The COPD Pipeline XV

Keywords: :

• FDA Approval process
• companion diagnostics
• nicotine replacement
• small-molecule ligand discovery
• staccato inhalation device.

FDA Approval Process

Twenty years ago Congress authorized the Prescription Drug User Fee Act (PDUFA) to address the public and industry's concerns about the slow pace of drug approvals at that time. In effect, the intent was for the Pharmaceutical industry to pay fees in part to enable the FDA to hire sufficient staff to approve their products and accelerate the process. It was successful. The law has been re-authorized every 5 years, the next time being this year. The FDA and Pharma worked on the draft agreement last year, and it was reviewed at an open meeting last September (Congress usually attaches its own amendments).

Seven substantial changes were recommended; these are reviewed by a trade journal (1). Very briefly, these are:

1. To enhance communication with sponsors, -quicker responses.

2. Evaluate ‘best practices for meta-analysis’, specifically to establish guidelines for their conduct and set standards (my comment, -a minefield of arbitrary assumptions and sloppy methods yielding “conclusions” that are often appallingly wrong despite being published in widely read journals. An injection of rigor into their use is long overdue).

3. Augment its scientific and statistical capabilities to evaluate the role of biomarkers and pharmacogenetics. Outcomes of these kinds, as opposed to clinically centered ones, must be important but presently occupy a sort of limbo in which both the FDA and sponsors are nervous and uncertain.

4. Increase the use and rigor of patient-reported outcomes (PROs). These will be developed, standardized, and validated as acceptable endpoints. In our field, EXACTPRO, a PRO measure of acute exacerbations of COPD, is being developed.

5. Facilitate the rare disease drug development program. In our field, the program has just yielded dividends with the approval of Kalydeco, formerly VX-770, an agent described as a CFTR potentiator. Kalydeco was approved for the treatment of 3 rare forms of cystic fibrosis in February this year.

6. Enhance and expand its risk-benefit assessments. This will include obtaining testimony from patients.

7. Modernize the drug safety system. A current tool, the risk evaluation and mitigation strategies (REMS), while valuable is burdensome. Ways to standardize and maybe streamline it will be sought.

I think it is no exaggeration to say that all of these changes are extremely important and, if well thought through, would signify a quantal improvement in the quality of FDA's decisions.

Companion Diagnostics

The significance of the COPDGene initiative is that we are now in the era of COPD phenotyping. One anticipates important discoveries in the molecular pathogenesis of these diseases, as I hope we will soon call them. But new problems will be raised. Particularly in oncology, but also cardiology and diabetes, genome-wide association studies are identifying genetic abnormalities that are found in a minority or subgroup of patients. In those with the specific genetic abnormality, a biological treatment may be found, but it is unlikely to have any benefit for those without the specific abnormality. Candidate patients for the treatment will be identified by a diagnostic test, usually a genetic test of some kind, -a “companion diagnostic”. In a recent decision, the FDA rejected the new drug application (NDA) for such an agent, omacetamine for chronic myeloid leukemia, because the relevant genetic test was not a part of the application. If as seems likely, this requirement is widely applied, the drug may, in essence, become hostage to the diagnostic test. This could result in an uneasy relationship between two very different industries. This situation, which I believe is the first to require an approved companion diagnostic, is widely believed to signal a general requirement, -an extrapolation to future rulings on biologic therapies whose appropriate use depends on a diagnostic test. The ramifications are extensive and will quite possibly extend to new therapies arising from COPDGene and similar research. The FDA issued guidance on companion diagnostics in July last year. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf accessed 1/1/2012

Related to the above is a suit that will probably be heard and decided by the US Supreme Court this year. The Court will rule whether unique gene sequences such as BRCA-1 and BRCA-2 can be patented. Thousands of gene sequences, possibly 20% of the human genome it is said, have been patented in the 10 years since the debate first arose when the U.S. Patent and Trademark Office first began granting such patents. If the Court decides that genes can be patented, any gene sequences that form the basis of a diagnostic test for a COPD phenotype could presumably also be patented.

Nicotine Replacement

Another approach to this well tried strategy is to help smokers with no intention to quit by a behavioral intervention, -a trial of a 24-hour “practice quit attempt” with the aid of nicotine lozenges. A random control group made a similar “practice quit” without the support of nicotine replacement. The open-label trial enrolled 849 smokers. Any subsequent quit attempt was commoner in the nicotine replacement group, 49% vs 40% (P<0.04), although abstinence at 6 months was not different, 16% vs 14% (2). Resistance to smoking cessation messages may be driven in part by the fear and conviction that abstinence would be impossible. The goal of the practice quit attempt was that 24-hours of abstinence, supported by nicotine replacement, would reassure smokers that quitting was possible and perhaps even motivate some die-hard smokers to quit. Although nicotine replacement did not improve the quit rate at 6 months, quit rates of 16 and 14% in a hard-core group of smokers indicate success and suggests that a 24-hour practice quit attempt contributes to efficacy of a smoking cessation program.

Small-Molecule Ligand Discovery

Suppose you discover an agonist or its receptor whose activity needs to be tweaked. How do you go about finding the molecule that will do that for you? What pharmacologists do is to select hundreds of synthetic molecules to screen using high-throughput chemistry. Because it seems intuitive that potential ligands would chemically resemble ‘natural’ ligand molecules, the libraries that pharmaceutical companies have used for their screenings have been composed of natural-product-like libraries. This limits the size of the library, its structural diversity, and its conformational heterogeneity. Instead, ignoring the requirement of ‘natural-like’ makes it possible to synthesize a huge library of novel molecules for screening. Thus, as a proof of concept, a library of 160,000 novel compounds was used to identify one molecule that was a ligand for the DNA-binding domain of the p53 transcription factor (3), which could be a landmark in cancer chemotherapy. This relatively straight-forward strategy has the promise to provide small molecules that might be applied to diseases such as COPD.

Staccato Inhalation device

The biotech company Alexza has developed a unique new inhalation device called Staccato for the rapid delivery of the sedative loxapine to agitated psychiatric patients. It is a single-use device, consisting of a bottle-like container. The drug to be delivered is attached to a thin stainless steel surface about 2×3 cms suspended in the container. Inhalation from the container activates heating of the steel surface which vaporizes the attached drug which is entrained in the inhaled breath. No excipients, priming, or hand/breath coordination are needed. Nor is forceful inhalation necessary provided the patient's inspiratory flow rate exceeds 1.5L/min. As heating is so brief, thermal degradation of the medication is negligible. Particle size at around 1-2 micron is appropriate for penetration to small airways. Delivery from the container is complete in 200 msec and delivery to systemic circulation via lungs peaks at 1-2 min. Further details are available at http://alexza.com/about/the-staccato-system/staccato-platform-details

Some of the information found in this column was made available to the author through Citeline's Trial Trove©. For more information on Trial Trove, please visit www.citeline.com