Parkinson's Disease (PD) is one of the principal neurodegenerative diseases affecting the central nervous system. Symptoms appear gradually and progress slowly. The disease’s motor symptoms occur alongside a series of non-motor symptoms, which can begin to appear even before the motor symptoms do.www.parkinson.it

In 2020, Covid-19 had a dramatic impact on people living with Parkinson's: isolation, the inability to engage in physical activities and an increase in chronic stress led to a ening of motor and non-motor symptoms.Rick C. Helmich and Bastiaan R. Bloem Journal of Parkinson’s Disease 10 (2020) 351–354

Our commitment to the treatment of Parkinson’s Disease began in 2015, when Xadago® (safinamide) iwas first introduced in Europe, followed by launches in North and South America and in Australia. Safinamide, dual mechanism of action, which combines dopaminergic and non-dopaminergic action, works to treat the disease’s motor and non-motor symptoms alike, improving patients’ quality of life. Muller T, Foley P (2017) Clinical pharmacokinetics and pharmacodynamics of safinamide. Clin Pharmacokinet 56, 251-261

This multi-pronged commitment has allowed us to produce scientific evidence, conduct educational initiatives for clinicians and, first and foremost, provide support for patients, thanks to collaborations with associations for people affected by PD.

Launches of Xadago® (safinamide) continue around the world. Today it is available to clinicians and patients in 20 countries. In 2020, it was introduced in the United Arab Emirates. The results of the SYNAPSES study have confirmed the medication’s good safety profile and tolerability.

2020 saw us continue our commitment to educational activities focused on the importance of remote monitoring systems and on the adoption of a multidisciplinary approach to treating PD.

Xadago® recorded net revenues of 52.2 million euros (+8.9% YoY) thanks to excellent performance in Spain (+9.4%) and Germany (+10.2%).

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease characterised by progressive muscular paralysis. There is no cure for ALS; treatment consists of symptomatic pharmacotherapy with drugs to slow the disease's progress, physical exercise and home care.

During the course of the year—as a result of a 2019 agreement with Aquestive —studies and regulatory approval activities have moved forward to make a new riluzole oral film available on European market for the treatment of patients with ALS. Our goal is to make this drug available to people suffering from this highly debilitating disease.

93% of the world’s population has experienced a headache or physical pain at least once during the past year. A headache, which affects 84% of the world’s population, is the most common type of pain. Global Pain Index Report 2020

Severe pain (mild and moderate) often has an impact on social relationships and on the emotional sphere, so much so that 65% of the world’s population believe that pain interferes with their ability to fully enjoy their professional and personal lives and worklives. Spidifen Customer Centric Model 2021

Spidifen® is a non-steroidal anti- inflammatory drug containing ibuprofen and arginine salt that offers a front-line treatment solution for mild-to-moderate severe pain.

In 2020, thanks to its presence in 54 countries, Spidifen® , earned revenues in the amount of 52.5 million euros, despite an extremely complex market context.

Spidifen®’s mid-term strategy continues to be based on two key elements: growth in the OTC sector and updating communications that target healthcare providers. In particular, we published a scientific monograph entitled “Nonsteroidal anti-inflammatory drugs, ibuprofen and ibuprofen-arginate” , by Prof. Patrono, which highlights the distinct mechanisms of action of different NSAIDs.

Lastly, in 2020 Zambon worked to gain a deeper understanding of the needs of both doctors and patients to provide increasingly targeted and effective solutions..

Cystic fibrosis (CF) is the most common of the severe genetic diseases . It is characterised by chronic infections of the respiratory tract that cause a progressive decline in lung function, which has a serious impact on patients’ quality of life. The life expectancy of people suffering from CF has increased considerably over the years. This remarkable outcome is attributable to ongoing progress in the medical and pharmaceutical spheres, the use of antibiotic therapies to treat chronic infections, and improvements in diet. Natalie E. West, Patrick A. Flume. Unmet needs in cystic fibrosis: the next steps in improving outcomes, Expert Rev Respir Med. 2018 July; 12(7): 585–593

In 2020, Zambon strengthened its commitment to severe respiratory diseases.

Cystic Fibrosis

The company has continued to work on colistimethate sodium (Promixin®) as a treatment for chronic pulmonary infections caused by Pseudomonas aeruginosa in patients with Cystic Fibrosis. In particular, Promixin® can be administered using the I-neb® Adaptive Aerosol Delivery (AAD) device jointly developed with Philips, which, thanks to third-generation AAD technology and the ability to monitor real adherence data, offers concrete support to healthcare providers and patients.

Ongoing clinical trials focused on Non-cystic Fibrosis Bronchiectasis (NCFB)

2020 was a decisive year for Phase III trials of PROMIS 1 and PROMIS 2, involving patients with NCFB, an incurable pulmonary disease characterized by permanent bronchial dilation and inflammation, chronic productive cough and recurrent aggravation of infection. Despite the pandemic, the enrolment of patients for the PROMIS 1 study was completed in 2020, while a mitigation plan was put into effect for PROMIS 2 which ensured that enrolment could continue. The two trials stand out for the number of clinical centres involved worldwide, and the number of patients enrolled: over 700 globally. Our goal is to obtain, by 2023/24, an indication for colistimethate sodium in combination with I-neb® for the prevention of exacerbations in patients with NCFB and chronic Pseudomonas aeruginosa infection, both, in Europe and the US.

Ongoing clinical trials focused on Bronchiolitis Obliterans Syndrome (BOS)

Zambon renewed its commitment to patients with BOS, the most common form of chronic lung allograft dysfunction after lung transplantation. BOS is a rare and rapidly progressive inflammatory disease that irreversibly destroys the airways of the lungs, usually leading to respiratory insufficiency and death. Chambers DC, et al. J Heart Lung Transplant. 2018;37(10):1169–1183.

The BOSTON development program is evaluating liposomal Cyclosporine A for inhalation (L‐CsA-i) for the treatment of BOS. It is an immunosuppressive drug used in post-transplant treatments. The innovative L-CsA-i is encapsulated in liposomes, which distribute the medication directly to the lungs via a drug-specific nebulisation system. Patients with BOS represent a risk category for Covid-19 infection. To ensure the safety of the patients enrolled, their continuous treatment and the integrity of the data collected, Zambon implemented a contingency plan including remote visits and at-home spirometry tests.

Urinary tract infections (UTIs) are a frequent occurrence that largely affects the female population. It is estimated that one in two women suffers from a urinary tract infection during her life, with an annual incidence of 12.6%. Foxman, B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon 49, 53–70 (2003).

The pathogen that most frequently causes this type of infections is Escherichia coli even if, less frequently, other bacteria, viruses or fungi can also be responsible. Chambers, ST. Cystitis and Urethral Syndromes. in Infectious Diseases (Mosby, 2004).

Urinary tract infections can also affect men, especially during invasive diagnostic investigations such as prostatic transrectal biopsy. Because of this, Zambon is currently conducting a Phase I clinical study that analyzes the prostatic penetration of fosfomycin trometamol in healthy male volunteers, with the aim of assessing whether a prophylactic use during diagnostic investigations can be valid. The study will conclude by the end of 2021.

Monuril® (fosfomicina tromentamolo) has been available to women across the world for over 30 years . A single dose is recommended, as a first-choice treatment for uncomplicated acute urinary infections by the European Association of Urology (EAU) and two doses for antibiotic prophylaxis in men undergoing transrectal prostate biopsy posology (before and after surgery). Bonkat, G. et al. EAU Guidelines on Urological Infections 2021. (2021).

In this regard, we mention "REWIND" (REWIND "(Real World International Database) a clinical practice study that has analyzed data from over 50 thousand patients (Italy, Belgium, Russia and Brazil). Despite the use of different methods for the study of data and sources, fosfomycin trometamol was found to be the most used antibiotic in all four countries considered.

The “SURF” study ( SUsceptibility and Resistance of uropathogens to Fosfomycin in comparison with other antimicrobial agents) also came to a conclusion in 2020, with the aim of demonstrating once again the susceptibility of E. coli (the most responsible pathogen for cystitis) to fosfomycin trometamol in recent times.

In 2020 we kept on with our commitment to providing scientific information healthcare providers through educational activities and disease awareness campaigns.

Finally, we conducted two International Advisory Boards with the aim of clearly defining the role of Monuril® in different clinical settings in light of new scientific findings.

In 2020, sales of Monuril® remained stable, coming in at 91.3 million euros (-1.0% in comparison with 2019). These results are significant, considering the introduction of generic drugs in the Central/Southern European and US markets.

Respiratory diseases encompass a broad spectrum of conditions, which range from relatively basic acute seasonal disorders, such as cough, flu and acute bronchitis, to chronic progressive illnesses, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis.

In 2020, the measures implemented to fight Covid-19, such as social distancing, mask wearing and the use of flu vaccines, deterred acute respiratory illnesses, the flu first and foremost among them, from manifesting in many countries, and also limiting the number of exacerbations of chronic conditions. medrxiv.org (1)medrxiv.org (2)theatlantic.comsciencedirect.comthorax.bmj.com

Although Fluimucil® (N-Acetylcysteine, NAC) is one of Zambon’s historic products, scientific investments into this molecule are ongoing.

In 2020, the company focused on understanding the role of NAC in continuous administration. A symposium was organised for the scientific community, “Which Target to Protect and Preserve Lung Health” , during the European Respiratory Society (ERS) International Meeting. A new communication campaign was also launched, “Break the Loop, Breathe Free” which aimed to highlight the drug’s protective antioxidant effect on lung tissue.

2020 was a significant year for NAC, when it comes to clinical trials. In China, Phase I and III studies related to the registration of intravenous NAC in patients with mucosal hypersecretion have been completed. The results represent a step forward in the approval process for the use of NAC IV for the treatment of COPD in the market.

Lastly, 2020 saw the launch of a number of investor initiated trials (IITs) involving the use of NAC in the treatment of Covid-19. Despite the negative impact the pandemic has had on the market for drugs to combat respiratory diseases, Zambon's revenues stood at 291.8 million euros, a 14.9% (51.1 million euros) decrease in comparison with 2019, a fall in line with market trends.

2020 was one of the most challenging years in the history of Zambon’s production facilities . The pandemic had a strong impact on all fourindustrial facilities, but our timely intervention first in our Haikou plant and then in all of the Group’s other facilities, allowed us to proactively manage the waves of the pandemic in China, Europe and South America.

The pandemic forced us to act rapidly and respond flexibly to market volatility. During the first six months of 2020, we reached a peak in production, mantained thanks to our organisational system and investments made in prior years: streamlining initiatives and technological innovation and digitalisation projects were fundamental to our ability to deliver 156 million pieces and supply every market.

In 2020, in line with our strategic objectives, we also invested 36.7 million euros for the purpose of continuing to improve efficiency and technological innovation at our facilities.

Our Chinese plant in Haikou was the first to feel the impact of the pandemic. Despite all, we installed new pieces of machinery and production equipment, in line with our strategic plan. Thanks to work carried out in synergy with our Corporate departments, we were able to validate the new processes and get the new systems up and running, allowing us to increase efficiency and production capacity.

In our plant in Vicenza (Italy), many actions were taken to prevent the virus from spreading and provide continuity to the business. We concentrated on re-engineering processes and activities and adhered to our plans for the construction of the new Marco Polo facility , destined for the production of 300 mg vials of Fluimucil® for the Chinese market.

It is important to point out that we recorded no accidents or injuries in 2020, a noteworthy outcome generated by our effort put into training and investments in safety.

In Cadempino, in Switzerland, we invested in training and in process optimisation.

From a production standpoint, we started new production activities and guaranteed our biggest customers larger volumes.

At our Barueri plant (São Paulo) in Brazil, investments continued to guarantee insourcing activities of Zambon products. Moreover, additional SKUs (Stock Keeping Units) were approved, expanding the product portfolio for the Brazilian market.

It was an intense and busy year for Global Quality as well, which ran virtual audits and implemented internal systems for sharing information and policies remotely in all production facilities and all Group’s subsidiaries.

The coronavirus pandemic has highlighted how vulnerable many supply chains are to sudden interruptions. At Zambon, we were able to contain this problem thanks to the efforts of our supply chain and to our pool of solid and reliable suppliers.

Once again, as in previous years, our Virtual Plant (our organisational model for the centralised management of contract production of Zambon products) played an integral part in programmes to optimise synergies between the different facilities in a streamlined and integrated fashion.

Research into the unique mechanism of action of safinamide (Xadago®) led to the publication of three articles in scientific journals in collaboration with research centres.
The Phase IIa clinical trial focused on Multiple System Atrophy (MSA) . The results will be available during the first half of 2021.
A Phase IIIb trial focusing on Levodopa-induced dyskinesia (PD-LID) was redefined, and all of the related preparatory activities have been successfully completed.
Lastly, the Phase IV trial focusing on pain related to Parkinson’s Disease completed its patient enrolment. It is expected to be completed and its results analysed during 2021 .

Colistimethate sodium (Promixin®) via I-neb®

Important progress was made in the international program dedicated to the potential treatment of pulmonary infections caused by gram-negative Pseudomonas aeruginosa bacteria in patients suffering from Non-cystic fibrosis bronchiectasis (NCFB) using colistimethate sodium administered by inhalation through the use of the I-neb® nebuliser.
A recalculation of the number of patients needed for the PROMIS 1 trial to have the statistical validity allowed to achieve its recruitment goals without any impact on the quality of the study. The report on this trial is due in 2021.

The impact of the pandemic on the PROMIS 2 trial was mitigated by actions aimed to ensure the recruitment that was completed in 2021.

A liposomal formulation of Cyclosporine-A for inhalation (L-CsA-i) via eFlow®

Bronchiolitis Obliterans Syndrome (BOS) is a progressive inflammatory and fibrotic disease of the respiratory system that commonly develops in patients who have undergone a lung transplant. L-CsA-i is an innovative liposomal formulation of the immunosuppressant drug Cyclosporine-A and created for use via inhalation utilizing a specially designed version of the eFlow® Technology nebulizer system (PARI Pharma GmbH).

Two Phase III trials are currently ongoing (BOSTON-1 and BOSTON-2), involving patients suffering from BOS following lung transplantation. Patients who complete the treatment period in the BOSTON-1 or BOSTON-2 studies will, if eligible, be recruited for the BOSTON 3trial, an observational study to gather long-term efficacy and safety data for the drug. A Phase II clinical trial (BOSTON-4) to evaluate the safety of L-CsA-i for the treatment of adult patients suffering from BOS following allogeneic haematopoietic stem cell transplantation is also underway.

Additional projects in Clinical Phase

In 2020 a Phase I three part, single ascending dose (SAD), multiple ascending dose (MAD) & Cross-Over Study in healthy and asthmatic subjects has been carried out to test the safety and pharmacokinetics of a new dry powder inhaled formulation of the fungicide Voriconazole produced using proprietary E-dry® technology .
The project’s goal is to obtain a new inhalable formulation of Voriconazole to use as a new treatment for Allergic Bronchopulmonary Aspergillosis (ABPA).

Projects in the Preclinical Phase

E-dry® technology is at the basis of two other projects coming down the pipeline in preclinical phase . The first envisions the development of an inhalable formulation of a drug to treat pulmonary infections caused by atypical mycobacteria. . In 2020 the necessary experiments were planned to advance the process of developing the candidate for clinical development. The second project involves a new inhalable formulation of an antioxidant recommended for prophylactic treatment for exposure to particles and chemical substances that are toxic to the organism. In 2020, we concentrated on the preliminary activities necessary for subsequent planning of formulative research.

The Central Nervous System (CNS)

In 2020, Zambon continued to present data about Safinamide (Xadago®) with a symposium at the Movement Disorders Society (MDS) Virtual Congress and a poster at the European Academy of Neurology Virtual Congress. Furthermore, two new articles on the effectiveness of Xadago® for treating pain and cognitive impairment in patients with Parkinson’s Disease were published in the Journal of Neural Transmission.

In 2020 the approval from EMA (European Agency for Medicines) of the clinical study report for the Phase IV observational study “Synapses" was obtained; meanwhile, the Phase IV observational study “Synapses”; meanwhile, the Phase IV European observational study “Success” and the Phase III study “Xindi” for the registration of the drug in China are currently ongoing. Finally, we have 11 investigator-initiated trials (IITs) assessing the effectiveness of safinamide to treat non-motor symptoms, cognitive impairment, freezing of gait, apathy and chronic pain in Parkinson’s Disease. And finally, we received fast-track authorisation for the registration of safinamide in Turkey.

Respiratory diseases

Once again in 2020, Fluimucil® (N-acetylcysteine, NAC), one of the company's historic drugs, was the focus of a series of scientific dissemination activities. The results of the International Expert Panel Meeting held in 2019 were published in the Current Neuropharmacology journal. The purpose of the meeting and, consequently, of the article was to clarify the benefits of using Fluimucil® in different clinical settings. A study was also published in Drug Safety which confirms the tolerability of Fluimucil® when administered off-label at high doses.
In September, at the ERS (European Respiratory Society) International Congress, Zambon sponsored a virtual symposium on the role of Fluimucil® in the treatment of chronic respiratory diseases.

In China, Phase I and III pivotal trials involving approximately 350 patients were completed for the use of intravenous N-acetylcysteine in patients with mucus hypersecretion. The results of a Phase I trial conducted on healthy ethnic Chinese and Caucasian volunteers were also significant. This study showed the same safety and pharmacokinetics results for both groups. The study was published in Advances in Therapy.
An extension phase study on the use of Fluimucil® in patients with retinitis pigmentosa — a rare and serious orphan disease, genetic in nature, which affects the retinal pigment epithelium and the retina, leading to gradual and progressive vision loss — is currently ongoing in the United States.

Urinary tract infections

Monuril® (fosfomycin trometamol) has also been the focus of numerous scientific activities. We are awaiting the publication of data from the international SURF study ,aimed at assessing the rate of antibiotic resistance to fosfomycin trometamol and other antibiotics commonly used in urinary tract infections. Zambon is working with the EMA to conduct a Phase I pharmacokinetic/pharmacodynamic study , which will conclude at the end of 2021. Finally, 2020 saw the organisation of two virtual due Advisory Board on the role of fosfomycin trometamol in different clinical contexts.

Pain

Spidifen® (ibuprofen and arginine salt) was also the focus of important activities, such as the publication of the scientific monograph entitled “Nonsteroidal anti-inflammatory drugs, ibuprofen and ibuprofen-arginate”, by Professor Patrono, which aims to highlight the distinct mechanisms of action of different NSAIDs. A scientific Advisory Board was held on the interaction between ibuprofen and Covid-19, with the objective to clear that no connection has been demonstrated between ibuprofen use and a higher risk of being infected by Covid-19 infection.