Investors are currently focusing upon the anticipated demand for $36,000 six-month courses of Arikace from the estimated 110,000 in the US, Europe and Japan each year currently treated for NTM lung infection with off-label therapies.
But let's not forget how badly CF patients need a therapy capable of delivering both sustained efficacy and the far better compliance expected with a once-daily regimen -
[ In documents released ahead of an FDA panel meeting September 5, agency staff questioned whether Novartis' inhaled antibiotic powder tobramycin, dubbed TIP, improved lung function in patients with cystic fibrosis, or whether it is as safe and effective as the current version of the product ...
"The sustainability of improvements in (lung function) found...may raise concern regarding the clinical significance of these findings," FDA staff wrote. ]
[ Of the two placebo-controlled trials provided, results from one showed TIP improved lung function more than placebo, but the other study failed to meet its goal of demonstrating a statistically significant improvement in lung function.
FDA staff noted that patients receiving TIP reported more side effects ]
TIP % vs TIS %
48.40 ... 31.10 ... Cough
33.80 ... 30.10 ... Lung disorder / exacerbation
18.20 ... 19.60 ... Productive cough
15.60 ... 12.40 ... Dyspnea
15.60 ... 12.40 ... Pyrexia
14.00 ... 10.50 ... Oropharyngeal pain
13.60 ... 03.80 ... Dysphonia
13.00 ... 12.40 ... Hemoptysis
11.40 ... 12.00 ... Headache
08.10 ... 07.20 ... Nasal congestion
07.50 ... 09.60 ... Nausea
07.10 ... 06.20 ... Rales
06.80 ... 06.20 ... Wheezing
06.50 ... 02.90 ... Chest discomfort
06.20 ... 05.70 ... Vomiting
04.50 ... 01.90 ... Throat irritation
04.20 ... 01.90 ... Diarrhea
03.90 ... 00.50 ... Dysgeusia
02.60 ... 01.90 ... Epistaxis
02.30 ... 02.40 ... Rash
01.60 ... 00.50 ... Bronchospasm
01.90 ... 02.40 ... Tinnitus
01.00 ... 00.50 ... Hearing loss
03.90 ... 01.00 ... FEV-1 deterioration
27.00 ... 18.00 ... Discontinuation
An estimated 110,000 with NTM in the US, Europe and Japan currently treated with off-label therapies
plus an estimated 630,000 Worldwide each year with MDR-TB for whom aminoglycoside injection is equal-first on the list of recommended therapies
plus an estimated 65,000 with CF in the US and Europe for whom Tobi is currently the most widely-used therapy.
How many of those CF patients would turn down the opportunity to use once-daily Arikace instead of this? -
How much TOBI Podhaler to take
Inhale the content of 4 capsules twice a day (4 capsules in the morning and 4 capsules in the evening), using the Podhaler device.
Side effects may occur with certain frequencies, which are defined as follows:
. very common: affects more than 1 patient in 10
. common: affects 1 to 10 patients in 100
. uncommon: affects 1 to 10 patients in 1,000
. rare: affects 1 to 10 patients in 10,000
. very rare: affects less than 1 patient in 10,000
. not known: frequency cannot be estimated from the available data.
Some side effects can be serious
. Unusual difficulty in breathing with wheezing or coughing and chest tightness (common).
If you experience any of these, stop taking TOBI Podhaler and tell your doctor straight away.
. Coughing up blood (very common)
. Decreasing hearing (ringing in the ears is a potential warning sign of hearing loss), noises (such as hissing) in the ears (common).
If you experience any of these, tell your doctor straight away.
Other side effects may include:
. Shortness of breath
. Cough, productive cough, voice alteration (hoarseness)
. Sore throat
. Wheezing, rales (crackles)
. Chest discomfort, chest pain from muscles or skeletal origins
. Blocked nose
. Vomiting, nausea
. Disturbed sense of taste.
Since this product has been marketed, the following side effect has also been reported:
loss of voice (frequency not known, cannot be estimated from the available data).
I suspect few appreciate the significance for Arikace of the reservations voiced by FDA personnel concerning the approval of Tobramycin Inhalation Powder.
What business had the FDA in approving a drug which not only failed in one of its clinical trials to demonstrate better efficacy than the placebo the subjects in the control group were inhaling, but was associated with significantly worse side effects?
When 27% of individuals trailing a drug drop out before completion and the efficacy is so poor - presumably because there is now such a high level of resistance to Tobramycin within the CF patient population - there must have been a powerful incentive for approval which outweighed the concerns voiced by the FDA personnel.
That incentive was surely that patients were considered more likely to take both of their daily doses of TIP than they do of the less-convenient inhalation solution - and better compliance equals less opportunity for resistant strains of bacteria to evolve.
Once-daily Arikace, which is effective against Tobramycin-resistant strains of Pseudomonas and doesn't come with those nasty TIP side effects? The patients will want to use it instead of Tobi and the medical community will want them to use it instead of Tobi.
La taupe, your initial comment was -
"I appreciate it but I think that ARDM's leading drug is as effective as this one."
I think we now agree you were unaware of the possibility that the considerably smaller Aradigm liposomes could make a significant difference to the pharmacodynamic effect of its leading drug to that of Arikace.
You tell me that rehdvm "seems to have all the details." My experience of rehdvm is that he's only really interested in "seeming" to be knowledgeable, and more often than not has a poor grasp of the information he posts.
Why don't YOU discuss this with rehdvm, and get back to us in the (imo) unlikely event he can contribute anything of value?
Here are four questions you might ask him -
1. What info is he aware of which would help in predicting the pharmacodynamic effect of the Aradigm liposomes - particularly concerning the potential for systemic toxicity?
2. What is known about the safety studies in animals - particularly the two-year rat study one assumes the FDA will require?
3. Can he think of a reason for the FDA not to approve Arikace (assuming the NTM data due this quarter is supportive) for the treatment of serious pulmonary infections caused by amikacin-susceptible pathogens?
4. If the FDA does indeed issue such a label for Arikace, what are the implications for competition with Aradigm's leading drug in the treatment of Non-CF Bronchiectasis?
From memory that technology utilises much smaller liposomes. Three questions immediately occur to me -
1. Is it being developed as a once-daily therapy?
2. Will it be able to compete on cost given the more exacting manufacturing process?
3. Will the much smaller liposomes result in more of the therapeutic going straight through the lungs and into the bloodstream - rendering it less effective and having greater systemic toxicity than Arikace?
Snippets from the Company's Q3 quarterly filing -
1. [ We are currently conducting a Phase 2 clinical trial in the US and Canada for ARIKACE in adult patients with recalcitrant NTM lung infections. We began enrolling patients in June 2012 and during October 2013, we concluded patient enrollment with 90 patients enrolled in this Phase 2 clinical study.
In addition, during October 2013 Insmed commenced the Scientific Advice Working Party (SAWP) process with the European Medicines Agency (EMA) and expects to have discussions with the EMA regarding ARIKACE for NTM lung disease during the fourth quarter of 2013. ]
Assuming the EMA Scientific Advice Working Party process which commenced in October did indeed subsequently involve discussions with the EMA regarding ARIKACE for NTM, could the recent accumulation have been triggered by those discussions? Confirmation that the EMA is prepared to issue a label for Arikace based upon the totality of the data from the Arikace studies perhaps?
2. [ Additionally, on June 28, 2013, the FDA granted Fast Track designation to ARIKACE for the treatment of NTM. The Fast Track designation is intended to expedite the review of new drugs that have the potential to serve unmet medical needs in serious or life-threatening conditions. ]
[ Pursuant to ARIKACE's recently designated QIDP status, we expect to continue our dialogue with the FDA regarding the regulatory pathway for registration and approval of ARIKACE for the treatment of NTM, and we expect to complete our review of the results from this clinical trial and related dialogue with the FDA by the end of the first quarter of 2014. ]
Provided the NTM results warrant initiating a rolling application for FDA approval immediately after the Q1 "related dialogue" - how soon might the FDA issue a label for Arikace supported by the totality of the data from the Arikace studies?
Possible label - "For the treatment of serious pulmonary infections caused by amikacin-susceptible pathogens"?