With an FDA advisory committee recommendation for approval and a May 4 PDUFA date, InterMune holds a significant lead over the rest of the field and should be first to market with a drug to treat idiopathic pulmonary fibrosis.

InterMune's pirfenidone, an oral, small molecule dual inhibitor TGF-beta and TNF-alpha synthesis, obtained a 9-3 vote in favor of approval from the Pulmonary-Allergy Drugs Advisory Committee on March 9. The positive vote came even though the panel had voted only 7-5 that InterMune had demonstrated its drug was efficacious in slowing the deterioration of lung function associated with IPF (¹ Also see "Pirfenidone Panel Highlights Difficulty Of Selecting Primary Endpoint In IPF" - Pink Sheet, 15 March, 2010.).

An estimated 100,000 Americans are living with IPF, a scarring of the lungs of unknown origin, with more than 30,000 new cases diagnosed annually. (Statistics for Europe are thought to be similar to those in the U.S.) The five-year mortality rate for IPF is 50 percent to 70 percent, worse than the prognosis for ovarian, colorectal and breast cancer, and the only effective therapy at present is lung transplant.

IPF is designated an orphan disease in both the U.S. and EU, meaning a drug approved for that indication would enjoy market exclusivity of seven years in the U.S. and 10 years in Europe. However, even if pirfenidone is approved, it will be positioned only as a treatment to slow IPF progression, not a cure, leaving substantial room in the market for other IPF drugs.

In an interview, Lazard Capital analyst Terrence Flynn called IPF "at least a billion-dollar market," assuming that drugs for pulmonary arterial hypertension, which cost about $50,000 to $60,000 annually, will serve as a price proxy.

InterMune isn't likely to have that market to itself for very long, as more than a dozen companies have IPF drug development programs in place, some of which are line extensions of already approved drugs.

Robert W. Baird & Co. analyst Thomas Russo believes pirfenidone sales will ramp up quickly, more than doubling between 2011 and 2013, and nearing blockbuster status with $947 million in net sales in 2015.

"The likelihood that future drugs entering the space would be added on, rather than competing for share, is also favorable to the first mover," Russo wrote in a March 10 note on pirfenidone. "Our feedback from the medical community suggests very high intent to prescribe any approved therapy to these patients with no other effective options."

Besides lung transplant, the current standard of care is steroids and anti-inflammatory drugs, which have shown virtually no utility in IPF.

Even more bullish on pirfenidone's market prospects is Canaccord/Adams analyst Adam Cutler, who predicts 2011 EU approval to follow U.S. approval this year, and the drug eventually posting blockbuster net sales in both markets.

Blockbuster Sales Expected Quickly

In a March 10 note, Cutler projects U.S. sales to increase by more than 600 percent from 2010 to 2011 and then hit blockbuster status at $1.14 billion in 2012. By 2016, he expects U.S. sales of pirfenidone - to be marketed as Esbriet - to reach $2.06 billion.

In Europe, he also anticipates a quick ramp-up, with net sales more than quadrupling in 2012, the first full year of marketing, and hitting the billion-dollar mark in 2015 at $1.16 billion. In 2016, he projects worldwide sales of pirfenidone to near $3.3 billion.

InterMune CEO Dan Welch noted in an interview that his company has invested about $500 million in the development of pirfenidone to date, but would not provide any sales estimates or goals. He insisted the biotech's main concern is addressing the significant unmet medical need.

"Having worked in the field for 10 years, and having invested more than any other company, government [and] academic institution combined in the pursuit of new medicines for IPF, it would please us beyond what one can express to bring the first medicine to these patients," he said.

About six-and-a-half years ago, Welch added, there was hardly anything in clinical development for IPF other than pirfenidone, but that has changed, as there has been a "mushrooming" of therapies targeted at the disease. InterMune hopes other drugs will come along to help pirfenidone in the treatment of IPF, he said.

One of those second-generation drugs may be InterMune's own ITMN-520, a follow-on that the company believes could have pharmacokinetic and adverse-event advantages over pirfenidone. The '520 program is still in the preclinical stage, however.

PAH Drugs Investigated In IPF

Among the more advanced IPF programs have been a pair of label-extension efforts for drugs already approved for PAH, Actelion's Tracleer (bosentan) and Gilead Sciences' Letairis (ambrisentan), both of which are endothelin receptor antagonists.

On March 1, Actelion announced that its Phase III BUILD-3 study of bosentan in IPF failed to meet its primary endpoint of reduction in morbidity/mortality, despite "a consistent trend in favor of bosentan."

No further studies of that drug in IPF will be undertaken, the company said, while adding that it is developing a second endothelin receptor antagonist, macitentan. Macitentan currently is in Phase III study for PAH and Phase II for IPF, with the 150-patient IPF study expected to enroll fully in late 2010 and report data in second-half 2011.

Meanwhile, Gilead is testing ambrisentan in a Phase III placebo controlled trial of PAH patients with associated IPF. Begun in July 2009, the planned 225-patient study is expected to be complete in February 2012.

In addition, Novartis is testing its leukemia drug Gleevec (imatinib) in IPF. The program has reached Phase III, with a regulatory filing planned for 2011 or later, according to Elsevier's Inteleos database.

Low-Profile Biotechs Also Pursuing IPF

It's not just high-profile biotechs and pharma companies that are seeking a therapy or cure for IPF, however. Lesser-known, privately held companies like Arresto Biosciences, Amira Therapeutics and Promedior also have IPF candidates on the verge of entering the clinic.

Amira's focus is on a potentially disease-preventing approach to IPF - developing small-molecule antagonists of the LPA1 receptor. LPA1 is up-regulated in IPF, CEO Bob Baltera said in an interview, and preclinical testing in mice has shown that knocking out the LPA1 gene protects subjects from developing lung fibrosis.

The biotech has selected a lead compound and now is in the process of identifying backups, with a plan to begin clinical development during the second half of 2010. "We take what we call programs into the clinic and to us a program is a lead molecule and backups that are structurally and metabolically different," Baltera explained. "Because, in this business, with small molecules, you're often killing a lead compound or two until you find the right one, usually based upon the behavior of the molecule in a person."

He considers fibrotic disease one of the "last few holy grails" for the pharmaceutical industry. "Our approach to this is more Big Pharma-like than it is like small start-up biotech," he added. "We're not a 'bet the farm on one molecule in five different indications' type of company."

Arresto is led by CEO Peter Van Vlasselaer, who spent five years at InterMune during the early development of pirfenidone. More recently, he ran Avidia, focused on inflammation, cancer, neurological conditions and autoimmune disease, until it was purchased by Amgen for $380 million in 2006 (² [See Deal]).

His current company began with a focus on oncology, Van Vlasselaer explained, but found its approach of developing humanized monoclonal antibodies to block the lysyl oxidase 2 (LOXL2) enzyme also showed promise in fibrotic disease.

Like Amira, Arresto's approach seems to be more about preventing IPF than treating the disease after it manifests. Arresto plans to file an IND for its antibody AB 0024 this May, with clinical development to begin in July. That development program will focus on cancer first, but with a plan to take the same molecule into IPF by the end of the year, Van Vlasselaer said.

"Our approach to fibrosis is [about] preventing the recruitment and local activization of fibroblasts, which is probably a few steps upstream from where other drugs are positioned," he explained. "Most of the other compounds out there are dealing with inhibitors of growth factors and so forth and ... fibroblastic activation [must occur] before you get the growth factors. So by blocking that early pathologic activation pattern that is necessary to start the whole fibrotic cascade, you can actually prevent the downstream production of a lot of growth factors that [other companies] are going after as therapeutic targets."

Meanwhile, Promedior is about to advance its lead program, PRM-151, a recombinant form of human serum amyloid P, into Phase II in fibrotic disease, but prevention of fibrosis following glaucoma filtration surgery is the lead indication, CEO Dominick Colangelo said in an interview (³ Also see "Venture Rounds Help Promedior Advance Lead Program In Multiple Indications" - Pink Sheet, 16 March, 2010.).

Renal and pulmonary fibrosis, however, also are on the company's map, he added. "We've done a lot of work in pulmonary fibrosis models [and] we've seen great efficacy, so clearly it's one of the high-priority items on our list," he said.

Other IPF Candidates At Varying Stages

According to Inteleos, there are at least nine other IPF drug candidates in various stages of development, several advanced as far as Phase II.

Boehringer Ingelheim boasts one of the more advanced programs, BIBF-1120 ( Vargatef ), a novel, indoline derivative triple angiokinase inhibitor which targets three growth receptors key to the development of blood vessels. In August 2007, it launched a Phase II trial testing four doses of '1120 in patients 40 years and older with IPF.

United Therapeutics has advanced Aviptadil , a synthetic version of human vasoactive intestinal peptide (VIP), to Phase II, with a trial that began in late 2007 still ongoing.

Centocor launched a Phase II trial in 2008 of CNTO-888, a recombinant monoclonal antibody that targets the human CC chemokine ligand 2 (CCL2). The safety and efficacy trial, testing U.S. patients aged 40-80, has a primary endpoint of pulmonary function.

Fibrogen completed a Phase Ib study of FG-3019 in 2004 in IPF patients aged 21-80. Clinical development is ongoing with a Phase II study begun in 2005. FG-3019 is a fully human monoclonal antibody that targets connective tissue growth factor.

Hiyashibara Biochemical Labs initiated a Phase II trial in 2008 for an oral lozenge formulation of interferon alpha. Completion was expected in December 2009, with a primary endpoint of frequency/severity of cough.

A handful of other programs are in the IND stage, with at least three planned to enter clinical development later this year.

United Therapeutics is partnered with ImmuneWorks on IW-001, an immunomodulator that inhibits transforming growth factor-beta synthesis. The companies plan to launch a Phase I trial during the second half of 2010.

ImmuneRegen Biosciences filed an IND in May 2009 for homspera, a topical immunostimulator that the company says enhances stem cell proliferation. It plans to launch a clinical trial in the fourth quarter.

Neopharm has submitted an IND and plans a Phase I safety, maximum tolerated dose and efficacy trial for cintredekin besudotox (IL-13-PE38) in patients with advanced IPF. The compound is an interleukin-13 receptor antagonist with cell-growth inhibition and cell survival modulation properties, according to the company.

Finally, little has been disclosed about APT Pharmaceuticals' oral inhaler immunomodulator for IPF. The candidate has been in preclinical trials as of July 2009.

- Joseph Haas ( ⁴ j.haas@elsevier.com )

InterMune Likely First To Market In IPF, But Other Firms Poised To Follow

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