Two Novartis Phase III studies show twice as many Ph+ CML patients achieve deeper levels of response with Tasigna® compared to Glivec®

Phase III clinical trial data presented today contribute to the growing evidence that adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase who are treated with Tasigna® (nilotinib) have deeper levels of response compared to those treated with 

The findings from the ENEST (Evaluating Nilotinib Efficacy and Safety in clinical Trials) clinical research program were presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego.

ENESTcmr is the first exploratory randomized trial to investigate the impact of switching adult patients with residual disease after a minimum of two years of treatment with Glivec to Tasigna to determine if a deeper level of response could be achieved.

The study showed that twice as many patients switched to Tasigna 400 mg twice a day achieved undetectable Bcr-Abl levels by 12 months compared to Glivec (23% taking Tasigna 400 mg twice daily and 11% taking Glivec 400 mg or 600 mg once daily; p= 0.0202). The primary endpoint, which is more stringent than conventional measures, is undetectable Bcr-Abl level in two consecutive samples. Samples with any detectable level were not considered to be in complete molecular response (CMR). The lowest detected Bcr-Abl value was 0.00073%. This endpoint showed a two-fold difference in confirmed undetectable CMR for 13% of patients on Tasigna versus 6% of patients on Glivec, although statistical significance was not achieved (p=0.108). The study has a planned follow-up of four years.

After 36 months of follow-up, data from the Phase III ENESTnd clinical trial in adult patients with newly diagnosed Ph+ CML in chronic phase continued to show significantly more patients achieved CMR, defined in this study as at least a 4.5 log reduction from baseline or a trace amount of 0.0032% or less of Bcr-Abl compared to Glivec (32% taking Tasigna 300 mg twice daily and 15% taking Glivec 400 mg once daily). The ENESTnd study also continued to show that first-line treatment with Tasigna resulted in significantly fewer patients progressing to advanced phase and blast crisis (AP/BC) stages of disease compared to Glivec, leading to a significantly lower number of CML-related deaths in patients taking Tasigna versus Glivec (p=0.0356).

“Data from both ENESTnd and ENESTcmr reinforce that patients taking Tasigna have a greater chance of achieving CMR, the deepest level of response measurable today, compared to those taking Glivec,” said Timothy P. Hughes, MD, ENEST study investigator and Clinical Professor at the University of Adelaide, Australia. “We are encouraged by what we saw in ENESTcmr and further follow-up on both trials should help to determine if more patients can reach undetectable levels of CML over time, which could have important implications for determining criteria for future studies on discontinuation of therapy.”

CML is a disease in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which is comprised of a protein called Bcr-Abl that causes malignant white blood cells to proliferate[3]. The success of treatment for CML can be measured by a test called real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response means RQ-PCR shows a reduction in Bcr-Abl in the blood; a CMR means no Bcr-Abl is detected[4],[5]. In recent investigator-initiated studies, select patients who achieved durable CMR have been able to cease therapy without relapse for trial periods lasting from six months to a year[6-8].

“Data from the ENESTnd 36-month update and the ENESTcmr trial at ASH continue to reinforce the benefits of Tasigna over Glivec, and support the use of Tasigna for adult patients with chronic-phase Ph+ CML,” said Hervé Hoppenot, President, Novartis Oncology. “We look forward to even more progress in the future as we observe the impact of achieving deep and sustained molecular response with Tasigna for people living with this cancer.”

Worldwide, CML is responsible for approximately 10% to 15% of all adult cases of leukemia, with an incidence of one to two cases per 100,000 people per year.

ENESTcmr study details
ENESTcmr is an open-label, randomized, prospective, multi-center Phase III study of Tasigna 400 mg twice daily versus standard-dose Glivec (400 mg or 600 mg once daily) comparing kinetics of CMR for patients with Ph+ CML in chronic phase who had achieved complete cytogenetic response (CCyR) but were still Bcr-Abl positive (i.e., had evidence of residual leukemia) after at least two years of treatment with Glivec. The study enrolled 207 patients. The patients were randomized into one of two treatment arms: Tasigna 400 mg twice daily versus continuing Glivec 400 mg or 600 mg once daily (same dose as at study entry).

The primary endpoint was the rate of confirmed best cumulative CMR by 12 months of study therapy with Tasigna or Glivec. Samples with any detectable level were considered not to be in CMR. The lowest detected Bcr-Abl value was 0.00073%. Secondary objectives included the kinetics of CMR, duration of CMR, progression-free survival and overall survival in both arms. CMR was defined at three levels: CMR (CMR ≥4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of less than 0.0032%), CMR4 (CMR ≥4-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.01% or less) and CMR4.5(CMR ≥4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.0032% or less)[1].

These data showed that 23% of patients taking Tasigna achieved undetectable disease (24 patients) by 12 months compared to 11% (11 patients) taking Glivec..

A majority of patients in both treatment arms received prior Glivec treatment for at least three years before entering the trial. Patients randomized to receive Tasigna were given a new treatment while the others continued to receive a therapy that they had been taking for a minimum of two years[1].

During this study, discontinuation due to adverse events occurred in 8.9% and 1% for Tasigna- and Glivec-treated patients, respectively. The majority of these were asymptomatic laboratory adverse events. The adverse events seen in ENESTcmr were similar to other studies for patients switched from chronic Glivec therapy to Tasigna[.

ENESTnd study details
ENESTnd is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Glivec in adult patients with newly diagnosed Ph+ CML in chronic phase. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients.

The study is being conducted at 217 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 300 mg twice daily (n=282), Tasigna 400 mg twice daily (n=281) or Glivec 400 mg once daily (n=283). The primary endpoint was major molecular response (MMR) at 12 months; the key secondary endpoint was durable MMR at 24 months (patients having MMR when evaluated at both 12 and 24 months). MMR was defined in this study as 0.1% or less of Bcr-Abl as measured by RQ-PCR. Planned follow-up is for five years. Patients on the Glivec treatment arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to Tasigna in a separate extension study. These data, presented at ASH, were the 36-month minimum follow-up.

Results showed that fewer patients in the core treatment group progressed to accelerated phase or blast crisis while on treatment with Tasigna at 300 mg twice daily (n=2) and 400 mg twice daily (n=3) versus Glivec at 400 mg once daily (n=12) with 36 months of minimum follow-up. Analysis of the broader study group, including patients followed after discontinuation of the study, showed 9 patients on Tasigna 300 mg twice daily, 6 patients on Tasigna 400 mg twice daily and 19 patients on Glivec progressed.

Over the past three years a total of 38 patients (5%) died during the ENESTnd study (17 patients taking Glivec, 13 taking Tasigna 300 mg twice daily and 8 taking Tasigna 400 mg twice daily). Tasigna treatment was also associated with significantly lower rates of CML-related deaths (5 patients taking Tasigna 300 mg twice daily, 4 patients taking Tasigna 400 mg twice daily and 14 patients taking Glivec) consistent with the significant improvement observed with progression to AP/BC. Since the last data cut-off there were a total of five CML related deaths (4 with Glivec 400 mg once daily and 1 with Tasigna 400 mg twice daily).

The median follow-up for this study was 36 months. Overall, 90% and 88% of patients remained in the study on Tasigna 300 mg twice daily and Glivec 400 mg once daily, respectively[2].

Rates of discontinuation due to adverse events or laboratory abnormalities continued to be lowest for Tasigna 300 mg twice daily (10%) compared to Tasigna 400 mg twice daily (14%) and Glivec 400 mg once daily (11%).

About Tasigna (nilotinib)
Tasigna® (nilotinib) is approved in more than 90 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec, and for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. Tasigna should be taken twice daily 12 hours apart. Tasigna should not be taken with food and no food should be consumed for two hours after dosing. Patients taking Tasigna should avoid grapefruit juice and CYP3A4 inhibitors.

Tasigna Important Safety Information
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Uncommon cases (0.1 to 1%) of sudden death have been reported in clinical studies in patients with significant risk factors.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. Women taking Tasigna should not breastfeed.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia and thrombocytopenia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Monitor blood counts regularly. Pancreatitis has been reported. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea. Most of these adverse events were mild to moderate in severity.

About Glivec (imatinib)
Glivec® (imatinib) is approved in more than 110 countries for the treatment of all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST. Take with food and a large glass of water.

Glivec Important Safety Information
Glivec can cause fetal harm in pregnant woman. Glivec has been associated with severe edema (swelling) and serious fluid retention. Cytopenias (anemia, neutropenia, thrombocytopenia) are common, generally reversible and usually managed by withholding Glivec or dose reduction. Monitor blood counts regularly. Severe congestive heart failure and left ventricle dysfunction, severe liver problems including cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Use caution in patients with cardiac dysfunction and hepatic dysfunction. Monitor carefully.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. Skin reactions, hypothyroidism in patients taking levothyroxine replacement, GI perforation, in some cases fatal and tumor lysis syndrome, which can be life threatening, have also been reported with Glivec. Correct dehydration and high uric acid levels prior to treatment. Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use. In patients with hypereosinophilic syndrome and heart involvement, cases of heart disease have been associated with the initiation of Glivec therapy. Growth retardation has been reported in children taking Glivec. The long-term effects of extended treatment with Glivec on growth in children are unknown.

The most common side effects include fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.

Source:Novartis Release


Quantum tunneling results in record transistor performance

 Controlling power consumption in mobile devices and large scale data centers is a pressing concern for the computer chip industry. Researchers from Penn State and epitaxial wafer maker IQE have created a high performance transistor that could help solve one of the vexing problems of today’s MOSFET technology – reducing the power demand whether the transistors are idle or switching.

Today’s digital information processing systems, from data centers to mobile laptops to smart phones, consume and dissipate significant power due to the constant power demand of the billions of transistors packed into the logic circuits on digital electronic devices. In traditional MOSFETs (metal-oxide semiconductor field-effect transistors), the building blocks of today’s digital technology, a supply voltage of around one volt is required to gradually turn on the transistor. The current transistor technology faces inherent limits to reducing the power demand in electronic circuits due to physical laws related to the MOSFET design. Meanwhile, power demand will increase as the size of next generation transistors decreases and more devices are packed onto a computer chip.

In a paper to be delivered at the International Electron Devices Meeting in Washington DC on December 7th, Penn State doctoral candidate Dheeraj Mohata will discuss a new materials and device architecture that provides power savings and instant transistor on-off capability for future electronics. The paper, titled “Demonstration of MOSFET-Like On-Current Performance in Arsenide/Antimonide Tunnel FETs with Staggered Hetero-junctions for 300mV Logic Applications,” reports the fabrication of a heterojunction field effect tunnel transistor with a 650% increase in drive current.

“This is the first time a tunneling field effect transistor has had a MOSFET-like On-state current,” says Mohata’s adviser Suman Datta, professor of electrical engineering. “By choosing two dissimilar semiconductor materials, Indium Gallium Arsenide and Gallium Arsenic Antimonide, and adjusting their composition, Deheeraj was able to engineer Hetero Tunnel FETs with a 7.6x improvement in drive current over the control sample.” Tunneling FETs use the quantum mechanical property in which electrons are able to pass through a physical barrier if the barrier is thin enough. By increasing the drive current, the team was able to operate the Tunnel FET at reduced voltage, 300 milliVolt compared to one V, thereby offering considerable power savings.

“If one can pick a proper combination of two different semiconductors and adjust their composition such that their band alignment results in a staggered configuration, it’s possible to significantly increase the tunneling rate and enhance the drive current of the Tunnel FET,” Datta explains.

The Penn State researchers designed and partnered with IQE, who produced the atomically precise multi-layer epiwafers using molecular beam epitaxy on which the transistors are built. The Penn State team then used advanced nanofabrication techniques to fabricate vertically oriented tunnel FET devices on the epiwafers in the Materials Research Institute’s Nanofabrication Facility, whose director, professor of electrical engineering Theresa Mayer, was the co-principal investigator on the project. Comparing experimental results against the computer models used in the design phase enabled the researchers to verify their device simulations, and determine that Hetero Tunnel FETs would perform in a similar manner in the next generations of semiconductor devices, including future 7nm technology node devices.

“Work has to go on to see if this device can be further scaled to smaller dimensions and integrated on an industrial scale,” Datta concludes. “If so, the impact will be significant in terms of low power integrated circuits that can work at 300 millivolts and below. This raises the possibility for self-powered circuits in conjunction with energy harvesting devices for active health monitoring, ambient intelligence, and implantable medical devices where the batteries haven’t scaled in step with the devices.”

New Phase III data shows Novartis JAK inhibitor INC424 significantly reduced disease burden in patients with myelofibrosis

Novartis today announced additional results from two pivotal Phase III trials evaluating Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in myelofibrosis. These data demonstrate the important potential role of INC424 in treating patients with myelofibrosis, a life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms.

Results are being presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego. Novartis and Incyte Corporation have a worldwide collaboration and license agreement for INC424.

A post-hoc analysis from the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study evaluated patient-reported health-related quality of life (HRQoL) measures for INC424 versus best available therapy (BAT). The results showed a substantial improvement in HRQoL and myelofibrosis symptoms compared with baseline for patients receiving INC424 but remained the same or worsened for patients receiving BAT. Results were based on a broad range of validated QoL instruments.[1]

“Myelofibrosis is a life-shortening disease with symptoms that significantly compromise patients’ everyday lives,” said Claire Harrison, MD, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, lead investigator for the COMFORT-II study. “As a result, therapies that address the severe burden of myelofibrosis are urgently needed. Data from large Phase III studies continue to show INC424 alleviates the manifestations and associated symptoms of myelofibrosis, potentially representing a major advance.”

In the second Phase III study, COMFORT-I researchers evaluated INC424 versus placebo in symptom improvement and spleen volume reduction, as well as overall survival. Results showed that patients receiving INC424 had higher response rates based on reductions in spleen volume and Total Symptom Score (TSS). The TSS evaluated changes in symptoms, such as abdominal discomfort, pain under the ribs on the left side, early satiety, itching, night sweats and bone or muscle pain. These benefits were consistent across all patient subgroups, including myelofibrosis disease subtype, age, risk group, presence or absence of JAK2 mutation, hemoglobin, spleen size and TSS.

In the COMFORT-I updated analysis, INC424 also demonstrated an overall survival advantage over placebo. A total of 13 INC424 and 24 placebo patients died during the study or during extended follow up after median follow up of 51 and 52 weeks, respectively, representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). Survival was estimated by the Kaplan-Meier method.[2]

“These data reinforce the dramatic effect INC424 has on improving the overall quality of life of patients battling this debilitating blood cancer,” said Hervé Hoppenot, President, Novartis Oncology. “We are committed to developing innovative therapies to address this unmet patient need and further support our ongoing research in myelofibrosis and other myeloproliferative neoplasms.”

COMFORT-II Predictors of Response and Post-Hoc HRQoL Study Details
A detailed analysis of predictors of spleen response in various patient subsets indicated that INC424 was more effective than BAT for all patient subgroups. In particular, responses to INC424 occurred and were superior to BAT regardless of the JAK2 mutation status.

The COMFORT-II study included an assessment of HRQoL and myelofibrosis symptoms using validated instruments, including the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym). Scores from these instruments were measured at baseline and weeks 8, 16, 24 and 48. A total of 219 patients were included in two treatment groups: INC424 (n=146) and BAT (n=73).

Based on a detailed analysis of the patterns of change of QoL scales over time, and compared with the BAT arm, INC424-treated patients experienced significant improvement in Global Health Status/QoL and in symptoms measured by the FACT-Lym symptom subscale including pain, swelling, fever, night sweats, itching, trouble sleeping, fatigue, weight loss, loss of appetite and trouble concentrating compared to BAT. In addition, the EORTC QLQ-30 showed that treatment differences in physical functioning, role functioning, fatigue and appetite loss were significantly better for INC424-treated patients as early as week 8 (p<0.05), and this effect was sustained throughout 48 weeks (p<0.05).[1]

The COMFORT-II trial was conducted by Novartis in Europe.

COMFORT-I Study Details for Symptom and Overall Survival Analyses
Patients were randomized to start INC424 or placebo at doses of 15 mg or 20 mg PO BID, depending on baseline platelet count (100-200 X109/L or >200X109/L, respectively). A total of 309 patients were randomized, 155 to INC424 and 154 to placebo. The dose was optimized for efficacy and safety during treatment.[2]

The COMFORT-I study was conducted by collaboration partner Incyte Corporation in the US, Canada and Australia.

About Myelofibrosis
Myelofibrosis is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, such as fatigue, night sweats and pruritus, poor quality of life, weight loss as well as shortened survival.[4] In the EU, the disease affects about 0.75 out of every 100,000 people annually.[5],[6] In the US, myelofibrosis affects about 1.5 out of every 100,000 people annually.[7] Myelofibrosis has a poor prognosis and limited treatment options.[3],[4]

Studies show that within 10 years of diagnosis, up to approximately 20% of myelofibrosis patients progress to fatal secondary acute myelogenous leukemia, which is virtually untreatable.[8],[9] Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality.[10] The five-year survival rate after transplantation is approximately 50%.[10]

About INC424 (ruxolitinib)
The investigational compound INC424 is an oral inhibitor of the JAK1 and JAK2 tyrosine kinases.[3] As part of Novartis’ clinical development program, INC424 is being investigated in primary myelofibrosis as well as post-polycythemia vera myelofibrosis (PPV-MF) and post-essential thrombocythemia myelofibrosis (PET-MF). INC424 is also being investigated in clinical trials for the treatment of polycythemia vera (PV).

Novartis licensed INC424 from Incyte for development and potential commercialization outside the US. Incyte has retained rights for the development and potential commercialization of INC424 in the US. Both the European Commission (EC) and the US Food and Drug Administration (FDA) have granted INC424 orphan drug status for myelofibrosis, and INC424 was recently approved by the FDA in the US under the name Jakafi(TM).

Source:Novartic release



Bisphosphonates ‘extend hip replacement life’.

Using a bone-strengthening drug could make joint replacements last longer, according to an analysis of GPs’ records.

The study, published on the British Medical Journal website, showed that the failure rate could be cut in half.

Researchers analysed data from patients who were taking bisphosphonates, which are used to prevent the loss of bone material.

However, scientists say further studies are still needed.

When joints become damaged or worn out, commonly due to osteoarthritis, it can be painful and limits movement.

An implant can dramatically improve a patient’s mobility. More than 50,000 hip and 70,000 knee, replacements take place in the UK each year.

While they can last for decades, some fail within years. This can happen when the bone around the implant is dissolved by the body meaning the replacement joint becomes loose.

The theory was that bisphosphonates, which are used by patients with osteoporosis to prevent bone being broken down, would prevent the loosening.

The researchers looked at data from General Practice Research Database for joint replacements and compared what happened to 1,912 patients taking bisphosphonates with 41,995 patients who did not.

After five years, 1.96% of implants failed without the drug, compared with 0.93% in those taking medication.

Prof Nigel Arden, a specialist in rheumatic diseases at the Universities of Oxford and Southampton, said the first implant would cost the NHS about £7,000, but replacements would cost £34,000.

He told the BBC: “It has the potential to have a huge impact.”

He said two of the risk factors, age and obesity, meant the number of cases was “increasing dramatically”.

Prof Arden is not arguing that people should be given the drug yet. He has applied for funding for a further trial to test the effectiveness of bisphosphonates and which patients would benefit most.

The chief medical officer for England, Prof Dame Sally Davies welcomed the findings.

“With such a high incidence of knee and hip replacement surgery, the possibility that the life of joint implants could be lengthened and reduce the number of complex revision surgeries means that these results have the potential to make significant improvements to the lives of many NHS patients,” she said.



What Are the Implications of Poor Immunologic Response to ART?

Among patients with virologic suppression, those with initially poor immunologic response continued to have persistently low CD4-cell counts and had an increased risk for morbidity and mortality.

Most HIV-infected patients who achieve virologic success on potent antiretroviral therapy (ART) also experience adequate CD4-cell recovery. However, a small proportion do not, and the clinical implications of this discordant response to treatment have been unclear.

In this retrospective observational study, participants in the Dutch ATHENA cohort who achieved viral loads <500 copies/mL during the first 2 years on ART were divided into four groups based on their CD4 counts at 1 to 2 years (<200, 200–350, 351–500, and >500 cells/mm3). Those with CD4 counts <200 cells/mm3 were considered to have poor immunologic recovery. Outcomes of interest included a composite endpoint (cardiovascular events, AIDS, cancer, cirrhosis, or death), non–AIDS-defining diseases overall, cardiovascular events, and non–AIDS-defining malignancies specifically.

The 3068 patients included in the analysis (83% male) had a median age of 41, a median nadir CD4 count of 170 cells/mm3, and a median baseline CD4 count of 360 cells/mm3; 6.5% had poor CD4-cell recovery. Independent predictors of poor CD4-cell recovery included older age, lower nadir CD4-cell count, and lower viral load at ART initiation.

During more than 10,000 person-years of follow-up, patients with poor CD4-cell recovery had the highest frequency of the composite endpoint, non–AIDS-defining diseases overall, and cardiovascular events. A key observation was that the patients with poor immunologic recovery had a median CD4 count of only 320 cells/mm3 after 7 years of potent ART.

Comment: The low median nadir CD4 count for the entire cohort (170 cells/mm3), together with the failure of many patients to achieve CD4 counts >500 cells/mm3 after years of suppressive ART, underscores the need for expansion of HIV testing and outreach efforts. The aim of those efforts would be to identify recently infected individuals, engage them in care, and initiate potent ART at higher CD4-cell counts, thus optimizing immune recovery and clinical benefit, with decreased transmission of HIV as a likely public health bonus. Although the potential benefits of early treatment seem clear, actual experience and the current economic outlook indicate that expanding provision of care to include most individuals with new HIV diagnoses will be difficult.

Source: Journal Watch HIV/AIDS Clinical Care


Rare gene links vitamin D and multiple sclerosis

Researchers say a variant gene which reduces vitamin D levels could be directly linked to MS

A rare genetic variant which causes reduced levels of vitamin D appears to be directly linked to multiple sclerosis, says an Oxford University study.

UK and Canadian scientists identified the mutated gene in 35 parents of a child with MS and, in each case, the child inherited it.

Researchers say this adds weight to suggestions of a link between vitamin D deficiency and MS.

Although the cause of MS is not yet conclusively known, both genetic and environmental factors and their interactions are known to be important.

Oxford University researchers, along with Canadian colleagues at the University of Ottawa, University of British Columbia and McGill University, set out to look for rare genetic changes that could explain strong clustering of MS cases in some families in an existing Canadian study.

They sequenced all the gene-coding regions in the genomes of 43 individuals selected from families with four or more members with MS.

This shines more light on the potential role of vitamin D deficiency on increasing the risk of developing MS.”

Dr Doug Brown MS Society

The team compared the DNA changes they found against existing databases, and identified a change in the gene CYP27B1 as being important.

When people inherit two copies of this gene they develop a genetic form of rickets – a disease caused by vitamin D deficiency.

Just one copy of the mutated CYP27B1 gene affects a key enzyme which leads people with it to have lower levels of vitamin D.

Overwhelming odds

The researchers then looked for the rare gene variant in over 3,000 families of unaffected parents with a child with MS.

They found 35 parents who carried one copy of this variant along with one normal copy.

In every one of these 35 cases, the child with MS had inherited the mutated version of the gene.

The likelihood of this gene’s transmission being unconnected to the MS is billions to one against, say the researchers.

Prof George Ebers, lead study author at Oxford University, says the odds are overwhelming.

“All 35 children inheriting the variant is like flipping a coin 35 times and getting 35 heads, entailing odds of 32 billion to one against.”

He added: “This type of finding has not been seen in any complex disease. The uniform transmission of a variant to offspring with MS is without precedent but there will have been interaction with other factors.”

Prof Ebers believes that this new evidence adds to previous observational studies which have suggested that sunshine levels around the globe – the body needs sunshine to generate vitamin D – are linked to MS.

He maintained that there was now enough evidence to carry out large-scale studies of vitamin D supplements for preventing multiple sclerosis.

“It would be important particularly in countries like Scotland and the rest of the UK where sunshine levels are low for large parts of the year. Scotland has the greatest incidence of multiple sclerosis of any country in the world.”

Dr Doug Brown, head of biomedical research at the MS Society, called it an important development.

“This shines more light on the potential role of vitamin D deficiency on increasing the risk of developing MS.

“This research is gathering momentum and will be the subject of discussion at an international expert meeting in the USA this month, the outcomes of which will shape future research that will give us the answers we so desperately need about the potential risks and benefit of vitamin D supplementation.”

Paul Comer, from the charity MS Trust, said the research strengthened the case for vitamin D being one potential contributory cause of MS.

“Current opinion suggests that a combination of genetic predisposition, environmental factors such as exposure to sunlight and possibly some sort of trigger, such as a viral infection, interact in some way to start the development of MS.

“We welcome any research that clarifies the interplay between these factors. This is another step towards finding ways to reduce the risk of developing MS, but it is likely to be some years yet before we can gauge the significance of vitamin D deficiency to MS.”



Nanoparticle hollowing method promises medical advances

A process to “carve” highly complicated shapes into nanoparticles has been unveiled by a team of researchers.

It involves a chemical process which hollows out the particles into shapes such as double-walled boxes and multi-chambered tubes.

The researchers said this would aid the creation of more complex nano-objects.

They said these could ultimately be used to revolutionise medical tests and aid drugs treatments.

The research was carried out by the Catalan Institute of Nanotechnology in Bellaterra, Spain and is published in the latest issue of Science.

To deliver their results the scientists refined a series of existing corrosion techniques including the “galvanic effect”.

This involved treating tiny silver cubes with cationic gold – a type of gold that had had some electrons removed from its atoms, turning it into an ion.

When brought together at room temperature the cationic gold “attacked” the silver, stealing its electrons.

The loss of the electrons turned the affected silver atoms into ions which dissolved into a provided solution.

Meanwhile, by gaining electrons the cationic gold was transformed into “normal” metallic gold which was then deposited onto the top of the silver cube.

“This protects the silver – and as the cube’s surface becomes covered, the reaction becomes more aggressive in other parts of the cube that have not been coated,” said Prof Victor Puntes, the team’s principal researcher.

“In the end you end up with a single hole on the surface of the silver which is not covered by gold where the reaction advances and then enters the cube from inside.”

The professor said this prompted a second process known as the Kirkendall effect where silver atoms from inside the cube started “migrating” to the gold outside “offering themselves up” thus creating a void inside the cube.

“We can control the process to make different holes resulting in different structures,” Prof Puntes added.

Although both the galvanic effect and the Kirkendall have been used for years, the scientists said that previous efforts to combine them in this way had failed because the galvanic effect was too aggressive.

They said their innovation was to introduce a range of factors which made the silver more resistant, the cationic gold less aggressive and dissolved by-products of the process which would have otherwise interfered with the structure’s development.


The technique allows a range of hollowed shapes to be created in metallic nanoparticles

Nano-device drugs

Although the process has only just been outlined, the scientists are excited by its potential uses for the medical industry.

They said particles could be hollowed out so that they absorbed different energy wavelengths, helping to create body scanners that would be more accurate than current magnetic resonance imaging (MRI) equipment.

The researchers added that the technique could also aid drug delivery.

“It’s a wonderful molecular suitcase,” said Prof Puntes.

“You can have different sizes of cavity meaning that different-sized molecules enter different rooms of a structure. So you can have complex and controlled relief on the nanoscale – like cell dosing – dosing with a mixture of drugs that would otherwise be difficult to carry out.”

Other examples given included the creation of components for nanoscale robots and new techniques to remove pollution from the environment.

However, the professor acknowledged that at this early stage he could only guess at the eventual uses such nanomaterials would have.

“When people first invented plastic they didn’t know what to do with it, we knew electricity was around for over a thousand years before we learned how to do something useful with it,” Prof Puntes said.

“This creates different materials so they will probably have lots of different properties.”

Source:Science/BBC technology update


Cord Clamping — Not So Fast!

Delayed umbilical cord clamping results in better iron status for the infant than does immediate clamping, a BMJ study concludes.

Some 350 full-term, low-risk infants in Sweden were randomized either to immediate clamping (within 10 seconds after birth) or to delayed clamping (3 minutes or more). At age 4 months, hemoglobin levels in both groups of infants were similar, but the delayed-clamping group had a higher mean ferritin level (117 vs. 81 micrograms per liter) and a lower prevalence of iron deficiency (0.6% vs. 5.7%).

The researchers calculate that delayed cord clamping of 20 infants would prevent one case of iron deficiency.

An editorialist reminds readers that delayed clamping allows “placental transfusion,” which increases the total blood volume by almost a third. He concludes that the study “is convincing enough to encourage a change of practice.”




Obesity Management in Primary Care Shown Feasible — Though Costs Unknown

Two federally sponsored studies examining the primary care management of obesity show that it’s indeed possible, but the cost-effectiveness remains unknown. Both were presented at the American Heart Association meeting and appear in the New England Journal of Medicine.

One study randomly assigned some 400 patients to usual care (quarterly office visits), lifestyle counseling (quarterly visits plus monthly sessions with lifestyle coaches), or enhanced care (visits, coaching, plus meal replacements or weight-loss medication). By the end of the 2-year trial, mean weight loss was greater with enhanced care (4.6 kg) than with lifestyle counseling (2.9 kg) or usual care (1.7 kg).

Another study randomized a separate cohort of 400 patients across three interventions: self-directed care, remote support (through the Web), and remote support plus occasional in-person support. At 2 years, both remote-support groups showed greater mean weight loss than the self-directed care group (5.1 kg with remote and in-person support, 4.6 kg with remote support only, 0.8 kg with self-directed care).


Ocrelizumab Demonstrates Efficacy in Relapsing MS

A phase II trial demonstrated impressive results in reducing magnetic resonance imaging lesions and clinical relapses in patients with multiple sclerosis.

Ocrelizumab is an investigational humanized antibody that selectively targets CD20 B cells. For this phase II, industry-sponsored trial, researchers randomized 220 patients with relapsing-remitting multiple sclerosis (MS) to receive placebo, 600 mg of ocrelizumab, 2000 mg of ocrelizumab, or weekly interferon beta-1a for 24 weeks. After the week-24 visit, all participants received open-label ocrelizumab (at different doses) and were followed through 48 weeks. The primary endpoint was the reduction of gadolinium-enhancing (GdE) lesions on magnetic resonance imaging (MRI). Secondary endpoints included relapse rates and freedom from relapse. Ocrelizumab was administered as two infusions, spaced 2 weeks apart, repeated every 6 months.

Of those randomized, 93% remained in the trial at 24 weeks; 89% were followed up at 48 weeks. Compared with the placebo group, the 600-mg ocrelizumab group had 89% fewer GdE lesions, and the 2000-mg group had 96% fewer lesions. Compared with placebo rates, annualized relapse rates were 80% lower over the 24 weeks with 600 mg of ocrelizumab and 73% lower with 2000 mg of ocrelizumab. Both ocrelizumab groups had significant improvements over interferon for these endpoints; interferon was not significantly better than placebo, as expected in this short-duration trial and relatively small comparator arm.

Adverse events included one death in the ocrelizumab group due to status epilepticus, disseminated intravascular coagulopathy, multiorgan failure, and brain herniation. Blood cultures for this fatality were lost, and so sepsis could not be confirmed. Overall, adverse events led to withdrawal in 2% to 4% of the ocrelizumab groups; the most common adverse events were no different from those with placebo. Mild-to-moderate reactions to the first infusion occurred in 35% to 44% of ocrelizumab recipients.

Comment: This phase II study demonstrates rapid efficacy for ocrelizumab, which represents the next-generation B-cell–depleting therapy after rituximab. Although opportunistic infections were not observed in this preliminary MS trial, in trials of ocrelizumab for rheumatoid arthritis (RA), serious opportunistic infections occurred in nine patients, and two other participants died of pneumonia. Although the dosing was lower in the RA trials, participants had prior and concomitant immunosuppression with other agents.

Ongoing phase III studies aim to randomize 800 patients with relapsing-remitting MS to ocrelizumab or interferon beta-1a three times weekly and to randomize 630 primary-progressive MS patients to ocrelizumab or placebo. The trials are expected to be completed by 2015 and 2017, respectively. Ocrelizumab may offer an additional treatment option for MS, with a different mechanism of action compared with the other available and forthcoming agents.

Source: Journal Watch Neurology