Arikace converted 31% of 68 patients to 'sputum culture negative' within 24 weeks - in a patient population for which the recommended duration of therapy is 18 - 24 months.
How does that stack up against a couple of examples from early this year where the FDA granted Breakthrough Therapy status?
1. GlaxoSmithKline plc (LSE: GSK) announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for Tafinlar® (dabrafenib) ... The Breakthrough Therapy designation was based on interim efficacy and safety results from an ongoing Phase II study of dabrafenib administered orally to 25 patients who had NSCLC with the BRAF V600E mutation and who had received at least one previous course of chemotherapy.
2. GlaxoSmithKline plc (LSE:GSK) announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for Promacta®/Revolade® ... The Breakthrough Therapy designation was based on the results from an open-label, Phase II National Institute of Health (NIH) study (09-H-0154) of eltrombopag in 43 heavily pre-treated SAA patients with an insufficient response to IST.
Sputum culture conversion alone qualifies for FDA approval.
The FDA and EMA approval of Bedaquiline is particularly relevant - as Phase II culture conversion in a drug-resistant pulmonary mycobacterial infection was interpreted as "preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint" there also.
1. Culture conversion in the Arikace study of infection with drug-resistant Non-tuberculous Mycobacteria -
(in patients who had been on therapy for 168 days at the cut-off point for the latest presentation)
Arikace Day 84: 11 of 44 (25%)
Placebo Day 84: 3 of 45 (7%)
Arikace Day 168: 21 of 68 (31%)
Placebo Day 168: N/A (treated with Arikace after Day 84)
2. Culture conversion in the bedaquiline study of infection with drug-resistant Mycobacterium Tuberculosis -
a) Stage 1
Bedqlin Day 56: 10 of 21 (48%)
Placebo Day 56: 2 of 23 (9%)
Bedqlin Day 168: 17 of 21 (81%)
Placebo Day 168: 15 of 23 (65%)
b) Stage II
Bedqlin Day 168: 52 of 67 (78%)
Placebo Day 168: 38 of 66 (58%)
Bedqlin Day 504: 47 of 67 (70%)
Placebo Day 504: 37 of 66 (56%)
In both studies the comparison was SOC plus study drug vs SOC plus placebo. The Arikace study only accepted patients who had been resistant to the SOC for some time. The patients in the bedaquiline study were expected to be treatable with the SOC, hence the higher conversion rates.
SOC = Standard of care.
In the Arikace study the SOC was a three-drug combo of rifampin, ethambutol and either azithromycin or clarithromycin.
In the bedaquiline study the SOC was a five-drug combo of ethionamide, kanamycin, pyrazinamide, ofloxacin and either cycloserine or terizidone.
Breakthrough Therapy definition:
A drug that is -
1. intended to treat a serious condition, and
2. preliminary clinical evidence indicates that the drug may demonstrate
3. substantial improvement on a clinically significant endpoint(s) over
4. available therapies.
Here are a few extracts from the FDA guidance regarding the four elements of the definition. As regards Arikace, multiple criteria apply to three of the four elements.
1. Serious condition -
a disease or condition associated with morbidity that has substantial impact on day-to-day functioning.
2. Preliminary clinical evidence -
a) Ideally, preliminary clinical evidence would be derived from a study that compares the investigational drug to an available therapy (or placebo, if there is no available therapy) in clinical testing and shows superiority, or from a study that compares the new treatment plus SOC to the SOC alone.
b) In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible.
3. Substantial improvement -
a) The new drug added to available therapy results in a much greater or more important response compared to available therapy in a controlled study or to a historical control. This trial also could be conducted in treatment naïve patients or in those whose disease failed to respond to available therapies.
b) The new drug has an important safety advantage that relates to serious adverse events compared to available therapies and has similar efficacy.
4. Available therapy -
a) a therapy that: Is approved or licensed in the United States for the same indication being considered for the new drug and is relevant to current U.S. standard of care (SOC) for the indication.
b) If no therapy exists for a serious condition, there is clearly an unmet medical need.
From the "substantial improvement" criteria for Breakthrough Therapy designation -
... The new drug added to available therapy results in a much greater or more important response compared to available therapy in a controlled study or to a historical control.
... The new drug has an important safety advantage that relates to serious adverse events compared to available therapies and has similar efficacy.
Intravenous amikacin is already approved by the FDA -
Amikacin Sulfate Injection, USP is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (Mima-Herellea) species.
In order to have approved IV amikacin the FDA must have on file extensive clinical trial data.
One would imagine a straight comparison between that "historical control" and the extensive Arikace safety data now available would establish "an important safety advantage that relates to serious adverse events" - the absence of the systemic toxicity which has historically caused damage to hearing and kidneys.
Insmed is already conducting a long term safety study in Cystic Fibrosis in Europe.
It seems to me the most likely outcome here is approval under the Breakthrough Therapy pathway for the treatment of -
"serious infections due to susceptible strains of Gram-negative bacteria" and mycobacteria
- subject to Insmed conducting a Phase IV clinical trial to establish the optimum period of therapy for mycobacterial infections.