Anna de Goede
More than 3000 participants from 75 countries gathered in Gothenburg for the 23rd congress of EAHP. The meeting covered a range of hospital pharmacy activities and highlights included biosimilars in oncology, advanced therapy medicinal products and post-operative analgesia
The launch of the first biosimilar trastuzumab could improve the affordability of treating HER2-positive breast cancer
but has also raised a number of challenges, according to speakers at a Synergy satellite event (supported by Amgen).
The identification (in the 1980s) of the HER2 oncogene as a prognostic marker for breast cancer and the subsequent development of trastuzumab, a monoclonal antibody directed against HER2, is a “unique story of success”, according to Rupert Bartsch (German Breast Group and Medical University of Vienna, Austria). Prior to the introduction of trastuzumab for metastatic breast cancer, patients had a median survival time of less than two years. Today, combination treatment with trastuzumab, pertuzumab and docetaxel is resulting in median survival times of nearly five years (after diagnosis of metastatic disease). “Effectively, this has turned a life-threatening disease into a chronic disease”, said Professor Bartsch. Recently the development of the antibody–drug conjugate, trastuzumab emtansine (T-DM1, Kadcyla®), in which trastuzumab is linked to the microtubular toxin mertansine, has provided effective, targeted therapy. The trastuzumab targets the breast cancer cells and delivers the cellular toxin.
Lapatinib in combination with trastuzumab is better than lapatinib alone and the combination has the advantage of providing a chemotherapy-free treatment. However, lapatinib is an EGFR inhibitor so it also causes diarrhoea. Some questions remain, for example, whether T-DM1 is effective after trastuzumab–pertuzumab treatment. There are a number of current treatment options for HER2-positive metastatic breast cancer. Professor Bartsch favours first-line treatment with a taxane (docetaxel), trastuzumab and pertuzumab and second-line treatment with T-DM1. Beyond second line treatment, “we should prolong HER2-directed therapy for as long as meaningfully possible because this is what prolongs overall survival”, he said.
Trastuzumab in the adjuvant setting is also effective. When given for one year after surgery, it resulted in a 50% reduction in breast cancer recurrences, making it “one of the drugs that had the greatest impact on breast cancer that we have ever seen, second only to tamoxifen”, said Professor Bartsch. HER2 -positive tumours are driven by their biology rather than by size; if small, node-negative tumours are treated with chemotherapy and trastuzumab “the prognosis is fantastic today”, and it might even be possible to reduce the intensity of chemotherapy, which would be good news for patients, he said. A recent Phase II trial of weekly paclitaxel and 12 cycles of trastuzumab resulted in a three-year, disease-free survival of 98.7%, he added.
Subcutaneous, fixed-dose trastuzumab is not inferior to intravenous trastuzumab and offers potential benefits in terms of time-saving, he noted.
Future developments could involve the use of tucatinib, a third-generation HER2-TKI that has 500-fold greater activity against HER2 compared with EGFR and so causes much less diarrhoea. Immune checkpoint inhibitors and CDK4/6 inhibitors could also be used in future.
Regarding biosimilars – extrapolation from neo-adjuvant settings to use in metastatic disease is likely to be more acceptable than the other way round. In the adjuvant setting, the success of biosimilars is likely to depend on the (pre-existing) uptake of subcutaneous trastuzumab, he said.
Testing of biosimilars
Most of the biologic drugs currently available have undergone changes to the manufacturing process; these are regulated by international guidelines and must be shown to have no impact on the identity, purity, potency, quality or safety of the product, explained João Gonçalves (iMed Medicines Research Institute, University of Lisbon, Portugal). Analyses of numerous batches of trastuzumab over a five-year period show that there have been changes in glycosylation, Fc receptor binding and antibody-dependent cellular cytotoxicity (ADCC). Biosimilars undergo rigorous analytical and functional testing before reaching the clinical evaluation stage. All critical quality attributes are considered and, taken together, they contribute to establishing that safety and efficacy do not differ from the originator product. Central to all this is the stability of the drug, said Professor Gonçalves.
The amino acid sequence of a biosimilar is exactly the same as the originator drug. Changes in immunogenicity can be expected if aggregates are formed as a result of formulation changes or the way that the drug is handled. For example, when albumin was replaced by Tween 80/glycine in the epoetin alfa formulation, many cases of anti-epoetin antibody-related pure red cell aplasia (PRCA) occurred. Clinical studies represent the last stage of analysis and the results should confirm the similarity determined during the extensive analytical and functional testing. It is important that manufacturers use appropriate study populations, endpoints and statistical design for the clinical studies. Results of clinical studies have been published for five different trastuzumab biosimilars, but the mixture of different clinical settings and different primary endpoints makes direct comparisons difficult. Nevertheless, the available evidence (science and real-world) suggests that biosimilars are more of a benefit than a risk, he said.
Pharmacovigilance is essential to monitor for variations in immunogenicity. When a biologic drug is first used, binding antibodies that do not affect drug action are formed, but later, when the immune system (B cells) recovers, neutralising antibodies are formed. Studies have shown that anti-drug antibody levels remain low during treatment but during the follow-up period they can rise considerably. Studies also show that subcutaneous Herceptin is more immunogenic than the intravenous product but this difference is not seen with the trastuzumab biosimilars, said Professor Gonçalves. It is important to consider how the processes of reconstitution and dilution of the drug might contribute to degradation of the monoclonal antibody and increase the risks of aggregation.
There are no published data about stability of original or biosimilar biologics once reconstituted and diluted, he noted. It is important to understand the effects of these manipulations and to optimise handling to minimise the risks of aggregation and particle formation during IV administration and much work remains to be done in this field, he concluded.
The main problem with biosimilar trastuzumab is not quality but affordability, according to Hanne Rolighed-Christensen (Head of Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital Denmark). In Denmark, uptake of biosimilar infliximab and etanercept had been faster than in other European countries as a result of an intensive information campaign. Danish doctors are now very much aware of the need to save money. The estimated annual savings in Denmark were about 180 million Danish kroner from biosimilar infliximab and 90 million Danish kroner from biosimilar etanercept.
So far, two biosimilar trastuzumab products have received marketing authorisations – Ontruzant® and Herzuma®. The main hurdle is that more than 80% of trastuzumab used in Denmark is the subcutaneous presentation, which can be administered in minutes, whereas the biosimilar products are all intravenous presentations that take longer to administer and require more ‘chair time’ in the hospital said Dr Christensen.
Advanced therapy medicinal products (ATMPs) are medicines and pharmacists should take responsibility for their safe use in hospitals, according to Anna de Goede (Pharmacist and Qualified Person, Radboud University Medical Centre The Netherlands).
ATMPs are biological medicines and the category includes gene therapy products, cell therapy products, tissue engineered products and combined ATMPs. Cell therapy products comprise cells that have been ‘substantially manipulated’. Stem cell transplants are not classified at ATMPs because the cells have not been substantially manipulated and they are for homologous use, said Dr de Goede. ‘Non-homologous use’ means that the cells have a different function from that which they had in donor.
A number of products now have marketing authorisations (in the USA), including two chimeric antigen receptor T-cell (CAR-T) products (Kymriah® and Yescarta®). The use of CAR-T cells is expected to grow rapidly and these may be the first ATMPs that many pharmacists encounter. ATMPs are subject to a large number of regulations including a new guideline for Good Manufacturing Practice (GMP) for ATMPs (1394/2007 Art.5) which came into force in May 2018. One of the provisions is that a person responsible for biosafety must be appointed when genetically modified organisms are used.
There are many challenges in the production of ATMPs because the starting materials are often living cells. They may have to be cultured in open systems and take days or weeks – one product in Dr de Goede’s department takes 42 days – but they are relatively fragile, sensitive products. Although they will eventually be injected into a patient, the product cannot be sterilised by filtration because that would result in cell loss. There are additional environmental issues for genetically modified organisms.
Turning to the usage of ATMPs, Dr de Goede emphasised that many ATMPs have a very short shelf life. They are usually shipped frozen and have to be transferred to a deep freeze at –80° C within 60 seconds – a task for which staff need protective clothing and correct training. Reconstitution of the products may require thawing and rinsing away of cryoprotectants. It has to be undertaken at the administration site but the matter of who undertakes the reconstitution procedure and where it is done requires careful planning because the techniques and procedures are very different from normal pharmaceutical reconstitution activities, she said.
When administered, the batch numbers must be recorded and there must be a procedure in place for disposal of ATMP waste. She emphasised that hospital pharmacists are responsible and accountable for the logistics, preparation and use of ATMPs and must therefore ensure that the products are of appropriate quality, and that there is governance in place for proper handling. At present, most departments do not have the necessary training or equipment, and there is limited guidance to help them, she noted. However, the advent of ATMPs presents opportunities for pharmacists – it will allow them to use both their expertise in disease management and in quality assurance for medicinal products. Multidisciplinary teams are needed to manage treatment with ATMPs and pharmacists need to be members of such teams. It is important to develop systems for pharmaceutical oversight of the handling processes although the product may not be stored or manipulated in the pharmacy, said Dr de Goede.
Post-surgical pain is an unmet need for patients, with many continuing to experience moderate–severe pain after leaving hospital, despite treatment with analgesics, Richard Langford (Professor of Anaesthesia, St Bartholomew’s Hospital, London) told the audience at a satellite symposium supported by Grünenthal. Pain relief is a key component of enhanced recovery after surgery and avoiding ‘analgesia gaps’ is critical. Intravenous (IV) patient-controlled analgesia (PCA) can help but analgesia gaps can still occur because of problems with IV lines, pump battery problems or empty reservoirs.
The use of PCA with oral sufentanil after knee surgery results in faster mobilisation and shorter stays in hospital according to Eric Viel (Department of Anaesthesiology and Pain Clinic, University of Nîmes Hospital France). Sufentanil is more potent than fentanyl but has a very high therapeutic index. It has a high lipid solubility, which allows effective transmucosal delivery. Furthermore, sufentanil has no active metabolites and less impact on respiratory function than other opioids. All of these factors make it particularly suitable for short-duration opioid treatment said Dr Viel.
The sufentanil sublingual tablet system (SSTS) comprises a hand-held device that is pre-programmed with a 20 minute lockout interval and is tethered to a secure location. The device is loaded with a cartridge containing 40 sufentanil 15 microgram sublingual tablets. The device is activated (to release a dose) by means of an RFID tag fixed to the patient’s thumb.
Rehabilitation after total knee arthroplasty can be problematic because patients are usually in pain when the physiotherapist arrives and then have to wait for a morphine injection. A study comparing morphine injection with sublingual sufentanil in such patients showed that patients were able to walk further sooner and, most importantly, were able to climb stairs two days earlier, said Dr Viel.
As a result, the duration of stay in hospital was reduced from 6.4 days to 4.2 days. The fact that an IV line is not required and that sufentanil provides immediate pain relief are two major factors in favour of the SSTS. Dr Viel concluded that it provides an effective alternative to opioid-based intravenous PCA for the management of acute moderate–severe post-operative pain.
The 23rd Congress of the European Society of Hospital Pharmacists, Hospital Pharmacists – show us what you can do! took place in Gothenburg, Sweden, 21–23 March 2018.