New trials started for Ivacaftor for those with mutations other than G551D or DF508
Nov 11th, 2012 by Tom

Things have finally cleared up on the path forward for those that have type IV (sans G551D) or V mutations in regards toIvacaftor. Four studies have started: three for phase III trial for type IV mutations and another for select type V mutations.
For those with a mutation in one of these 2 classes, it has been a frustrating couple of years as there has been very little news about how Vertex and CFFT would move forward with VX-770 and these defects. From the limited in-vitro studies, it has always been clear that Ivacaftor could have the potential to make a clinical difference if it could only be tested. With the very high price, off-labeling is unlikely for those impacted with waiting for clinical trials so waiting for any trial news is all those impacted by these defects.

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How things have changed.  Not too long ago, it was not clear how Vertex was planning on moving forward.  There were discussions on doing n-of-1 trials but that seems to be a distant memory (how likely was it to get the FDA to approve a non-standard approach?).  Now several trials are started and it looks like now all we have to do is wait and keep our fingers crossed that they all meet their end point measurements.  The interesting note here is that the trail for residual CFTR function is only a phase II trial meaning that we are many years away, best case, to have the drug approved for use with their defect.  It’s hard to understand why a phase II trial is needed considering a phase II was already completed for those with normal CFTR function and those with no function.  Are they are expecting different results or is this the FDA at their best once again?  The other possibility is they want to see if there is a significant change in lung function.  One could speculate that the baseline of FEV1 is already high and because these defects are not gating, the amount that Ivacaftor can help will not be nearly as significant.  It may require many more subtle measurements to know if Ivacaftor should be approved for this class of defects.  This is where it would be really nice if the CFF organization could be more open about the process.

Below is a list of the clinical trials with their primary completion dates:

Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis and Residual CFTR Function completes September 2013

Study of Ivacaftor in Subjects With Cystic Fibrosis Who Have the R117H-CFTR Mutation (KONDUCT) complets July 2013

Rollover for the above trials: Rollover Study of Ivacaftor in Subjects With Cystic Fibrosis and a Non G551D CFTR Mutation (KONTINUE) completes July 2016


Vertex releases in vitro data on gating mutations as well as residual functioning mutations with Kalydeco
May 23rd, 2012 by Tom

This site has a mix of items that are about the future (usually life changing if they make it to the CF public) and small items that may only have a small impact.  This post is about one of those far off treatments, however one that has a real short at making it to a decent portion of the CF community.

When I saw A Genetic Approach to the Treatment of Cystic Fibrosis by Peter Mueller, I was blown away.  We’re finally getting some in vitro data showing how well Kalydeco works against many other cystic fibrosis defects.

Kalydeco rescues residual CFTR defects

The PDF should be reviewed directly as there is so much meaningful information here.

After seeing the in-vitro data, the next logical question is what is the roadmap for making Kalydeco available to patients where in vitro results look promising?

The PDF touches on this as well at a very high-level.  Some of the defects that may benefit from Kalydeco are so rare, an clinical trial could never be performed under the current standards.  Vertex touches on this with an n-of-1 approach where trials could be as small as one individual.  There is a great slide in the PDF where a patient starting the trial would receive a trial kit from Amazon, load an app on their smart phone and start the trial.  It looks like this is just in the idea stage so far and getting this through the FDA seems daunting to say the least.  However, it does give hope for all those that fall into one of the 2 categories (gating defects and residual CFTR activity) where Kalydeco may be beneficial.

Again, please see the pdf for all the great information within.

Can Probiotics Make a Difference?
Jun 29th, 2011 by Tom

There have been many studies in the last decade on different strains of bacteria and how they can be of clinical value in humans.  While some have not shown efficacy, many others have.

The average human has at least 1,000 different types of bacteria in their body making up 100 trillion CFUs (Colony Forming Units), it’s hard to imagine that taking a single strain of 1 probiotic in quantities of billions could make a difference.  However, there is some evidence that it is possible.

Pulling together a number of different studies of probiotics in the area of infection, inflammation, allergies and the liver, there is some encouraging news that indicate taking probiotics may reduce the severity of a number of conditions that can affect those with CF.

This post highlights just a few modern studies on the subject and many more can be reviewed at PubMed through a simple search.

Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study

“RESULTS:The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0.002). PFT’s have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed.

CONCLUSION:Probiotics reduce pulmonary exacerbations rate in patients with CF. Probiotics may have a preventive potential for pulmonary deterioration in CF patients.”

STRAIN: Lactobacillus Rhamnosus LGG

Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis: a pilot study
“RESULTS:: Patients treated with LGG showed a reduction of pulmonary exacerbations (Median 1 vs. 2 , range 4 vs. 4, median difference 1, CI 95% 0.5-1.5; p=0.0035) and of hospital admissions (Median 0 vs. 1, range 3 vs. 2, median difference 1, CI 95% 1.0-1.5; p=0.001) compared to patients treated with ORS. LGG resulted in a greater increase in FEV1 (3.6% +/- 5.2 vs. 0.9% +/- 5; p=0.02) and body weight (1.5 kg +/- 1.8 vs. 0.7 kg +/- 1.8; p=0.02).
CONCLUSIONS:: LGG reduces pulmonary exacerbations and hospital admissions in patients with CF. These suggest that probiotics may delay respiratory impairment and that a relationship exists between intestinal and pulmonary inflammation.”

STRAIN: Lactobacillus Rhamnosus LGG

Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and ß-hemolytic streptococci)
“RESULTS: We found a significant reduction (19%; P < 0.001) in the occurrence of nasal PPB in the group who consumed the probiotic drink but not in the group who consumed yogurt. The effect was mainly on gram-positive bacteria, which decreased significantly (P < 0.05).
STRAINS: Lactobacillus GG (ATCC 53103), Bifidobacterium sp B420, Lactobacillus acidophilus 145, and Streptococcus thermophilus”

Use of a fermented dairy probiotic drink containing Lactobacillus casei (DN-114 001) to decrease the rate of illness in kids: the DRINK study. A patient-oriented, double-blind, cluster-randomized, placebo-controlled, clinical trial

“RESULTS: The rate of change of behavior because of illness was similar among active and control groups. However, the incidence rate for CIDs in the active group (0.0782) is 19% lower than that of the control group (0.0986) (incidence rate ratio=0.81, 95% CI: 0.65, 099) P=0.046.

CONCLUSIONS: Daily intake of a fermented dairy drink containing the probiotic strain L. casei DN-114 001 showed some promise in reducing overall incidence of illness, but was primarily driven by gastrointestinal infections and there were no differences in change of behavior.

STRAINS: Lactobacillus casei DN-114 001”

Probiotics Help Reduce Upper Respiratory Tract Infections in Day Care Children
“CONCLUSIONS: considering the significant decrease in the number of upper respiratory tract infections in children treated with LGG and knowing that the number needing treatment (NNT) was only five, we can recommend treatment with LGG as a valid measure for the prevention of upper respiratory tract infections in children who attend day care centres

STRAIN: Lactobacillus Rhamnosus LGG”

Bifidobacterium longum supplementation improved high-fat-fed-induced metabolic syndrome and promoted intestinal Reg I gene expression.
“Increasing Bifidobacterium in the gut improved HF-fed-induced metabolic syndrome by reducing metabolic endotoxin concentrations and intestinal inflammation, as well as upgrading the expression of intestinal Reg I as a regulator of growth factor
STRAIN: Bifidobacterium longum”

Effect of probiotic yogurt containing Lactobacillus acidophilus and Bifidobacterium lactis on lipid profile in individuals with type 2 diabetes mellitus
“CONCLUSIONS: The total cholesterol:HDL-C ratio and LDL-C:HDL-C ratio as atherogenic indices significantly decreased in the probiotic group compared with the control group. Probiotic yogurt improved total cholesterol and LDL-C concentrations in type 2 diabetic people and may contribute to the improvement of cardiovascular disease risk factors
STRAIN: Bifidobacterium lactis”

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.
“CONCLUSIONS: these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions
STRAINS: VSL#3 (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, Streptococcus thermophilus)”

Oral administration of Bifidobacterium bifidum G9-1 suppresses total and antigen specific immunoglobulin E production in mice
“CONCLUSIONS:  We conclude that oral administration of BBG9-1 selectively and powerfully suppresses total and antigen specific IgE production in mice. It is suggested that BBG9-1 is useful for the prophylactic treatment in IgE-dependent allergic diseases
STRAINS: Bifidobacterium bifidum G9-1 (BBG9-1)”

Improvement of intestinal function in cystic fibrosis patients using probiotics
“CONCLUSIONS:  Probiotics improved not only clinical but also biochemical intestinal function in cystic fibrosis patients. These could be given as a regular treatment in this type of patients and in those with bacterial overgrowth
STRAIN: Lactobacillus Rhamnosus LGG”

This is just a very small subset of positive studies on the subject. The studies thus far have been relatively small and many done with mouse models making it hard to draw firm conclusions but the trend is clearly going in the right direction.

One of the most promising probiotics in these studiesis the Lactobacillus Rhamnosus LGG strain.  It has been studied in several CF based studies and has shown efficacy in every trial I reviewed.
There also seems to be some value in mixed probiotics.  There is a study starting up with CF patients using a commercially available probiotic containing 12 strains totaling 25 billion CFUs taken twice daily: Effect of Probiotics on Sputum Inflammation and Pulmonary Infections in Patients With Cystic Fibrosis
It will be interesting to see the results from this study but based on all the other studies, trying a high potency, multi-strain probiotic from a reputable company may provide benefits based on everything in the literature.

With the evidence available, this is one therapy that you should consider talking to your doctor about.

Vertex to apply for approval of CF drug in 2011 | Reuters
Jan 13th, 2011 by Tom

Vertex has high hopes for VX-770.  In advance of publishing phase III trial results, Vertex is announcing that it will submit for NDA later this year.  This is very exciting news!

UPDATE 1-Vertex to apply for approval of CF drug in 2011 | Reuters.

There has been a lot of talk about Vertex here and elsewhere and for good reason.  Being the first drug to directly target the root cause, it’s the first hope of dramatically changing the lives of those effected by Cystic Fibrosis.

The trials have focused on G551D (where it will be the most effective) and DF508 (where it should be effective when combined with VX-809) but there are many others out there that may benefit from this compound. The in vitro studies have shown VX-770 to be effective on numerous defects.

Below is a simple graph of VX-770 and it’s impact on opening up the channel for ion efflux for the common defects as well as healthy CFTR.  For these examples, if the protein can get to the cell surface, then VX-770 will have a powerful impact:

VX-770 potentiated the gating activity of CFTR

Source: Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Since this drug is being marketed for the G551D defect, it will be interesting to see how/if it is applied to other defects.  I’ve been told that Vertex will work closely with physicians in cases where it is thought to have an impact for other, defects that are so rare trials could not be done for them.  However, this may be some time after the initial availability of the compound.  We may have to just wait and see.

Staying Positive in the New Year
Jan 6th, 2011 by Tom

With 2 important CF clinical trials not showing much success in the last year (Denufosol and KaloBios KB001), it would be easy to be more than a little disappointed.  However, there has been some good news as well.  Some even around KB001.  If you remember, the phase I/II study showed limited efficacy but not enough to make getting an IV worthwhile.  They are now reformulating KB001 into a formula that can be self given as a shot every 2 weeks – a few more details can be found here –  Hopefully this will be ready for trials by the end of this year.

In other good news, Bronchitol has been successful in all of its required trials and Pharmaxis is preparing to submit for an NDA.  Although that will take some time, it should eventually be approved.

Although VX-770 only gets press for the G551D defect (where it has the most efficacy), it may also be beneficial to any missense defect where a reasonable amount of the CFTR protein makes it to the cell surface.

On the antibiotic front, there are a several steps forward.  From a convenience perspective, the new Tobi Podhaler will make treatment time dramatically shorter.  There is also an inhaled (versus nebulized) Ciprofloaxin antibiotic in the works that will be a much needed alternative to Tobi and offer even quicker treatment times.

Although certainly not new, Azithromycin has also been studied in many small and a few large trials.  While everyone is always hopeful of finding a disease modifying solution, Azithromycin may already fit that bill to some degree.

This drug is believed to stimulate the sister protein of CFTR, the multi-drug resistant protein.  MRP shares a similar structure of CFTR and may be a pathway for chloride to escape the cell.  In addition to chloride, it also allows glutathione to pass out of the cell.  When stimulated with Azithromycin, a small in vivo study showed 6 out of 10 CF patients had statistically significant trending of nasal potential difference (another test to determine if someone has CF).

Glutathione status is important as it may be the reason for the anti-inflammatory benefits from Azitthrmycin.

The in vivo studies to date have shown the most benefit for those with Pseudomonas but there is still benefit for those without it as well.  Taken at low doses prophylactically, it is relatively safe and has shown to be very effective for some.

other references:

  1. Medscape Today: Therapy With Macrolides in Patients With Cystic Fibrosis: Mechanisms of Action
  2. Sharktank: MRP and CFTR
  3. Effects of Azithromycin on Glutathione S-Transferases in Cystic Fibrosis Airway Cells
  4. Azithromycin increases chloride efflux from cystic fibrosis airway epithelial cells
  5. Restoration of chloride efflux by azithromycin in CF human airway epithelial cells
The 24th Annual NA CF Conference news round-up
Oct 21st, 2010 by Tom

I always look forward to seeing all the press releases during the week of this conference.  Most of the news has been regarding the more mature pipeline drugs that are getting close completing the grueling trial requirements but there was news on other, newer entries into clinical trials as well.

All the news has been very positive but nothing earth shattering.  On the antibiotic front, ARIKACE showed very promising results agaist Pseudomonas at the highest dose in its phase II trial.  The exciting part about this eFlow inhaled drug is the once daily dosing and a 56 day off period (although it’s not clear if they wouldn’t recommend a 28 day off period if this eventually gets FDA approval).  Either way, an 8% lung function improvement is very encouraging.

The next antibiotic news came from phase III trial results of Cayston (already FDA approved).  In a head-to-head comparison against Tobramycin, Cayston provided superior results (2.05% FEV1 improvement versus 0.66% FEV1 improvement over six a month period).

Perhaps even more exciting are the results relating to the two large phase III trials with Pharmaxis’ Bronchitol.  The results showed a significant boost in FEV1 scores of 7.3% and the drug may actually slow down the progression of the lung disease.  Exacerbations were also down 25%; considering that the group being studied had a low level of exacerbations overall, that is significant.  The one big advantage Bronchitol has is it’s dry powder forumaltion so it’s inhaled relatively quickly as opposed to being nebulized.  This also makes it much more portable.  Lastly, it’s only needed once day as opposed to 2 times a day as most other treatments for CF.  Anything that can cut down on the daily burden of treatments is always welcome.  With the 2 required phase III trials complete, Pharmaxis could be available to patients sometime in ealry 2012.  It should be available in Europe much sooner than that.

One other compound close to completing phase III trials is Denufosol (the final trial required to submit to the FDA will complete late this year).  Although this one requires 3 nebulations a day through the eFlow, I believe it’s worth it.  Users shouldn’t expect to get close to a double-digit improvent in lung function scores like they can with Bronchitol, however, this one looks to be disease modifying by drastically slowing down lung damage.  In other words, 1 week after treatment, FEV1 scores would be essentially unchanged, but after six months, they will show an improvement over what they would have seen otherwise and it looks like the trend continues out past at least a year.  Interestingly, the effects seem to be more effective for this with minimal lung damage so getting this drug on the market as soon as possible will benefit a lot of people.

Last on the list but perhaps the most important for the majority of CF patients is Vertex’s new phase II trial of VX 770 combined with VX 809.  This is a trial a lot of people have been waiting for. VX 770 has shown to be a great stimulator for the CFTR protein that does make it to the cell surface (called a potentiator), however, for the majority of CF patients, most protein is degraded well before it gets to the surface.  VX 809 has shown to decrease sweat test scores by 8% in those with double DF508 defects.  It does this by rescuing the protein from the garbage collector mechanism in cells (this type of correction is a corrector).  However, once the rescued protein gets to the cell surface, it may not be operating optimally and that is where VX 770 may help.  Speculation has it that sweat test scores could be reduced 20 to 25% for those with double DF508 defects and taking both compounds.  For those with at least one mild defect, the combination holds out hope that both drugs could lower the sweat test scores down below 60 mEq/L putting those patients in the range where CF symptoms may not develop.

Gene therapy was the focus for so long but this only dealt with the lungs.  As health care improved and patients are living much longer today, it’s clear that just protecting the lungs is not good enough.  For the older population, other organs are starting to show signs of the disease.  Since the Vertex compounds treat the whole body, the hope is enough functional CFTR protein will be made to support healthy organs throughout the body to avoid the other impacts like pancreas clouging, liver disease, osteoporosis, diabetes and so on.  At least that’s the hope, we will need to wait and see if that pans out.

With all that said, there has been a little more news outside the coference on the exciting gene therapy trials ongoing the UK.  And although “curing” the lungs of the disease would not help the other organs in the body, it would be of tremendous benefit if it be developed.  The current gene therapy compound is a very specialized envelope of fat around the gene.  This has completely restored the CFTR protein level in some of the test subjects for a sustained period.  However, there are others (50%), where no benefit whatsoever was obtained.  The thinking is some of these patients have too much mucus or damage in their lungs that’s preventing the gene from making contact with healthy cells.  There must be other differences as well that would cause such significant variation in results.  Beyond this trial, the scientists are working on more effective delivery capsules.  They have developed a lentivirus, pseudo-typed with sendai virus envelope (as opposed to “simply” using a fat envelope) that has shown to be 500 times more effective in mice.  This will take time to develop for human use and may, like many others before it, not pan out in people like it did mice but either way, these trials have already shown more success than any others.

Overall, there is a lot to be hopeful for in CF with a good chance some of these first ever drugs that target the root cause being available as early as 2012 and having effective gene therapy here in the next 10 years.

Exercise reduces airway Na-reabsorption in cystic … [Eur Respir J. 2010] – PubMed result
Jun 13th, 2010 by Tom

It’s common sense that exercise has many health benefits, especially for those with CF.  Now there is an indication that it may have direct therapeutic effects as well by blunting the hyperactive sodium absorption seen in those with CF.  In a recently published article on the subject, a clear advantage was seen in those with CF after rigorous exercise.  This was an in vivo  test where they used nasal potential difference to measure the changes.

Exercise reduces airway Na-reabsorption in cystic … [Eur Respir J. 2010] – PubMed result.

Now there really are no excuses not to get out there and get active!

Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: A pilot study
May 26th, 2010 by Tom

The probiotic LGG (Lactobacillus rhamnosus GG) has been looked at in small studies and has had positive effects.  Another study looked at a mixed probiotic mix and that too had a positive effect on the number of exacerbations.

Hopefully larger studies will follow that will fine tune and optimize this form of therapy.

Probiotic supplementation affects pulmonary exacer… [Pediatr Pulmonol. 2010] – PubMed result.

Kalobios Kalo: Gr, good; Bios: Gr, life
May 17th, 2010 by Tom

With the American Thoracic Society’s conference in full swing, there is a lot of news releases from the biotechs.  One of interest is Kalobios.  Instead of going the antibiotic route to treat pseudomonas, they have developed what they call Humaneered antibody fragments, given via IV for this purpose.

They completed their phase II trial last fall and had an initial press release indicating it showed some efficacy but no details were provided.  Today they’ve released another press release as the potential treatment is being discussed in several sessions at the ATS conference – Kalobios Kalo: Gr, good; Bios: Gr, life.

Although this latest press release goes into more details and the antibodies clearly look effective for ventilated patients, they provide no results for the CF trials other than “Dose-dependent trends towards reduction in mucoid Pa burden and inflammatory parameters were observed over the 28 day observation period in the KB001 treated patients.”

It’s interesting that they provide all kinds of details about the patients at the start of the trial (bacterial load in CFUs for example) but don’t provide any detailed results.

I hope this is not an indication of low efficacy; I for one would really like to know if this is going to have a shot at being successful.

Aeroquin™ (MP-376) Looks Good in Phase IIb Trial
May 16th, 2010 by Tom

Mpex has been moving their aerosol formulation of levofloxacin forward and some positive news will be discussed at the American Thoracic Society’s event this year in New Orleans (MP-376 Safe And Effective For Treatment Of P. Aeruginosa In CF Patients).  Aeroquin has been cleared to start a Phase III trial slated for later this year.

Although these trial results only resulted in 10 fold reduction in bacterial load, the trial was only for one cycle and with the very impressive lung function test results this looks like an important new treatment to fight infections Cystic Fibrosis.

What may be even more promising however, but a longer ways off is Mpex’s efflux pump inhibitors (EPIs).  This class of drugs may be the most beneficial contribution in the area of reversing drug resistance and I hope it’s something that can be moved out of development and into trials quickly.

To understand more about Mpex’s strategy and roadmap, this presentation provides a wealth of information: – Mpex Pharmaceuticals Corporate Presentation.  Interestingly, it shows they plan on having Aeroquin on the market by the end of 2012.

We have have a long ways to go before this can become a manged disease but advancements like this are getting us closer to the day.

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