Kelly Davio

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,

 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.

 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.

 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. 

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 year

—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.

During ASH, researchers reported on an assessment of the relationship between PK parameters and antidrug antibodies (ADAs) for the proposed biosimilar and the reference.

 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.

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.

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

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.

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,

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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Results for Truxima, recently launched in the United States, and complement inhibitors were presented at the 61st American Society of Hematology Annual Meeting and Exposition.

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

Splenomegaly, or enlargement of the spleen, is common in patients with Philadelphia-negative myeloproliferative neoplasms, and it is associated with symptoms like early satiety and abdominal pain. The role that splenomegaly has in terms of quality of life and prognosis in primary myelofibrosis is fairly well understood, but it has been less frequently investigated among patients with essential thrombocythemia (ET) and polycythemia vera (PV).

, a group of authors sought to assess the impact that splenomegaly has on thrombotic risk and survival in patients with ET and PV. They studied 238 patients with ET and 165 patients with PV who were treated at a single center between 1997 and 2019.

The median follow-up was 45.96 months (range, 1.5-316.2 months) for patients with ET patients and 58.42 months (range, 1.2-298.39 months) for patients with PV. The investigators found that the frequency of thrombosis and cardiovascular events was higher in patients with splenomegaly than in patients without splenomegaly at the time of diagnosis in both groups of patients:

Thrombosis and cardiovascular events occurred in 39.87% of patients with ET and with splenomegaly versus 24.37% of patients without splenomegaly (

In patients with PV, thrombosis or cardiovascular events occurred in 44.44% of patients with splenomegaly versus in 30.39% of patients without splenomegaly (

The authors note that increased spleen size has not been shown to be a significant prognostic factor in major models, but, “In accordance with our data and our experience, we believe that the prognostic value of splenomegaly is underestimated in ET and PV and that should be evaluated the possibility to include it as an item of a prognostic scoring system.”

According to the authors, more studies will be needed to evaluate the role that splenomegaly plays in overall survival and thrombotic risk for patients with ET and PV.

Accurso V, Santoro M, Raso S, et al. Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: a single center study. 

2019;11(4):8281. doi: 10.4081/hr.2019.8281.

Splenomegaly Linked With Thrombosis, Cardiovascular Risk for Patients With ET and PV

Drug maker Alnylam Pharmaceuticals has announced that the ILLUMINATE-A trial, a phase 3 study of lumasiran, an investigational RNA interference product targeting glycolate oxidase, met its primary end point in a study of patients with primary hyperoxaluria type 1 (PH1).

The ultrarare disease causes calcium oxalate crystals to form in the kidney and urinary tract and can lead to recurrent kidney stones and nephrocalcinosis.

In the trial, the proposed treatment, which is a subcutaneously administered product that silences hydroxyacid oxidase 1 and depletes the glycolate oxidase enzyme, met its primary end point of percent change from baseline, versus placebo, in 24-hour urinary oxalate excretion averaged across month 3 to month 6.

The drug also revealed what the company called an “encouraging safety and tolerability profile,” and the company reports that there were no serious adverse events in the study period.

“We are very pleased to report positive topline phase 3 results for lumasiran, our third wholly owned investigational RNAi therapeutic,” 

 Akshay Vaishnaw, MD, PhD, president of research and development at Alnylam.

“Patients living with PH1 and their families are faced with the burden of recurrent and painful stone events and a progressive and unpredictable decline in kidney function that ultimately results in end-stage renal disease and the need for intensive dialysis as a bridge to dual liver/kidney transplantation. The results from ILLUMINATE-A demonstrate that lumasiran can significantly reduce the hepatic production of oxalate, which we believe can thereby address the underlying pathophysiology of PH1,” added Vaishnaw.

The company is also conducting ILLUMINATE-B, a phase 3 study of lumasiran in children aged under 6. Results in that trial are expected by the middle of next year. ILLUMINATE-C will investigate the drug in patients of all ages who have advanced renal disease, and results are expected in 2021.

Alnylam plans to submit a New Drug Application for the product to the FDA in early 2020.

Lumasiran Meets Primary End Point in Phase 3 Study in Patients With PH1

As healthcare companies, tech firms, and startups seek to use digital tools to help individuals manage their health, patients have growing concerns about how their data are used. During a panel discussion during the opening day of the FT Global Pharmaceutical and Biotechnology Conference 2019, held this week in London, United Kingdom, executives from across the pharmaceutical and digital health spaces discussed the critical importance of building relationships with patients as a means to not only reap high-quality data, but also improve patients’ outcomes and save healthcare systems money.

Kicking off the panel—which was moderated by the 

global pharmaceuticals editor, Sarah Neville—was Jessica Scott, MD, JD, head of research and development patient engagement for Takeda. According to Scott, Takeda has come to see the importance of including more patient perspectives in the drug development process, or what she called “developing medicines with patients rather than just for patients.”

One important way to better engage with patients, she noted, is to give patients their data from clinical trials. Allowing patients to have access to their own information directly benefits patients, who may also elect to donate that data to other research. “Let’s not leave the patient out of this mix,” she said of clinical trials, noting that engaging with patients in a meaningful way is part of the pharmaceutical industry’s job of repairing its declining reputation.

Scott also highlighted the fact that patient perspectives can and should be used to bring value to the research process, particularly insofar as patient voices can help to identify truly unmet needs. She pointed to Takeda’s recent study of a therapy for Friedreich ataxia in which, after consulting with patients and learning that fine motor skills and coordination were the most important factors to patients in their daily lives, the company worked with the FDA to change one of the measures in its clinical trial. The company needed patients’ input, she said, to know “not what we could do, but what we should do.”

Speaking from a tech company perspective was Dan Vahdat, chief executive officer (CEO) of Medopad, a company that is working to validate algorithms that can predict complications across disease states. Vahdat agreed that relationships with patients—and their data&mdash;have to provide value back to the patients themselves.

Among Medopad’s offerings is a digital pulmonary hypertension app that allows a patient to measure symptoms, track vital signs, and take a quality of life test, all linked with the patient’s care team. While patients are providing their data to Medopad, “to be able to quantify their disease and tell them where they are and how they’re doing” provides a benefit back to the patient at an individual level.  

Eddie Martucci, cofounder and CEO of Akili Interactive, which develops digital therapeutics that are designed to target cognitive impairment, agreed that “humans tend to want to do things when they can get something back out of it.” Thus, using data to improve patients’ experiences in a timely way is “key to unlocking loyalty.” In the case of Akili, the company seeks to immediately adapt its product to the individual user when it receives that information, improving the product “almost in real time.”

Given that consumers are increasingly aware of the pitfalls of companies such as Facebook that collect large amounts of data that are used in ways that do not necessarily align with individuals’ benefit, companies that will succeed in the digital therapeutics space, Martucci predicted, are those who can respond to patients’ data by fulfilling patients’ needs.

Finally, the Right Honourable Lord Paul Drayson, PhD, CEO of Sensyne Health—which works with anonymized patient data from the UK National Health Service (NHS) to facilitate drug discovery and development&mdash;agreed that patients are keenly aware that society has changed in the past several years with respect to how individuals’ data are used, and that the public is increasingly concerned that not all of these changes have been beneficial.

In order to gain back the trust and confidence of patients, “we need to make sure the way we do it is seen to be the right way.” Part of demonstrating responsibility will be engaging with patients and demonstrating that data are being used appropriately, particularly with respect to data sets like those from the NHS.

In Drayson’s view, part of showing responsibility with data includes demonstrating to the public how investment in digital tools can reduce costs for national health systems like the NHS by getting the right drug to the right patient at the right time, perhaps allowing for enough cost savings to fund drugs that, today, remain out of reach.

Author | Kelly Davio

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