The 2017 International Society on Thrombosis and Haemostasis (ISTH) Congress: KOVALTRY®1,2 (octocog alfa, BAY 81-8973) product theatre presentation
The XXVI ISTH Congress and 63rd Annual Scientific and Standardization Committee (SSC) meeting took place in Berlin, Germany, on 8–13 July 2017. A total of 9,515 delegates from 110 different countries attended this event,3 which saw the world’s leading experts on thrombosis, haemostasis and vascular biology come together to share the latest scientific and clinical data relating to bleeding and clotting disorders.4
The congress was one of the largest global meetings in the field of thrombosis and haemostasis that has been held to date.4 More than 3,000 abstracts were presented, and the programme also included a record-breaking number of industry-sponsored symposia and product theatres.4,5
Bayer’s product theatre, entitled ‘KOVALTRY®1,2 in practice: Insights from real-world experience’, provided delegates with the opportunity to hear an expert panel talk about the very latest real-world data obtained for KOVALTRY®1,2, Bayer’s newest recombinant factor VIII (rFVIII) product, used for the prevention and treatment of bleeds in children, adolescents and adults with haemophilia A.1,2
The data presented provided important insight into how KOVALTRY®1,2 performs in the real-world setting and whether its performance reflects the positive outcomes that were observed in the LEOPOLD clinical trial programme.6–8 The product theatre featured presentations from Dr Alfonso Iorio and Dr Natascha Marquardt. Dr Iorio considered the KOVALTRY®1,2 pharmacokinetic (PK) profile and how data derived from the Web-Accessible Population Pharmacokinetic Service (WAPPS) can be used to support the results of clinical studies previously undertaken.6–10 Dr Marquardt provided insight into the experience of the haemophilia treatment centre (HTC) in Bonn, Germany, after its decision to transition all patients being treated with Kogenate® FS/Bayer*,11,12 to KOVALTRY®1,2. The presentation included an overview of how the transition process was managed in the HTC and a series of clinical case studies that captured the experiences of some of the early adopters of KOVALTRY®1,2. Dr Marquardt’s presentation was made possible using data that she collected and analysed in collaboration with her colleague, Dr Georg Goldmann, at the Bonn HTC.
*Bayer is the marketing authorisation holder for Antihemophilic Factor (Recombinant), which is marketed by Bayer as Kogenate® FS/Bayer11,12 and by CSL Behring as Helixate® FS/NexGen.13,14
An introduction to KOVALTRY®1,2 manufacturing, pharmacokinetics and clinical profile
KOVALTRY®1,2 is a full-length, unmodified rFVIII product that has the same amino acid sequence as Kogenate® FS/Bayer11,12; however, KOVALTRY®1,2 is manufactured using state-of-the-art processes.15 It utilises the same expression cell line as Kogenate® FS/Bayer11,12, but the cells have been modified to co-express the gene encoding human heat shock protein 70, a chaperone protein that may increase FVIII expression by facilitating proper protein folding and improve cell survival by inhibiting apoptosis.15,16 Other advances in the manufacturing process for KOVALTRY®1,2 include:
- Removal of human- and animal-derived raw materials from the cell culture, purification and formulation processes15,16
- Use of an optimised and simplified purification process16
- Addition of a 20 nm filtration step to remove nonenveloped viruses and protein aggregates16
These manufacturing changes have resulted in a product with consistently high levels of sialylation of N-linked glycans relative to Kogenate®FS/Bayer11,12 and Antihemophilic Factor (Recombinant) plasma-/albumin-free method (rAHF-PFM17,18).16,19 Sialic acid capping of glycosylated proteins is known to interfere with binding to the asialoglycoprotein receptors expressed by hepatocytes and to reduce clearance.19–21
In head-to-head PK crossover studies, KOVALTRY®1,2 showed a statistically significant increase in area under the curve (AUC) and terminal half-life (t1/2), and a statistically significant reduction in clearance relative to Kogenate® FS/Bayer9,11,12 and rAHF-PFM10,17,18. The results of these trials were shared as part of Dr Iorio’s presentation. The efficacy and safety of KOVALTRY®1,2 were evaluated in the LEOPOLD clinical trial programme, which comprised three clinical studies and enrolled more than 200 previously treated children, adolescents and adults with severe haemophilia A.1,2,6–8 KOVALTRY®1,2 demonstrated efficacy for prevention of bleeds in selected previously treated patients (PTPs) in the LEOPOLD I Part B and LEOPOLD Kids Part A trials, in which dosing regimens were assigned by the investigator.6,8 These results were confirmed in the LEOPOLD II trial, in which PTPs were randomised to receive KOVALTRY®1,2 for prophylaxis in 2×/week and 3×/week dosing regimens.7 KOVALTRY®1,2 was also effective for the treatment of breakthrough bleeds in all three clinical trials.6–8 There were no major safety concerns in PTPs in the completed LEOPOLD trials; the majority of the adverse events reported were mild or moderate, and none of the PTPs developed inhibitors.6–8
Figure 1. The WAPPS-Hemo network22
Pharmacokinetics in practice – what can we learn about KOVALTRY®1,2 from WAPPS?
Dr Alfonso Iorio
Information on the PK profile of a patient for a specific drug can be used to predict their response to treatment and identify the dosing regimen required to keep the concentration of the drug within the therapeutic range. Whether or not PK-guided dosing approaches are of value depends on the inter-patient (between different patients) and intra-patient (same patient at different time points) variability of the drug being prescribed. For example, if the inter- and intra-patient variability for a drug are both low, the same fixed dose will result in a predictable response; in contrast, if the inter- and intra-patient variability are both high, knowledge of the PK profile for a particular patient has no predictive value. In the case of FVIII concentrates (where the inter-patient variability is high but the intra-patient variability is low), knowledge of the PK profile for a particular patient can be used to predict their response to treatment and, when considered in conjunction with their bleeding phenotype, physical activity level and joint status, may enable physicians to tailor the dosing regimen to best suit the needs of that patient.
In order to predict how a particular patient will respond to FVIII replacement therapy, classical PK approaches require multiple (typically 9–11) blood samples to be taken 24–72 hours after FVIII administration, which places a considerable burden on the patient.22 To address this issue, popPK applications, such as WAPPS, are being developed to enable physicians to estimate key PK parameters from sparse data sets (≥1 sample) at the individual level. Reliable estimation of PK parameters is made possible using such applications because they are based on mathematical models derived from PK data from the entire available population.22 Using popPK approaches to assess an individual’s PK profile offers several advantages, such as not requiring a wash-out or standardised test dose and enabling the use of measurements gathered after multiple infusions.23 Recommendations for ensuring optimal performance of limited-sample individual popPK assessments have recently been issued by the ISTH SSC.24
The pharmacokinetic properties of KOVALTRY®1,2
Two head-to-head, crossover studies have been performed to compare the PK profile of KOVALTRY®1,2 versus Kogenate® FS/Bayer11,12 (Figure 2 and Table 1)9 and versus rAHF-PFM17,18 (Figure 3 and Table 2)10. In both studies, a statistically significant increase in t1/2 and AUC and a statistically significant reduction in clearance were observed for KOVALTRY®1,2 versus its comparator (Tables 1 and 2).9,10 The mean t1/2 obtained for KOVALTRY®1,2 was similar in both studies (13.8 hours [Table 1] and 13.9 hours [Table 2]); however, t1/2 varied markedly between individual patients (7.7–23.7 hours [Table 1] and 9.95–22.2 hours [Table 2]).9,10 Based on these data, it is clear that using average PK parameters, such as the mean t1/2, will not be suitable to guide dosing for all patients.
Figure 2. Geometric mean FVIII levels after 50 IU/kg doses of KOVALTRY®1,2 and Kogenate® FS/Bayer11,12 (chromogenic assay)19
Table 1. PK results after single doses of KOVALTRY®1,2 and Kogenate® FS/Bayer11,12 (chromogenic assay*)†,9
Figure 3. Geometric mean FVIII levels after 50 IU/kg doses of KOVALTRY®1,2 and rAHF-PFM17,18 (chromogenic assay)10
Table 2. PK results after single doses of KOVALTRY®1,2 and rAHF-PFM17,18 (chromogenic assay*)10
The time to reach a desired critical threshold, for example 1%, 3% or 5%, can be predicted using popPK models and may be a more useful parameter for determining the optimal dosing regimen for a specific patient than t1/2 or AUC. Simulated data from 1,000 patients suggest that the time to reach a 1%, 3% or 5% threshold is extended for KOVALTRY®1,2 compared with rAHF-PFM17,18.10 The simulated data were based on a single intravenous dose of 25, 30, 40 or 50 IU/kg (Table 3).
Table 3. Median time to FVIII threshold level after a single infusion dose (simulation of 1,000 patients)10
At the time of presentation, data from 96 patients treated with KOVALTRY®1,2 had been processed through the WAPPS-Hemo network22 (Table 4).26
The predictions made using the WAPPS model for KOVALTRY®1,2 reflect those made for the majority of the other factor concentrates modelled using WAPPS (including data [not shown] obtained for >500 patients receiving rAHF-PFM17,18) in that the results obtained are comparable with those reported in the published studies. In summary, the real-world experience with KOVALTRY®1,2 captured via WAPPS fully supports the PK data reported from the clinical trials.1,2,6,9,10,17,18,27–30
Table 4. Predictions made using the WAPPS-Hemo model22 for KOVALTRY®1,2 (parameter estimate summary of a two-compartment model)26
Successfully integrating KOVALTRY®1,2 into clinical practice: Lessons from the Bonn Haemophilia Treatment Centre (HTC)
Dr Natascha Marquardt
After the launch of KOVALTRY®1,2 in Germany, and based on the results of the LEOPOLD clinical trials,6–8 in which KOVALTRY®1,2 was associated with improvements in several key PK parameters compared with Kogenate® FS/Bayer9,11,12, the Bonn HTC team decided to transition all of their patients receiving Kogenate® FS/Bayer11,12 to KOVALTRY®1,2. To establish whether the transition had been successful, details of the patients’ experience, FVIII trough levels and any bleeds that had occurred were recorded during their scheduled visits to the HTC. In her presentation, Dr Marquardt described the experience of the Bonn HTC to date, including details of how the switch was achieved and the outcomes observed, and presented four case studies.
Managing the switch to KOVALTRY®1,2
Subsequent to the decision to introduce KOVALTRY®1,2 at the Bonn HTC, the transition rate was initially low, with 3–5 patients per month transitioning to KOVALTRY®1,2. During this time, KOVALTRY®1,2 was introduced to patients during routine face-to-face clinic appointments. Patients were informed that KOVALTRY®1,2 is the same basic molecule as Kogenate® FS/Bayer11,12, although improvements in the manufacturing process mean that KOVALTRY®1,2 has a longer half-life.9,15 The transition rate accelerated, and the final 50 patients transitioned to KOVALTRY®1,2 within a 3-month period. During this period, patients were informed about the impending transition by telephone. No objections to the transition were expressed by patients in response to the face-to-face or telephone-based approaches. However, some patients expressed a desire to continue treatment with Kogenate® FS/Bayer11,12 for as long as possible because they were more familiar with this product than with KOVALTRY®1,2. All patients maintained the same dosing regimen upon transitioning to KOVALTRY®1,2, which was provided to them with their next monthly FVIII concentrate order. Details of their experience, FVIII trough level and any bleeds that had occurred were recorded at the next scheduled visit to the clinic.
At the time of the presentation, 72 patients were receiving KOVALTRY®1,2 at the HTC; 66 of these patients had transitioned from Kogenate® FS/Bayer11,12, 2 had remained on KOVALTRY®1,2 after participating in the LEOPOLD clinical trial programme,6–8 3 had switched from another rFVIII product and 1 had switched from a plasma-derived FVIII product. The majority of the 72 patients were adults; however, a number of children and adolescents also transitioned to KOVALTRY®1,2 (Figure 4). Of the 72 patients, 55 have severe haemophilia A, 11 have moderate haemophilia A, 4 have mild haemophilia A and 2 are symptomatic carriers of haemophilia A. All 55 patients with severe haemophilia A are receiving prophylaxis, as are 3 patients with moderate haemophilia A (Table 5). These patients have been monitored for 48 patient-years (mean: 8 months) and, as of 1 May 2017, more than 16 million IU of KOVALTRY®1,2 had been administered at the HTC.
Figure 4. Distribution of PTPs treated with KOVALTRY®1,2 at the HTC in Bonn, Germany, by age
Table 5. Summary of patients receiving KOVALTRY®1,2 for prophylaxis at the HTC in Bonn, Germany
Outcomes with KOVALTRY®1,2
To date, the experience with KOVALTRY®1,2 at the HTC in Bonn has been positive. Efficacy for prophylaxis was described as very good, with only 7 joint bleeds observed in 55 patients during 8 months of follow-up (mean value per patient). Of these 7 bleeds, 5 were spontaneous bleeds in joints affected by haemophilic arthropathy (3 bleeds were rated as mild/moderate, and 2 as severe) and the remaining 2 bleeds were trauma-induced bleeds to the ankle. Where available, data indicate that bleeds resolved after treatment with KOVALTRY®1,2; in addition, patients receiving KOVALTRY®1,2 during surgery responded well to treatment (Table 6). Surgical interventions include one patient with severe haemophilia A who underwent bariatric surgery and received KOVALTRY®1,2 at 105 IU/kg on the day of surgery followed by 28 IU/kg twice daily in the postoperative period. No inhibitor development has been observed in any of the PTPs receiving KOVALTRY®1,2.
Table 6. Surgical intervention and treatment of breakthrough bleeds in patients receiving KOVALTRY®1,2 at the HTC in Bonn, Germany
Where available, analysed data also demonstrate improvements in PK with KOVALTRY®1,2 compared with the patients’ previous product, with both children and adults consistently recording improvements in FVIII trough levels (Table 7 and case study results). Analyses are ongoing but the early data, as described here, are encouraging.
|Key outcomes: Where available, individual data show that all children switching to KOVALTRY®1,2 have higher FVIII trough levels after an equivalent dose of KOVALTRY®1,2 versus their previous FVIII product.|
Table 7. Dosing regimens and FVIII trough levels for children receiving KOVALTRY®1,2 at the HTC in Bonn, Germany*
In summary, clinical trial data from head-to-head PK studies9,10 have demonstrated a statistically significant increase in t1/2 and AUC and a statistically significant reduction in clearance for KOVALTRY®1,2 compared with Kogenate® FS/Bayer11,12 and rAHF-PFM17,18. The WAPPS database contains PK data for a number of existing FVIII products, including KOVALTRY®1,2 and Kogenate® FS/Bayer11,12, that have been obtained from both clinical trials and real-world clinical practice. The real-world experience with KOVALTRY®1,2 captured via WAPPS fully supports the available PK data reported from the clinical trials.1,2,6–10 The predictive capability of WAPPS will enable physicians to obtain tailored estimates of key PK parameters for patients with specific factor concentrates and, therefore, to explore different treatment scenarios for individual patients. Furthermore, WAPPS is an important source of PK data at the population level and will allow inter-patient and intra-patient PK comparisons to be made. Real-world data for KOVALTRY®1,2 obtained from patients treated at the HTC in Bonn, Germany, showed that many of the children, adolescents and adults treated at the HTC had increased FVIII trough levels at the same time point, or similar FVIII trough levels for an extended period after infusion of an equivalent dose of KOVALTRY®1,2 versus their previous FVIII product. Furthermore, data from the clinical cases presented (where available) confirmed that patients remained bleed-free throughout the follow-up period after transitioning from Kogenate® FS/Bayer11,12 to KOVALTRY®1,2 or after reducing the dosing frequency with KOVALTRY®1,2, with only two patients reporting minor, trauma-related bruising.
Medical writing support was provided by Porterhouse Medical Ltd and funded by Bayer, Basel, Switzerland. The KOVALTRY®1,2 product theatre presentation was moderated by Dr Snejana Krassova, Head of Medical Affairs, Hematology, Bayer, Basel, Switzerland. Additional reviewing support was provided by Dr Jose Francisco Cabre Marquez, Dr Emilio Musi, Dr Stephan Rauchensteiner, Dr Martin Sanabria and Dr Guido Senatore from Global Medical Affairs, Bayer, Basel, Switzerland.
Dr Natascha Marquardt: Research support (none); speaker bureau/honoraria (Baxalta, Bayer, Octapharma, Pfizer, Roche, SOBI); investments (none); other (Baxalta, Novo Nordisk). Dr Georg Goldmann: Research support (none); reimbursement for attending symposia/congresses and/or speaker bureau/honoraria (Bayer, BPL, CSL Behring, Novo Nordisk, Octapharma, Shire, Swedish Orphan Biovitrum); investments (none); other (none). Dr Alfonso Iorio: Research support to McMaster University (Bayer, Pfizer); speaker bureau/honoraria (none); personal funds received for the work reported in this publication (none); investments (none); other (none).
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KOVALTRY▼ This medicinal product is subject to additional monitoring. Adverse events should be reported. Please report any suspected adverse reaction to the Medicines and Healthcare products Regulatory Agency (MHRA), Website: www.mhra.gov.uk/yellowcard. Name of the medicinal product: Kovaltry 250 / 500 / 1000 / 2000 / 3000 IU powder and solvent for solution for injection (Refer to full SmPC before prescription.) Composition: Each vial contains nominally 250/500/1000/2000/3000 IU human coagulation factor VIII. Excipients: Powder: Sucrose, Histidine, Glycine, Sodium chloride, Calcium chloride, Polysorbate 80. Solvent: Water for injections Indication: Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Kovaltry can be used for all age groups.
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Known allergic reactions to mouse or hamster proteins. Warnings and Precautions: Allergic type hypersensitivity reactions are possible. The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. Haemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-haemophilic patients when clotting has been normalised by treatment with FVIII. If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bactaeremia and catheter site thrombosis should be considered. Undesirable effects: common: lymphadenopathy, palpitation, sinus tachycardia, abdominal pain, abdominal discomfort, dyspepsia, pyrexia, chest discomfort, injection site reactions (incl. injection site extravasation, hematoma, infusion site pain, pruritus, swelling), headache, dizziness, insomnia, pruritus, rash (rash, rash erythematous, rash pruritic), dermatitis allergic; uncommon: FVIII inhibition (PTPs), hypersensitivity, dysgeusia, urticaria, flushing. On prescription only. Marketing Authorisation Holder: Bayer, 51368 Leverkusen, Germany. Date of revision of the underlying Prescribing Information: 11/2017
KOGENATE Bayer 250/500/1000/2000/3000 IU Powder and solvent for solution for injection. Composition: Active ingredient: recombinant human coagulation factor VIII (INN: octocog alfa), 250/500/1000/2000/3000 IU/vial (100/200/400/400/600 IU/ml after reconstitution). Excipients: Powder: Glycine, Sodium chloride, Calcium chloride, Histidine, Polysorbate 80, Sucrose. Solvent: Water for injections. Therapeutic indications: Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency) in adults, adolescents and children of all ages. This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand’s disease. Contraindications: Hypersensitivity to the active substance, to any of the excipients, or to mouse or hamster protein. Warnings/Precautions: Allergic type hypersensitivity reactions are possible. The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication. Haemophilic patients with cardiovascular risk factors may be at the same risk to develop cardiovascular events as non-haemophilic patients when clotting has been normalised by treatment with FVIII. If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia, catheter site thrombosis should be considered. Pregnancy and lactation: KOGENATE Bayer should be used during pregnancy and breast-feeding only if clearly indicated. Undesirable effects: very common: FVIII inhibition in previously untreated patients (PUPs); common: infusion site reaction, skin associated hypersensitivity reactions (pruritus, urticarial, rash); uncommon: FVIII inhibition in previously treated patients (PTPs); rare: Infusion related febrile reaction (pyrexia), systemic hypersensitivity reactions (including anaphylactic reaction, nausea, blood pressure abnormal, dizziness); very rare/not known: dysgeusia. The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A during treatment with all Factor VIII medicines. Patients should be monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. Medicinal product subject to medical prescription. Version: EU/14 Date: July 2018. Marketing Authorisation Holder: Bayer AG, 51368 Leverkusen, Germany.