Although the US sees about 10,000 cases of TB each year only about 100 of those are MDR-TB.
But given the seriousness of the disease, and the side-effects of the antibiotics to which the mycobacteria are still susceptible, in July 2012 Janssen submitted a New Drug Application to the FDA with a request for an accelerated approval of bedaquiline.
The NDA was supported only by interim Phase II data.
Furthermore, although bedaquiline delivered better culture conversion results - 10 of the 79 patients in the bedaquiline arm actually died vs just 2 of the 81 patients in the placebo arm.
The FDA nevertheless granted fast-track and priority review, and approved bedaquiline in December 2012 -
[ The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease ]
The approval came with a Black Box warning -
[ the drug can affect the heart's electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. ]
One assumes the FDA linked that to the greater number of deaths in the bedaquiline arm.
I can't help but feel, given the following rationale, that the FDA will consider Arikace far more preferable as an MDR-TB therapy -
[ Nonetheless, treatment for resistant TB is complex, costly, toxic and prolonged, requiring at least 5 second-line drugs for up to 2 years. Second-line drugs include injectable drugs (amikacin, kanamycin, capreomycin) and oral fluoroquinolones (FQs) and other second line drugs; the optimal use of which has not been well studied in randomized controlled trials and whose safety when used in concert with various doses and regimens is not sufficiently described. ]
Arikace has a massive advantage over other TB therapies. The FDA won't have those concerns about interaction with, and cumulative toxicity from, other TB and HIV drugs in the bloodstream.
"The inclusion of the three-month course of Arikace which converted 25% of the Arikace arm in the NTM study to culture-negative would cost around half as much as bedaquiline."
OK - we know -
1. from that CDC guidance about off-label use of bedaquiline that most drugs used to treat TB are off-label.
2. that amikacin injection is routinely used to treat both drug-resistant NTM and drug-resistant TB.
3. that two companies (undisclosed) approached Insmed some time ago with a view to a deal to commercialise Arikace in Asia.
4. that the Chinese regulatory authority is expediting its approval process for bedaquiline.
5. that the $30,000 price of a 24-week course of bedaquiline (assuming the Chinese health authority pays that much) is around twice the anticipated price of a 12-week course of Arikace.
6. that a 12-week course of Arikace converted 11 out of 44 patients with drug-resistant NTM to culture-negative within 12 weeks - the majority within 4 weeks.
7. that China is currently seeing around 120,000 new cases of MDR-TB each year on the mainland alone.
What we don't know is the extent to which China will be motivated by the risk of loss of hearing and kidney damage which comes with a six-month course of aminoglycoside injections to pay the difference in price between amikacin injection and Arikace.
A few obervations by speakers at the FDA-sponsored Non-CF Bronchiectasis workshop in 2012 - which explain why the FDA approved bedaquiline as a therapy for a drug-resistant mycobacterial infection on the basis of Phase II culture-conversion -
1. [ Our next speaker is Joe Toerner, Associate Director for Medical Affairs in the Office of Antimicrobial Products at CDER.
He, in his responsibilities, deals a lot with guidance development for various infectious diseases, and so is in a good position to give us a regulatory perspective on clinical trial endpoint measures. ]
[ And for pulmonary tuberculosis, we consider sputum culture conversion to no growth, which is a biomarker, but we consider that a surrogate endpoint that could be used for the purposes of accelerated approval. ]
2. Speaker: Anne O'Donnell, MD
Primary Endpoint in Clinical Trials
[ I still think, with NTM infections, that we've got to use sputum culture as the primary endpoint.
I think we could probably discuss that a little bit more, but I think for right now that is the one type of bronchiectasis that we still need to stick with the sputum culture conversion. ]
Anne O'Donnell later in her talk referred to the case history of one of her patients (below) - a tale which will have done no harm at all to the chances of the FDA approving Arikace :-)
If there's no logical reason to believe the NIAID and FDA are particularly interested in a new NTM therapy - by a process of elimination they can only be interested in a new amikacin therapy.
[ But when she came back from the Mayo Clinic she was followed by her community physicians, actually here in Silver Spring.
And they never really got it that she had pseudomonas, and ultimately she got in the hands of somebody who had her on a prolonged IV course of amikacin.
And it knocked off her kidneys, so she had aminoglycoside renal toxicity, developed renal failure.
She ultimately came to us and she's doing well now. She's had a renal transplant. ]
Re your -
"The WHO approval of bedaquiline was supported by an analysis which concluded that adding a six-month course of bedaquiline to the currently-recommended regimen for MDR-TB is likely to be cost-effective in China, and highly cost-effective in Estonia and Russia.
The inclusion of the three-month course of Arikace which converted 25% of the Arikace arm in the NTM study to culture-negative would cost around half as much as bedaquiline."
- I also saw this -
Average length of hospitalisation during treatment for MDR-TB -
Estonia: Almost 8 months
Russia: Over 6 months
China: 2 months
The fact that MDR-TB is currently killing around 250,000 people each year is indicative of a serious unmet medical need - doubtless justifying the approval of bedaquiline by the WHO, FDA and EMA on Phase II success in conversion to culture-negative, despite 10 of the 79 patients on bedaquiline actually dying during the study.
The Arikace Phase II success in so quickly converting drug-resistant NTM patients to culture-negative - accompanied by just a single death adjudged unrelated to the therapy - asks a question the WHO will not ignore -
whether or not incorporating Arikace into the antibiotic regimen for MDR-TB instead of the injected aminoglycoside could both increase survival and significantly shorten the currently recommended 20-24 month antibiotic regimen.
The release of the bedaquiline data prompted the World Health Organisation Stop TB Department to set up a process to guide development of policy guidance aiming at rational introduction and use of new TB drugs - which could be very good news for Insmed.
The WHO Expert Group were split on whether or not benefit outweighed harm with bedaquiline, recommending it be added to a WHO-recommended regimen -
. when an effective treatment regimen containing four second-line drugs in addition to pyrazinamide, according to WHO recommendations, cannot be designed;
. when there is documented evidence of resistance to any fluoroquinolone in addition to multidrug resistance.
But the following snippet from the subsequent WHO Interim Guidance suggests a very high opinion of amikacin as TB therapy -
[ MDR-TB patients with strains resistant to either fluoroquinolones or the second-line injectable drugs (kanamycin, amikacin, capreomycin) represent a particular concern given that these are the two most effective classes of second-line drugs. ]
Amikacin was only relegated to a second-line drug in the first place because of the risk of loss of hearing and kidney damage. How will react to this latest proof that amikacin can be delivered to a pulmonary mycobacterial infection with unprecedented efficacy and negligible risk of serious side-effects?
World Health Organisation approval of Arikace just as a scecond-line therapy - replacing the injected aminoglycoside - would be a game-changing development for Insmed -
[ WHO estimates that up to half a million new cases of multidrug-resistant tuberculosis (MDR-TB) occur worldwide, each year. Current treatment regimens for MDR-TB present many challenges: treatment lasts 20 months or more, requiring daily administration of drugs that are more toxic, less effective, and far more expensive than those used to treat drug-susceptible TB. Globally, less than half of all patients who start MDR-TB therapy are treated successfully ]
Group 1 First-line oral agents - isoniazid; rifampicin; ethambutol; pyrazinamide; rifabutin.
Group 2 Injectable agents - kanamycin; amikacin; capreomycin; viomycin; streptomycin.
Why would the WHO continue to recommend treatment of around half a million new cases of MDR-TB each year with an injected antibiotic known to cause loss of hearing and kidney damage now that the antibiotic can be delivered via a route which is more effective and far safer?
And the primary reason for around half a million new cases of MDR-TB each year is that those first-line drugs all come with side-effects sufficiently nasty to result in poor compliance. The inclusion of Arikace in the first-line antibiotic regimen would be guaranteed to improve compliance - saving considerable expense further down the line in the treatment of MDR-TB and XDR-TB.
The WHO approval of bedaquiline was supported by an analysis which concluded that adding a six-month course of bedaquiline to the currently-recommended regimen for MDR-TB is likely to be cost-effective in China, and highly cost-effective in Estonia and Russia.
The inclusion of the three-month course of Arikace which converted 25% of the Arikace arm in the NTM study to culture-negative would cost around half as much as bedaquiline.
The current charade with the share price is intended to convince you there must be a catch.