Wednesday, 2 September 2015

ResearchSpeak: treating end-organ failure requires combination therapies

Will Novartis transfer what they have learnt in cardiac failure to progressive MS? #ResearchSpeak #MSBlog

When will we realise progressive MS requires a combination therapy approach?  #ResearchSpeak #MSBlog

"In the moneyed world of big Pharma the biggest news this year has the been the licensing of a new combination therapy to treat cardiac failure. Novartis the company behind the development of this combination therapy are ecstatic. Their drug, Entresto, is a first in class medicine, or more importantly a combination therapy, (an ARNI, Angiotensin Receptor Neprilysin Inhibitor) that reduces the strain on the failing heart. In summary, compared to the old standard drug enalapril, it: (1) reduced the risk of death from cardiovascular causes by 20%, (2) heart failure hospitalisations by 21% and the risk of all-cause mortality by 16%. Believe me when I say these results are the biggest development in the treatment of cardiac failure since the 1980's. Why did it take so long to get here? Simple, it required research, new biology, a change in the treatment paradigm, a bold group of investigators, risk and deep pockets."

"What has cardiac failure got to do with MS? A lot. Cardiac failure is the final result of end-organ damage to the heart. It is the equivalent of dementia or the wheelchair in MS. What this study is telling us that to make a big difference to end-organ pathology you need understand the mechanisms underlying the pathology and to target them with different therapeutic strategies. This is almost certainly why we have failed to make a difference to clinically-apparent progressive MS. Up until now we have simply tried one approach; an anti-inflammatory approach. It hasn't worked. What we need is to learn is how to combine therapies that target multiple mechanisms. We need to build our pyramid. If there is one company who has the nous to do so it is Novartis; let's hope their insights from cardiology will diffuse into the field of MS. We certainly owe it to the thousands of desperate people who have progressive MS."

"In summary, to develop an effective treatment for progressive MS it will take research, new biology, a change in the treatment paradigm, a bold group of investigators, willing MSers, risk and deep pockets."

Packer et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015 Jan 6;131(1):54-61.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients.

METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril.

CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition.
CoI: multiple


  1. "In summary, to develop an effective treatment for progressive MS it will take research, new biology, a change in the treatment paradigm, a bold group of investigators, willing MSers, risk and deep pockets."
    What have all the research teams been doing over the last ten years! Same old position - more research needed, more money needed.... In ten years' time we will see the same again. Gladly swap my MS for heart disease or cancer. At least I'd have a chance of getting my health back. Neurology = worst diseases and worst treatments. I hold my breath for some exciting news from Ectrims 2015. My predictions - ocrellizumab results are impressive, but not quite as good as expected, charcot project fails to show any benefit, mesenchymal stem cell trials hint at benefit, but longer trials needed. I don't expect to see any other breakthrough announcements.

    1. My prediction is ocrellizumab data will be impressive and every bit as good as expected so if you cant see that as breakthrough news then there there is not pleasing you.

      Mesenchymal stem cells in animals studies only showed marginal benefit with a small immunosuppressive effect and so why should you expect anything startling

  2. Why can't practicing neurologists prescribe more than one treatment for MS? Is this the question of cost? This approach will be equivalent to developing and trying combination therapies.

  3. I think a change in treatment paradigm is the most important. MS is not only immunological illness. When immunological systems stop his fight begin the worst face. I choose treat my RRMS with neuroimmunological approach and Vit D for balancing th1/th2 . Neuroprotectants and antioxidants for my future SPMS. I don´t want DMT immunosuppressives because in the future I maybe in wheelchairs with opportunistic infection.


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.