For those here who missed the recent heads-up about the following article -
GAIN Act, FDA stance only first steps to refilling antibiotic pipeline in U.S.
- here are a few extracts of particular relevance to Insmed -
1. There is a consensus among the U.S. government, industry and the medical community that the failure of antibiotic development to keep pace with the evolution of bacterial pathogens constitutes a public health crisis, and that new regulatory policies and economic incentives are needed to create a continuous stream of new antibacterial products.
The Generating Antibiotics Incentives Now (GAIN) Act, which came into effect on Oct. 1, is a building block for creating some of the changes that will be needed to get antibiotic drug development back on track. And political changes have allowed FDA to begin shifting its risk-benefit calculus.
2. There is also an urgent need to create a regulatory pathway that will facilitate the development of new drugs to combat emerging, rare pathogens, especially those that are resistant to multiple antibiotics.
3. The GAIN Act, which was incorporated in the FDA Safety and Innovation Act that reauthorized prescription drug user fees, provides added exclusivity for antibiotics and earmarks antibiotics for Priority Review.
It also mandates the creation of a pathogen-focused antibacterial drug development pathway.
4. The ability to develop drugs for emerging multi-resistant pathogens based on the bugs they kill - regardless of the site of infection - should stimulate the creation of new drugs as FDA and sponsors agree on minimum efficacy datasets that can be obtained practically and rapidly.
5. Attitudes at FDA mirror the evolution in the political environment.
"The whole tone of the conversation has gone from 'no' to 'go,'" said John Rex, VP and head of infection, global medicines development, at AstraZeneca plc.
Senior FDA officials say the agency is committed to rapidly replacing infeasible requirements for antibiotics with pragmatic standards based on the realities of clinical practice at a pace commensurate with the public health threat posed by rapidly evolving pathogens.
FDA is going to "reboot our effort," said Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). "It is not going to be on my watch that we fail to develop antibiotics for the next generation of bugs," she told BioCentury.
Rachel Sherman, associate director of CDER's Office of Medical Policy, stressed the public health mandate during an interview on BioCentury This Week television (see BioCentury This Week, Nov. 18).
"The slowdown in development of these products is a public health crisis of the greatest magnitude," she said. . "We at the agency are aware of that, and we are on top of it ..."
6. But relatively few of the products in development are targeted at Gram-negative bacteria, one of the most serious short-term threats.
7. "We are having meetings for development of drugs for multi-resistant organisms with different companies," Woodcock told BioCentury.
FDA recognizes it will be difficult or impossible to enroll large numbers of patients with infections caused by a rare pathogen, but it is important to get new drugs into physicians' hands before the bugs become common enough to study in traditional trials.
"That's a life-threatening situation, so we are treating it differently" from typical drug development, Woodcock said.
The most important takeaway for me is the mindset of key FDA personnel such as Janet Woodcock and Rachel Sherman.
That last comment from Woodcock is of particular significance when one considers that the amikacin payload delivered by Arikace is already FDA-approved for the treatment of infection by susceptible strains of ALL FOUR Gram-negative pathogens singled out by the new legislation as having the potential to pose a serious threat to public health - multi-drug resistant Acinetobacter, Klebsiella, Pseudomonas, and E.coli. The official 2009 mortality stats show that over 50,000 died in the US that year from pneumonia.
The preliminary report due mid-year from the ongoing Arikace EU clinical trial will, if the study replicates the unprecedented level of efficacy seen at Phase II, establish that Arikace delivers an effective concentration of amikacin to Pseudomonas infection in the lungs of an individual with Cystic Fibrosis. One of the outcome measures is as follows -
"Change in density in Pseudomonas aeruginosa in sputum".
But that particular pathogen crops up time and time again in reports of life-threatening lung disease. It was singled out in the FDA-sponsored workshop last year focussed upon the development of therapies for Non-CF bronchiectasis -
"I think you can say that more severe bronchiectatic patients tend to end up getting pseudomonas at one point, compared to the milder forms"
An estimated 30,000 in the US have Cystic Fibrosis. Referring back to the fourth extract I picked out above, and bearing in mind the comments of Woodcock and Sherman, is it unrealistic to predict that compelling results from the CF study will be deemed adequate to support an FDA approval of Arikace as a therapy for all pulmonary infection by susceptible strains of multi-drug resistant Acinetobacter, Klebsiella, Pseudomonas, and E.coli?
Or will the FDA proceed as though nothing has changed, and deny approved access to Arikace for the estimated 250,000 in the US with Non-CF bronchiectasis, a population for which there are currently no approved inhaled antibiotics?
Btw - Rehdvm obviously fears that the data from this study will be compelling. I've lost count of the number of posts from him recently which simply skipped past the ongoing study as though it didn't have massive potential implications for the share price, and singled out the follow-on long-term safety study as the only CF study worth mentioning. The topics of interest our resident expert shows no interest in discussing betray his true agenda.
Rehdvm, your -
"Now we are to believe the Justice Department, with this precedent, would ignore Arikace for unlimited inhalational antibiotic use blathered by the poster of the above information."
- suggests a lack of awareness on your part of the recent change in the regulatory environment.
Kindly read the initial post in this thread. I'll be happy to discuss this with you when you are better-informed - both with regard to the new legislation and with regard to the new stance of the FDA.
With regard to the suggestion that Insmed will be a beneficiary of the FDA's new strategy of pathogen-focused antibacterial drug development - with proof from the ongoing Cystic Fibrosis study of the efficacy of Arikace against Pseudomonas Aeruginosa being deemed adequate to support the approval of Arikace to control that pathogen both in Cystic Fibrosis and in Non-CF bronchiectasis - it's worth bearing in mind that as well as the data from the current and prior Cystic Fibrosis studies, the FDA will also have the data from the following 64-patient study completed in 2009 -
1. From the clinical trial record -
A Placebo Controlled, Randomized, Parallel Cohort, Safety And Tolerability Study Of 2 Dose Levels Of Liposomal Amikacin For Inhalation (Arikace™) In Patients With Bronchiectasis Complicated By Chronic Infection Due To Pseudomonas Aeruginosa
Primary Outcome Measures:
Treatment emergent adverse events up to end of treatment [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Treatment emergent marked laboratory abnormalities up to 28 days after study medication discontinuation [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
Treatment emergent pulmonary function test (PFT) abnormalities post-dose for acute tolerability assessment [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Treatment emergent pulmonary function test (PFT) abnormalities up to end of treatment [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
Adverse events leading to permanent discontinuation of study medication [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Serious adverse events up to 28 days after study medication discontinuation [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
To access pharmacokinetics (PK) of Arikace™ in serum and urine, and evaluate sputum amikacin levels [ Time Frame: 28 days dosing ] [ Designated as safety issue: Yes ]
To evaluate change in Pulmonary function [ Time Frame: 28 days dosing ] [ Designated as safety issue: Yes ]
To evaluate change in density of Pseudomonas aeruginosa in sputum [ Time Frame: 28 days dosing ] [ Designated as safety issue: Yes ]
To evaluate time to and duration of systemic anti-Pseudomonal rescue therapy [ Time Frame: 28 days dosing ] [ Designated as safety issue: Yes ]
To evaluate change in St. George's Respiratory Questionnaire measurements [ Time Frame: 28 days dosing ] [ Designated as safety issue: No ]
2. From the Transave PR -
MONMOUTH JUNCTION, NJ, Sept. 13, 2009 – Transave, Inc., today reported positive results from a Phase II clinical trial in non-cystic fibrosis (CF) bronchiectasis patients for its lead investigational drug, ARIKACE™ (liposomal amikacin for inhalation).
The Phase II data indicated that ARIKACE, delivered once daily for 28 consecutive days, demonstrated superior clinical benefit compared to placebo as measured by patient and physician reported outcomes and reduction in Pseudomonas aeruginosa density. In addition, ARIKACE™ was well-tolerated with overall adverse events comparable to placebo.
Results were presented today at the European Respiratory Society Meeting in Vienna, Austria by Anne E. O'Donnell, MD, Professor of Medicine and Chief of the Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University Hospital, and co-lead investigator of the study.
"The positive efficacy and tolerability profile demonstrated by ARIKACE™ in this study is encouraging for non-CF bronchiectasis patients that have pseudomonas lung infections and for physicians who treat them," said Dr. O'Donnell. "These successful results with ARIKACE™ are especially important since there is nothing currently approved to treat bronchiectasis patients with these types of infections."
The study also revealed that ARIKACE™ – administered at both the 280 and 560 mg doses – was well-tolerated. Adverse events were consistent with underlying chronic lung disease in bronchiectasis patients. Patients in the 560 mg cohort had a slightly higher frequency of dry cough than those in the 280 mg cohort, but the cough was of short duration, was self-limiting, and did not result in any physician choosing to discontinue a patient from the trial. Patients in the placebo arm of the study had a greater frequency of both hospitalizations and pulmonary exacerbations.