Tag: Pharmaceuticals

The decade-long quest to hack the body’s immune system with electricity

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If you were superstitious, what happened next might have looked like an omen. The word “electroceutical” already belonged to someone else—a company called Ivivi Technologies had trademarked it in 2008. “I am fairly certain we sent them a letter soon after they started that campaign, to alert them of our trademark,” says Sean Hagberg, a cofounder and then chief science officer at the company. Today neither GSK nor SetPoint can officially call its tech “electroceuticals,” and both refer to the implants they are developing as “bioelectronic medicine.” However, this umbrella term encompasses a wide range of other interventions, some quite well established, including brain implants, spine implants, hypoglossal nerve stimulation for sleep apnea (which targets a motor nerve running through the vagus), and other peripheral-nervous-system implants, including those for people with severe gastric disorders.

Kevin Tracey has been one of the leading proponents of using electrical stimulation to target inflammation in the body.
MIKE DENORA VIA WIKIPEDIA

The next problem appeared in short order: how to target the correct nerve. The vagus nerve has roughly 100,000 fibers packed tightly within it, says Kip Ludwig, who was then with the US National Institutes of Health and now co-directs the Wisconsin Institute for Translational Neuroengineering at the University of Wisconsin, Madison. These myriad fibers connect to many different organs, including the larynx and lower airways, and electrical fields are not precise enough to hit a single one without hitting many of its neighbors (as Ludwig puts it, “electric fields [are] really promiscuous”). This explains why a wholesale zap of the entire bundle had long been associated with unpredictable “on-target effects” and unpleasant “off-target effects,” which is another way of saying it didn’t always work and could carry side effects that ranged from the irritating, like a chronic cough, to the life-altering, including headaches and a shortness of breath that is better described as air hunger. Singling out the fibers that led to the particular organ you were after was hard for another reason, too: the existing maps of the human peripheral nervous system were old and quite limited. Such a low-resolution road map wouldn’t be sufficient to get a signal from the highway all the way to a destination.

In 2014, to remedy this and generally advance the field of peripheral nerve stimulation, the NIH announced a research initiative known as SPARC—Stimulating Peripheral Activity to Relieve Conditions—with the aim of pouring $248 million into research on new ways to exploit the nervous system’s electrical pathways for medicine. “My job,” says Gene Civillico, who managed the program until 2021, “was to do a program related to electroceuticals that used the NIH policy options that were available to us to try to make something catalytic happen.” The idea was to make neural anatomical maps and sort out the consequences of following various paths. After the organs were mapped, Civillico says, the next step was to figure out which nerve circuit would stimulate them, and settle on an access point—“And the access point should be the vagus nerve, because that’s where the most interest is.”

Two years later, as SPARC began to distribute its funds, companies moved forward with plans for the first generation of implants. GSK teamed up with Verily (formerly Google Life Sciences) on a $715 million research initiative they called Galvani Bioelectronics, with Famm at its helm as president. SetPoint, which had relocated to Valencia, California, moved to an expanded location, a campus that had once housed a secret Lockheed R&D facility.

How it’s going

Ten years after electroceuticals entered (and then quickly departed) the lexicon, the SPARC program has yielded important information about the electrical particulars of the peripheral nervous system. Its maps have illuminated nodes that are both surgically attractive and medically relevant. It has funded a global constellation of academic researchers. But its insights will be useful for the next generation of implants, not those in trials today.

Today’s implants, from SetPoint and Galvani, will be in the news later this year. Though SetPoint estimates that an extended study of its phase III clinical trial will conclude in 2027, the primary outcomes will be released this summer, says Ankit Shah, a marketing VP at SetPoint. And while Galvani’s trial will conclude in 2029, Famm says, the company is “coming to an exciting point” and will publish patient data later in 2024.

The results could be interpreted as a referendum on the two companies’ different approaches. Both devices treat rheumatoid arthritis, and both target the immune system via the peripheral nervous system, but that’s where the similarities end. SetPoint’s device uses a clamshell design that cuffs around the vagus nerve at the neck. It stimulates for just one minute, once per day. SetPoint representatives say they have never seen the sorts of side effects that have resulted from using such stimulators to treat epilepsy. But if anyone did experience those described by other researchers—even vomiting and headaches—they might be tolerable if they only lasted a minute.

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May 30, 2024
LabVantage celebrates customer success with record number of software deployments in FY 2024

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LabVantage Solutions, Inc., the leading provider of laboratory informatics solutions and services, including purpose-built LIMS solutions that allow labs to go live faster and at a lower total cost, today announced the global achievement of more than 100 software deployments or ‘Go-Lives’ by customers in fiscal year 2024 across all of the industries it supports, including pharmaceuticals, biotechnology, healthcare, oil and gas, and food and beverage.

The global life sciences LIMS market, currently valued at $1 billion, is expected to grow at an annual rate of 12-14% over the coming years, driven by a 10-12% yearly increase in user base.1 In this rapidly evolving sector, the demand for bespoke LIMS solutions that address the complexities of modern laboratory environments and deliver an integrated approach for scientific data management has become critical.

LabVantage has been at the forefront of this evolution, seamlessly integrating LIMS with ELN, LES, and SDMS into a unified lab informatics platform. This platform, developed in collaboration with its clients, not only streamlines laboratory processes but also provides critical business intelligence. The robust growth of LabVantage’s professional services organization has enabled the company to support customers anywhere in the world and increase the number of global software deployments by more than 50% year-over-year.

The successful implementations of LabVantage LIMS in the past year can be categorized into three distinct business cases as follows:

1. Transition to Automated Data Management: Clients have moved from manual recording processes to the LabVantage LIMS platform for enhanced data management, retrieval, and traceability.
2. Upgrading to Advanced LIMS: Organizations previously using in-house LIMS systems or other commercial solutions embedded with limited LIMS functionalities have now adopted LabVantage LIMS for more robust capabilities.
3. Scaling Up Existing LIMS Use: Existing customers of LabVantage LIMS have extended the system to additional laboratories, driven by its proven effectiveness in enhancing laboratory productivity.

“Achieving more than 100 Go-Lives in a single year reflects the strength and scalability of our professional services. Our ability to support clients across diverse industries worldwide demonstrates our expertise in navigating complex laboratory ecosystems,”

Craig Bowie, Vice President of Professional Services at LabVantage Solutions.

“The growth we’ve experienced is not just in numbers; it’s in the value we bring to our clients, helping them to manage scientific data more efficiently at every stage. We see our growth as directly aligned with our clients’ success – as they upgrade to more sophisticated systems or expand their usage of LabVantage LIMS, they are seeing tangible improvements in their operational productivity. This is the driving force behind our exceptional increase in global software deployments.”

Craig Bowie, Vice President of Professional Services at LabVantage Solutions.

For more information on LabVantage and its LIMS solutions, visit www.labvantage.com or email [email protected].

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April 15, 2024
Lancet Commission predicts sharp increase in global prostate cancer cases

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Cases of prostate cancer are projected to double from 1.4 million per year in 2020 to 2.9 million per year by 2040, with low- and middle-income countries (LMICs) predicted to see the highest increases in cases, according to The Lancet Commission on prostate cancer which will be launched by a presentation at the European Association of Urology Congress.

The number of annual prostate cancer deaths worldwide is predicted to rise by 85% over the 20-year period, from 375,000 deaths in 2020 to almost 700,000 deaths by 2040. The true numbers will likely be much higher than the recorded figures due to under-diagnosis and missed opportunities for data collection in LMICs.

Most of these deaths are expected to be in LMICs, due to the rising number of cases and increasing mortality rates in these countries. Deaths from prostate cancer have declined in most high-income countries (HICs) since the mid-1990s.

Prostate cancer is already a major cause of death and disability, accounting for 15% of all male cancers. It is the second most common cause of cancer deaths in UK men and the most common form of male cancer in more than half of the world’s countries.

Aging populations and increasing life expectancy will lead to higher numbers of older men in coming years. As the main risk factors for prostate cancer – such as being aged 50 or older and having a family history of the disease – are unavoidable, it will not be possible to prevent the upcoming surge in cases through lifestyle changes or public health interventions.

Professor Nick James, lead author of the Commission, Professor of Prostate and Bladder Cancer Research at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust, said: “As more and more men around the world live to middle and old age, there will be an inevitable rise in the number of prostate cancer cases. We know this surge in cases is coming, so we need to start planning and take action now. Evidence-based interventions, such as improved early detection and education programs, will help to save lives and prevent ill health from prostate cancer in the years to come. This is especially true for low- and middle-income countries which will bear the overwhelming brunt of future cases.”

Global need for new and improved early detection programs

In HICs, screening for prostate cancer often involves the PSA test, a blood test that measures levels of a protein called prostate-specific antigen (PSA). However, PSA tests often detect prostate cancer which may never cause symptoms and needs no treatment. The current approach to prostate cancer diagnosis in the UK and many other HICs relies on ‘informed choice’ PSA testing – when men aged 50 or over with no disease symptoms can request a PSA test from their doctor after a discussion of the risks and benefits. The Commission argues there is evidence to suggest this approach leads to over-testing in low-risk older men but does not increase detection of prostate cancer in younger men at higher risk. The authors also highlight huge variations in the likelihood of men being diagnosed with advanced prostate cancer with the ‘informed choice’ PSA testing strategy, for example The National Prostate Cancer Audit in the UK found that in 2022, 1 in 8 men (12.5%) with prostate cancer are diagnosed with advanced prostate cancer in London, whereas in Scotland more than 1 in 3 (35%) were diagnosed late.

Instead, the authors recommend using MRI scans in combination with PSA testing to screen men at high risk of prostate cancer in HICs, such as those with a family history of the disease, those of African origin and those carrying the BRACA2 mutation. They argue that this approach would both reduce over-diagnosis and over-treatment, while detecting potentially lethal disease. MRI is effective in imaging cancers and can be used to provide information as to whether the disease is aggressive and likely to be life-threatening. However, biopsies are more effective at identifying aggressive cancers, so MRI alone should not be used to investigate men at high risk of disease.

The effectiveness of population-level PSA testing has not been tested in LMICs and there is an urgent need for cancer screening trials in these countries. New approaches to enable earlier diagnosis in LMICs are vital, as most men in these countries present with metastatic cancer – an advanced form of disease where the cancer has spread to other parts of the body, often the bones. Men with late-stage prostate cancer are much less likely to survive for a long period of time than those who are diagnosed early.

“With prostate cancer we cannot wait for people to feel ill and seek help – we must encourage testing in those who feel well but who have a high risk of the disease in order to catch lethal prostate cancer early. Pop-up clinics and mobile testing offer cost-effective solutions that combine health checks and education. In the UK we recently trialled a new innovative outreach programme called The Man Van which provided free health checks – including PSA tests – to high-risk men in London aged 45 and over. By bringing a van with quick and easy testing straight to men at work and in the community, and targeting those who have a higher risk of prostate cancer, we provided thousands of health checks which resulted in almost 100 cancer diagnoses in men who might otherwise have only seen a doctor once their cancer has progressed to a more advanced stage. The mix of education, outreach, testing and referral used in The Man Van trial may also be successful in LMICs and we hope to see similar initiatives rolled out globally to improve early detection of prostate cancer,” said Professor Nick James (also project lead for the ‘Man Van’).

As well as being a major growing challenge, prostate cancer is also an indicator of a wider need to tailor future healthcare to cope with increases in several diseases, as the numbers of men reaching middle and old age increase worldwide. The Commission calls for trials of prostate cancer screening in LMICs to form part of holistic approaches with a broader focus on men’s health.

Raising awareness of advanced prostate cancer and available therapies

There is a need to raise awareness of the dangers and symptoms of metastatic prostate cancer among men and their families in LMICs. Public awareness of the key features of advanced prostate cancer – such as bone pain, caused by metastatic disease – is poor in many LMICs. Similarly, there is generally low public awareness that treatments can prolong survival and decrease suffering – including cheap, effective ones such as hormone therapy – are available in many LMICs. As with early diagnostic capacity, there is a need to scale-up availability and improve access to treatments for advanced disease in LMICs.

Improving education about the disease is critical, and the Commission authors suggest that programs should involve new technologies and channels such as smartphones, social media, and influencers. They highlight Project PINK BLUE, an organization that delivers a range of programs to raise awareness of breast, cervical, and prostate cancer in Nigeria, and provides free cancer screening. Many of Project PINK BLUE’s programs utilize digital technologies and involve well-known public figures and celebrities.

Professor James N’Dow, Chair in Surgery, University of Aberdeen and Founder of Horizons Trust & Horizons Clinic, Gambia, said: “The issue in low- and middle-income countries is that late diagnosis of prostate cancer is the norm. Improved outreach programs are needed to better inform people of the key signs to look out for and what to do next. Implementing these in tandem with investments in cost-effective early diagnostic systems will be key to preventing deaths from prostate cancer as cases inevitably rise with a global aging population.”

He continues, “As well as the obvious direct effects on individual men’s health, rising numbers of cases and deaths from prostate cancer could have huge economic and social impacts on families in LMICs. Men in these countries are very often a family’s main breadwinner, so if they die or become seriously ill, this can lead to families facing major economic hardship. By preparing now for the upcoming surge in prostate cancer cases, with a particular emphasis on improved education and earlier diagnosis programs, many of these harms could be reduced substantially.”

Building capacity to diagnose and treat prostate cancer early in LMICs

Optimal management of prostate cancer requires the availability of specialist staff and infrastructure to support diagnosis, surgery and radiotherapy to treat localized prostate cancer, and radiotherapy and hormone therapy for metastatic disease.

A major barrier to improved prostate cancer care in LMICs is a lack of trained staff and specialist facilities. These shortages are not limited to prostate cancer, and the 2015 Lancet Commission on Surgery found that 9 out of 10 people in LMICs cannot access basic surgical care. [4]

Expanding early diagnostic capabilities in LMICs will increase the rates of detection of early-stage prostate cancer, further increasing demand for surgery and radiotherapy. Urgent measures are therefore needed to build surgical and radiotherapy capacity in these countries. The Commission authors state that establishing regional hubs could provide the infrastructure needed to increase specialist training and improve patient access to radiotherapy and surgery.

For men with metastatic disease, earlier diagnosis and starting hormone therapy earlier will reduce deaths and prevent serious complications like painful spinal cord compression and urinary retention, which can lead to infection and kidney damage.

More research is needed on ethnic inequities in care and survival

The Commission authors highlight the need for more research to better understand prostate cancer in men who are not of White European origin, to enable improved detection and care in these groups. Research and knowledge of prostate cancer is heavily focussed on White European men, and most studies have been done in HICs. However, Black men, especially those of West African descent, have a higher risk of developing prostate cancer than White or Asian men, though the reasons for this are unclear. There is also a higher death rate from prostate cancer among Black men, but it is not known if this is driven by the differences in case rates or by other factors such as differing disease biology or societal factors such as deprivation or racism. More data is needed to identify the driving factors behind these trends.

The Commission authors call for mandatory recording of ethnicity in clinical trials, and that trials should reflect the ethnic mix of the populations being studied to ensure that the findings apply to all groups. The Commission authors also call for trials examining prostate cancer screening, early diagnosis, and treatment in LMICs.

Source:

Journal reference:

James, N. D., et al. (2024) The Lancet Commission on prostate cancer: planning for the surge in cases. The Lancet. doi.org/10.1016/S0140-6736(24)00651-2.

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April 5, 2024
Pembrolizumab enhances breast cancer treatment regardless of age or menopausal status

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New data from the KEYNOTE-756 phase 3 clinical trial show that adding the immunotherapy drug, pembrolizumab, to chemotherapy before and after surgery for breast cancer leads to better outcomes for patients regardless of their age or menopausal status.

The findings, presented at the 14^th European Breast Cancer Conference (EBCC 14) today (Wednesday), add to information available on the effect of pembrolizumab in patients with early-stage breast cancer that is at high risk of recurring or spreading further, and that is oestrogen receptor positive (ER positive) and HER2 negative.

KEYNOTE-756 is an international trial, which has been running for eight years. It randomised 1278 patients to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy (given before surgery) followed by adjuvant (given after surgery) pembrolizumab or placebo in combination with an endocrine therapy. The patients had invasive ductal carcinoma (IDC), meaning the cancer had started to spread out of the milk ducts into the surrounding breast tissues.

Professor Javier Cortés, Director of the International Breast Cancer Centre in Barcelona, Spain, said: “We have already reported that there was a statistically significant increase in the pathological complete response rate in patients receiving pembrolizumab compared to those receiving the placebo. The pathological complete response rate, meaning that no cancer cells remained in the breast or lymph nodes, was 24.3% in patients treated with pembrolizumab compared to 15.6% in patients treated with the placebo.

“Now we can show that these pCR rates occurred regardless of the patients’ age or menopausal status. In patients younger than 50 years old, the pCR rate was 23.8% in those on pembrolizumab (76 out of 319 patients) compared to 16.9% (55 out of 326) for those receiving placebo, and was 24.7% (78 of 316 patients) versus 14.2% (45 of 317) respectively in those aged 50 or older. In pre-menopausal women, the pCR rate was 23.4% (83 out of 354 patients) versus 16.1% (57 out of 353) respectively, and in post-menopausal women, it was 24.8% (69 out of 278 patients) versus 14.6% (42 out of 287), respectively.

“We also found that adding pembrolizumab to neoadjuvant chemotherapy did not delay the time to surgery. The average time to surgery in both groups of patients was about a month. The average time after surgery to the start of adjuvant treatment was 1.2 months in both groups.”

The study found there were similar rates of breast-conserving surgery and mastectomy in both groups. Among the patients who had breast-conserving surgery, 41.3% (262 patients) received pembrolizumab and 43.7% (281 patients) received placebo. Among those who had a mastectomy, 55.3% (351 patients) were treated with pembrolizumab and 54.4% (350 patients) had the placebo.”

Tissue collected at the time of surgery was analysed to see if any cancer cells remained after the neoadjuvant treatment, known as residual cancer burden (RCB). Neoadjuvant pembrolizumab resulted in a lower RCB for more patients, regardless of how well the immunotherapy had blocked a protein called PD-L1, which also drives some breast cancers.

Pathology reports found that 35% of patients (222 patients) treated with pembrolizumab had no or very small amounts of cancer cells remaining (RCB 0-1) versus 23.6% of patients (152) receiving placebo. A moderate amount of RCB (RCB-2) was found in 40.8% of patients treated with pembrolizumab versus 45.3% (259 versus 291 patients), and extensive RCB (RCB-3) was found in 20.5% versus 28.9% of patients respectively (130 versus 186 patients).

When the researchers looked at the effect of pembrolizumab according to whether patients had cancer that was ER positive in less than 10% of cells or in 10% or more, they found that 64.7% of patients (22 out of 34) with less than 10%, who were treated with pembrolizumab, had an RCB status of 0-1, compared to 37.2% of patients treated with placebo (16 out of 43). In patients with 10% or more ER positive cells, 33.3% compared to 22.7% had an RCB 0-1 status (200 out of 601 patients versus 136 out of 600 patients respectively).

Dr Fatima Cardoso, Director of the Breast Unit of the Champalimaud Clinical Centre, Lisbon, Portugal, is the principal investigator for the trial. Speaking before EBCC 14, she said: “Keynote 756 trial showed that the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased pathological response at the time of surgery, and this was true regardless of PD-L1 levels and estrogen receptor positivity. However, we saw a bigger benefit with higher PD-L1 levels and in ER-low tumors.

“Keynote-756 is also the only trial that is powered to analyze the impact of immunotherapy in long-term outcomes for this subtype of breast cancer.”

Adverse events from the treatments were unchanged from previous reports from the trial and were consistent with what is known already about each regimen.

The trial continues to follow the patients, and information is being collected on survival rates and whether there are any recurrences of cancer or other related symptoms.

Professor Michail Ignatiadis from the Institut Jules Bordet in Brussels, Belgium, is Chair of the 14th European Breast Cancer Conference and was not involved in the research.

We have heard more data from the KEYNOTE-756 trial about which ER positive / HER2 negative patient subgroups benefit most from pembrolizumab in terms of pathological complete response. Longer follow-up is needed in order to see whether the improvement in pCR rates will result in more patients living for longer without their disease recurring, and we look forward to these data in due course.”

Professor Michail Ignatiadis, Institut Jules Bordet in Brussels, Belgium

Source:

European Organisation for Research and Treatment of Cancer

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March 20, 2024
Innovative Levodopa infusion pump trial shows promise for reducing Parkinson’s symptoms

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An international, multisite phase 3 trial co-led by a University of Cincinnati researcher found Parkinson’s disease medication delivered through an infusion pump is safe and effective at reducing symptoms for longer periods of time.

These results, published March 15 in the Lancet Neurology journal, could lead to additional treatment options for patients with the condition.

Parkinson’s symptoms such as tremors, slowness and stiffness are caused by low levels of dopamine in the body. For decades, doctors have treated Parkinson’s by giving patients levodopa, the inactive substance in the brain that once converted makes dopamine.

“Levodopa is a replacement strategy. We all make levodopa, but Parkinson’s patients make less of it,” said Espay, co-principal investigator of the trial, James J. and Joan A. Gardner Family Center for Parkinson’s Disease Research Endowed Chair in UC’s Department of Neurology and Rehabilitation Medicine and a physician at the UC Gardner Neuroscience Institute.

Espay said oral levodopa is effective and typically helps people regain normal motor function, but its benefits tend to last less than a few hours after a few years, requiring increases in doses or its frequency.

Levodopa is most commonly administered orally, but this trial tested continuous, 24-hour levodopa delivery through a subcutaneous infusion pump. A total of 381 patients with Parkinson’s disease in 16 countries enrolled in the trial and were randomized to receive levodopa through the infusion pump or through traditional oral medication.

The researchers found levodopa delivered through the infusion pump was safe and led to almost two hours of day (1.72) of additional “on time,” or the time when the medication is working and symptoms are lessened, compared to taking levodopa orally.

Espay said the results of this trial pave the way for this specific infusion pump delivery system to be approved by the Food and Drug Administration and other countries’ respective governing bodies.

Once approved, this will become an important treatment strategy to consider for patients with Parkinson’s disease experiencing motor fluctuations not adequately controlled with medication. Future studies will need to determine the durability of the long-term benefits and whether any safety issues could emerge, as well as how it might compare with deep brain stimulation.”

Prof Alberto J Espay, James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati

Two additional subcutaneous delivery systems are also expected to be approved this year, Espay said, and researchers are continuing to study how to improve levodopa formulations and delivery to optimize its effect for patients.

“Levodopa delivery systems are expected to continue to improve over time,” he said. “This is a thriving area of research for the benefits of our patients.”

Source:

Journal reference:

Espay, A. J., et al. (2024). Safety and efficacy of continuous subcutaneous levodopa–carbidopa infusion (ND0612) for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00052-8

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March 15, 2024
BU study reveals key to combating high-risk neuroblastoma

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The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy-;a treatment that uses the body’s immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness.

As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness. Understanding how tumor cells utilize this molecule to communicate with immune cells will facilitate the development of effective immunotherapeutic strategies to provide more effective treatments with fewer toxicities for children with high-risk neuroblastoma.”

Hui Feng, MD, PhD, corresponding author, associate professor of pharmacology, physiology & biophysics, Boston University School of Medicine

The researchers studied an experimental model, clinical patient samples, and in-vitro cell culture. The experimental models of neuroblastoma with and without overexpression of the signaling molecule, CKLF, were compared for their ability to increase tumor aggression through the suppression of anti-tumor immune responses.

According to Xiaodan Qin, PhD, the first author of the study and a research scientist in the Feng Lab, the research is critical to understanding the mechanisms by which tumor cells induce a tumor microenvironment that compromises the function of immune cells, and it uncovered additional therapeutic approaches to evoke anti-tumor immune responses. “The long-term goal of this research is to uncover effective drugs that are much less toxic than chemotherapy and radiotherapy for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancers,” Feng says.

The findings appear online in Science Advances.

Source:

Boston University School of Medicine

Journal reference:

Qin, X., et al. (2024). CKLF instigates a “cold” microenvironment to promote MYCN-mediated tumor aggressiveness. Science Advances. doi.org/10.1126/sciadv.adh9547.

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March 15, 2024
Study highlights growing burden of neurological disorders worldwide

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Globally, the number of people living with, or dying from, neurological conditions such as stroke, Alzheimer’s disease and other dementias, and meningitis has risen substantially over the past 30 years due to the growth and aging of the global population as well as increased exposure to environmental, metabolic, and lifestyle risk factors. In 2021, 3.4 billion people experienced a nervous system condition, according to a major new analysis from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, published in The Lancet Neurology journal.

The analysis suggests that worldwide, the overall amount of disability, illness, and premature death-;a measurement known as disability-adjusted life years (DALYs)-;caused by neurological conditions increased by 18% over the past 31 years, rising from around 375 million years of healthy life lost in 1990 to 443 million years in 2021.

The absolute number of DALYs is increasing in large part due to aging and growing populations worldwide. However, if the impact of demographics is removed through age-standardization, rates of DALYs and deaths caused by neurological conditions have declined by around a third (27% and 34% respectively) worldwide since 1990-;largely due to better awareness, vaccination, and global prevention efforts for some conditions such as tetanus (93% decrease in age-standardized rates of DALYs), meningitis (62% decrease), and stroke (39% decrease).

The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy (brain injury), migraine, Alzheimer’s disease and other dementias, diabetic neuropathy (nerve damage), meningitis, epilepsy, neurological complications from preterm birth, autism spectrum disorder, and nervous system cancers. Neurological consequences of COVID-19 (cognitive impairment and Guillain-Barré syndrome) ranked 20th, accounting for 2.48 million years of healthy life lost in 2021.

The most prevalent neurological disorders in 2021 were tension-type headaches (around 2 billion cases) and migraines (about 1.1 billion cases). Diabetic neuropathy is the fastest-growing of all neurological conditions.

The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes.”

Dr Liane Ong, co-senior author from the Institute for Health Metrics and Evaluation (IHME), University of Washington, USA

The current study builds on previous GBD analyses [2] to provide the largest and most comprehensive analysis to compare the prevalence and burden (illness and death) of nervous system disorders between countries on a global scale between 1990 and 2021-;expanding the number of studied neurological conditions from 15 to 37 that span from birth to later life.

To better reflect that neurological disorders can occur at any stage of life, for the first time the GBD 2021 Nervous System Disorders Collaborators studied neurodevelopmental disorders and neurological conditions in children, and found that they were responsible for almost a fifth (18%) of all DALYs in 2021, accounting for 80 million years of healthy life lost worldwide.

“Every country now has estimates of their neurological burden based on the best available evidence,” said lead author Dr Jaimie Steinmetz from IHME. “As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies.”

The study, conducted to inform ongoing advocacy and awareness efforts, will support the WHO’s Intersectoral Global Action Plan on epilepsy and other neurological disorders 2022–2031 (IGAP) that aims to reduce the impact and burden of neurological disorders and improve the quality of life of people with neurological disorders as well as their caregivers and families.

Over 80% of neurological deaths and health loss occur in low- and middle-income countries (LMICs)

Overall, estimates reveal striking differences in nervous system burden between world regions and national income levels. In high-income Asia Pacific and Australasia – regions with the best neurological health – the rate of DALYs and deaths were under 3,000 and 65 per 100,000 people, respectively in 2021. In these regions, stroke, migraine, dementia, diabetic neuropathy, and autism spectrum disorders accounted for most health loss.

In contrast, in the worst-off regions of western and central sub-Saharan Africa, the rate of DALYs and deaths were up to five times higher (over 7,000 and 198 per 100,000 people respectively) in 2021, with stroke, neonatal encephalopathy (brain injury), dementia, and meningitis the biggest contributors to years of healthy life lost.

“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” said Dr. Tarun Dua, Unit Head of WHO’s Brain Health unit and one of the co-senior authors of the study. “Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries.”

The authors highlight that, as of 2017, only a quarter of countries globally had a separate budget for neurological conditions, and only around half had clinical guidelines. What’s more, the medical personnel who care for people with neurological conditions are unevenly distributed around the world, with high-income countries having 70 times more neurological professionals per 100,000 individuals than LMICs.

Prevention needs to be a top priority

“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” said co-lead author Dr Katrin Seeher, Mental Health Specialist at WHO’s Brain Health Unit.

The study quantified the proportion of nervous system burden that was potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.

The analysis suggests that modifying 18 risk factors over a person’s lifetime-;most importantly high systolic blood pressure (57% of DALYs)-;could prevent 84% of global DALYs from stroke.

Additionally, estimates suggest that controlling lead exposure could reduce the burden of intellectual disability by 63%, while reducing high fasting plasma glucose to normal levels could reduce the burden of dementia by around 15%.

“The worldwide neurological burden is growing very fast and will put even more pressure on health systems in the coming decades,” said co-senior author Dr Valery Feigin, Director of Auckland University’s National Institute for Stroke and Applied Neuroscience in New Zealand. “Yet many current strategies for reducing neurological conditions have low effectiveness or are not sufficiently deployed, as is the case with some of the fastest-growing but largely preventable conditions like diabetic neuropathy and neonatal disorders. For many other conditions, there is no cure, underscoring the importance of greater investment and research into novel interventions and potentially modifiable risk factors.”

“Nervous system conditions include infectious and vector-borne diseases and injuries as well as non-communicable diseases and injuries, demanding different strategies for prevention and treatment throughout life,” said Steinmetz “We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world.”

Despite these important findings, the authors note several limitations, including that, while they have done their best to capture all nervous system health loss, some conditions were left out because they could not isolate the neurological component, including infections such as HIV, which has a large impact in many parts of the world. And while the study uses the best available evidence, estimates are constrained by the quantity and quality of data, especially in LMICs.

Writing in a linked Comment, Professor Wolfgang Grisold, President of the World Federation of Neurology, London, UK (who was not involved in the study) says, “This important new GBD report highlights that the burden of neurological conditions is greater than previously thought. In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging, because the effects on the individuals vary substantially.”

Source:

Journal reference:

GBD 2021 Nervous System Disorders Collaborators. (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00038-3.

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March 15, 2024
Weight Loss Drug From Highly Toxic Plant Can Now Be Produced Simply and Sustainably

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Root of Tripterygium wilfordii Celastrol is produced in the root of the traditional medicinal plant Tripterygium wilfordii. Credit: Nikolaj Hansen

A traditional Chinese medicinal plant has huge potential as a weight loss drug. However, due to the plant’s notorious toxicity, no one has yet succeeded in exploiting it effectively. Researchers from the University of Copenhagen have not only found the formula for the synthetic production of the compound – they have even found a simple and sustainable recipe using ordinary yeast as the main ingredient.

In China, children are taught to steer clear of this plant. The plant, Thunder god vine (Chinese: 雷公藤), which in China has earned the nickname “Seven Steps to Death,” is so poisonous that a person risks death only a few steps after consuming it.

But despite its deadliness, the Thunder god vine (Tripterygium wilfordii) hides something quite beneficial to us humans as well. Within its roots, the plant produces the compound celastrol, a chemical agent with powerful anti-obesity properties.

Experiments using mice on a high fat diet have shown that the mice given celastrol gained 45% less weight than the control group. Experiments with human cells have shown similar effects.

HOW THE DRUG WORKS

Some people are able to eat a lot without gaining weight because our metabolism knows when we eat a lot and secretes certain hormones that cause us to burn more calories. One of these hormones is leptin.

People who are overweight become resistant to leptin due to an overproduction of the hormone, which leads to an inflammation of the hypothalamus. As a result, the body does not receive the signal. Celastrol re-sensitizes the body to leptin.

The effect is due to the fact that celastrol reactivates the body’s sensitivity to leptin, a hormone to which overweight people become resistant. Leptin is one of the hormones that causes the body to burn more calories and thereby regulate weight.

How does one get their hands on the ‘good’ substance without the toxicity that typically accompanies it? That is the question.

“For obvious reasons, a person cannot just eat the plant and benefit from the drug. So what do we do? The problem with extracting celastrol from the nature source is that it is very hard to separate it from the other toxic molecules that the plant is full of. So far, there has been no effective method to achieve this,” says Sotirios Kampranis, professor at the Department of Plant and Environmental Sciences.

Yong Zhao and Sotirios Kampranis
Yong Zhao and Sotirios Kampranis with celastrol produced in yeast cells Credit: Yao-Tao Duan

Yeast as ‘surrogate mother’

In approaching the problem, the research team from the Department of Plant and Environmental Sciences sought to find a way to produce the substance biotechnologically. Led by Assistant Professor Yong Zhao, the researchers were the first to map the pathway with all 15 biochemical steps that the plant undergoes as it forms celastrol. These steps are vital to know in order to recreate the substance biosynthetically.

THUNDER GOD VINE

The plant, Thunder god vine, which in Latin is called Tripterygium wilfordii, has been used for thousands of years in traditional Chinese medicine to treat rheumatoid arthritis and as a contraceptive.

The plant grows in the mountainous regions of Southern China, where local collectors harvest it. Thus, in addition to being extremely toxic, it is also difficult to find.

“The compound is extracted from the plant root. And the plant takes at least three years to grow large enough for it to be harvested. Therefore, an entire plant must be sacrificed to acquire the drug. So it is not a tenable way,” Sotirios Kampranis points out.

“We found out how the plant forms celastrol by finding all of the steps in the manufacturing process. This means that we could take the genes and enzymes that make the substance and put them into another organism that does not produce toxic substances. And that’s what we’ve done with yeast,” says Yong Zhao.

The researchers were able to produce synthetic celastrol in a tank with ordinary yeast that was used as a host organism within which the substance was produced.

“Imagine, you just need to feed the celastrol molecule table sugar, and by doing so, you get a compound that is almost in pure form without the toxic compounds that otherwise come with it in nature. The process is simple and effective – it only takes around a week to get the final product. And it takes place without the toxic solvents or catalysts that are typically used in chemical syntheses. I believe there is a huge potential here,” says Sotirios Kampranis.

Isolated celastrol
Isolated celastrol produced by the Kampranis lab. Celastrol is a complex plant specialized metabolite with a reddish color. Credit: Yong Zhao

The greenest – and only – method

Today, most pharmaceuticals are created through synthesis based on crude oil-based petrochemicals. And the traditional ways of developing synthetic drugs are actually not even an option, as Yong Zhao explains:

“Because the celastrol molecule is so complex, there are currently only very inefficient chemical synthesis methods which are not applicable for large-scale production. So our method is not only a green method – it is also the only real method that exists.”

The researchers point out that yeast is widely used in the biotech industry, where one finds all the necessary know-how and infrastructure to produce celastrol at a large scale.

“That is precisely why we have chosen to use yeast as an organism. While academics develop the technology, it is important that it comes in a form that is useful for industry, where the technology can be further developed to make products that can help us all,” says Sotirios Kampranis.

The next step is more closely investigating the drug’s potential to treat obesity in humans. The researchers hypothesize that a potential treatment can either be done with celastrol alone or combined with other therapies.

“For example, one can imagine a treatment where celastrol is combined with other anti-obesity drugs to achieve a more robust effect. Because the more targets in the body that are hit, the better. Indeed, one often sees a synergistic effect when several agents are at play simultaneously. But here, of course, the pharmaceutical industry must take over,” says Yong Zhao.

Reference: “Biosynthesis and biotechnological production of the anti-obesity agent celastrol” by Yong Zhao, Nikolaj L. Hansen, Yao-Tao Duan, Meera Prasad, Mohammed S. Motawia, Birger L. Møller, Irini Pateraki, Dan Staerk, Søren Bak, Karel Miettinen and Sotirios C. Kampranis, 26 June 2023, Nature Chemistry.
DOI: 10.1038/s41557-023-01245-7

The researchers behind the study are: Yong Zhao, Nikolaj L. Hansen, Yao-Tao Duan, Meera Prasad, Mohammed S. Motawia, Birger L. Møller, Irini Pateraki, Dan Staerk, Søren Bak, Karel Miettinen and Sotirios C. Kampranis, all from the Department of Plant and Environmental Sciences and the Department of Drug Design and Pharmacology at the University of Copenhagen.

The University of Copenhagen has filed for a patent application for the invention and is currently in talks with potential partners about commercializing the method.

The project is supported by the Novo Nordisk Foundation.

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March 12, 2024
Supply chain assessment and management, optimizing pharmaceutical supply chains

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In this interview, News Med talks to Joseph P. Ivan about the Comprehensive Assessment and Management Approach to Optimizing Pharmaceutical Supply Chains.

How do you optimize supply chain strategies while navigating the complexities of international regulation guidelines?

Navigating international regulations involves various strategies. Consolidating supplies into a single global source is ideal, yet often impractical due to numerous factors, such as differing timelines necessitating strategic adjustments.

A specific approach might involve prioritizing locations like Georgia for early implementation, with plans for subsequent inclusion in resupplies.

Regulatory filings, such as IMPD, require attention to detail, varying by country within Europe and extending to regions like Latin America and Asia Pacific.

Each country’s acceptance of stability data — for instance, Georgia’s 12-month and Bosnia’s 18-month periods — demands careful consideration. Managing this complexity across numerous countries involves meticulous organization, typically using tools like Excel to track country-specific regulations, product details, expiry dates, IMPD versions, and any other relevant supply chain specifics. This process is labor-intensive.

Could you describe a strategy you have employed to harmonize supply chain processes internationally in addition to the Excel files?

To carry out processes in countries like Georgia and Bosnia, one might initiate with individualized panels, even as plans include a broader range of European nations and those within its vicinity, considering the Quality Person (QP) aspect.

The strategy involves beginning with simpler countries using these panels, progressing to a comprehensive guidebook encompassing all targeted nations, and ensuring alignment with various health regulatory filings. This approach requires careful regulatory considerations.

Subsequently, joining supplies into a unified global inventory results in a single, possibly extensive guidebook, potentially spanning 100 pages, detailing each country’s specific requirements. However, this method may not be universally acceptable due to certain nations’ unique formulations or expiry date regulations. In such instances, a tailored approach is necessary.

India, for example, necessitates specific manufacturer and manufacturing date details on labels, a requirement not universally shared across Europe. Therefore, maintaining India on an individual panel basis is sensible to avoid presenting unnecessary information to countries with differing regulations, aiming for a harmonized supply strategy.

In pharmaceutical supply chains, what proactive steps have you found to be most successful in reducing risk?

The proactive answer is you need a supply chain expert asking the right questions when building your strategy. Brazil has unique requirements at the port of entry for pharmaceuticals.

For instance, after completing global supply preparations and assembling the booklet, including the expiration date, it is dispatched to a depot in Brazil amidst an ongoing trial. As the trial progresses smoothly, an update to the expiration date becomes necessary. This requires sending new labels to Brazil, which World Courier can deliver to apply over the old expiration date, offering a simple solution for updates.

However, importing these labels into Brazil involves regulatory considerations, as the labels, due to their adhesive component—a chemical—must be listed on the import license, health authority filing, and pro forma invoice, attracting taxes. This requirement stems from Brazil’s customs and health authorities’ efforts to safeguard their population by ensuring the adhesive’s legality within the country, reflecting the unique regulatory landscapes across nations. The emergence of regulations like biodegradable plastic bag mandates illustrates the complexity of adapting supply chains to environmental and health standards globally.

These details underscore the importance of early and frequent discussions, necessitating guidance from a professional or subject matter expert adept at navigating such intricacies. Without such expertise, even a highly competent Clinical Operations (ClinOps) professional with a directorial role might struggle, lacking the insight to ask appropriate questions for effective supply chain management.

Image Credits: DS InPharmatics (DSI)

Could you give an example of how risk-based management strategy improves the overall supply chain compliance?

You have a couple of steps of manufacturing. You have API, drug substance, and the drug product. There are several lengthy steps of manufacturing whereby there is a risk associated with each one. For example, the specification may fail, impurities may increase, or the capsules may not press together correctly.

From a risk-based standpoint, there are multiple tools out there. It can be something as simple as an Excel document that helps you to identify risk.

You need to be able to ask the right question and understand if there is a risk or not. If it is, you can identify it and then categorize it.

How does technological integration affect the regulatory compliance and product quality of pharmaceutical supply chains?

Consider the situation in the United States, similar to that in other nations, where various government agencies scrutinize incoming shipments. These include Customs and Border Protection, which aims to collect taxes; the Food and Drug Administration (FDA), serving as the health authority; and the United States Department of Agriculture (USDA), which ensures compliance with regulations on animal-derived products.

Depending on the nature of the product, involvement from the Environmental Protection Agency or the Nuclear Regulatory Commission may also be necessary, among others. These agencies leverage a technological platform accessible by customs brokers at entry points, allowing for the efficient coding and processing of shipments.

This platform, known as Automated Commercial Environment (ACE), enables seamless interaction between these agencies by facilitating the submission and review of tariff codes, FedEx details, FDA product codes, and USDA guideline exemptions for items containing animal parts but classified as pharmaceutical grade, thereby exempting them from certain permits.

The system’s efficiency hinges on the accurate entry of these codes, which, if correctly done, allows shipments to bypass manual inspection, directly proceeding to logistics providers like FedEx or DHL for delivery. However, inaccuracies can trigger a halt in the system, necessitating inspection by a compliance officer and potentially causing delays. While random inspections are possible, accurate code submissions typically ensure expedited clearance, with officials essentially confirming the shipment’s compliance without further scrutiny.

In what ways does DSI’s methodology improve clinical and commercial supply chain management and overrides?

If you have a trained professional, somebody that has the right level of experience either supporting your commercial supply chain or your clinical supply chain, they are going to ask the right question of the right person.

DSI is able to bring in a professional like me. In the world of consultancy, if you are a smaller company, you cannot afford a full-time employee, nor do you need one. You go the consultant route, and you have this wealth of information at your fingertips and only pay for what you use.

From a business and cutting purchase orders standpoint, it is really easy for clients to add and subtract services as they need. Supply chain is one of those services.

Similarly, in the commercial realm, it is common for organizations to attempt reassigning a Clinical Supplies Director to oversee a commercial product launch.

While the underlying principles may appear similar, the practicalities of clinical and commercial operations differ significantly. A clinical expert without commercial experience might find themselves ill-equipped and unaware of the relevant inquiries required for a successful commercial debut.

This is where DSI steps in, offering the expertise of professionals like me, who are experienced in navigating commercial launches.

We formulate the necessary questions and facilitate connections with essential partners for acquiring state licenses or implementing supply chain security measures, which now often include the assignment of unique serial numbers to products.

Ensuring the selection of an appropriate partner for these tasks is crucial, and we show clients how to engage with these companies effectively, emphasizing the importance of asking the right questions during the contracting process.

What benefits have you seen from optimizing and assessing the end-to-end supply chain?

The biggest benefit is cost. If you have done it right the first time, you are going to save millions of dollars on your supply chain.

Optimizing your supply chain requires an initial investment of effort, time, and overhead expenses. However, this investment proves to be cost-effective in the long run, as the savings generated from optimization ultimately outweigh the initial costs.

How can ERP software help to modernize pharmaceutical supply chain operations?

Clinical Enterprise Resource Planning (ERP) are third party services available for purchase. That acronym in clinical space is IRT, which stands for Interactive Response Technology. This is software used to help with randomization.

In a blinded clinical trial, managing inventory and coordinating shipments are crucial, with specialized software handling these tasks from the outset, including dispatching supplies to depots or sites.

This system allows site personnel to easily select medications for patients with a simple click. Such management tools are particularly vital in extensive, blinded trials, where without them, the added costs and complexity offer little benefit. In contrast, for a smaller trial, the additional expense and complexity of these tools may not yield significant advantages.

For larger, double-blinded trials spanning numerous countries and involving thousands of patients, utilizing Interactive Response Technology (IRT) becomes indispensable. Without IRT, coordinating inventory across potentially hundreds of sites in multiple countries would require manual oversight, a task far more efficiently handled by software.

The commercial sector parallels this with Enterprise Resource Planning (ERP) systems, which serve a similar function by managing resources and information across the enterprise. However, for startups or small companies with a limited product range, investing in an ERP system may not be cost-effective, potentially leading to unnecessary expenditure and frustration.

Initial reliance on simpler solutions, like spreadsheets or basic financial software, can suffice until the business scales up. As the product range, geographic footprint, and operational complexity grow, the investment in an ERP system becomes justifiable despite its high cost and maintenance requirements, because it streamlines operations across multiple sites and distribution centers. Yet, it is essential to remember that an ERP’s effectiveness is directly tied to the accuracy of the data entered into it, and it is not advisable for companies with only a few products.

What are some of the difficulties in integrated cloud-based ERP solutions in the biomedical and pharmaceutical industries?

Imagine a biotech company that decides to forego an Enterprise Resource Planning (ERP) system when launching its first commercial product, viewing it as an unnecessary expense. Later, the company acquires an additional asset from another entity or develops a second product in-house. Over a few years, this pattern continues, and the company finds itself with three commercial products. The challenge then becomes integrating the extensive data accumulated from these products over six or seven years into an ERP system, necessitating a significant data management project.

Following the integration, the focus shifts to the resources required for system maintenance. With the ERP system being cloud-based, the company benefits from reduced risk; even in the event of physical disasters like fires or tornadoes, the data remains secure on remote servers with backup systems in place, ensuring data preservation.

However, the utility of the ERP centers on the quality and accuracy of the data entered. Integrations with other systems, such as Interactive Response Technology (IRT) or external commercial vendors like McKesson or its subcontractors, introduce additional complexities. Ensuring seamless communication between different ERP systems presents a logistical challenge, emphasizing the importance of effective data flow management both into and out of the system.

How can specialized ERP solutions for the pharmaceutical industries help with supply chain optimization and cost reduction?

Some of the IRTs have optimizers built in. Some of them work really well. Again, you have to have an intimate working knowledge of how that software works.

Some of the other IRTs are a little bit more simple, where you can put a buffer stock in there. You can define it, and that will help optimize your supplies so you are not getting orders for one unit triggered. You wait for orders of 50 units to be triggered, and you save on your shipping costs in that regard. Every time a shipment comes, somebody has to receive it, take it out of the box, look at what it is, go over to that online solution, say that they received it.

If they are doing that every single day for one unit, or if they only do it once every 50 days, it is quicker and easier. You are saving money from a bandwidth perspective. Again, it is a value prop question. You have to balance that with how much you have spent on your IRT or your ERP, versus how much bandwidth and shipping costs that you may or may not incur. From an optimization standpoint, again, you go to Excel. Excel is a fantastic program. If you do not want to spend a lot of money, you have something in there called optimize.

You really need to have a subject matter expert programming or building that. They might have tools that they have used in the past that they can tweak to make it work for that scenario.

About Joseph P. Ivan

Mr. Ivan has over 20 years of experience in the pharmaceutical industry, 8 years in manufacturing and 12 years in supply chain. He has designed, implemented, and managed both clinical and commercial supply organizations for various sized companies.

Joe’s experience includes protocol development and review, forecasting, label management, inventory management, IRT management, ancillary supply management and global logistics management for all clinical phases, protocol types (blinded, open) and world regions. His specialties include North America, Asia Pacific, the European Union, Eastern Europe, and Latin America. In particular, he is a subject matter expert for importing clinical drug into China. He has authored and managed site and subject facing materials such as Pharmacy Manuals and Dose Card instructions. He is International Trade Compliance Certified (ITCC) for Import/Export in the US.

As a leader for bioanalytical laboratory testing, his experience includes assay development, validation and execution for clinical laboratory operations supporting clinical operations.

Our Supply Chain Services team has experience that spreads across branded and generic pharmaceuticals with a focus on contract manufacturing organizations (CMOs) while it also includes scheduling, logistics, forecasting, API and excipient sourcing, comparator sourcing and contract packaging and labeling organizations.

About DS InPharmatics LLC

DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.

Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.

Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.

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March 4, 2024
SickKids study offers new path for pediatric rare disease clinical trials

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Using a novel methodology, researchers at The Hospital for Sick Children (SickKids) are the first in pediatric research to use data from an international real-world cohort to overcome the barriers associated with conducting randomized clinical trials in children with rare diseases.

The gold standard for evaluating new therapeutics is through randomized clinical trials, where one group of individuals receives treatment while another does not. Unfortunately, conducting this type of clinical trial proves challenging for many rare conditions due to the limited number of individuals with the condition, making meaningful comparisons difficult. Additionally, in pediatrics, it can be unethical to give a potential treatment to some children and not others.

In a study published in Hepatology, a team of SickKids scientists developed an innovative and robust statistical approach which may eliminate the need for traditional randomized clinical trials, demonstrating the effectiveness of a medication in reducing disease progression and liver transplants in children with Alagille syndrome (ALGS).

By using a global database, we were able to mimic high-quality clinical trial results by comparing present-day outcomes to historical data. Not only do our findings show a marked improvement in liver-related outcomes for children with ALGS treated with this medication, but they also present a path forward for randomized clinical trials for other rare diseases.”

Dr. Binita Kamath, Senior Associate Scientist in the Developmental & Stem Cell Biology program and Principal Investigator and senior author of the study

ALGS is a rare genetic disorder in which a patient has an inadequate number of bile ducts, which usually drain bile from the liver into the intestine. The bile then builds up and causes liver damage. Between 60 to 75 percent of patients with ALGS undergo a liver transplant before they reach adulthood.

Due to the rarity and severity of the condition, clinical trials have historically been difficult to conduct, especially over longer durations of time, since it is unethical and not feasible to have children take a placebo for several years.

In a previous study describing an international cohort of children with ALGS, Kamath and Shannon Vandriel established an international database of clinical, genetic and laboratory data in children and young adults with ALGS called The Global ALagille Alliance (GALA) study.

In this study, using the data of 469 untreated patients from GALA, the research team were able to compare their long-term outcomes to 84 children being treated with maralixibat, a medication approved in the US and Europe and recently in Canada for symptomatic relief of the severe itching experienced by patients with ALGS.

Using this innovative approach, the research team found that over six years, children taking maralixibat showed a 70 per cent improvement in event-free survival and a 67 per cent improvement in transplant-free survival.

“While the current indication for maralixibat is for itching, our data showed that over a longer period, the medication actually reduces the rate of liver transplants in patients with ALGS,” says Kamath, who is also a Staff Physician in the Division of Gastroenterology, Hepatology and Nutrition.

In addition to these benefits, the methodology used by the research team has ground-breaking implications for the development and implementation of clinical trials for patients with rare diseases.

Kamath and Vandriel believe similar approaches could be applied to any rare disease with enough historical data.

“Our research provides an alternative to the challenges associated with recruiting patients with life-threatening conditions or debilitating symptoms for long-term clinical trials,” says Kamath. “While our study was specific to patients with ALGS, I hope this sparks a renewed interest in international databases of individuals with rare diseases which can provide real-world data that can be used to help evaluate new therapies.”

Funding for The GALA study was provided by grants from The Alagille Syndrome Alliance, Ipsen Pharmaceuticals and Mirum Pharmaceuticals to SickKids Foundation.

Source:

The Hospital for Sick Children

Journal reference:

Hansen, B. E., et al. (2023) Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA. Hepatology. doi.org/10.1097/HEP.0000000000000727.

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February 29, 2024