Forest Runs Into Tree by Steve Usdin Biocentury This Week Washington Editor the Presentation Forest Laborato- Ries Inc
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WEEK OF APRIL 12, 2010 BioCentury THE BERNSTEIN REPORT ON BIOBUSINESS Volume 18 Number 17 Page A1 of 19 Regulation Forest runs into tree By Steve Usdin BioCentury This Week Washington Editor The presentation Forest Laborato- ries Inc. made at last week’s Pulmonary- Cover Story was able to identify and in-license what the newco believes to be best-in-class topical Allergy Drugs Advisory Committee about Forest Runs into Tree — An FDA panel Rho kinase inhibitors for glaucoma from Daxas roflumilast to treat COPD would voted against Daxas for COPD because Asahi Kasei./A11 have been perfect — if it had been made Forest did not address the agency’s de facto a decade ago. For better or worse, FDA has moved on, so instead of the endorse- comparative effectiveness hurdles. Approval Emerging Company Profile for life-long use based on modest efficacy ment Forest hoped for, a regulatory strat- vs. placebo was possible a decade ago, but Impossible to Ignore — Selecta is egy and procedural tactics out of synch the agency now wants clear benefit over building nanoparticle vaccines that can with the realities of 2010 produced a 10- standard of care. stimulate a strong response in lymph node 5 recommendation against approval. cells against antigens that the immune Forest’s experience hammers home Strategy system otherwise would ignore./A12 some of the changes a decade’s focus on drug safety have wrought. pRED: Making the Transition — Roche Ebb & Flow Simply showing an incremental, statis- has refined the structure of its early R&D tically significant improvement over pla- organization to put decisions into the Crunch Time — Tengion’s down round. De- cebo for a broad, undifferentiated popula- hands of scientists while defining success as risking: Horizon-Nitec. Dinove, Neovacs ready tion with multiple treatment options is no the number of projects that make the to IPO. DRI hits a triple. Orbimed in Israel. longer a safe regulatory strategy. handoff to later-stage development./A7 Revisiting Achaogen. Tongjitang tries again. Submitting an NDA for chronic use of gRED: Small Company Sensibilities — Also: Carlyle Group. Cell Therapeutics; Keryx; a compound with known adverse effects Former Cytokinetics Chairman and CEO Basilea, Crucell et al./A13 without a proposed risk evaluation and James Sabry says he will bring small biotech mitigation strategy (REMS) invites skepti- experience and expertise in neurology as Online this week/A18 cism from advisory committee members. And the need to cram additional time- the new VP of Genentech partnering./A8 Stock charts & tables/A17 consuming safety reviews into drug Stahel Sees Scale in India — Indian Company index/A18 evalutions has squeezed flexibility out of diabetes company Connexios is patterning the process, making the agency reluctant itself after Western biotechs. A big research to consider changes to an indication sub- TM team focused on understanding of disease BioCentury 100 Indicators See next page biology has attracted former Shire CEO Week ended 4/9/10 Rolf Stahel as chairman./A10 PRICES VOLUME Mining its Rho-lodex — Based on its 2001.04 1302.3M shrs Global Health Forum founders’ relationships in Japan, Altheos up 0.8% up 76% Registration is open for the Partnering for Global Health Forum 2010 in Chicago. Please see announcement following A19. This Week in SciBX BIO India The first BIO India International Partnering Managing Microglia in Alzheimer’s — New research indicates microglia play opposing roles Conference includes a special tour of the in AD, and provide a road map for how to clear ß-amyloid plaques without destroying healthy nation’s top biotech sites. Please see announce- neurons. Please see Table of Contents on A9. ment following A19. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 12, 2010 PAGE A2 OF 19 Regulation, varies based on disease severity and smok- efits are minimal, or if efficacy is restricted from previous page ing status. Smokers with severe COPD to a small portion of the total population have a life expectancy of 8.5 years, ac- (see “Modest Efficacy”). mitted six months after filing of an NDA. cording to a study by Robert Shavelle and Daxas was developed based on the As a result, the Daxas NDA, which has colleagues at the Life Expectancy theory that a selective phosphodiesterase- an undisclosed mid-May PDUFA date, is Project published in the International Jour- 4 (PDE-4) inhibitor would target systemic virtually certain to receive a complete nal of Chronic Obstructive Pulmonary Disease and pulmonary inflammation, and that it response letter. in April 2009. would be free of the off-target adverse The questions going forward are what Moreover, Forest is pursuing a com- effects associated with theophylline, a ge- needs to be done to salvage the NDA — pound that has demonstrated only modest neric non-selective PDE-3 and PDE-4 in- whether FDA will be satisfied with essen- efficacy and that has no discernable ben- hibitor approved for COPD. A range of tially repackaging the application with a efit for at least half the patients who take serious cardiac and other adverse effects revised indication and a REMS, or if it will it. This is bound to raise questions in an prevent widespread use of theophylline. require lengthy clinical trials — and era in which FDA is becoming increasingly However, Nycomed and Forest have whether Forest will be willing to invest concerned about exposing massive num- not determined Daxas’s precise mecha- sufficient additional resources to meet the bers of patients to adverse effects if ben- See next page agency’s demands. The specialty pharma company, which Modest efficacy faces patent cliffs for its Namenda memantine for Alzheimer’s disease and Forest Laboratories Inc. (NYSE:FRX) submitted four one-year Phase III trials comparing Daxas to Lexapro escitalopram for depression and placebo. Co-primary endpoints were the number of moderate or severe exacerbations and forced anxiety, paid Nycomed $100 million last expiratory volume at one second (FEV1). Studies M2-111 and M2-112 evaluated a broad population summer for U.S. rights to Daxas (see of patients with severe COPD, while the subsequent M2-124 and M2-125 trials included only patients BioCentury, Nov. 23, 2009). with a defined history of exacerbations, signs of chronic bronchitis and a defined cough/sputum The asset was attractive because Daxas symptom score at randomization. Studies 124 and 125 allowed concomitant treatment with long is intended to address a serious and large- acting beta-2 agonists (about 50% of the patients in each study took LABAs) but prohibited the use scale unmet medical need. If approved, it of inhaled corticosteroids and long-acting muscarinic antagonists during the treatment period. would be the first new type of therapy in Conversely, studies 111 and 112 allowed inhaled corticosteroids and prohibited use of LABAs and 30 years, and perhaps the only disease- LAMAs altogether. modifying drug, for the estimated 7.6 million Americans who suffer from COPD Daxas produced a statistically significant reduction in the annual rate of moderate or severe associated with chronic bronchitis. exacerbations in the 124 and 125 trials. However, about half the patients had no exacerbations during That potential emerged unscathed the trials, meaning no treatment benefit could be measured based on the primary endpoints.There from the advisory committee meeting, as was an increase of 3-5% in FEV1 in the Daxas arms of the Phase III trials. FDA concluded the increase patients have few good treatment options. was statistically significant but not clinically meaningful. (A) Intent to treat (ITT) population. (B) The But a number of problems, including exacerbation endpoint for Study 112, but not 111, reached statistical significance when the sponsor some that could be expensive and time- performed an FDA-requested post hoc analysis using the same exacerbation definition and analysis consuming to overcome, also came to method used in Studies 124 and 125. Source: FDA briefing documents light. Annual rates of moderate or severe exacerbations (A) Trial Daxas 500 µg Placebo Rate ratio P-value Pooled rate ratio De facto realities M2-124 1.1 (n=765) 1.3 (n=758) 0.85 0.028 0.83 The Daxas clinical development pro- M2-125 1.2 (n=772) 1.5 (n=796) 0.82 0.004 gram, which started with an IND filing in M2-111 (B) 0.6 (n=567) 0.7 (n=606) 0.86 0.129 0.85 1999, left Forest ill-equipped to deal with FDA’s current de facto comparative effec- M2-112 (B) 0.5 (n=760) 0.5 (n=753) 0.85 0.085 tiveness and safety requirements. Frequency of exacerbations (%) (A) Although more than 15,000 COPD patients have received Daxas in four 52- week and two 24-week Phase III trials, it has never been compared to or combined with standard of care, which is use of a long-acting muscarinic agonist (LAMA) and an inhaled corticosteroid in combina- tion with a long-acting adrenergic recep- tor beta 2 (ADRB2) agonist (LABA). Forest is seeking a maintenance indica- tion, with the expectation that patients might take Daxas for the rest of their lives. But in over a decade of clinical develop- 'D[DV 3ODFHER 'D[DV 3ODFHER ment, no one has taken it for longer than 12 months. Life expectancy for COPD patients BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 12, 2010 PAGE A3 OF 19 Regulation, Late revision from previous page “It takes five years to get the At the start of the meeting, Badrul benefit of not having one Chowdhury, director of the Division of nism of action, so they can’t explain why Pulmonary, Allergy, and Rheumatology it causes its own adverse effects, particu- exacerbation.” larly weight loss and neuropsychiatric Products, reported that Forest had sub- mitted a revised indication to FDA in symptoms.