April 2021
clinical initiatives, research and current updates in treatment
mRNA Vaccines – A New Era in Vaccinology Ben Evans, Priya Iyer, Icon River City Pharmacy The COVID-19 pandemic has seen an unprecedented acceleration in vaccine development. With it has come the approval of the first mRNAbased therapeutics in the form of the Moderna and Pfizer vaccines. Although considered novel in design, these represent the culmination of decades of research into the utilisation of mRNA as a viable vaccine technology. Vaccination relies on the ability of the immune system to produce an antibody mediated immune response against foreign pathogens such as bacteria and viruses. The portion of a pathogen that is recognised by the immune system is referred to as an antigen. An antigen-presenting cell (APC) is an immune cell that stimulates the initial immune response by phagocytosing (engulfing) a pathogen and digesting it to form antigens. These antigens are then transported to the surface of the APC where they serve as an indicator to other immune cells. In traditional vaccines, antigens are introduced by administering an attenuated (weakened) or inert version of the causative organism, its products, or a synthetic substitute. This exposes the body to the antigen and stimulates the production of targeted antibodies without inducing the disease.1 mRNA vaccines utilise this same exact principle, with the major difference being that the vaccine carries
information that triggers our bodies own protein production machinery to produce the antigen of interest.2 This technology led to the rapid development of the COVID-19 vaccine. In the case of the SARS-Cov-2 virus, the antigen of interest is the “spike” surface protein that is a feature unique to coronaviruses.3 By administering an mRNA strand that has been engineered with the instructions to produce this spike protein, the immune system is triggered to produce antibodies directed against the protein, without risking exposure to the virus itself. To understand how this is achieved, it is important to understand what mRNA is, and how it functions.
What is mRNA? mRNA or messenger RNA is an intermediate molecule involved in normal protein synthesis. It is responsible for carrying genetic information encoded in our DNA which guides the production of proteins necessary for normal biological functions. This is achieved via a twostep process known as transcription and translation. Transcription occurs within the nucleus of cells, where portions of DNA unwind and are copied onto an mRNA strand. Following this process, the mRNA exits the nucleus and is presented to ribosomes located within the cytoplasm, where the instructions are translated into a corresponding protein that is used for a particular function.4 (See Figure 1)
Figure 1: https://medlineplus.gov/genetics/ understanding/howgeneswork/makingprotein/ 4
The ability of mRNA to encode for proteins makes it a powerful potential therapeutic tool. mRNA is a noninfectious, non-integrating platform with no potential risk of infection or DNA mutations. Additionally, mRNA is degraded by normal cellular processes and therefore has a safe risk profile.5 Not only is mRNA safe, but producing vaccines in this way is faster than traditional methods of vaccine production.6
mRNA vaccine production Utilising mRNA as a therapeutic tool has been the focus of research for several decades now. However, translating this theory into clinical practice has proved challenging. An early limiting factor in the development of mRNA-based therapeutics was that “naked” mRNA is rapidly broken down within the body. Continued on page 2
Fortunately, the introduction of nanoparticle encapsulation as a delivery method in the last decade has enabled mRNA to be administered in a way that protects it from degradation.7 Encapsulating mRNA strands within a lipid nanoparticle bi-layer protects the mRNA strand until it is taken up by antigen presenting cells. (Figure 2)
a desired physiological response. This technology has several applications including infectious disease, genetic conditions and cancer. 9, 10
Figure 3: https://www.genengnews.com/uncategorized/ mrna-based-drugs-prepare-to-go-the-distance/ 2
Figure 2: https://gut.bmj.com/content/68/7/1323 9
Here the mRNA is released from its lipid capsule into the cell where it can then be translated into a protein. (Figure 3) Advances in next generation sequencing means we can now determine the amino acid sequence of any antigen of interest.8 The instructions for producing these antigens can then be transcribed onto an mRNA backbone, resulting in a therapeutic mRNA molecule that can be administered to patients to produce
mRNA as a potential cancer therapy Since 2006, early phase clinical trials investigating the safety and efficacy of mRNA-based therapies for the treatment of cancer have been underway. The use of mRNA for the treatment of cancer relies on the same principles of antigen production and immune priming that underpins its use for infectious diseases. As genetic mutations drive cancer growth, the tumour’s mutanome results in changes in gene expression which leads to the tumour cells possessing a unique antigen signature. This differentiates them from normal cells
and makes them ideal targets for immune priming. 11 By analysing each patient’s tumour sample, it is possible to identify a set of tumour specific antigens. This information can then be used to produce an immune priming mRNA sequence which is personalised to that individual's tumour mutanome. This represents a future direction in fully personalised cancer therapies. 10 Several phase 1 and 2 trials are currently underway using these methods in Australia.
Future considerations and challenges The future of mRNA vaccines is promising; however, it is not without challenges. As therapeutics that utilise this technology move towards commercialisation, options for scaling production will need to be considered. Furthermore, guidance and oversight from leading regulatory bodies such as the FDA and TGA will be paramount. There are also still several questions about mRNA vaccines that require further research, including the duration of immune response following vaccination and whether follow-up doses are required to maintain efficacy. References are available on request.
Highlighting the safety points associated with the supply and administration of medications used to treat Parkinson’s Disease. Thomas Giles, Epic Pharmacy Hollywood Parkinson’s disease (PD) is a neurological condition characterised by a progressive loss of dopamineproducing neurons in the brain.1 Patients with PD experience a range of symptoms, commonly including tremor, rigidity, stiffness, impaired posture and balance, and slowness of movement. PD patients are admitted to hospital more frequently and for longer than the general population, with up to one quarter of PD patients being hospitalised each year.2 The hospital setting can pose serious risks to the pharmacological management of PD patients.3 Medications for PD provide symptom relief however, there are a wide range of formulations and regimens are unique and can be complicated; this,
accompanied by a variety of risk factors, if not properly recognised, can lead to suboptimal therapy.4 Risks include errors in drug, dose and formulation selection, delays in medication administration, drug interactions, as well as altered response to medication resulting from dietary changes while in hospital. It is critical that the right medications are given at the right time for the proper control of PD. As a consequence of suboptimal treatment, PD patients may experience a deterioration in symptoms including worsening tremors, increased rigidity, loss of balance, confusion, agitation and difficulty communicating.3 These deteriorations in symptoms can lead to complications during the patients hospital admission such as confusion
and an increased risk of falls and infection, potentially prolonging length of admission and leading to poorer patient outcomes. 2, 3, 5
Large number of various products Levodopa is the first line treatment for PD and is converted to dopamine in the brain.7, 8 It is given with benserazide or carbidopa to prevent it from being broken down before it reaches the brain. 8 There are approximately twenty different levodopa containing products available, differing in drug combinations, strengths, and formulation types (see table 1).8 The large range of available levodopa products increases the risk that the wrong medication or formulation may be given, particularly if healthcare
staff are unfamiliar with these medications or are not aware that different formulations are not always directly interchangeable. Many products also have similar packaging, increasing the risk of incorrect product selection. It is important that medication orders are clear and complete, containing the generic and brand name, the type of formulation (e.g. rapid or controlledrelease), dose, strength and frequency (according to the patients unique dosing schedule).9 Other types of medications used in the management of PD include dopamine agonists (such as pramipexole) and monoamine oxidase type-B (MAO-B) inhibitors (such as rasagiline and selegiline). Staff unfamiliarity with antiparkinsonian medications, can increase the risk of delayed or missed doses. It is important to ensure patient’s antiparkinsonian medicines are readily available and checked in advance if supply is running low, to make sure additional supply can be organised from pharmacy well before time of administration.
Delay in Administration Each case of PD is unique and
medication regimens are highly specialised, with some patients requiring levodopa doses as frequently as every 1 to 2 hours.3 PD medications are ‘time-critical’, as delays in administration of as little as 15 minutes are enough to worsen PD symptoms.4, 6 Hospital environments present challenges to PD patients with respect to receiving antiparkinsonian medications on time. Studies show that three out of four hospitalised patients with PD do not receive their medicines on time, or have had doses entirely omitted.3 Many PD patients take their medications at times that would not fall within scheduled drug administration rounds at the hospital. PD patients should receive prompt medication reconciliation on admission to hospital and patient’s individualised dosing schedules should be documented and clearly communicated, to ensure they are not overridden by standard hospital dosing times.3 Alerting staff to the time critical nature of PD medicines is key to avoiding delays in administration. Patients may also be unwilling or unable to question hospital staff if they are not receiving their PD
medicines correctly. 3,4 Patients and carers should be encouraged to be vigilant when dealing with healthcare staff and to speak up if they find they are not receiving medication in a timely matter or notice a worsening of symptoms.3 Inappropriate withholding of antiparkinsonian agents in PD patients undergoing surgical procedures is also a risk. Fasting patients may take their levodopa medications with a sip of water up until surgery and these medications should be given as close as possible to and after surgery according to the patient’s usual schedule. 3, 10 If a prolonged nilby-mouth period is anticipated after surgery, it is important to receive advice from the patients specialist prior to surgery to help guide PD management, including conversion to non-oral products. 3, 7 It is crucial that the right PD medications are given at the right time, every time. Taking measures to prevent administration errors and delays are essential to maintain good control of Parkinson’s disease and to improve health outcomes for the hospitalised patient.
Table 1: Summary of oral levodopa-containing formulations8 Product Name
Strength/Formulation
Release
Madopar
50mg/12.5mg cap 100mg/25mg cap/tab 200mg/50mg cap/tab
Standard release
Madopar Rapid
100mg/25mg disp-tab 50mg/12.5mg disp-tab
Rapid release
Madopar HBS
100mg/25mg SR cap
Controlled release
Kinson a Sinemet a Sinadopa a
100mg/25mg tab
Standard release
Sinemet a Sinadopa a
250mg/25mg tab
Standard release
SinemetCR
200mg/50mg CR tab
Controlled release
50mg/12.5mg/200mg tab 75mg/18.75mg/200mg tab 100mg/25mg/200mg tab 125mg/31.25mg/200mg tab 150mg/37.5mg/200mg tab 200mg/50mg/200mg tab
Standard release
Levodopa + Benserazide
Levodopa + Carbidopa
Levodopa + Carbidopa + Entacapone Stalevo a Carlevent a Lecteva a
a
PBS Brand Equivalent
References are available on request.
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What’s New Lorlatinib - Drug brief Emily Fletchett, Pharmacy NSW Lorlatinib (Lorviqua) – 25mg and 100mg tablets Approved indication: non-small cell lung cancer Increased genetic knowledge of nonsmall cell lung cancer (NSCLC), in combination with evolving treatment options, has led to improved outcomes for patients with this disease. Anaplastic lymphoma kinase (ALK) is one such gene of significance, as a mutation in this gene leads to an overexpression of the signalling protein, ALK receptor tyrosine kinase, and the potential development of a rare subtype of lung cancer, ALKpositive NSCLC. 1, 2 Understanding these genetic mutations has led to the development and use of newer tyrosine kinase inhibitors (TKI) in the treatment of NSCLC. Lorlatinib is a ‘third-generation’ TKI that inhibits the ALK and ROS1 tyrosine kinases and has been given provisional approval in Australia due to ongoing studies. This approval is for patients with ALK-positive advanced non-small cell lung cancer (NSCLC) that has progressed despite treatment with alectinib, ceritinib,
or crizotinib and at least one other tyrosine kinase inhibitor.3 Approval was granted based on the rate of tumour response and on the duration of the response. In a phase II trial, 90% of previously untreated patients and 47% of previously treated patients (with at least one TKI) achieved an objective response with lorlatinib.4 For the approval to continue in Australia, the degree of benefit will need to be verified in further trials. The recommended dosing is 100mg taken orally once daily. The dose can be taken with or without food and the tablet should be swallowed whole. It is encouraged that the dose is taken at the same time each day. Due to the way lorlatinib is metabolised, this drug may interact with other medicines causing increased lorlatinib concentrations and in more serious cases, severe hepatotoxicity.3 Therefore, it is important the patient consults their doctor or pharmacist before starting any new medicines.
Adverse reactions from lorlatinib may require the drug dose to be modified or stopped. The most frequent adverse effect is hyperlipidaemia. It is important that cholesterol levels are monitored before commencement of lorlatinib and for a period after starting treatment. In many cases this adverse reaction must be managed with lipid-lowering drugs. Less frequent but serious adverse reactions include interstitial lung disease and atrioventricular block.4 These side effects need to be reviewed by a doctor immediately, as often this means the patient needs to be closely monitored and lorlatinib may need to be withheld until symptoms return to baseline. References are available on request.
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