Aptahem is developing the drug candidate Apta-1 as an emergency treatment for sepsis, a life-threatening condition that is relatively unknown to the general public. BioStock had the opportunity to talk about this and what place Apta-1 might play in future sepsis care with the company’s scientific advisors, Anders Bylock and Mats Eriksson.
Associate Professor and licensed physician Anders Bylock is an expert in pre-clinical cardiovascular development conditions, clinical studies and registration applications. Bylock has been Director of Clinical Research at MSD Sweden and held several senior positions at AstraZeneca. Bylock has also been Senior Global Director at the Division of Global Clinical Development & Medical Affairs at Boehringer Ingelheim GmbH & Co KG in Germany.
Mats Eriksson, also Associate Professor and licensed physician, has many years of experience at the Anaesthesia & Intensive Care Clinic, Uppsala University Hospital, Uppsala. Eriksson has authored more than 60 original scientific peer-reviewed articles, published in reputable international journals, as well as more than 70 other scientific works, such as book chapters, overview articles and lecture abstracts. The research has largely focused on the influence of coagulation in sepsis. Eriksson has also worked for several pharmaceutical companies, e.g. as Medical Director at Orexo.
For starters, can you explain what the course of the disease looks like for sepsis?
Anders Bylock: There are two main scenarios, one where sepsis is caused by bacteria in the bloodstream and the other where sepsis can occur for reasons other than bacteria, but these differences matter relatively little. What often happens is that the body’s immune system overreacts to an infection or some other stimulus, causing damage to organs. Often there is also a sharp drop in blood pressure, which in itself is harmful. The condition can be further exacerbated by blood clot formation that can interfere with blood circulation and oxygenation of organs. This is the clinical picture, and this process can go very quickly.
Mats Eriksson: In medicine, the word “shock” has a very distinct meaning, namely a sharp drop in blood pressure and subsequently compromised blood circulation and impaired organ perfusion. So, it is quite different from how we use the word shock in everyday speech. A patient with sepsis or septic shock has very low blood pressure, and an expressed feeling of illness. Usually, the skin becomes warm due to peripheral vascular dilation. This is different from, for example, shock caused by excessive bleeding, when the peripheral vessels tighten to increase the central blood volume, which leads to cool, pale skin.
– Patients with sepsis or septic shock have relatively low circulating blood volume due to generalized vascular dilation, which is mainly expressed in the peripheral vessels. At the same time, sepsis has a serious negative impact on heart function, which contributes to low blood pressure and, as a worst case scenario, organ failure. This is a consequence of the relatively low blood volume combined with impaired force with which the heart muscle contracts. Treatment with antibiotics should be initiated as soon as possible. Intravenous fluids are administered to restore the relative hypovolemia back to normal. Treatment with vasopressors are given intravenously in order to increase blood pressure by increasing the strength of the heart beats and also to constrict peripheral blood vessels.
– Quite naturally, it is important to know what type of sepsis the patient has suffered; there are several types of sepsis and the course of one disease is not similar to another one. If you take the simplest scenario, different types of bacteria may cause different clinical situations. Furthermore, it is not only bacteria that can cause sepsis; especially in seriously ill intensive care patients, treated for a long period, the course of the disease can be complicated by sepsis caused by a fungal infection. Besides, for a year now, because of Covid-19, we have seen an increased incidence of sepsis patients with what is frequently called viraemia — the presence of viruses in the bloodstream which corresponds to the septic shock with all its complications and consequences.
– The inflammatory reaction caused by sepsis leads to an activation of the immune system, which might develop into an exaggerated defence response, commonly denoted “systemic inflammatory response syndrome (SIRS)”. This reaction affects the body’s immunological response and may cause further negative effects on different organs and their functions. Aptahem’s Apta-1 acts in a very interesting way, as the substance may dampen some inflammatory mechanisms. Apta-1 also has an anticoagulant effect, which is important as coagulation can sometimes get out of hand. Meningococcal sepsis is, thankfully, relatively rare, yet a well-known infectious condition that leads to a severe inflammatory reaction and pronounced formation of blood clots that ultimately risk causing damage to virtually all organs and often even to limbs, which can lead to amputations.
Has the pandemic affected the perception of sepsis?
Anders: I think it should be emphasised that the past year has given us a broader view of sepsis and what it can do due to Covid-19, which is a virus, a foreign agent that leads to the destruction of one or more organs. This is one of the reasons why it is important to emphasise that it is not just about bacteria. But — and this is important to point out — sepsis is not really a disease, but rather a bodily response that, in the worst-case scenario, can lead to one or more organs to stop working.
Mats: Yes, it can also be difficult to say what is caused by the low blood pressure and what is caused by the inflammatory response or by blood clots. What I think about, especially regarding Covid-19, is not only lung function, but also kidney function, and we know that with decreasing blood pressure, the kidneys are at high risk of injury. If we get into a situation where kidney function has deteriorated to the point where dialysis is needed, then, of course, the situation is critical. The inflammatory response is a jungle of reactions and events. Thus, the interaction between different pathogenetic factors is crucial; the more organ failures that occur, influencing each other by augmentation and feedback systems, the more severely ill the patient becomes.
Comparatively, there is less talk of sepsis compared to major common diseases such as cancer. Why do you think that is?
Mats: Despite the complicated appearance of sepsis, or perhaps precisely because of it, sepsis has had too little impact on general health awareness. Globally, sepsis is estimated to cause 19 million cases of disease and five million deaths annually. In Sweden, sepsis is expected to cause more deaths than breast, bowel and prostate cancer combined. Despite this, cancer is much more discussed than sepsis, which is often referred to as the silent killer. Many people die from sepsis in the postoperative process, that is, when they have contracted an infection that cannot be lifted after an operation. Of course, patients who undergo a surgical procedure complicated by an infection and who also undergo a strong inflammatory response have a worse prognosis than those who have not contracted an infection post-operatively. Especially since many of the inflammatory responses trigger each other — once the reaction has begun in one part of the immune system, the next part is potentiated, creating an inflammatory storm that is difficult to interrupt. If we take Covid-19 as an example, one of the biggest problems with this infection is that it leads to such an exceptional inflammatory response and with extensive formation of blood clots, and this is actually the great danger of the disease. Nevertheless, we see that sepsis receives an inadequate degree of attention when health and diseases are discussed.
Anders: In the case of postoperative death, the surgical code and what went wrong, such as for example pneumonia or a spread of bacteria caused by a build-up of pus, is noted as the cause of death. But, in fact, it is sepsis that leads to death or organ damage: you have something foreign in the blood that causes the immune system to derail and blood pressure to collapse, after which some organs, usually the kidneys stop working. Another example is when a cancer patient dies, and the cancer is listed as the cause of death. An underlying part of the process is then listed as the cause of death instead of sepsis.
Mats: Even young, previously healthy people can suffer from a severe sepsis infection and die in a few days from a rapidly progressing disease that cannot be reversed. The link between genetics and various types of infections is not fully understood, but it is important to point out that sepsis is not a process that only occurs post-operatively in hospitals or affects older, more easily infected people.
What are today’s treatment options?
Mats: The septic patient has contracted bacteria in the bloodstream and it is important to find out as soon as possible which type or types of antibiotics that should be given for the best efficiency, in combination with fluid therapy and heart-strengthening medicines. In fact, a ventilator can become relevant quite early in the process. The problem with antibiotics, of course, is that we are seeing an increase in antibiotic resistance, and I fear that this risks becoming one of the new pandemics of the future. In this context, it can be assumed that drugs that shorten the time from onset of infection to recovery, thereby shortening the time of antibiotic therapy, also reduce the risk of developing infectious agents that are less sensitive, or even, resistant to today’s antibiotics.
Anders: What I can say from our preclinical attempts at targeting sepsis with Apta-1 is that we have seen an opportunity to extend overall survival time, which is extremely important. In this context, however, I would like to emphasize that this must first be tested in clinical trials. Treatment for sepsis is divided into emergency treatment to keep the patient alive, as well as basic treatment where you choose the right antibiotic(s) for precisely what has caused sepsis in the patient. What we have seen in our experiments with Apta-1 is that you can gain quite a lot of time, and that time can be used to determine which antibiotic treatment is most suitable, which, in turn, would be a huge benefit as people can often die in a few hours as they go into septic shock. If that can be delayed by several hours, or maybe even 24 hours as our experiments suggest, it could help find which virus or bacterium is present and choose the right treatment for that particular patient. I see this as very stimulating and interesting.
Anders: The other part that we haven’t talked much about yet is the coagulation, i.e., where the blood clogs in the small vessels, which is a disaster whether it happens in the heart, lung or brain. This is often seen in Covid patients, for example. The blood thinning effects we have seen from Apta-1 are therefore interesting to mention in this context.
Do you see any potential in other indications?
Anders: Apta-1 acts more or less direct, at least so far, therefore we focus on the very important first 24 hours, when the patient is most exposed. However, since sepsis is not a disease but a final result or syndrome of another disease, Apta-1 can be beneficial in many different medical conditions and at the most dangerous stage of that condition. The candidate could also theoretically be useful in organ rejection during transplantation.
What are the benefits of a multifunctional drug like Apta-1?
Anders: In addition to our preclinical studies showing that Apta-1 supports and modulates the body’s own immune response and provides significantly improved survival in established models of sepsis and sepsis-like conditions, we have seen that the candidate counteracts coagulation, inhibits hyperinflammation and repairs tissue. This suggests that Apta-1 has the potential to counteract the damage caused by an inflammatory storm. One of the reasons why a multifunctional treatment is attractive is because of the varying course of the disease. One patient may have problems with coagulation that occurs in many small vessels in the body, while another patient may have an overreaction of the inflammatory system that causes blood pressure to plummet. Therefore, if many such effects can be handled by the same medicine, then a wider spectrum of conditions can be covered more quickly compared to other medicines that are currently available.
Does the pharmaceutical industry show interest in Apta-1 and sepsis?
Anders: Yes, but many companies are a little burned by previously expensive and unsuccessful attempts in the industry. Having said that, we recently signed a very interesting non-binding cooperation agreement with a European pharmaceutical company, which would not have come about without the interesting results we have. This is extremely stimulating now that this work has borne fruit in the form of a real interest. I would like to point out that what we have so far is something more than just positive results in test tubes, but rather very promising results in established sepsis models.
Mats: I fully agree here. In this context, I can mention that in 2019 I gave a talk at one of the world’s largest intensive care congresses (14th World Congress of Intensive Care; Melbourne, Australia) where the results I was able to present on the effects of Apta-1 were received very positively, something that has not received as much attention here at home. The healthcare professionals at the congress were impressed by the significantly positive results, in terms of survival in preclinical models (i.e. Apta-1’s effect), in combination with the antithrombotic and anticoagulant properties exhibited by Apta-1. The pharmaceutical industry is a bit burnt, but given that sepsis is a multifactorial condition, it is very difficult to find a causal treatment. As far as Apta-1 is concerned, one should not be pessimistic but rather the opposite: if the golden treatment had already been found for the great medical need caused by sepsis, then there would have been no real room for Apta-1.
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