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RARE INSIGHTS

Phase 3 'Proof-HD' trial begins in Europe for people with Huntington Disease

28/1/2021

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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.
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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
Prof. Ferdinando Squitieri
"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.
Ralf Reilmann, MD, PhD, FAAN
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. 
ProofHD Trial
Prof. Hayden Presentation
ClinicalTrials.gov
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Research grant of over 2 million euros offers new hope for children with rare condition Schinzel-Giedion syndrome

26/1/2021

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​PRESS RELEASE 
January 27th 2021, UK:

Funding from two major European grants has been awarded to an international group of researchers to find treatments for the devastating rare genetic disease Schinzel-Giedion syndrome (SGS)

​The grants are the first major funding awarded for SGS research.
Nuala Summerfield, Founder and Chair of UK based patient group The Schinzel-Giedion Syndrome Foundation said:
​"As a parent of a child with SGS, I am encouraged and excited that our rare genetic condition is now receiving the attention that it deserves. This grant provides our patient group and our community with the unique opportunity to work closely with scientists to help develop new epilepsy treatments for our children. We also hope that the results of this work can benefit other rare epilepsies."
Dr Carl Ernst PhD, from McGill University, Montreal said "We could not be happier to partner and collaborate with families affected by SGS to advance treatments for this disease.  With this EU support, our international group of experts has the opportunity drive science forward and hopefully reduce suffering in children with this neglected rare disease."

The funding comes from the European Joint Programme on Rare Diseases (EJP RD), co-funded by the European Commission. The focus for the 2nd EJP RD Joint Transnational Call for Rare Diseases Research Project (JTC 2020) was pre-clinical research to develop effective therapies for rare diseases.

The TREAT-SGS project was selected from 173 eligible proposals and will receive 1.6 million Euros. The project is a collaboration between the UK based patient group The SGS Foundation and academic researchers in Canada, Italy, Sweden and Germany, facilitated by Dr Carl Ernst PhD.

Dr Alessandro Sessa PhD, a co-collaborator in the EJP RD project, has also been awarded a grant from the Italian Ministry of Health for SGS research of 450,000 Euros.

Identical genetic mutations that cause SGS are also known to trigger cancer including certain types of leukaemia. This SGS research may therefore have a direct benefit of advancing cancer research.

What is Schinzel-Giedion syndrome?

Schinzel-Giedion syndrome is an ultra-rare genetic disorder. Fewer than 100 children worldwide have been diagnosed with SGS but the true incidence is expected to be higher. SGS is caused by mutations in the SETBP1 gene, located on chromosome 18.

SETBP1 protein appears to play an important role in the developing embryo. Children with SGS have too much SETBP1 protein and this is thought to cause abnormal brain development, as well as gastrointestinal, urinary and respiratory tract problems, together with an increased risk of certain types of cancer.
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Severe epilepsy is a major health and quality-of-life issue for children born with SGS. Most children with SGS have severe uncontrollable seizures, which are often the reason why many will die before their 4th birthday.

About The Schinzel-Giedion Syndrome Foundation 

​The Schinzel-Giedion Syndrome Foundation is a registered UK charity (Number 1186327), established in 2019 by an international group of parents of children with Schinzel-Giedion Syndrome (SGS). The charity is supported by a Scientific and Medical Advisory Board (SMAB), including researchers at renowned institutions, medical geneticists, paediatric clinicians and industry-level therapeutic developers. The Schinzel-Giedion Syndrome Foundation is the only SGS patient group and serves to represent the international SGS community. https://www.sgsfoundation.org

About The European Joint Programme on Rare Diseases (EJP RD)

​The European Joint Programme on Rare Diseases (EJP RD) 
brings together over 130 institutions from 35 countries to create a comprehensive, sustainable ecosystem allowing a virtuous circle between research, care and medical innovation https://www.ejprarediseases.org/

Contact The Schinzel-Giedion Syndrome Foundation
Nuala Summerfield, Founder and Chair
Tel: +44 (0)7957 168815
nuala@sgsfoundation.org
https://www.sgsfoundation.org

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The Transition to Precision Medicine “One Size Fits All” to “My Medicine”

7/1/2021

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Sean Gordon is our #RARETech columnist
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​​​Sean is a patient with Adult polyglucosan body disease (APBD). APBD is a late-onset, slowly progressive disorder affecting the central and peripheral nervous systems, presenting from the mid 40s onward.

He features in RARE Transition, Winter 20/21 and this is his extended column.


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.
  • Cancer – The American Cancer Society estimates that 600,000 people will die of cancer causing an economic impact of $80 Billion.  “[M]any cancers are the result of predispositions to certain diseases inherited along ethnic, racial, or familial lines.”[4]
  • Neurological diseases –The Alzheimer’s Association predicts that 16 million individuals will be living with Alzheimer’s by 2050. The financial costs will skyrocket to $1.1 trillion. “Fully unlocking the secrets of how an individual’s genetics impacts his or her likelihood of developing or surviving a particular condition would produce a fundamental revolution in the way providers approach the practice of medicine”.[5]  

  • Diabetes – The idea of precision diabetes medicine is gaining momentum, based upon the promise of reducing the enormous and growing burden of diabetes worldwide. The Harvard School of Public Health estimated that “The global cost was 825 billion dollars per year” with the cost to the US at 105 billion dollars.[6]

  • Rare Diseases – The inherent nature of the over 7,000 diseases rare diseases: its geographic spread, long period until diagnosis (average 5-6 years) and treatment for less than 10% demand a new approach. Moreover, the majority of the 350 million people with rare conditions have genetic causes best suited to genomic and the digital foundation of Precision Medicine.
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
  2. Massive amounts of confidential Electronic Health Records (EHR) mined from patients with similar conditions irrespective of geography
  3. Analysis derived from artificial intelligence and other systems.  

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] 
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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]
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 Precision Medicine success stories 


Although 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:
  • Cystic Fibrosis patients.[19]
  • Nic Volker: Fatal bowel inflammation and colocutaneous fistula a mutation in the X-linked inhibitor of apoptosis protein (XIAP) gene by Whole Genome Screening (WES), which has important roles in inflammatory signaling and immunity.
  • 14-year-old twins: Dopa (3,4-dihydroxyphenylalanine)-responsive dystonia was identified with Next Generation Screening (NGS)
  • 6-year-old girl: NGS was used to identify a rare form of cancer
  • 14-year-old girl: A dramatic case of a girl who had suffered from autoimmune enteropathy since she was 3 months old. A novel de novo mutation in the ligand binding domain of cytotoxic T lymphocyte antigen 4 (CTLA-4) was discovered by WES.
​

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:
  • Poor predictive values: “Google researchers ended up looking at a range of different AI applications… They found that underspecification [known issue in statistics, where observed effects can have many possible causes] was to blame for poor performance in all of them. The problem lies in the way that machine-learning models are trained and tested, and there’s no easy fix.”[20]
  • Lack of education/training: “As interest in commercial genetic testing rises among consumers, primary care physicians have increasingly had to put clinical context around patients’ test results. However, most providers have not had in-depth training in genomics or genetics in medical school.”[21]
  • Errors in DNA testing: Because databases that genetic testing companies use to interpret DNA tests often contain errors, "we're starting to see a lot of fumbles," with physicians telling patients they have disease-causing genetic mutations when they really do not.[22]
  • Security and privacy protection – EHR: As EHRs are critical to Precision Medicine the vulnerability to cybercrime is a major concern. “United States hospitals were targeted by two major cybersecurity attacks this fall: the first taking down Universal Health Services, a chain of hundreds of hospitals, and the second by a group called UNC1878 threatening hundreds of individual health care facilities all around the country. Targeting health care institutions directly marks a new approach for cybercriminals.”[23]
  • Precision Medicine Can Exacerbate Health Disparities and Create Ethical Dilemmas:
          The AMA Journal of Ethics points out:
          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]

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Sean features in RARE Transition, Winter 20/21 and this is his extended column. To read his column visit RARE Transition

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)

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