Therapies and Diagnostics

In focus: Rare diseases & Oncology

Rare diseases

Approximately 8,000 diseases, that is, the majority of existing diseases, are considered “rare” and have an incidence lower than 1 in 7,000 people. Fewer than 1,000 of these diseases are documented with minimal scientific knowledge, and only 5% of them have an effective treatment. This huge blind spot of pharmaceutical research has started to receive more interest, and it is one of the biggest opportunities for innovative drug developers to break into the market and make a real difference, provided they can withstand the challenges associated with orphan drug discovery and commercialization. Italy formally reimburses more orphan drugs than any other European country, according to specialist consultancy focused on rare diseases, Rareg. Also, there has been an upward trend in the number of clinical trials for orphan drugs in the country, and the percentage of advanced therapy products (ATMPs) is growing at 11% in Italy, compared to the global average of 4.7%. These numbers suggest a greater interest in the market for developing and commercializing orphan drugs. Large Italian pharma company Recordati has been running a rare disease division ever since 1990, and other leading companies are officializing this interest; in 2020, big Italian pharma Chiesi inaugurated the Chiesi Global Rare Diseases with a headquarter in Boston. The company was already marketing Lamzede, a drug for an ultra-rare genetic condition called Alpha-mannasidosis.


The highly fragmented, incredibly heterogeneous and loosely competitive rare disease sector gathers a large space of unmet medical needs that smaller developers can tap into, though the challenges are even greater for smaller companies. Low profitability prospects have precluded more pharmaceutical interest in this field, despite the overwhelming medical need. Giovanni Sala, the general manager of Medac Pharma explained the investment and the number of clinical trials is as high, if not more, as for high-incidence diseases: “This issue cannot be left on the shoulders of pharma companies alone. With regulators, we should jointly find a rewarding system to enable pharma companies to recover their investment made to find optimal treatments for small groups of patients. The orphan drug status currently offers additional market protections, but more innovative and creative rewarding systems must be jointly identified.” Besides running a special 500 million euros fund for orphan drugs reimbursement, Italy has endowed the “orphan” drug status with different protections in a bid to incentive research in this space. For example, orphan drugs are exempted from the payback system. However, Laura Crippa, the managing director of Rareg, commented this has led to a complicated situation in which the difference is paid by other commercial players operating in different therapies, which becomes even more problematic when these players also commercialize orphan drugs; in other words, they’ll pay themselves the discount that the government is granting. The other special exception for orphan drugs is a shorter price-and-reimbursement procedure timeframe, which is 100 days long versus the standard 180 days. Crippa again clarified how this looks like in practice: “The 100 days’ timeline is a nice thought, but difficult to execute. The process remains lengthy before an agreement is found, because companies seek to maximize their return on investment, while AIFA does its duty to negotiate a lower price for patients. This timeframe is also slowed down by the lack of possibility for early discussion between companies and AIFA before they submit a dossier to predict and avoid potential challenges. Early dialogue would surely help the process.” What slows down the approval process is also the sophisticated nature of the medicines and the diseases themselves, many having no close precedent or similar counterpart in the market. AIFA reviews dozens of submissions every day, and it can spend months to understand both the unique disease and the presented clinical evidence and therapeutic effect. For example, Holostem received the market authorization for its Holoclar therapy for limbal stem cell deficiency (LSCD) seven years after starting development. When approved, another challenge comes from market strategy and connecting a very disparate group of patients. For example, LSCD has an incidence of 3.3 out of 100,000 people in Europe, which translates to about 700 new cases every year in Europe. However, there are many other patients who may have suffered the condition ten or twenty years ago, and who can have a chance to see again. “The big difference ATMPs make is that they have a long-term restorative effect rather than offering a temporary solution. Based on different variables, ATMPs have an efficiency rate of 30% to 50% and are only administered only once or twice, having a life-changing impact,” said Marco Dieci, the CEO of Holostem. Dieci’s vision is to create a pan-European, single payer for orphan drugs and bring these patients together. Operating from a single pocket would centralize and consolidate the European rare disease market.

Background image courtesy of Pexels, Artem Podrez


Cancer therapies

If rare diseases are one of the least researched pharmaceutical territories, cancers are at the other end of this spectrum: Over 34% of all pharma assets under development are related to oncology, estimates PwC, and the top ten oncological drugs are blockbusters selling over US$1 billion each year. Causing one in six deaths (according to the WHO), cancer is one of the biggest killers of the 21st century, and finding the right treatments one of the biggest pursuits of the pharmaceutical industry. The European Medicines Agency (EMA) recommended 97 drugs for approval across different therapies in 2020. Of these, oncology led the charts with 21 recommendations. EMA marked as “outstanding contributions to public health” three new oncological substances: Blenrep (by GSK), an ATMP used in patients with relapsed and refractory multiple myeloma; Rozlytrek (by Roche), used for solid tumours with a specific kinase gene fusion; and Tecartus (by Gilead), a cell therapy for a rare cancer with relapsing symptoms after various lines of treatment. The focus on rare cancers can also be seen with Menarini, who recently came in possession of ELZONRIS (tagraxofusp) after acquiring its developer, Stemline Therapeutics. ELZONRIS is a monotherapy used as a first-line treatment of plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer. Menarini announced at the beginning of 2021 that it received EMA marketing authorization, the drug becoming the first approved treatment for BPDCN patients in Europe. These examples offer a snapshot of the variety and complexity of what are summarized as “cancers,” but which exist in over 100 different types, according to the US National Cancer Institute. The range of therapeutic approaches is just as varied, including chemotherapy, hormone therapy, immunotherapy, radiotherapy, stem cell transplant, targeted therapy, and of course surgery. Small molecules Italy has the highest cancer survival rate in Europe, according to the “State of Health in the EU” 2019 report. Coming from a culture of excellent cancer research and medical treatment, Italian innovators are energetically driving forward different oncological therapies. One of the largest companies in oncological kinase inhibitors, Nerviano Medical Sciences (NMS) Group has been a pioneer in the science since the mid-1990s. “Kinases, over 1000 of them, are the largest classes of enzymes and they are involved in the cell cycle, including the oncogenesis - or the malignant proliferation of cells. Therefore, kinases control the body’s inflammatory and immunological reactivity by controlling the gene expression. Our kinase platform comprises more than 100 biochemical assets,” shared Nanding Zhao, CEO of NMS Group. (not approved) Kinase inhibitors are one of the most established weapons in the battle with cancers, gaining traction at the same time as precision medicine. The FDA approved 37 kinase inhibitors for the treatment of malignancies, and another 150 are in clinical phase. Also working with small molecules, but this time with a different type of inhibitor, Virostatics is developing a new class of CDK 4/6/9 inhibitors for breast cancer patients who no longer respond to the first-line therapy, the CDK 4/7, in metastatic cancers. Virostatics’ candidate is an oral drug called VS 2-370 and is in advanced pre-clinical work. Small molecules are incredibly versatile with a high number of potential targets that are still little understood, but the next wave since the discovery of small molecules should come from vaccines combined with AI, said Franco Lori, the CEO of Virostatics: “We are discovering more of the intricate connections between anatomy, histology, molecular biology and immunology of cancers; what we are lacking is an understanding of how cancers evade the immune system and how to tackle cancers by inducing an appropriate immune response. The complexity of our immune systems exceeds our brain (collective) capacity to understand how exactly the target interacts with the body’s defense system. AI could thus guide the new generation of immunology-based drugs.” AI is gradually becoming an important factor in the drug discovery process. Recently, UCB expanded its partnership with Microsoft to deploy AI for its discovery pipeline. Pfizer also partnered with Concreto HealthAI to advance work in precision oncology, while Bayer collaborates with UK-based AI drug discovery company Exscientia in cardiovascular and oncology drug discovery. AI and machine learning platforms can speed up the search for a drug candidate and enable much better customization according to different factors, genetic or otherwise. Genetic vaccines Alongside developments in AI, research in immunogenicity has also made substantial progress. Luigi Aurisicchio, the CEO and founder of Takis Biotech, explained: “When we started working on cancer vaccines, scientists focused on using molecules that were expressed by both the tumors and the normal tissues, which made it very challenging to channel the immune response to the cancer only - and not the healthy tissue. With the advent of bioinformatics and next-generation sequencing, we can now identify specific antigens found only in tumors and induce a much stronger immune response, comparable to vaccinating against a virus. Genetic vaccines have enormous potential.” The science of genetic vaccines is also benefiting from the breakthroughs achieved during research for the coronavirus. Before the pandemic, there were no vaccines using adenoviral vectors or messenger RNA technology outside of some small-scale clinical trials in oncology. With billions vaccinated today, these technologies have been given a vote of confidence and can be extended to cancers. Proton Therapy Though Italy benefits from top-class cancer treatments, the infrastructure for some select therapies is missing. Proton therapy is one of the most advanced and efficient forms of radiotherapy, but the high equipment costs have constricted wide-scale development. While in the US there is one proton therapy for every three million people, Italy has a total of two machines – that is one for every 30 million people, with a third machine under construction. Italian company Itel Group set out to change this. Itel is an Italian leader in the medical and clinical engineering fields. In 2015, it obtained a 15 million euros grant from the European Investment Bank and created LinearBeam, a spin-off focused on creating a proton linear accelerator used in proton therapy against cancers. This would be the world’s first proton therapy system based on a P-Linac machine (a linear accelerator of protons); the technology would not only be cheaper compared to a typical proton machine (which can cost up to US$150 million), but it would also be more effective. The prototype is currently pending validation having been transferred to the first oncological center in Italy. The opening of this facility could make a big difference to Italian patients, proton therapy being both more effective and less invasive compared to traditional radiotherapy: “Traditional radiotherapy works by delivering a dose of electrons or photons to the tumor; however, tumors are typically located in the center of the body, and thus more distanced from the electron input, requiring a higher dose to reach the target. The passage of healthy tissue between the target and the electron is therefore also affected, while there is also a 50% probability of a returning tumor. In proton therapy, the difference is made in the physics of the particles because 100% of the protons’ energy is delivered 30 cm away from the beam, the doctor deciding precisely where the proton releases most of its energy burst. This point is called the Bragg Peak. The exact target causes minimum harm to nearby tissue, and a lower dosage is required,” said Michele Diaferia, CEO, Itel Group. The next big issue is funding. According to the latest figures from Assobiotec, 25 financing transactions worth 152 million euros were carried out in 2019, which makes Italy the recipient of 5% of European funds and 1% of global investments. For the average biotech investment, Italy receives 6 million euros, compared to a European average of 20 million euros. While it may be easier for big pharma companies to attract investment, Italy’s biotech sector is very early stage – out of the 375 new therapeutic projects under development in Italy, only 73 are in clinical phase. This is the stage when funding is both most critical and most difficult to pin down.

Image courtesy of National Cancer Institute on Unsplash

Cancer diagnostics and AI

Despite the concentrated pharmaceutical and medical efforts, a cure for cancer has yet to be found. However, the availability of different therapies together with better diagnostics have led to improved survival rates for many types of cancers. At the same time, longer lifespan expectations also mean that more people are diagnosed with cancer than at any other time in history. Early detection and diagnosis are essential in completing the circle of better treatment, better survival chances, and better quality of life. These factors have made cancer diagnostics a booming industry. Growing at a CAGR of 11.5%, the global cancer diagnostics market is projected to reach US$ 26.6 billion by 2026. One of the biggest trends impacting the diagnostics market, both in-vitro and clinical, is the use of AI and digitalization. Gastrointestinal (GI) pharma leader Cosmo Pharmaceuticals has introduced the first AI-enabled device that can detect colorectal polyps during a colonoscopy. This is the first medical device the company launched, though Cosmo has been very active in the field of diagnostics through its pharmaceutical offer, the company owning a unique Multi-Matrix Technology (MMX Technology), which allows tablets to dissolve evenly across the length of the colon’s lumen to improve diagnostic conditions. Cosmo’s CEO, Alessandro Della Chà, thinks AI will be taking over the world of diagnostics: “AI can perform the tasks of a highly qualified and skilled physician without getting tired or becoming prone to mistakes. When a lesion in the colon is sent to the histopathology lab, the physician visually analyses the sample to determine its nature. Going forward, this task will clearly be performed more effectively by a computer with less likelihood of error.” A similar dynamic takes place in the cytology space, where pathologists are more and more replaced by digital pathology. Cytology is the part of cancer diagnostics engaged with looking at a single cell type, reading slides on a microscope to identify abnormalities and cells indicating a tumoral presence. The challenge is that many countries, especially in Africa, have no active pathologists, and more developing countries will see the number of practicing pathologists halved in the next five years. Meanwhile, patients in developed countries struggle with long waiting times to get their diagnostic test results back after a test. Florence-based Hospitex, a supplier of lab instruments for cytology, comes to the market with an offer of digital pathology, which combines digitalization and software to make an interpretation on the slide. The company’s CEO Francesco Trisolini explained how this technology differs from traditional cytology: “Our technology has an efficiency factor of 10 times higher than the conventional method and we can return the results within 24 hours.” On the other side of cancer diagnostics, histology, the study of the entire block of tissues in samples like biopsies, is also shaped by AI. Integrated Systems Engineering (ISE), a leader in tissue microarray (TMA) technology, has recently received financing from the European Commission for a project that sees the full automation of Tissue Microarray workflow using AI and deep learning algorithms in order to bring the technology in diagnostics. Pasquale de Blasio, ISE’s CEO, explained how this works: “Typically, a histology slide is made from a surgically resected biopsy sample embedded in paraffin and sliced with a microtome. The pathologist examines the slide studies and the cancer cells in order to make a diagnosis. This process is repeated for all histology slides. The new platform will perform quantitative visual imaging of histology slides, select the area of interest (enriched with cancer cells) and core this section to create the TMA block. The TMA gathers the tissues (selected by the pathologist) into one block (an array) and >400 spots can be placed in a single TMA slide, allowing simultaneous analysis using the same histology conditions.” The improved technology would be of particular value in diagnosing rare cancers; to identify a rare cancer that affects 5% of the population, the pathologist has to conduct about 100 analyzes, but the TMA can help identify the 5% incidence in a single analysis.