The first two Italian patients enrolled into the ProofHD trial on the January 20, 2021, in Rome, at the CSS-Mendel Institute, section of IRCCS Casa Sollievo della Sofferenza and Coordinating Center for Italy, under the guidance of Principal Investigator Prof. Ferdinando Squitieri. The trial aims to test the efficacy of the molecule on the course of the disease by investigating the functional capacity of people with Huntington Disease. The main expected result (primary endpoint) is, in fact, a significant improvement in autonomy, measured through the assessment scale TFC (Total Functional Capacity). The impairment of functional capacity, i.e. the inability to conduct normal daily activities, is what regulatory authorities believe has the most significant impact on patients' lives. Over the years, patients and their families have stressed the disease's impact on the impairment of daily activities: such as, not being able to work, drive, carry out simple household activities, feed themselves, take care of their own personal care and practice their hobbies and sports. Patients themselves highlighted what it had been taken from them in becoming increasingly dependent on others as the symptoms of the disease worsened (Source: Food and Drug Administration's 'Voice of Patient', September 22, 2015). The ProofHD study aims to demonstrate efficacy of its molecule in its ability to affect autonomy, if successful this would result in an improvement in the quality of life for people with Huntington's disease. Preliminary data encourage the belief that pridopidine may represent the first drug capable of acting on these specific patient challenges, although, to date, definitive confirmation of its efficacy has not yet been found. Previously the aim was to investigate a symptomatic effect of the molecule on the motor aspect, now instead it will be explored the effect on the autonomy of people. Today, moreover, unlike the past, we know much more about the relationship between the drug dosage and mechanism, so this is the right time to conduct this trial, designed to verify the impact on autonomy "Previously the aim was to investigate a symptomatic effect of the molecule on the motor aspect, now instead it will be explored the effect on the autonomy of people. Today, moreover, unlike the past, we know much more about the relationship between the drug dosage and mechanism, so this is the right time to conduct this trial, designed to verify the impact on autonomy" - says Prof. Ferdinando Squitieri, who explains the action of Pridopidine stating that "the drug interacts with the Sigma-1 receptor, thus playing a biological and potentially neuroprotective role". Therefore, no longer a symptomatic effect, but a potential neuroprotective effect able to slow down the course of the disease. The study is conducted in the United States, Canada and Europe and involves 480 patients. Ralf Reilmann, MD, PhD, FAAN, Founding Director of the George-Huntington-Institute in Münster (Germany) and European Global Principal Investigator of the study, said: “Pridopidine has shown promising efficacy signs on everyday function and motor symptoms in earlier studies, making me confident of the potential of this orally available drug to have a positive effect for HD patients. Similarly to Prof. Squitieri’s clinic, my team has already had the opportunity to care for more than 50 patients treated with Pridopidine in previous studies where we observed a positive safety profile. We are excited that PROOF-HD now allows us to jointly explore a new therapeutic option for HD patients by assessing the efficacy of Pridopidine in early-HD patients in a properly powered global Phase 3 study. I would like to thank Prof. Squitieri and his committed team and all study participants and their families in Italy for their support for this international collaborative study.” We are excited that PROOFHD now allows us to jointly explore a new therapeutic option for HD patients by assessing the efficacy of Pridopidine in early-HD patients in a properly powered global Phase 3 study. In Italy, the sites involved are the Mendel Institute of Genetics/Fondazione IRCCS Casa Sollievo della Sofferenza (Coordinating Center), the IRCCS Carlo Besta of Milan, the University Hospital "Federico II" of Naples, the Policlinico di Bari "Ospedale Giovanni XXIII", the IRCSS - Institute of Neurological Sciences of Bologna. It is expected the involvement of 40 patients. To learn more
PROOF-HD (PRidopidineOutcome On Function in Huntington Disease) is a Phase 3, randomised, double-blind versus placebo, multinational, multi centre trial to evaluate the efficacy and safety of Pridopidine in patients in the early stage of Huntington's disease.
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Contact The Schinzel-Giedion Syndrome Foundation Nuala Summerfield, Founder and Chair Tel: +44 (0)7957 168815 nuala@sgsfoundation.org https://www.sgsfoundation.org Sean Gordon is our #RARETech columnist
What is Precision Medicine?[1] And why is it precise? The twin terms, Personalised Medicine and Precision Medicine came into the vernacular in the late 1990s and early 2000s as a consequence of the sequencing of the human genome.[2] Today it is a hot topic much discussed in blogs, journals and at conventions. It also become an initiative of the US Government through the Precision Medicine Initiative[3] This new paradigm has the potential to save and improve the lives of millions of people worldwide as well as saving billions of dollars.
Past medical theory and practice assigned patients to groups, “averages”, placing humanity along the so-called bell-shaped curve. However, none of us are average and those things which make us different are hidden deeply in our genomic code and other so-called ‘omics’[7] (more later) and how these omics interact with our environment and lived experience. What appear to be obvious similarities are superficial and mask deep differences. “A pair of random individuals from two different populations is genetically more similar than a pair of individuals randomly selected from any single population.”[8] There are many definitions, but at its core Precision Medicine looks at patients as individuals rather than an average or even members of specific groups. Precision medicine has been defined as a novel approach for disease treatment and prevention that considers the genetic information, environment, and lifestyle of each patient to ultimately establish specific strategies based on these factors. To this end, precision medicine aims to create the most effective treatment plan for each individual patient in the hope of eliminating unnecessary diagnostic testing and therapies [emphasis mine].[9] It is precise because the treatment’s foundation is based upon the motto, “the right treatment for the right patient given at the right time.” The treatment is focused on a specific patient rather than all patients who share the particular indication. What is driving the transition to Precision Medicine? The transition comes at the intersection of three major technological trends which have put treatment strategies in the doctor’s hands unimaginable even a decade ago[10]:
1. Omic medical research Omics relates to the broad category of biological/molecular information (data) providing a holistic view of a living system. This analysis began with sequencing of the Human Genome and has spread into numerous sub-specialties each offering greater granularity into the complex processes of biological systems. The deeper molecular level information goes beyond medical knowledge from as little as a decade ago. “This omic era has allowed the introduction and development of a medicine much more optimised and personalised, which is considered by many professionals as the medicine of the 21st century.”[11] 
2. Massive amounts of confidential health record data EHRs are real-time, patient-centered, digital records of health information and clinical care generated and maintained by healthcare providers.[12] Among Organisation for Economic Co-operation and Development countries there is a high level of adoption. The benefits to the health system and doctors are significant: …structured and unstructured data are important in providing a complete story around patients’ clinical data, offering multidimensional insight into health and disease, provider and patient behaviour, and healthcare outcomes across populations and health systems.[13] And By harnessing the power of electronic health records (EHRs), we are increasingly able to practice precision medicine to improve patient outcomes.[14] 3. Analysis derived from artificial intelligence and other systems The beating heart of Precision Medicine is data-driven AI. At the centre of this strategy is a set of computer algorithms that identify patterns in multidimensional datasets that are then used to predict or optimise based on the availability of similar data on individual patients.[15] The returns of this harnessing AI for medicine can be significant: “The algorithm could accelerate the approval of powerful treatments for many cancers, improve clinical outcomes, and reduce costs for treating cancer,” said Randall Holcombe, director of the UH Cancer Center.”[16] The AI based systems offer the following benefits to the medical community: [17] 
Precision Medicine success storiesAlthough in its infancy, Precision Medicine is beginning to develop success stories across different disease types. Next-generation sequencing (NGS) has achieved great advances in medicine and clinical practice, as well as in basic research field. NGS-based precision medicine has mainly focused on cancer [1,2], given the prevalence, availability of drugs targeting major oncogenic factors, and impact on human health. Another sector of focus through NGS-based precision medicine is ultra-rare diseases.[18] The following are rare diseases which have benefited by Precision Medicine:
Postscript – Are there clouds on the horizon? The consensus is, Precision Medicine is a force for good. Precision Medicine multiplies the tools of doctors and medical professionals many times using advanced technology. However, are there are factors that should cause us to use these advanced tools with care. The following are some of these areas:
Recent examples of innovative targeted and precise therapies based on genetic diagnosis that have had implications for patients beyond effectiveness. High-cost and high-risk interventions that are available primarily to those with power, money, and access will likely exacerbate existing health disparities and potentially exacerbate the burdens of specific diseases or disease risks. As precision health evolves, researchers, clinicians, and policymakers will need to develop strategies for proactively identifying some of these ethical challenges in therapeutic translation as well as policies and guidance to mitigate adverse impacts of successful precision-based therapies.[24]
References and further information [1] Also called personalised medicine. [2] G.S. Ginsburg and J.J. McCarthy, Trends Biotechnol., 19 (2001), pp. 491-496 [3] The Precision Medicine Initiative is a long-term research endeavor, involving the National Institutes of Health (NIH) and multiple other research centers, which aims to understand how a person's genetics, environment, and lifestyle can help determine the best approach to prevent or treat disease. https://medlineplus.gov/genetics/understanding/precisionmedicine/initiative/ [4] https://healthitanalytics.com/features/what-are-precision-medicine-and-personalized-medicine [5] Ibid [6] https://www.hsph.harvard.edu/news/press-releases/diabetes-cost-825-billion-a-year/ [7] Omics are novel, comprehensive approaches for analysis of complete genetic or molecular profiles of humans and other organisms. For example, in contrast to genetics, which focuses on single genes, genomics focuses on all genes (genomes) and their inter-relationships. [8] Genetic Similarities Within and Between Human Populations, D. J. Witherspoon, S. Wooding, A. R. Rogers, E. E. Marchani, W. S. Watkins, M. A. Batzer, L. B. Jorde,Genetics. 2007 May; 176(1): 351–359. doi: 10.1534/genetics.106.067355 [9] The Past, Present, and Future of Precision Medicine, https://www.news-medical.net/life-sciences/The-Past-Present-and-Future-of-Precision-Medicine.aspx. [10] We are only providing a high-level view of how these new technologies and practices are driving Precision Medicine. [11] https://www.peertechz.com/articles/doi10.17352-jcmbt.000018.php [12] https://doi.org/10.1016/j.cell.2019.02.039 [13] Ibid [14] Sitapati, Amy & Kim, Hyeoneui & Berkovich, Barbara & Marmor, Rebecca & Singh, Siddharth & El-Kareh, Robert & Clay, Brian & Ohno-Machado, Lucila. (2017). Integrated precision medicine:the role of electronic health records in delivering personalized treatment: Integrated precision medicine. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 9. e1378. 10.1002/wsbm.1378. [15] https://www.nature.com/articles/s41746-019-0191-0 [16]https://www.forbes.com/sites/nicolemartin1/2019/08/30/how-healthcare-is-using-big-data-and-ai-to-cure-disease/?sh=2f8053c145cf [17] Rare Revolution (eZine), Summer 2020, pp.67-70 [18] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951399/ [19] https://www.nature.com/articles/d41586-020-02988-w [20]https://www.technologyreview.com/2020/11/18/1012234/training-machine-learning-broken-real-world-heath-nlp-computer-vision/ [21] https://healthitanalytics.com/news/top-3-challenges-of-integrating-precision-medicine-with-routine-care [22]https://www.beckershospitalreview.com/healthcare-information-technology/problems-with-precision-medicine-tools-can-have-devastating-consequences.html [23] https://www.theverge.com/21551050/cyberattacks-hospitals-coronavirus-deadly-tactics [24] What Precision Medicine Can Learn from Rare Genetic Disease Research and Translation | Journal of Ethics | American Medical Association (ama-assn.org) |
