Biological treatment – everything the patient should know

Biological treatment is a rapidly growing branch of pharmacotherapy [1] that is used in many areas of medicine, including:

• oncology (e.g. for the treatment of lymphoma and cancers of the breast, colon, lung, cervix),
• rheumatology (e.g. for the treatment of rheumatoid arthritis, psoriatic arthritis, osteoarthritis),
• allergology (e.g. for the treatment of asthma, atopic dermatitis, chronic spontaneous urticaria),
• gastroenterology (e.g. for the treatment of ulcerative colitis, Crohn’s disease),
• transplantology (in post-transplant therapy) [2].

It is an innovation created by integrating the achievements of genetic engineering and molecular biology [1]. It still holds many secrets. Therefore, it may sound enigmatic – especially to patients. This therapy is based on the use of living organisms or cells in a complex, multistage process to produce biological drugs [3,6]. It is based on biotechnological methods. It often involves the use of complex cellular systems as well as recombinant DNA technology [3].

Biological drugs have changed the outlook for the treatment of severe, chronic conditions unresponsive to classical therapies and even considered incurable [3,6]. Although it is a new form of therapy, it has already been included in guidelines and recommendations of medical societies. Biological treatment is therefore not experimental, but follows current standards [4].

Biological drugs are divided into original (reference) and biosimilars (biosimilars). The second ones show high similarity to approved biological drugs (in terms of structure, structure and therapeutic equivalence), but are never identical [3,6]. They are subject to assessment by registration authorities [6]. Biosimilarity is confirmed by appropriate clinical trials according to the regulations applied by agencies such as the European Medicines Agency (EMA) [7].

The active substances of biological drugs are mainly proteins, e.g. insulin, growth hormone, monoclonal antibodies or blood clotting factors [3]. It is from the production of synthetic insulin by recombinant DNA methods that the beginning of biological treatment dates. This treatment has experienced a real boom since the last decade of the last century [7]. In 1986, the first antibody, Muromonab-CD3, was introduced into therapy and found application in transplantology (as a drug to prevent transplant rejection) [8].

How do biologic drugs work?

The mechanisms of action of biological drugs are extremely diverse Biological preparations can, for example, mimic the function of human proteins (such as insulin) or influence interactions between individual molecules (such as monoclonal antibodies) [2]. Monoclonal antibodies are specific proteins produced by cells of the immune system. These proteins form bonds with and neutralise specific antigens, or molecules that may be considered hostile by the body. They only bind to one specific molecule or fragment thereof [8].

Drugs based on the action of monoclonal antibodies have the particle ‘-mab’ in their name:

• chimeric – “-xymab” (e.g. infliximab),
• humanised – “-zumab” (e.g. omalizumab),
• human – ‘-umab’ (e.g. dupilumab) [8,12].

The exact mechanism of action of biological drugs has not been determined and cannot be 100% predicted. In terms of physicochemical properties, these drugs are very sensitive to sunlight and temperature changes. For this reason, their storage (usually at 2-8°C) must be strictly followed [6]. Biological drugs are typically administered parenterally or inhaled [6].

However, they are not the first line of treatment. According to current guidelines, biological treatment should be preceded by classical methods, which are effective and well tolerated in a large group of patients. Only in the absence of a response can qualification for biological therapy be initiated [7].

In Poland, there are various biological treatments included in drug programmes, i.e. reimbursed to patients. Such treatments are also administered off-label (outside the registered indications) or outside the drug programme [4]. Despite this, in Poland only 1-3% of patients receive biologic medicines. In the European Union, this percentage is much higher and amounts to 25-30% [7].

A significant barrier that may account for such low interest in this type of therapy is a lack of trust – on the part of both patients and doctors [7]. And lack of trust is a result of insufficient knowledge. Access to biologic therapy is also limited by a complicated and long qualification pathway, as well as the fact that it can only be provided in designated centres [7]. In addition, the manufacturing process of biologic drugs requires an extensive and costly infrastructure, which affects the high price of these preparations and prevents many patients from using them outside the drug programme [9]. Biological treatment is also a heavy burden on the healthcare system.

Biological drugs from the group of monoclonal antibodies (with the common suffix “-mab”) are primarily intended for the treatment of allergic diseases[2]. Their biological action focuses on one element of the entire immune response cascade. Each acts at a different stage of this cascade and on different elements of the inflammatory process [4].

* Reimbursement data are current as at the date of publication of the article.

As many as four reimbursable biological drugs are available for patients with asthma (severe form). Nevertheless, in Poland, only about 10% of patients who could benefit from such treatment have access to it [11]. Biological therapy for asthma involves the precise elimination of a specific element of the cascade of complex processes regulating the inflammatory response of the airways [9]. Biologic drugs used in the treatment of asthma are produced by recombinant DNA amplification of cells derived from the Chinese hamster ovary [9].

Biological treatment allows:

• reducing the frequency of exacerbations,
• reduction of glucocorticosteroids,
• control of asthma and other comorbidities,
• improvement of the patient’s quality of life [4].

Various factors are considered  when qualifying for such treatment, such as lung function, comorbidity, and biomarkers, such as the number of eosinophils in peripheral blood [4,6]. The drug programme for severe allergic asthma is run by dozens of centres in Poland. Drugs are administered in an outpatient procedure or as part of a one-day hospitalisation [9].

What is the effectiveness of such treatment?

Response to biological treatment can vary. It is assessed 4-6 months after starting therapy. Treatment failures are most often since  patients who notice an improvement (after only 3-4 doses) sometimes discontinue other disease-controlling drugs on their own. Lack of efficacy of biological treatment may also be due to inappropriate drug selection [4].

14-44% of patients respond very well to biological treatment, with a large reduction in inflammatory parameters and a marked improvement after just 6 months. These are patients with clinical features such as lower BMI or higher values of volume indices in spirometry (FEV1) [4]. Professor Maciej Kupczyk, president of the Polish Society of Allergology, spoke about such cases during a meeting with journalists:

– ‘After the initiation of biological treatment, we observe spectacular improvements in patients. Patients do not believe what is happening to them. They do not need to use steroids, they do not have unscheduled medical appointments. The need for other medications also decreases.

Full remission of asthma in response to biological treatment (found after 12 months) means:

• absence of clinical symptoms,
• stabilised lung function,
• no use of systemic corticosteroids,
• agreement between physician and patient to achieve remission [4].

According to experts from the Polish Society of Allergology, biologics are a promising alternative when severe asthma co-occurs with chronic sinusitis, nasal polyps, and hypersensitivity to aspirin and other NSAIDs [9].

Researchers are seeking answers to the questions of whether biologic treatment applied to mild asthma would prevent its progression and could protect high-risk individuals from developing asthma. The long-term efficacy of such treatment also remains to be assessed [4].

Biological treatment does not exclude the inclusion of allergen immunotherapy – it can even be carried out in parallel with it. A contraindication to desensitisation is uncontrolled asthma, which can be managed precisely with biological drugs, in numerous instances a prelude to immunotherapy [4].

Biological drugs are not free of side effects, although the formulations recommended for the treatment of severe asthma, for example, have a very good safety profile [9]. Omalizumab has so far been used for the longest time and in the largest number of people with allergic conditions, so it is the best studied in terms of safety [9].

However, scientific studies note that the increasing use of biologic drugs is associated with an increase in the number of hypersensitivity reactions in patients (organ symptoms are more common in oncology patients) [2,5]. The U.S. Food and Drug Administration monitors the risks of lymphomas and cancers after biologic therapy, but data on these risks are disparate [9,10].

Another controversial issue remains the potential immunogenicity of biologic drugs. Immunogenicity is the ability to induce an immune response and the formation of anti-drug antibodies (ADAs), which can develop over many months or even years [6]. There are concerns about long-term side effects of these drugs, as well as a decrease in treatment efficacy [6]. Due to immunogenicity, it may be necessary to increase the dose during treatment to maintain clinical response [6].

Aleksandra Lipiec

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translation: Julia Majsiak