The COPD Pipeline XVIII

Keywords :

• FDA Committees
• human microbiome
• PA401
• smoking cessation vaccine
• Relovair
• Umeclidinium
• GSK961081
• InterVapor

FDA Advisory Committees

We are very aware that developing new agents and devices is extremely expensive. Each new drug application (NDA) or biologics license application (BLA) is the culmination of several years’ investment of time, money, and resources so a great deal depends on its outcome; not only for the developer, a pharmaceutical company, but also the user, a patient, and us, the prescribers. To help it reach the right decisions the FDA often uses an independent advisory committee, of which there are currently 50, consisting of a spectrum of physicians and scientists with ‘expertise’ in that subspecialty. (In the interests of disclosure, I was a member of the Pulmonary and Allergy Drug Advisory Committee (PADAC) for 4 years in the early 2000's. That division is now The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)).

A review of the advisory process has recently been published (1). It's not known what factors prompt the relevant division of the FDA to call a meeting of its advisory committee; -seemingly it is when the agent in question is controversial for medical or societal reasons. New biologics, priority status applications and orphan drugs were disproportionately the subject of advisory committee meetings, as might also be expected. In the decade 2001-2010 there were 543 advisory committee meetings, less than 5% of them for a pulmonary or allergy drug. FDA's use of advisory committees has increased in the last decade from about 30% of applications to a little over 40%.

Broadly, the FDA's ultimate decision has been consistent with the prior advisory committee's decision, if one was requested. Thus the FDA approved 88% of the applications that were endorsed by the advisory committee, and did not approve 86% of those that the advisory committee did not endorse. The concordance was particularly strong when the committee's numerical vote was a clear ‘yes’ or ‘no’, e.g. by more than 2/3 of members. Possibly related to that outcome, the FDA's ultimate decision came more quickly when the committee's meeting was clear. The review found no evidence that the FDA selectively pre-screened applications for advisory committee meetings.

The authors suggest that industry should make more use of ‘mock’ advisory committees and be a major driver for improved decision-making. For anyone interested in the Pulmonary, Allergy, and Rheumatology Division activity, the former web-site is cited (2), the new web site is http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm269647.htm

The Human Microbiome

The fact that each of us (even the well washed) caries around ìtrillions of microorganismsî has recently been bruited in the popular press. The topic is entirely novel and represents a new frontier in medicine. Initiated in 2008, the NIH-sponsored human microbiome project is funded by $174M. Its ultimate goal is to identify the association(s) of the biome with human health and disease. Up to 1,000 microorganism genomes, certainly the majority of which will be previously unknown, will be sequenced. Five body sites will be emphasized: oral, skin, vaginal, gut, and nasal/lung. For general information the link is http://www.hmpdacc.org/. The human microbiome is the subject of five trials in asthma or allergy on the clinicaltrials.gov website, but none yet in COPD. Surely the lung microbiome in COPD would be a fruitful research field.

PA401 is a genetically engineered and recombinantly expressed variant of human IL-8 (CXCL8). It is the lead product of ProtAffin Biotechnologie AG and its action is to act as a glycan-binding decoy that will prevent the IL-8 mediated pro-inflammatory attachment and infiltration of neutrophils at sites of inflammation. The action of the agent is shown in a video http://www.protaffin.com/index.php/technology/celljammer_discovery_platform

The only published data on its action I can find is an ATS2012 poster of a study in mice http://protaffin.com/pressrelease/TADAGE_ATS2012.pdf. A Phase I trial of the parenterally administered agent in man began in June 2012 with safety, tolerability and pharmacokinetic endpoints. The normal subjects will also receive inhaled lipopolysaccharide followed by sputum induction, presumably for the measurement of pro-inflammatory mediators (NCT01627002).

Smoking cessation vaccine Smoking cessation, of-course, remains one of our most important goals. Our present modalities help but more effective therapies are still needed. Scientists at Weill-Cornell in New York have taken an interesting new molecular approach, -an attempt to absorb nicotine in the blood stream before it can reach its brain receptors. As a small molecule, nicotine evades immune system recognition and elimination by conventional antibody generation. The group, headed by Ron Crystal,î..hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector expressing high levels of an anti-nicotine antibody would persistently prevent nicotine from reaching its receptors in the brainî and prompting continued use.

From the Fab fragment of an anti-nicotine monoclonal antibody NIC9D9 (AAVantiNic), they constructed an AAVrh.10 vector that expressed a full-length, high-affinity, anti-nicotine antibody. In mice thus transfected, the antibody mopped up systemically administered nicotine, reducing brain nicotine concentrations to 15% of those in non-transfected mice. A single administration of a gene transfer vector in mice ìblocked nicotine-mediated alterations in arterial blood pressure, heart rate, and locomotor activityî. The effect elicited persistent antibody titers against nicotine and its systemic effects for 18 weeks (3). This could be an effective therapy for nicotine addiction if such efficacy were translated to humans.

Relovair In partnership with Theravance, this is GSK's once-a-day ICS-ULABA combination which is intended to take the place of Advair, their blockbuster which will lose patent protection quite shortly. The components of Relovair are fluticasone furoate and vilanterol. Its efficacy is similar to that of Advair. The new combination will have the brand name BreoTM in the US, and RelvarTM elsewhere; the dry powder delivery device will be known as ElliptaTM.

Although Relovair has not been approved for COPD or asthma in either USA or Europe, the companies are taking the unusual step of conducting what they call a ìreal-worldî trial in 4,000 patients with COPD and 5,000 patients with asthma, which seems more like a post-marketing study. (Is Phase III the new Phase IV, one wonders?) Reading between the lines, one suspects that this is a response to the less than enthusiastic reception that Relovair received from analysts, -the aim being ìto enable healthcare decision-makers to more fully assess the medicine's potential value at an earlier stageî in the words of GSK.

The 12-month COPD trial of relovair versus usual therapy will be conducted entirely in UK and will have acute exacerbation rate as the primary outcome, and safety as a secondary. It will be known as the ìSalford Lung Studyî (NCT01551758).

Umeclidinium, GSK 573719, is a further collaboration between GSK and Theravance. It is a once-daily LAMA that has been in 22 ongoing or completed trials listed in clinicaltrials.gov. A Phase I trial in healthy volunteers was reported in February this year. The only significant drug-related side effect was headache. Reportedly the drug, now in a Phase III trial, will be developed as a monotherapy for COPD. Two doses, 125 mg and 62.5 mg, are being tested. The agent will also be paired with GSK's vilanterol for a ULAMA-ULABA combination. Theravance also has a ULAMA, TD-4208, that concluded a successful Phase IIa study late in 2011 with clinically significant FEV1 peak and trough outcomes.

MABA, GSK961081 The GSK-Theravance collaboration is also developing this MABA. A phase I study on 24 healthy subjects was concluded in mid-2011. But a more interesting trial was a Phase I study of the combination of this MABA with fluticasone that was recently completed (NCT01449799). I am not aware of the results, but this represents the advance towards what amounts to a triple combination which could be regarded as the holy grail of COPD controller medications.

InterVaporTM or bronchoscopic thermal vapor ablation (BTVA) is another approach to minimally invasive lung volume reduction that I reviewed previously (4). Two Phase I studies have recently been completed by the sponsors, Uptake Medical Corporation. Enrollment criteria included heterogeneous distribution of emphysema with upper lobe predominance. Up to 3 unilateral lobar segments, selected by severity, were treated with a thermal dose of 10 calories per gram of lung tissue. Delivery of the heated water vapor produces a localized inflammatory response which resolves in 4–12 weeks by fibrosis and atelectasis of the segments distal to the thermal injury. Coprimary outcomes in one study were an increase in FEV1 of about 10% and a decrease in St. George's Respiratory Questionnaire (SGRQ) score of an amazing 11-14 units. Safety was the primary outcome in the other study. Improvements in lung function and SGRQ were more-or-less stable for 12 months with some decline after 6 months. Patients with more severe disease, GOLD stage IV, and those with greater heterogeneity experienced better outcomes. Preliminary outcomes have been reported (5, 6), and a visual of the technique is provided by the sponsors http://medgadget.com/2012/01/the-future-of-intervapor-qa-with-uptakes-chief-medical-officer-steven-kesten.html

The Unpipeline. Darotropium the ULAMA being developed by GSK has been discontinued presumably, it is said, because of lack of efficacy.

Some of the above information was provided by TrialTrove.