Soluble Guanylate Cyclase for use in treatment of CFS with B-cell depletion

[deleder2k]

New patent application from Øystein Fluge and Olav Mella:

ACTIVATORS OR STIMULATORS OF SOLUBLE GUANYLATE CYCLASE

FOR USE IN TREATING CHRONIC FATIGUE SYNDROME

Some key points:

ACTIVATORS OR STIMULATORS OF SOLUBLE GUANYLATE CYCLASE

FOR USE IN TREATING CHRONIC FATIGUE SYNDROME

The present invention relates in a first aspect to a method for the treatment of chronic fatigue syndrome (CFS) comprising administering to a patient in need thereof a therapeutically effective amount of a stimulator of the soluble guanylate cyclase and/or a therapeutically effective amount of an activator of the soluble guanylate cyclase. In a further aspect, the present invention relates to a combination of the stimulator and/or activator of the soluble guanylate cyclase with a B-cell depleting agent in the treatment of chronic fatigue syndrome. In addition, a combination of stimulator and/or activator of the soluble guanylate cyclase and B-Cell depleting agent are described. Said combination may be provided in form of a kit comprising suitably effective dosages of said compounds.

The guanylate cyclase, also known as guanylyl cyclase or guanyl cyclase, EC 4.6.1 .2, (GC) is a lyase enzyme catalysing deformation of guanosine 3', 5'- monophosphate (cGMP) from guanosine triphosphate (GTP) and is found in tissues throughout the animal kingdom. Soluble GC (sGC) is the receptor for nitric oxide (NO) in vascular smooth muscle. In the cardiovascular system, NO is en- dogenously generated by endothelial NO synthase. Involvement of NO and sGC is described in stress and it appears that the NO-sGC-cGMP pathway is relevant for the control of a number of physiologic processes, including neuronal transmission, host defense, cell growth and proliferation as well as vascular and platelet homeostasis.

Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation and thrombosis. Hence, sGC represents a target for drugs in the treatment of various diseases. In general, two classes of compounds have been developed, that can directly activate sGC in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. That is, heme-dependent stimulators and heme- independent activators of sGC have been described. For example, potent stimulators are described in a series of patent applications, e.g. WO 03/097063, WO 02/42302, WO 02/42299, WO 03/095451 and WO 03/004503.

However, as indicated above, using B-cell depletion by the monoclonal an- ti-CD20 antibody Rituximab in CFs, there is a significant delay from start of the treatment and the beginning of the symptoms relief. Also, the clinical studies performed with Rituximab, approximately 2/3 of CFS patients have a clinical response. This is not only true for treatment with Rituximab, but can also be seen with treatment of methotrexate, a small molecule known as an active agent for B- cell depletion useful in the treatment of various kinds of diseases.

Thus, there is an ongoing need to provide additional compounds useful in the treatment of chronic fatigue syndrome. In particular, there is an ongoing need for providing compounds which act fast in the patients without the lag period described for the B-cell depleting agent. In addition, there is a continuous demand for compounds which may also be effective in patients not susceptible to B-cell depleting agent treatment.

CFS patients have a marked endothelial dysfunction assessed by Flow- Mediated Dilation (FMD), a test that (under standardized conditions) largely reflect Nitric Oxide (NO) synthesis in endothelial cells after shear stress. A markedly reduced FMD, transient clinical responses after long-acting nitrates (like isosorbide mononitrate) and the clinical picture of CFS, are the basis for a hypothesis according to the present invention in which a main mechanism for CFS symptom maintenance is a relative lack of endothelial-cell derived Nitric Oxide (NO) availability. This results in reduced NO diffusion from endothelial cells to surrounding cells such as smooth muscle cells in blood vessel walls, and with a resulting inadequate regulation of blood flow to meet the metabolic demands of tissues. Also a relative lack of endothelial-cell derived NO may result in cognitive disturbances, sleep problems, a low anaerobic threshold, and lactate accumulation in tissues after modest exertion, a low NK cell function, all reported to be associated with CFS.

Description of the present invention

In a first aspect, the present invention relates to a method for the treatment of chronic fatigue syndrome (CFS) comprising administering to a patient in need thereof a therapeutically effective amount of a stimulator of the soluble guanylate cyclase (sGC) and/or a therapeutically effective amount of an activator of the soluble guanylate cyclase.

That is, the present inventors recognized that administration of an activator of sGC and/or a stimulator of sGC, e.g. Cinaciguat or Riociguat, relieve the symptoms of CFS and, thus, may be useful in the treatment of CFS, accordingly.

In particular, the present inventors recognized that an immediate relief, e.g. within a week, from start of administration of said activator or stimulator of sGC, e.g. by carefully increasing the dose, can be observed. In contrast to medication such as Rituximab for a treatment of CFS, which is characterized by a remarkable lag time before clinical responses, as described, e.g. WO 2009/083602. Hence, the administration of the stimulator and activator of sGC surprisingly allow a treatment of CFS patients for early relief of symptoms without a long delay as described for e.g. a B-Cell depleting agent, like Rituximab. It is has been recognized by the inventors that the sGC is involved in therapy of CFS patients.

Source: http://worldwide.espacenet.com/publ...T=D&ND=3&date=20150507&DB=EPODOC&locale=en_EP


Looks interesting. And it seems that this is more potent than isosorbide mononitrate (Imdur).

A major drawback is the price of Riociguat. In Norway a pack of 28 costs $4000. The drug was recently introduced. Trade name is Adempas.

 

[Bob]

Thank-you deleder.

My brain's not working at the moment, and the above text looks rather complicated, with lots of words I've never seen before. Is anyone able to give a brief explanation of what it means?

 

[deleder2k]

Here is the patent filing for the use of nitric oxide in CFS thread: http://forums.phoenixrising.me/inde...ith-or-without-b-cell-depletion-in-cfs.36592/

This drug looks even more efficient in restoring endothelial function.


@Bob, I don't understand much of this. Hopefully someone can explain how the drug works for normal human beings . Take a look at the other thread in the meantime.

This is their hypothesis (at least it was like this a few months ago):

 

[A.B.]

@Bob, I don't understand much of this. Hopefully someone can explain how the drug works for normal human beings . Take a look at the other thread in the meantime.

I can't say I fully understand it either but Wikipedia says that soluble guanylate cyclase (sGC in short) is an enzyme in cells that is activated by NO and involved in vasodilation.

Taking a stimulator of sGC is just another way to achieve vasodilation, and apparently one with fewer side effects.

A shame the drug is so expensive. Isosorbide mononitrate gives me a nasty headache.

Edit: I think I finally got it.

 

[Marky90]

I can't say I fully understand it either but Wikipedia says that soluble guanylate cyclase (sGC in short) is an enzyme in cells that is activated by NO and involved in vasodilation.

Taking a stimulator of sGC is just another way to achieve vasodilation, and apparently one with fewer side effects.

A shame the drug is so expensive. Isosorbide mononitrate gives me a nasty headache.

Edit: I think I finally got it.

Yeah i felt quite lousy on Imdur as well... Only tried one day though. I rather wait for this!

 

[leokitten]

This is just so compelling thank you @deleder2k. It almost shocks me that before Fluge and Mella no one was looking into this other than the small paper done by Newton et al. (Dundee)

The reduced endothelial NO vascular dysfunction theory really does explain most if not all the symptoms of ME/CFS, including low NK function which some people might not know.

Now I keep asking myself what is going on that is causing us to not produce enough endothelial NO? And how is this possibly linked to some b-cell mediated process? Very interesting...

 

[Jon_Tradicionali]

Yes this patent was filed recently after Fluge/Mella noticed 'instant remission' as they're now being termed, in some of his patients.
This came after they noticed NO donors were working in some patients but not all.

As per cGMP, it is formed from NO stimulation of GC-C receptor. Its thought provoking (or not ) that it is found predominantly in the intestine.

A proven way (in animal testing) to restore the glutamate-NitricOxide-cGMP pathway:

• a)
  phosphodiesterase 5 inhibitors (sildenafil, zaprinast), that increase cGMP levels by reducing its degradation
  
  
• b)
  extracellular cGMP
  
  
• c)
  antagonists of type A GABA receptors (bicuculline)
  
  
• d)
  neurosteroids that modulate GABAergic tone (pregnenolone sulfate)
  
  
• e)
  inhibitors of cyclooxygenase (ibuprofen) which reduce neuroinflammation
  
  
• f)
  inhibitors of MAP- kinase p38 (SB239063), that reduce microglial activation and neuroinflammation

http://www.newhorizonsintranslationalmedicine.com/article/S2307-5023(14)00047-2/abstract

SGC stimulator is second-line choice. sGC activator Cinaciguat is what we would require as Fluge/Mella also themselves acknowledge.
However the activator is still in experimental stages.

 

[alex3619]

Isosorbide mononitrate gives me a nasty headache.

In my case the headache disappeared after about a week. This is a common finding on isosorbide mononitrate.

Phosphodiesterase inhibitors include resveratrol, though this targets phosphodiesterase 4 primarily. I will not willingly give this up, its effects are too useful.

Restoration of the NO pathways may be specific to our problems though. Treatments for other causes might not work. However these create a list of things that can be tried and formally tested.

 

[leokitten]

From what I read the already available riociguat is actually better than cinaciguat, because riociguat can stimulate sGC independently of NO, from Wikipedia:

In contrast to NO- and haem-independent sGC activators like cinaciguat, the sGC stimulator riociguat directly stimulates sGC activity independent of NO [4] and also acts in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects.[5][6]

 

[Navid]

Hi:

Is this a drug that a US Dr. if willing can prescribe to a ME/CFIDS patient off label. Are there tests that would show whether or not this would be an appropriate drug for one to take. Finally, how is this drug delivered (IV, SUBq....etc). Sorry for stupid questions. I am scientifically ignorant....but bedbound w/ME. I have tried almost every treatment out there and nothing has helped.....desperate like so many others out there. Thanks for any and all help. Is there a US ME Doc who is up on this work of Fluge and Mella and the results they have been having with drug.

Thanks : )

 

[duncan]

God. I feel embarrassed posting this, but it may have relevance in some of these endothelial NO ME/CFS cases:

Borrelia Burgdorferi have been demonstrated in vitro to invade endothelial cells intracellularly. I don't know the significance of that, or whether enteroviruses do the same, or some other pathogen. I think it's clear Fluge and Mella don't think Bb is pertinent.

I realize, too, there are significant reasons why Bb cannot equate to ME/CFS. For instance, the heavy female portion of the ME/CFS community runs counter to Bb demographics.

I point out these Lyme data not to undermine a thread or be contentious. I post them because I have questions about how they play into a development, and because others besides me may find the data interesting.

I also realize how sometimes I can sound like a broken record, and for that, my apologies in advance.

 

[leokitten]

Both CMV and HHV-6 invade vascular endothelial cells as well but...

We have to not confuse things and remember here that Fluge and Mella are seeing significant symptom remission from Rituximab alone for 2/3rds of patients and if this turns out to be real then it goes against the chronic infection theory of ME/CFS for this subset.

The reason they are also experimenting with these other other drugs is because they have been seeing vascular dysfunction in patients and believe this is driving symptoms so are trying therapies that can give more immediate relief in conjunction with rituximab therapy.

 

[Bob]

That is, the present inventors recognized that administration of an activator of sGC and/or a stimulator of sGC, e.g. Cinaciguat or Riociguat, relieve the symptoms of CFS and, thus, may be useful in the treatment of CFS, accordingly.

In particular, the present inventors recognized that an immediate relief, e.g. within a week, from start of administration of said activator or stimulator of sGC, e.g. by carefully increasing the dose, can be observed.

I'm not so tired this morning, and managed to read it all. The above quote sums it up in a nutshell. So it looks like Fluge and Mella have now found a fast acting drug (Cinaciguat and/or Riociguat) for improving a range of symptoms in ME patients. The 'example' at the end of deleder's opening post outlines the fast positive response that they've seen in a (mild to moderately affected) CCC ME patient (of ten years) after six days of administering Riociguat. The patient had not previously been prescribed rituximab. Improvements were seen in: energy, fatigue, brain fog, concentration, sore throat, and hyper-sensitivity to sound and light. The improvements were thought to be significant and beyond the range of normal fluctuation.

 

[Jon_Tradicionali]

From what I read the already available riociguat is actually better than cinaciguat, because riociguat can stimulate sGC independently of NO, from Wikipedia:

Riociguat and all other sGC stimulating compounds are inferior to Cinaciguat and sGC activators.

If that's quoted from Wiki then it's incorrect as stimulators are NO independent BUT they are haem dependant. This is contrast to activators which are both NO and haem independent which makes them much superior in activating sGC receptors burdened by oxidative stress (which applies to us).

"The second group comprises the sGC activators (including BAY 58–2667 and HMR-1766), which have been found to require neither NO nor haem, and demonstrate even more pronounced action on the oxidized form of sGC."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225477/

 

[Asa]

"A major drawback is the price of Riociguat. In Norway a pack of 28 costs $4000. The drug was recently introduced. Trade name is Adempas."

Is Riociguat something an ME/CFS patient would take for life?

 

[deleder2k]

I don't think so. I think they write that it can be used until b-cell depletion (Rituximab, MTX) gives effect after weeks or months.

This is just a proof of concept. As far as I am concerned they haven't done any large studies on this. If they have only tested this on one patient we have a long way to go. Hopefully they will do a phase 2 trial soon with either isosorbide mononitrate or this.

 

[cigana]

I do not know how similar isosorbide mononitrate is to isosorbide dinitrate in its mechanism of action, but I thought it was worth pointing out other PWMC's have had instant remission from the dinitrate (as discussed here).

 

[leokitten]

Does anybody know with what % of PWME are Fluge/Mella finding endothelial/vascular dysfunction? And secondly for this group what % have POTS/OI and what % are like me who got sudden higher blood pressure and blood volume and no POTS/OI?

Still trying to understand how a person could have vascular/endothelial dysfunction and POTS/OI, because in vascular/endothelial function there is
reduced NO like they've seen and this results in arteries and capillaries that do not expand, higher blood pressure, and sympathetic nervous activation resulting in further constriction of arteries and higher pressure. With POTS/OI your blood pressure gets very low.

 

[deleder2k]

Good evening, @leokitten

I dug this up:

This is from their application to the Research Council of Norway. You can find it here: http://forums.phoenixrising.me/inde...tion-to-the-research-council-of-norway.31258/

I don't know whether this their own data or if this is from the Newcastle FMD study.

 

[Hutan]

@leokitten, yes, I'm confused too. I tried to explain this endothelial dysfunction theory to my husband and got tangled up at the part where the vessel walls aren't expanding. My blood pressure has always been low and my body is flexible - so I had the idea that overly-flexible arterial walls might have been part of my POTS problem. I ended up muttering to my husband 'umm, I think I need to read about this theory a bit more'.

I have self-diagnosed POTS (reliably >30 bpm increase in heart rate from supine to standing, and dizziness). If I stand still, the heart rate and blood pressure increase. I think this started about six months after the ME onset. I'm waiting to see the specialist for confirmation.

But actually, I am finding now that I am monitoring things more closely, I am having episodes of high blood pressure after exertion. As getting to my doctor involves exertion, my doctor is beginning to think I have hypertension. Dysregulation seems to be a word that applies to much about ME.