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Cristiana Bernini

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Voices raise against the proposed deregulation of medicines approval process

The last position against the proposal to deregulate the approval of new medicines by the Food and Drug Administration, made by the US President Donald J. Trump during the recent speach at the Congress, has been published by the medical journal Nature.

According to the report, such a deregulation of the drug testing and approval processes will harm health everywhere, not just in the US. A move, argue the authors, that will also stifle innovation and waste patients’ and taxpayers’ money. The paperi s signed by Douglas Sipp, researcher at the RIKEN Center for Developmental Biology in Kobe, Japan, and visiting professor at Keio University School of Medicine and Global Research Institute, Tokyo, Christopher McCabe, an health economist at the University of Alberta, Edmonton, Canada, and John E. J. Rasko, head of the Department of Cell and Molecular Therapies at Royal Prince Alfred Hospital in Sydney, Australia.

Trump’s claims reinforce comments he made in January during a meeting with the pharmaceutical industry executives, where Mr. President said: “We’re going to be cutting regulations at a level that nobody’s ever seen before,” and added that up to 80 per cent of regulations could be slashed. But, according to the three authors of the report, relaxing the FDA’s regulatory system will subject patients to drugs that may be toxic.

For professor John Rasko, Trump’s argument is consistent with a history of neoliberal economic thinking that claims regulatory agencies are systematically biased towards excessive caution, and that the burden of testing a drug’s efficacy before it comes to market outweighs the benefits. “They argue that potentially harmful drugs can be identified quickly after they go on sale,” says professor Rasko, “and that the FDA runs an overly stringent system that withholds or delays safe and effective drugs from patients”.

The authors of the report also put into evidence the possible risks if reliable information on safety and efficacy would be be collected just after a drug is on sale, through observational studies or using biomarkers. Risk that can be resumed with the iconic example of thalidomide, that in the 1950s caused more than 10,000 birth defects worldwide. “Even in the past dozen years, initially promising drugs, such as torcetrapib (for reducing cholesterol and heart-disease risk) and semagacestat (for improving cognition in people with Alzheimer’s disease), were found to cause harm only after they had been tested in large, mandatory trials — effects that were not seen in the smaller trials,” say the authors. The current regulatory system is working well, say Rasko and his colleagues.

Another potential pitfall is recognised by the authors in the fact that untested drugs might result of no benefit: ‘futile drugs’, according to profossor Rasko, who adds: “We only have to consider the multibillion-dollar industries in homeopathy and other pseudo-medicines to see this”. In January 2017, the FDA released a report identifying 22 products that were initially promising but disappointed in later-stage clinical trials: 14 for lack of efficacy, one for lack of safety, and seven for both reasons.

As per the new legislation introduced in 1962, marketed drugs have to also pass through well-controlled studies to test for therapeutic benefit, and not only to the demostration of safety required by the 1938 US Food, Drug, and Cosmetic Act. The more stringent requirements resulted in the withdrawal of more than 1,000 medical products with little or no evidence of efficacy. “The free market that existed before 1962 revealed no connection between a drug’s ability to turn a profit and its clinical usefulness”, says Rasko. The same is likely to be true of any future deregulated market, the experts warn in Nature, also adding that reliable information costs money and no one will invest in producing good quality evidence if they can make the same profit on a drug or technology without it. “Rigorous clinical studies are still the best way to learn whether a drug works, and regulation is essential to ensure that these studies are conducted.”
Source: ScienceDirect
Journal Reference: Douglas Sipp, Christopher McCabe, John E. J. Rasko. Show drugs work before selling them. Nature, 2017; 543 (7644): 174 DOI: 10.1038/543174a

A collaboration for targeted immunotherapies

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The French company Transgene signed a new a collaboration agreement with Merck KGaA and Pfizer, under which it will sponsor a phase 1/2 study evaluating the potential of the therapeutic vaccine candidate TG4001 in combination with avelumab – an investigational fully human anti-PD-L1 IgG1 monoclonal antibody – for the treatment of human papilloma virus-positive head and neck squamous cell carcinoma, after failure of standard therapy.

The combination of TG4001 and avelumab aims to target two distinct steps in the immune response to target cancer cells. TG4001 is an active immunotherapeutic designed by Transgene to express the coding sequences of the E6 & E7 tumor-associated antigens of HPV-16 and the cytokine, IL-2. Avelumab is an investigational, fully human antibody specific for PD-L1 protein found on tumor cells. In 2014 Merck and Pfizer signed a strategic alliance to co-develop and co-commercialize avelumab.

New combo empagliflozin and linagliptin in type 2 diabetes

The European Commission granted a marketing authorisation valid throughout the European Union for Glyxambi on 11 November 2016. Glyxambi is a diabetes medicine that contains two active substances, empagliflozin and linagliptin. Type 2 diabetes is a disease in which the body does not make enough insulin to control the level of glucose in the blood or when the body is unable to use insulin effectively. The two active substances in Glyxambi work in different ways to lower glucose levels: empagliflozin works by blocking a protein in the kidneys called sodium-glucose co-transporter 2 (SGLT2); linagliptin is a dipeptidyl-peptidase-4 (DPP-4) inhibitor. Empagliflozin in combination with linagliptin (the same combination as in Glyxambi) was evaluated in 3 main studies involving 1,221 adults with type 2 diabetes. The main measure of effectiveness was the change after 24 weeks of treatment in the level of a substance in the blood called glycosylated haemoglobin (HbA1c), which gives an indication of how well the blood glucose is controlled. The first study included patients whose blood glucose levels were not satisfactorily controlled with metformin and linagliptin. Patients were then given either empagliflozin or placebo in addition to their existing treatment.

Results showed that when empagliflozin was added to linagliptin and metformin, HbA1c levels decreased by 0.7-0.8 percentage points after 24 weeks, compared with no reduction when placebo was added. HbA1c levels were just below 8% at the start of the study. The second study included patients whose blood glucose levels were not satisfactorily controlled with metformin and empagliflozin. Adding linagliptin to treatment with empagliflozin and metformin for 24 weeks reduced HbA1c levels from 7.8% to 7.2%, compared with a reduction from 7.9% to 7.7% when placebo was added. A further study compared a fixed dose combination of empagliflozin and linagliptin (given in addition to metformin) with treatment with metformin plus either empagliflozin or linagliptin in patients who were not sufficiently controlled with metformin alone. The HbA1c levels were around 8% before treatment. After 24 weeks treatment the fixed dose combination reduced HbA1c levels to under 6.9% whereas they were around 7.3% with empagliflozin and linagliptin used alone. The most common side effects with Glyxambi are urinary infections. The most serious side effects are ketoacidosis, pancreatitis, hypersensitivity and hypoglycemia.

Palbociclib to treat breast cancer

The European Commission granted a marketing authorisation valid throughout the European Union for Ibrance on 9 November 2016. Ibrance contains the active substance palbociclib and is a cancer medicine used to treat locally advanced or metastatic breast cancer but can only be used when the cancer cells are HR-positive and HER [human epidermal growth factor] negative. It has been approved because it has been shown to prolong the time patients live without their disease getting worse by an average of 6 to 10 months, which is considered of clear clinical value. The active substance blocks the activity of cyclin-dependent kinases (CDK) 4 and 6, which play a key role in regulating the way cells grow and divide. In some cancers, including HR-positive breast cancer, the activity of CDK 4 and 6 is increased, which helps the cancer cells to multiply uncontrollably. By blocking CDK4 and CDK6, palbociclib slows the growth of HRpositive breast cancer cells. Palbociclib has been studied in two main studies of women with HR-positive, HER2-negative breast cancer. In both studies, the main measure of effectiveness was how long patients lived without their disease getting worse (progression-free survival). The first study involved 521 women with metastatic breast cancer that had got worse after treatment with a hormonal medicine. They received either I palbociclib and fulvestrant or a placebo and fulvestrant. Women taking palbociclib and fulvestrant lived on average 11.2 months without their disease getting worse compared with 4.6 months for women taking placebo and fulvestrant. The second study involved 666 women who had been through the menopause and whose breast cancer had started to spread and who had not yet received cancer treatment. They received either palbociclib and letrozole (an aromatase inhibitor) or placebo and letrozole. Women taking palbociclib and letrozole lived on average 24.8 months without their disease getting worse compared with 14.5 months for women taking placebo and letrozole. The most common side effects with palbociclib are neutropenia, infections, leucopenia, tiredness, nausea, stomatitis, anaemia, alopecia and diarrhoea. The most common severe side effects with Ibrance are neutropenia, leucopenia, anaemia, tiredness and infections.

Omecamtiv mecarbil Phase 2 results in chronic heart failure

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The Lancet (http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32049-9/fulltext ) published recently results from a Phase 2 clinical trial evaluating omecamtiv mecarbil in patients with chronic heart failure. The COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) trial met its primary pharmacokinetic objective and showed statistically significant improvements in all pre-specified secondary measures of cardiac function in the treatment group receiving pharmacokinetic-based dose titration. It is a double-blind, randomized, placebo-controlled, multicenter, Phase 2 trial.

The trial, which evaluated 448 patients with chronic heart failure and left ventricular systolic dysfunction, showed that dose titration controlled patient exposure to omecamtiv mecarbil. Patients were randomized 1:1:1 to receive either placebo or treatment with omecamtiv mecarbil dosed as 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily, depending on plasma concentrations of omecamtiv mecarbil after two weeks of treatment. The pharmacokinetic-based dose titration strategy was designed to maintain patient exposure to omecamtiv mecarbil in the targeted plasma concentration range. Approximately 53 percent of patients in the dose titration group were escalated to a dose of 50 mg twice daily. Following 20 weeks of treatment, statistically significant improvements were observed in all pre-specified secondary endpoint measures of cardiac function in the dose titration group, compared to placebo. Systolic ejection time increased by 25.0 msec (p<0.0001), stroke volume increased by 3.6 mL (p=0.0217) and heart rate decreased by 3.0 beats per min (p=0.0070). Left ventricular end-systolic and end-diastolic dimensions decreased by 1.8 mm (p=0.0027) and 1.3 mm (p=0.0128), respectively, and were associated with statistically significant reductions in left ventricular end-systolic and end-diastolic volumes. N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased by 970 pg/mL (p=0.0069). In pre-specified exploratory analyses of the dose titration group, placebo-corrected reductions in NT-proBNP persisted four weeks after stopping omecamtiv mecarbil, decreasing further to 1,306 pg/mL (p=0.0006). The data also showed increases in fractional shortening at week 20 compared to placebo in the dose titration group.

Alirocumab ODYSSEY trial on alirocumab will continue as planned following interim analysis

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The ODYSSEY outcomes trial is designed to prospectively assess the effect of alirocumab on cardiovascular events in high-risk patients. Based on an announcement of Sanofi and Regeneron Pharmaceuticals, Inc., the ongoing Praluent (alirocumab) ODYSSEY outcomes trial will continue as planned, based on the recommendation of an independent Data Monitoring Committee (DMC) after it completed a second pre-specified interim analysis. The DMC will continue to monitor the ongoing safety and efficacy of alirocumab as planned. The Phase 3, multi-center, randomized, double-blind, placebo-controlled ODYSSEY outcomes trial involves more than 18,000 patients from 57 countries. All patients who entered the trial had experienced a heart attack or unstable angina requiring hospitalization within a year of entering the trial, and were unable to control their LDL cholesterol despite receiving maximally-tolerated statins and potentially other lipid-lowering therapies. Patients receiving maximally-tolerated statin therapy were randomized to receive either alirocumab 75 milligrams (mg) every two weeks or placebo. Patients on alirocumab had their dose increased to 150 mg every two weeks at week 8 if their LDL cholesterol remained above 50 milligrams/deciliter (mg/dL).

Alirocumab is a human monoclonal antibody that inhibits the binding of PCSK9 (proprotein convertase subtilisin/kexin type 9) to the LDL receptor and thereby increases the number of available LDL receptors on the surface of liver cells, which results in lower LDL cholesterol levels in the blood.It is the only PCSK9 inhibitor available in two dosages with two levels of efficacy (75 mg and 150 mg), allowing physicians to select the dose based on a patient’s LDL cholesterol lowering needs. Praluent is currently approved in approximately 40 countries worldwide, including the U.S., Japan, Canada, Switzerland, Mexico, Brazil and the European Union (EU). In the U.S., alirocumab is approved for use as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic CV disease, who require additional lowering of LDL cholesterol. In the E.U., alirocumab is approved for the treatment of adult patients with primary hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as an adjunct to diet: a) in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach their LDL cholesterol goals with the maximally-tolerated statin or b) alone or in combination with other lipid-lowering therapies for patients who are statin intolerant, or for whom a statin is contraindicated. The effect of alirocumab on CV morbidity and mortality has not yet been determined.

New wound care solution launched in the U.S.

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The Italian pharmaceutical company Angelini announced the commercialisation of its AOS Wound Care Solution in the United States, after clearance for sale by the FDA. The operation is the result of an exclusive partnership with the Swiss Company APR Applied Pharma Research, the owner and developer of the proprietary, patented technology Tehclo®, for the production of acidic super-oxidizing solutions. The product helps cleanse and moisten the wound environment by removing dirt, debris and foreign material by flushing across the wound and is intended for use, under the supervision of healthcare professionals, to treat acute and chronic dermal lesions (such as leg ulcers, post-surgical wounds or 1st and 2nd degree burns) and minor cuts, burns, skin irritations and superficial abrasions.

The Wound Care Solution has an acidic pH between 2.5 and 3.0 and an excellent cell viability preservation features that do not interfere with the natural physiological healing process and epthelialization. Its antimicrobial preservative effectiveness has been demonstrated by in vitro testing against P. aeruginosa, E. coli, S. aureus, S. epidermidis, S. pyogenes, E. gergoviae, C. albicans and A. niger.

Microbiome-derived immuno-oncology collaboration

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A new collaboration agreement signed between Bristol-Myers Squibb and Enterome SA will focus on immuno-oncology in order to discover and develop innovative microbiome-derived biomarkers, drug targets and bioactive molecules. According to the companies, the new products shall represent potential companion diagnostics and therapeutics for cancer. The identification of novel microbiome-derived biomarkers in an effort to improve clinical outcomes for patients treated with Bristol-Myers Squibb’s immuno-oncology portfolio is another target of the collaboration. Enterome’s proprietary metagenomic technology platform and BMS’s expertise in the discovery and development of novel immunotherapies will act synergistic to achieve the final goal of the project.

Under the terms of the agreement, BMS will be granted exclusive rights to intellectual property and therapies generated during the collaboration. Enterome will receive an upfront payment of $ 15 million for access to its technology plus R&D funding. The company is also eligible to receive preclinical and clinical milestone payments for each licensed therapeutic candidate plus royalties on net sales. According to the companies, additional milestone payments are possible in relation to new diagnostic products discovered and developed during the collaboration.

First cross-company deal for Cancer Research UK

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A new trial on 50-60 patients with a new combination of immunotherapy drugs in mesothelioma, non small cell lung and pancreatic cancers will run through the Experimental Cancer Medicine Centre (ECMC) Combinations Alliance network at centres in Edinburgh-Dundee, Southampton, Glasgow, Leicester and Belfast. The trial is the first cross-company deal announced by Cancer Research UK as part of its ECMC initiative and is organised in collaboration with MSD and Verastem.

The phase 1b/2a trial will investigate whether the focal adhesion kinase (FAK) inhibitor drug VS-6063 (defactinib) from Verastem can boost the effectiveness of the PD-1 immunotherapy drug pembrolizumab from MSD. Scientists at the Edinburgh Cancer Research UK Centre showed that inhibiting FAK can release the cancer immune response. Defactinib may be able to take down a barrier of immune cells which are tricked into protecting the cancer cells, while pembrolizumab can activate cancer-killing immune cells to attack those exposed cancer cells.

New investment fund for early stage opportunities

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The new Helsinn Investment Fund S.A. is an initiative of Swiss-bases pharmaceutical company Helsinn Group which aims to fund early-stage investment opportunities in areas of high unmet patient need. The initial investment commitment of the fund is of three years, followed by up to five years via follow-on rounds, for a total commitment of $ 50 million. The Fund aims to help companies working across a range of areas in healthcare to develop early-stage technologies into commercial solutions that will impact health-related quality of life of patients. Through the Fund, Helsinn will invest directly in 10 to 15 companies, providing scientific and clinical strategy guidance, operational and board support alongside on going investment. The initiative comes in the Helsinn Group’s 40th year of operations, and applies its fundamental core values of quality, integrity and respect.

The target companies wishing to attract investments from the Fund should have achieved at least preclinical proof of concept, ideally with clinical data.

The Board of Directors of the Helsinn Investment Fund includes Riccardo Braglia, Helsinn Group vice chairman and chief executive officer, Luigi Caletti, financial advisor at Helsinn, Dr Francesco Granata, consultant, senior advisor at Warburg Pincus International LLC and chairman of Circassia Plc, and Betty Prudhomme, senior vice president, Tax Department, SGG Luxembourg.

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