Biosimilars at ASH 2019: Data on Truxima and Competitors for Eculizumab

At ASH, Data on Truxima Underscore the Biosimilar's Safety and Efficacy

Celltrion and Teva's Biosimilar Rituximab, CT-P10 (Truxima), recently launched in the United States. The product is the first rituximab biosimilar to become available to patients in the United States,¹ and during the 61st meeting of the American Society of Hematology (ASH) held from December 7-10, 2019, a pair of research teams presented data that highlight the biosimilar’s safety and efficacy in patients with lymphoma.

New phase 3 data show similar safety and efficacy between CT-P10, reference

First, a team presented on updated phase 3 study results from a clinical trial of the biosimilar in 140 patients with newly diagnosed advanced-stage follicular lymphoma.² Previously reported results from the same trial showed similarity between the biosimilar and the reference product, Rituxan, in terms of progression-free survival (PFS) and overall survival (OS) at a median follow-up of 22.6 months. In the study, 70 patients received biosimilar rituximab with cyclophosphamide, vincristine, and prednisone, and 70 patients received the reference with the same regimen, for 8 cycles. Of these patients, 62 in the biosimilar group and 60 in the

reference group entered the rituximab monotherapy maintenance period after induction therapy, and 46 and 38 patients, respectively, completed the maintenance

period of 2 years. After 2 years, patients were followed for tumor evaluation up to 3 years from the last patient’s first infusion.

For investigator-assessed PFS, time to progression (TTP), and OS, medians have not been reached in either group (median follow-up durations: 40 months in the CT-P10 group and 39 months in the reference group). There were no significant differences between the groups in terms of PFS (hazard ratio [HR], 1.33; 95% CI, 0.67-2.63; 4-year PFS for CT-P10, 60.9%; 95% CI, 46.5%-72.5%; 4-year PFS for reference, 54.7%; 95% CI, 36.1%-70.0%).

There were also no signifi cant diff erences in TTP (HR, 1.17; 95% CI, 0.58-2.37; 4-year TTP for CT-P10, 64.2%; 95% CI, 49.4%-75.7%; 4-year TTP for reference,

55.8%; 95% CI, 36.8%-71.1%). OS was comparable between the groups (4-year OS for CT-P10, 88.0%; 95% CI, 77.5%-93.8%; 4-year OS for reference, 93.3%; 95% CI, 83.2%-97.4%; P = .287).

In total, 30% of patients in each group experienced disease progression. Five patients in the biosimilar group and 2 patients in the reference group died during the study period. No new safety signals were identified, and similar numbers of patients in each group experienced at least 1 treatment-emergent adverse event.

Rapid infusion with CT-P10 is well tolerated

Second, another group of researchers reported on a postauthorization safety study of the biosimilar that is currently underway in several European nations.³ The study concerns rapid infusion of the biosimilar, over a period of 90 minutes or less, during routine clinical practice.

In Europe, the recommended protocol for rituximab infusion is a slow initial infusion rate with a gradual upward titration, but rapid infusion is often used in second or subsequent infusions for patients who had no serious complications with a first infusion.

In the study, 112 patients with lymphoma who had between 1 and 4 prior infusions with CT-P10 were given subsequent rapid infusions over a 6-month observation. In total, 19 patients experienced 1 or more infusion-related reactions (IRRs). Of these patients, 9 had 1 IRR, 5 had 2 IRRs, and 5 had 3 or more IRRs.

The best responses to rituximab therapy during the observation period were complete response in 74% of patients, partial response in 21% of patients, stable disease in 3% of patients, and progressive disease in 2% of patients, said the investigators.

References

1. Davio K. First rituximab biosimilar Truxima launches in the United States. The Center for Biosimilars® website. centerforbiosimi lars.com/news/first-rituximab-biosimilar-truxima-launches-in-the-united-states. Published November 7, 2019. Accessed December 11, 2019.

2. Buske C, Kwak LW, Jurczak W, et al. Long-term efficacy and safety results of CT-P10 and reference rituximab in patients with newly diagnosed advanced stage follicular lymphoma: phase III updated study results with median follow-up of 40 months. Presented at: 61st Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 1528.

Data on Complement Inhibitors and Proposed Biosimilars Featured at ASH

3. Bishton M, Zinzani PL, Marshall S, et al. Rapid infusion with CT-P10 in patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia: interim six month follow-up from a European non-interventional post-authorization study. Presented at: 61st Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 4135.Eculizumab, a C5 complement inhibitor, has changed the treatment landscape for several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, and atypical hemolytic uremic syndrome. However, the drug, sold by developer Alexion as Soliris, is among the most expensive biologic therapies in the world—carrying a cost of approximately $500,000 per patient per year¹—and that cost has an impact on patient access.

Multiple biosimilar developers are taking aim at eculizumab, however, and at the same time, Alexion is continuing to invest in a longer-acting successor to eculizumab as biosimilars draw closer. During the 61st meeting of the American Society of Hematology (ASH), investigators reported on eculizumab, a prospective biosimilar, and the longacting ravulizumab.

Investigators report on PK and ADAs for proposed biosimilar eculizumab, ABP 959

Amgen is developing ABP 959, a proposed biosimilar to eculizumab, and the product has’previously been reported to have pharmacokinetic (PK) and pharmacodynamic equivalence with the reference Soliris.²

During ASH, researchers reported on an assessment of the relationship between PK parameters and antidrug antibodies (ADAs) for the proposed biosimilar and the reference.³ Their data derive from a randomized, double-blind, single-dose, 3-arm, parallel-group study in healthy male volunteers.

In the study, the 219 participants were randomized to receive 300 mg of either the biosimilar (n = 71), its US-licensed reference (n = 74), or its EU-licensed reference (n = 74), and serum samples for PK evaluation were collected over 57 days.

No neutralizing antibodies were detected during the study. At any time, the incidence of binding ADAs was 9.9% in the biosimilar group, 6.9% in the US reference group, and 9.5% in the EU reference group. At the end of the study, 1.9% of participants had binding ADAs, with 1.4% in the biosimilar group, 2.9% in the US reference group, and 1.4% in the EU reference group testing positive for these ADAs.

In those who had binding ADAs, PK was within the same range as it was in those without any ADAs detected, per the authors. Furthermore, the incidence of ADAs was similar between products and did not aff ect the overall PK similarity assessment.

Relatively few US patients with PNH start treatment with eculizumab Complement inhibition is becoming the standard of care in treating PNH, but given the fact that PNH is a rare disease, little is known about how patients are managed after diagnosis in real-world practice.

Using Truven US MarketScan commercial and Medicare data from 2015 to 2018, researchers sought to estimate the incidence and prevalence of PNH and to describe real-world treatment in patients who are newly diagnosed with the blood disease.⁴

They found that the incidence rate over the study period was 5.7 per 1,000,000 person-years, or 257 new diagnoses. Over a mean follow-up time of 385.6 days (SD, 253.2), just 10.3% of patients started eculizumab (95% CI, 6.3%-14.1%), initiating the drug 60.5 days (SD, 55.9 days) after diagnosis. At 1 year, approximately one-third of patients had discontinued eculizumab or taken a break in treatment.

Future studies should explore factors related to initiating eculizumab, say the investigators, as well as those related to treatment persistence.

Successor to eculizumab proves effective, safe at week 52

Meanwhile, ravulizumab, Alexion’s longeracting C5 complement inhibitor that offers’less frequent administration than eculizumab, was also the subject of a presentation of new data. Researchers presented 1-year safety and efficacy data from a phase 3 study in patients with PNH who had received eculizumab and transitioned to ravulizumab.⁵

Previously, treatment every 8 weeks with ravulizumab was shown to be noninferior to treatment every 2 weeks with eculizumab at 26 weeks. The new data, up to 52 weeks, derive from an extension of the open-label trial. In the extension, patients who had received ravulizumab continued maintenance therapy, and those who had received eculizumab switched to ravulizumab. In total, 191 of 192 patients in the study entered the extension, and 96 were in the ravulizumab-only group, whereas the

other 95 were in the switch group.

Patients in both groups showed a durable response for percent change in lactate dehydrogenase at 52’weeks; patients in the ravulizumab-only group had an 8.8% increase in lactate dehydrogenase from baseline (SD, 29%), whereas patients in the switch group had a 5.8% change (SD, 27%).’

During weeks 0 to 26, 88% of patients in the ravulizumab-only group avoided transfusion, versus 87% of patients in weeks 27 to 52. In the switch group, 83% avoided transfusion during both periods. During the extension period, 79% of patients in the ravulizumab-only group and 75% in the switch group had a treatment-emergent adverse event. Eight patients (8%) in the ravulizumab-only group and 5 (5%) in the switch group experienced serious adverse events, none of which led to discontinuation or death.

According to the researchers, ravulizumab continues to be well tolerated at week 52, with no new safety concerns arising in the extension, and the drug appears to have durable efficacy.

References

1. Elgin B, Bloomfield D, Chen C. When the patient is the gold mine. Bloomberg Businessweek website. www.bloomberg.com/news/features/2017-05-24/when-the-patient-is-a-gold-mine-the-trouble-withrare-disease-drugs. Published May 30, 2017. Accessed December 11, 2019.

2. Amgen’s eculizumab biosimilar ABP 959, shows PK, PD bioequivalence to Soliris. The Center for Biosimilars® website. www.centerforbiosimilars.com/conferences/eha-2019/amgens-eculizumab-biosimilar-abp-959-shows-pk-pd-bioequivalence-to-soliris-. Published June 18,

2019. Accessed December 11, 2019.

3. Hanes V, Pan J, Mytych DT, Chien D, Chow V. Relationship between pharmacokinetics and antidrug antibody status of ABP 959, a biosimilar candidate to eculizumab: results from a pharmacokinetic similarity study. Presented at: 61st Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 3520. www.ash.confex.com/ash/2019/webprogram/Paper128621.html.Accessed December 10, 2019.

4. Jalbert JJ, Chaudhari U, Zhang H, Weyne J, Shammo JM. Epidemiology of PNH and real-world treatment patterns following an incident PNH diagnosis in the US. Presented at: 61st Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 3407. www.ash.confex.com/ash/2019/webprogram/Paper125867.html. December 10, 2019.

5. Kulasekararaj A, Hill A, Langemeijer S, et al. One-year efficacy and safety from a phase 3 trial of ravulizumab in adult patients with paroxysmal nocturnal hemoglobinuria receiving prior eculizumab treatment. Presented at: 61st Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 2231. www.ash.confex.com/ash/2019/webprogram/Paper128746.html. December 10, 2019.

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