ( 31 %) with evidence of disease at baseline while progression occurred in 17 / 39 patients ( 44 %). In patients with relapse / refractory disease , the response rate was 10 / 36 ( 28 %).
The 303 Study results were compared with historical controls from a retrospective study performed by Garaventa and colleagues of the Italian Neuroblastoma Registry for patients diagnosed during or after 1999 , 24 because treatment was deemed comparable to the treatment used prior to immunotherapy in patients included in study APN311-303 . Furthermore , comparison was restricted to patients with relapsed neuroblastoma , patients who were ≥1 year of age at initial diagnosis / relapse and who presented with stage 4 at initial diagnosis . The difference in OS between the two cohorts was highly significant in favour of dinutuximab beta . Finally , APN311-302 ( or HR-NBL-1 / SIOPEN ) evaluated safety and efficacy of ch14.18 / CHO from data collected in the high risk neuroblastoma ( HRNBL1 ) study of SIOP- Europe ( SIOPEN ), a multinational , open-label , randomised , controlled Phase III trial in HR-NB patients conducted by SIOPEN to control minimal residual disease after induction chemotherapy , myeloablative therapy with stem-cell rescue , and radiation therapy . Study APN311-302 evaluated the effect of IL-2 to the ch14.18 / CHO + CRA regimen . Patients were randomised to ch14.18 / CHO ( 100mg / m 2 per cycle in five daily eight-hour infusions ) with or without IL-2 ( 60 x 10 6 IU by cycle ) and all received 13-cis RA . Ch14.18 / CHO was administered as an eight-hour IV infusion , at a dose of 20 mg / m 2 / day over five days , every four weeks over five courses . A total of 406 patients from ten countries were enrolled from November 2009 until August 2013 . A total of 187 patients received cho14.18 + CRA only ( group 1 ) and 198 cho14.18 + IL-2 and CRA ( group 2 ). Three-year EFS and OS for group 1 was 55.4 % and 64.1 %; and for group 2 , 61.2 % and 69.1 %, respectively . Historical comparison for the use of dinutuximab beta with patients enrolled in the same SIOPEN protocol but in an earlier phase where these patients did not receive immunotherapy but only CRA showed three-year OS of 59 % for the non-immunotherapy group vs 71 % for the ch14.18 / CHO group , statistically significant .
In studies APN311-202 and 303 , the most frequent toxicities were fever , pain , vomiting , cough , increased weight , skin reactions , constipation , tachycardia , hypotension , and
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