Pharmaceutical industry
Aplagon is a pharmaceutical development company.
The pharmaceutical industry develops, produces, and markets drugs for use as medications. The size of the global pharmaceutical market was USD 1.25 trillion in 2019 [Statista]. The pharmaceutical industry is the largest investor worldwide in R&D [Schuhmacher et al. J Transl Med 2016]. 50% of the R&D pipelines of multinational pharmaceutical companies came from external sources (smaller R&D-focused companies like Aplagon and universities) already in 2013 [Schuhmacher et al. Drug Discov Today 2013]. The figure is today likely higher.
Development process for pharmaceuticals
Before a pharmaceutical product can be granted marketing approvals, it must go through a rigorous development process, which includes preclinical and clinical testing in compliance with international regulations. The testing is required to generate evidence on the safety and efficacy of the drug in the treatment of its target indication. It is often estimated that the development of a new drug takes 10–15 years.
The development process for pharmaceuticals consists typically of the following phases:
- Preclinical studies: Before clinical studies the candidate drug is extensively studied in preclinical setting. Such studies of the candidate drug involve both in vitro (test tube or cell culture) and in vivo (animal model) experiments to obtain preliminary efficacy, safety and pharmacokinetic (absorption, distribution, metabolism, and excretion) information.
- Phase 1 studies aim to study the safety, dosing, and key features of the candidate drug and are typically carried out in healthy volunteers. However, in some circumstances Phase 1 studies are carried out in patients, e.g. if surgery is involved (such as in hemodialysis access failure study with APAC).
- Phase 2 studies aim to assess the efficacy of the drug and gather further safety information.
- Phase 3 studies aim to provide a definitive assessment of the efficacy of the drug in comparison with the current best treatment. Phase 3 studies are typically randomised, controlled multi-center studies in a large number of patients. Market authorisation application can be submitted following successful Phase 3 studies.
Aplagon has carried out numerous preclinical in vitro studies using human blood and plasma, and in vivo studies in many animal models to test and show the function and efficacy of APAC. Aplagon has also carried out all toxicology studies in different animal species required by regulatory authorities to study dosing and to establish safety margins for the planned clinical studies for the selected indications. APAC is now ready to enter clinical studies in humans (Phase 1 & 2 studies).
Aplagon’s business model
Aplagon’s goal is to demonstrate preliminary efficacy and safety (clinical proof-of-concept) of APAC in at least two indications, COVID-19 and hemodialysis access failure, in the next 12-18 months and then find a commercialisation partner(s) for late-stage development and commercialisation of APAC outside India.
The partnering deal is expected to include significant milestone and royalty payments. Milestone payments alone for clinical stage pharmaceutical products typically exceed EUR 100 million.
The commercialisation deal for APAC would also provide an exit opportunity to the investors. The exit is likely to be through a trade sale to the commercialisation partner, license deal giving rights for APAC to the partner, or a merger with a listed company.
Source: a modified version of the chart in Herantis Pharma’s Annual Report 2019 .
Example of a partnering deal in a related indication:
- AM-Pharma, based in the Netherlands, develops a recombinant human alkaline phosphatase, a novel anti-inflammatory compound, for sepsis-associated acute kidney injury (SA-AKI). In May 2015, AM-Pharma entered an agreement with Pfizer. Under the terms of the agreement, Pfizer made an upfront payment of $87.5 million for a minority equity interest, and obtained an exclusive option to acquire the company, with additional potential payments of up to $512.5 million upon option exercise and potential launch of any product that may result from the agreement. AM-Pharma had at the time a Phase 2 clinical study ongoing in SA-AKI and had earlier completed a Phase 2 study with a bovine form of alkaline phosphatase.
Collaboration agreement with Cadila Pharmaceuticals
Aplagon and Cadila Pharmaceuticals (“Cadila”) entered in May 2017 into a development collaboration for APAC. Cadila is one of the largest private-held pharmaceutical companies in India. The collaboration covers the initial clinical proof-of-concept studies in hemodialysis access failure and COVID-19, and manufacturing of APAC for clinical studies. Aplagon has also an option for a Phase 2/3 clinical study in hemodialysis access failure in up to 360 patients. The clinical studies will be performed in India in a way that the data generated are fully acceptable also to the FDA (United Sates) and EMA (Europe). Cadila has the marketing rights for the Indian market whereas Aplagon retains the rights for all other markets. Aplagon’s responsibility is to make a commercialisation deal, once sufficient clinical data have been generated, for the late-stage clinical development and marketing and sales of APAC outside India. Cadila will pay Aplagon a modest royalty on Net Sales in India and Aplagon will pay Cadila a (reasonable) profit share on the ex-India commercialisation proceeds. In case Aplagon is sold, the profit share will be paid on the exit-proceeds instead of commercialisation proceeds.
The collaboration with Cadila provides Aplagon a highly cost-effective way of achieving preliminary efficacy and safety results in patients in two indications in parallel.
Initial target indications
Aplagon’s first clinical indications will be COVID-19 (systemic administration) and hemodialysis access failure (local administration). Aplagon is also planning to initiate a clinical program in advanced peripheral arterial disease / critical limb ischemia.
Aplagon expects APAC to be eventually used in a broad number of indications. The underlying causes – vascular injury, platelet activation and aggregation and activation of the coagulation system – play a key role in a wide range of diseases and disorders.
COVID-19
Description
COVID-19 is to a large extent a thrombo-inflammatory disease. Coronavirus disease 2019 (COVID-19) has caused an unprecedented health emergency, which was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. The incidence, severity and mortality of COVID-19 is three times higher than that of ordinary influenza A. Patients hospitalized with COVID-19 are at high risk of developing venous and arterial thrombotic events (blood vessel occlusions) and microangiopathy (small vessel disease in lungs and other organs), leading to poorer outcomes and increased mortality especially in patient groups at high risk of thrombotic complications. [Zhou et al. The Lancet 2020; Cattaneo et al. Thromb Haemost].
Role of coagulation in COVID-19
Dysregulated blood coagulation drives disease progression and mortality in COVID-19.
The systemic activation of coagulation is reflected among others by the biomarkers fibrinogen and D-dimer. Fibrin is formed from fibrinogen in the coagulation process. D-dimer, a fibrin degradation product, appears in blood circulation, when blood clots are broken down by fibrinolysis.
A marked increase in D-dimer level is strongly associated with disease progression and mortality, as shown in the figure below.
D-dimer in COVID-19 patients
Zhou et al. The Lancet, 2020
The loss of oxygen and breathing problems as a result of lung inflammation and microvessel occlusions lead to the need for mechanical ventilation, which is typical for severe cases of COVID-19. Microvessel occlusions develop due to vascular damage caused by viral infection and severe inflammation. In autopsy reports, platelet-rich thrombi were detected in the lung, liver, kidney, and heart microcirculation. [Ackermann et al. New Eng J Med. 2020]. One third of severe COVID-19 patients have also venous thrombosis, which can cause life-threatening dislodging occlusions (embolisms) to lung arteries.
The picture to the right depicts a healthy (left side) and COVID-19 infected (right side) lung structures. Oxygen delivery through the infected lungs to blood microcirculation is further blocked due to fibrin formation and thrombosis. The outcome is acute respiratory distress syndrome (ARDS) needing critical care.
COVID-19 causes abnormal systemic coagulation escaping local regulation
Iba T et al, 2020
Mortality of COVID-19 patients developing disseminated intravascular coagulopathy (DIC) / sepsis-induced coagulopathy (SIC), i.e., systemic dysregulated coagulation, can be up to 70%, vs 0.6% in non-DIC/SIC (Tang et al. JTH 2020). Severe COVID-19 often leads to multiorgan failure (lung, renal, heart, gut) due to microthrombosis (blood clots in small arteries). Acute kidney injury (AKI) carries extremely poor prognosis in patients suffering from COVID-19, with a high mortality of 76.5% (95%CI: 61.0–89.0) in a meta-analysis [Chen et al. Crit Care 2020].
APAC for COVID-19
APAC’s unique functionalities are a good fit with COVID-19 disease, as shown in the figure below.
APAC is targeted as a treatment for hospitalised, high-risk COVID-19 patients. In the planned clinical study, APAC will be intravenously administered in patients who need additional oxygen but are not yet in mechanical ventilation and critical care, and who simultaneously have clear signs of enhanced coagulation activity (such as elevated D-dimer). The goal is to prevent the progression of the disease to a more severe stage.
COVID-19 – a stepping stone to other inflammatory coagulation disorders – a multi-billion euro market opportunity
Sepsis is defined as the body’s extreme, life-threatening reaction to infection or other severe inflammation, which can rapidly lead to vascular damage, organ failure, and death (Centers for Disease Control and Prevention, US). Sepsis-induced coagulation disorder, coagulopathy (SIC) – leading to systemic dysregulated coagulation – is a strong predictor of mortality in sepsis patients, with mortality rate over 30%. Microthrombosis in small arteries causes multiorgan failure and plays a key role in all forms of SIC, including COVID-19.
Sepsis is the leading cause of death in critically ill patients and the most expensive condition treated in hospitals. SIC is thus a multi-billion euro market opportunity.
Current treatment and competition
Treatment options for COVID-19 are limited. Certain antiviral drugs, corticosteroids and heparins have provided some benefits in addition to organ supportive care (e.g. hemodialysis). Treatment options for sepsis are quite similar, but in bacterial infections antibiotics are used.
There are many different therapies in development for COVID-19. However, none of these therapies has similar mechanisms of action to APAC, and most of them rather complement than compete with APAC (e.g. anti-virals and anti-inflammatory drugs).
Hemodialysis access failure
Description
Kidneys filter blood to remove wastes and extra fluids to produce urine and to maintain a healthy balance of water, salts and minerals, critical functions for the body. There are several conditions where kidneys lose most or all their function. Patients with end-stage renal disease (kidney failure) require hemodialysis, a life-saving treatment that cannot be conducted without a functioning vascular access. In hemodialysis the patient is regularly connected via a vascular access to a dialysis machine, which acts as a surrogate kidney. The patient’s blood is circulated through the dialysis machine to remove excess water, solutes and toxins. Dialysis treatment is usually administered three times a week and lasts a couple of hours.
The optimal choice for vascular access is an arteriovenous fistula (AVF). AVF is created by a vascular surgeon by connecting an artery and vein in the nondominant arm of the patient. Radio-cephalic AVF (radial artery sutured to cephalic vein) above the wrist is the recommended choice for hemodialysis vascular access. This site preserves the potential access sites further up in the arm for future AVF creation. AVF typically matures in four weeks and then dialysis therapy can be started. The figures below show how an AVF is created.
Creating and maintaining vascular access is challenging. Vascular access failure or dysfunction continues to be a leading cause for hospitalisation and morbidity in patients with advanced chronic kidney disease. In a recent Phase 3 clinical study in patients with a newly created radio-cephalic AVF, 47% of the AVFs did not mature properly and 69% lost their primary patency (failed) within the first year in the control group.
AVF failure is managed with surgical or interventional reconstruction procedures, but high rate of AVFs has to be abandoned and rebuilt. Morbidity, mortality and costs of care are high. FDA has designated hemodialysis vascular access failure as a fast-track indication, i.e. a serious or life-threatening condition for which there is no effective treatment.
Current treatment
There is currently no effective treatment for the prevention of AVF failure. Opening of AVF is usually attempted with balloon angioplasty (a dilation of the AVF site with a balloon) or a surgical revision. These procedures are costly, invasive, and associated with a number of complications, and often these interventions are unsuccessful or have to be repeated. For instance, according to the US guidelines the treatment goal for an AVF balloon angioplasty is to maintain AVF open for 6 months [National Kidney Foundation (US): Clinical Practice Guidelines and Recommendations for Vascular Access 2006].
Market opportunity
There is a high unmet need for an effective therapeutic treatment for prevention of hemodialysis vascular access failure. The cost of managing hemodialysis vascular access dysfunction in the U.S. is estimated to be USD 2.9 billion annually. In 2013-2014 there were approximately 429,000 hemodialysis patients in the U.S, 315,000 in Europe, 315,000 in Japan and more than 2 million worldwide, with an annual growth rate of 6-7%, mostly due to increasing incidence of diabetes. Approximately 130,000 AVFs are created in the U.S. each year. AVF patients on average require more than 1.5 procedures per year to maintain their AVF. Each operation typically costs between USD 5,000 and USD 15,000. An AVF costs on average more than USD 17,000 in the first year after surgical placement [Proteon Therapeutics 2017 10K filing]. According to equity analyst estimates a peak sales potential in radio-cephalic AVF maturation alone amounts to approximately USD 500 million worldwide.
Competition
An external blood vessel support device made of nitinol (VasQ) by Laminate Medical and sirolimus-eluting collagen implant by Vascular Therapies are in randomised clinical study phase for hemodialysis vascular access failure in the US. Both devices are placed around (outside) the AVF at the time of its creation. VasQ has received a CE-mark in Europe and is available for sale in Europe and Africa.
There are three segments within hemodialysis vascular access failure market: AVF maturation, AVF reinterventions and AVF maintenance. APAC is first targeted to the AVF maturation market but is expected to be applicable to all these market segments. VasQ device and the sirolimus-eluting collagen implant will only suit for the AVF maturation segment. APAC could also be used in combination with these devices in the AVF maturation segment, given APAC’s synergistic mechanism of action and as APAC is administered inside AVF, whereas the devices are placed outside the AVF. APAC could also be used as an anticoagulant in the weekly dialysis sessions.
Peripheral arterial disease / critical limb ischemia
Peripheral arterial disease (PAD) is caused by reduced blood flow (ischemia) to lower limbs due to atherothrombotic peripheral arteries. In PAD fatty inflammatory plaques build up on artery walls, triggering blood clot formation. PAD is associated with significant morbidity and mortality, as vascular atherosclerosis is typically wide-spread in PAD patients. PAD significantly increases the risk of heart attack and stroke, the leading causes of death due to arterial thrombosis, and lower limb amputation. Symptoms in the affected limb include claudication (leg pain when walking), reduced peripheral blood circulation, poorly healing wounds, acute or repetitive thrombosis, and tissue death. The treatment options are limited and include mainly life-style changes, the management of risk factors (hypertension, cholesterol) and long-term systemic antiplatelet/anticoagulation treatment, and revascularisation of the affected limb, and in unsuccessful cases leg amputation.
Dysregulated coagulation in the sick peripheral arteries supports the disease progression in PAD. Coagulation biomarkers, such as fibrinogen and D-dimer, correlate with the disease severity and functional outcomes. Coagulation disorder typically continues even after a successful revascularisation of the affected limb.
Critical limb ischemia (CLI) is the most advanced form of PAD (Rutherford scale 4-6), with highest mortality and amputation rates as shown in the figures below:
CLI alone is estimated to be a USD 12 billion market opportunity, with up to 7-8 million patients in the US and Europe alone.
Only a limited number of pharmaceutical therapies are in development for CLI and none with a similar mechanism of action to APAC. Most of the therapies in development are gene or cell-based therapies. These therapies aim to grow new vasculature in the affected limb in the subset of CLI-patients that are not candidates for revascularisation. The results to date have been inconsistent.
APAC targets the atherothrombotic blood vessels where it reduces the overactive platelets, coagulation and inflammatory processes. APAC can be used in connection with the revascularisations of the affected limb (surgery or balloon angioplasty and subsequent hospital stay) and as a maintenance therapy by intravenous infusions. Most of the therapies on the market or in development would likely be complementary rather than competitive to APAC.
Development plan
Aplagon’s main goal is to complete the Phase 1+2 study in COVID-19 and the Phase 1/2 clinical study in hemodialysis access failure (AVF maturation). Aplagon will also prepare for a Phase 2a clinical study in advanced peripheral arterial disease / critical limb ischemia and continue R&D work supporting the clinical development and partnering efforts. The studies will be performed in accordance with European (EMA) and US (FDA) regulations.
- Phase 1+2 clinical study in COVID-19
- The clinical trial application (CTA) for the COVID-19 study was submitted to DCGI, Indian regulatory authority, in early March 2021. Aplagon expects the study, given its focus on COVID-19, to be fast-tracked in the regulatory review process. The study is expected to start in Q2/2021 and be completed by end of 2021. The study is planned to be divided in two parts, Phase 1 and Phase 2.
- In the Phase 1 part, 10 healthy volunteers will receive four different dose levels of APAC. The primary objective of the Phase 1 part is to establish the safety and tolerability profile of ascending single dose and multiple dose IV (intravenous) administration of APAC in healthy subjects. Phase 1 will also determine the dose for the Phase 2.
- In the Phase 2 part, 60 COVID-19 patients will be randomised into two treatment arms. 30 patients will receive APAC and the standard of care (SoC, but without low-molecular weight heparin) and 30 patients will receive SoC. The primary objective of the study is to demonstrate the preliminary safety and efficacy of APAC in the study patients. Safety evaluation will include bleeding risk and potential other adverse effects. The efficacy endpoints include the change in disease severity based on the WHO ordinal scale, change in biomarkers (such as fibrinogen and D-dimer), duration of hospital stay and the need for invasive/mechanical ventilation. The patients will be followed up to 28 days.
- Phase 1/2 clinical study in hemodialysis access failure
- The clinical trial application (CTA) for the hemodialysis access failure study was submitted to DCGI, Indian regulatory authority, in Q2/2020. The review of CTA was delayed due to the COVID-19 lockdown in India but is now underway. The study is expected to start in Q2/2021 and take up to one year to complete. The study is expected to enrol 30 patients with end-stage renal disease, divided into three APAC dose groups of ten patients. In each group, eight patients will receive APAC and two will receive the vehicle. APAC will be administered locally in the arterio-venous fistula (AFV) during the surgical creation of a radio-cephalic (wrist-area) AVF. The primary endpoint will be safety. The secondary endpoints will include efficacy assessments related to the AVF-maturation (suitability for use in dialysis). The patients will be followed up for 4 weeks.
Other activities
- Aplagon is planning to continue among others the following activities:
- Preparations for a Phase 2a clinical study in advanced peripheral arterial disease (PAD) / critical limb ischemia (CLI) patients that show ongoing coagulation activity. The study will include a PET-imaging part with a radiolabeled APAC to determine the distribution and retention of APAC at vascular injury sites in these patients, and a short-term treatment part with an outcome and biomarker based follow up of the patients.
- R&D-work at the Company’s Biomedicum laboratory in Helsinki and with several international collaborators to support the clinical development and partnering activities.
- Formulation development work with Cadila Pharmaceuticals to optimise the formulation of APAC for commercial use.
- Discussions with potential commercialisation partners for APAC.
Patents
Aplagon has a strong IP protection for APAC through patents and data protection.
- Aplagon filed in August 2014 a patent application covering APAC and related molecular conjugates. The patent application entered national phase in February 2017 after receiving a favorable international patent examination in 2016. The patent has already been granted in Australia, China, Europe, Hong Kong, Japan, Mexico, Russia, Singapore and South Africa. The patent provides patent protection for APAC, without any patent term extensions, until August 2035. Aplagon is seeking to obtain patent coverage in all key territories worldwide.
- Aplagon filed in May 2020 a second patent application which is not yet public.
- The patents and patent applications are owned by Aplagon.
- In addition, Aplagon expects APAC to be entitled to 10 years of data exclusivity in Europe and 12 years in the U.S. after obtaining market authorisation.
Lassila. Veritaudit, oppikirja, Blood diseases, textbook, Eds Porkka, Lassila, Remes, Savolainen, Duodecim, 2015.
