ASCEND Data Put InterMune’s Pirfenidone On Top

Phase III trial of idiopathic pulmonary fibrosis drug puts company in strong position for FDA approval of first treatment for orphan disease and strong reimbursement in U.S. and abroad.

Positive results from InterMune Inc.’s ASCEND trial of the idiopathic pulmonary fibrosis drug pirfenidone have strengthened the orphan product’s position for both regulators and payers.

Top-line data from the ASCEND trial, conducted following a 2010 “complete response” letter, have been extremely well received by Wall Street. The company’s stock was up about 170% Feb. 25 following the data release. UBS analysts said the findings “are a near best-case,” “suggest an approvable drug in the U.S.,” and set a high bar for competitors. “We believe the clinical bar is now set significantly higher and now see Boehringer Ingelheim data as more likely positioning [its competitor as] a second-line agent,” the analyst note adds.

Boehringer Ingelheim GMBH is the furthest along of any other company seeking approval for an IPF indication (Also see "After Pirfenidone: Broad Competition To Bring First Therapy For Underlying Cause Of IPF To Market" - Pink Sheet, 26 Mar, 2012.). BI’s candidate, nintedanib, has completed Phase III trials, but no data have been released.

JP Morgan analyst Mike Kotecki said comparison of the pirfenidone data to the nintedanib data is still key at this point, but “we’d argue that BI is less relevant given that nintedanib data isn’t likely to be materially better than ASCEND and our model already assumes BI and InterMune in the marketplace. The upside case that nintedanib Phase III trials are mixed or undifferentiated from Esbriet is still very much intact.”

On a Feb. 25 investor call, InterMune also said the results of ASCEND position the company for potentially better reimbursement in countries where the drug, marketed as Esbriet, has already received regulatory approval. Pirfenidone is the only product approved anywhere to treat IPF.

InterMune described ASCEND as “very, very strong in every respect,” and stronger than the one already positive Phase III study submitted as one of two pivotal trials in the original NDA.

The company said its health economics group and outside consultants are “very enthusiastic” about the ASCEND study results. Conservatively, the data “put some high-impact shield around our pricing and reimbursement status today. Another way of saying it is these data make our current pricing and reimbursement even stronger and then we can hope to maintain the prices we have longer than we might have and in some cases seek to find a price increase. Although I wouldn’t want to lead you to an expectation of increases in European [pricing] because this is quite rare,” he said (Also see "U.K.’s NICE Backs Esbriet, Xolair And Orencia After Getting Price Discounts" - Pink Sheet, 23 Apr, 2013.).

InterMune plans to resubmit its NDA to FDA in the third quarter and anticipates a six-month review, positioning it for a second-quarter 2015 U.S. launch. It said it has not heard from FDA regarding a potential advisory committee but is preparing for one.

BioMedTracker analyst Peter Chang noted that Boehringer could file its drug around the same time as InterMune and, if granted a priority eight-month review, the two drugs could be approved around the same time as well.

Grounds For Ascension?

Pirfenidone hit the primary endpoint of significantly reducing IPF disease progression as measured by change in percent predicted forced vital capacity (FVC) from baseline to week 52 in the ASCEND trial. At week 52, 16.5% of patients in the treatment group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group, representing a 47.9% reduction in the proportion of patients who experienced a meaningful change in FVC or death.

Additionally, 22.7% of patients in the treatment group experienced no decline in FVC at week 52, compared with 9.7% in the placebo group, the company announced.

Chang said that while there was some question about the clinical meaningfulness of FVC changes at the last advisory committee meeting, according to meeting minutes panel members felt “although there are still not enough data, the change in FVC of 10% or more may be related to a clinically meaningful effect size” (Also see "Pirfenidone Panel Highlights Difficulty Of Selecting Primary Endpoint In IPF" - Pink Sheet, 15 Mar, 2010.).

Pirfenidone also met key secondary endpoints demonstrating significant treatment effects on the six-minute walk test and progression-free survival. A 50-meter decrease in walk distance is considered an independent predictor of mortality in an individual patient with IPF and in ASCEND the drug reduced by 27.5% the proportion of patients who experienced a decline in six-minute walk distance of 50 meters or greater.

ASCEND also had pre-specified secondary endpoints looking at all-cause mortality, treatment-emergent IPF-related morality and change from baseline to week 52 in dyspnea, including pre-specified analyses for the pooled population of the ASCEND study and the previous Phase III CAPACITY studies for the mortality analyses.

Chang said supportive data on the six-minute walk distance test and mortality endpoints could help overcome concern regarding the clinical meaningfulness of the FVC endpoint.

The trial did not meet the dyspnea endpoint.

Mortality Data Promising, Could Help U.S. Pricing

There were fewer all-cause mortality events and treatment-emergent IPF-related mortality events in the treatment arm of the ASCEND study, but the study was not powered to show a difference on this endpoint. However, the pre-specified analyses of the pooled population from ASCEND and the CAPACITY studies showed the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group, and the risk of treatment-emergent IPF-related death in the pirfenidone group compared to placebo was reduced by 68%.

FDA expressed preference for seeing a mortality analysis at InterMune’s March 2010 advisory panel and InterMune said on its Feb. 25 call that the pooled data on mortality were one of the agency’s requests for the NDA resubmission (Also see "Despite Positive Advisory Committee Vote, InterMune Gets Complete Response For Pirfenidone" - Pink Sheet, 4 May, 2010.).

Chang said the fact that mortality was adjudicated in ASCEND “should help bolster confidence since there were questions at the last [advisory committee] meeting whether lack of adjudication could be an issue.” But he also noted that because the deaths in CAPACITY were not centrally adjudicated there could be questions on how to combine these, “especially IPF-related deaths.”

And while the pooled mortality data are positive, Chang noted that more details are needed for a precise estimate since the analysis excluded deaths in the CAPACITY trials after a year.

Because InterMune and BI’s development programs used different primary endpoints – Boehringer is measuring annual rate of FVC decline – comparing the two drugs will depend on secondary endpoints, Chang pointed out. In Phase II, BI’s nintedanib had a trend for a benefit on repository-related mortality though not on all-cause mortality, he said. However, the earlier study was quite small, so it could still show a mortality benefit in Phase III.

The positive mortality data seen in a pre-specified pooled analysis of data from ASCEND and previously conducted Phase III trials of pirfenidone should help reimbursement prospects, InterMune said.

In countries that use quality-adjusted life year (QALY) metrics or an incremental cost-effectiveness ratio (ICER) where a big component of that metric is mortality and hospitalizations, such as in the U.K., the ASCEND data should “strongly bolster our file that has already led to reimbursement,” InterMune said. “In some cases you can see price increases in some countries; it has happened in the NICE setting in the U.K. where new data have led to a stronger ICER or stronger QALY that has led to an increase in price.”

Chang said he thinks it will be difficult to convince European authorities to increase reimbursement much “since they know the company will supply the drug even if they do not.” But he added, “unless the mortality analysis comes out much different when the FDA looks at it, the data could help them secure better pricing in the U.S.”

InterMune said it believes the well-established safety and tolerability of the drug will be an important differentiator on top of the efficacy and probably the mortality differentiator.

There were more serious adverse events in the placebo arm of the trial than the drug arm, and analysts were not very concerned about the case of Hy’s law seen in ASCEND. Chang said the Hy’s law case “is of concern, but given other benefits of the drug and no other treatment, we tend to think that will not stop it from being approved depending on how the FDA views the supportive data, like mortality.”

UBS forecasts $750 million in U.S sales of the drug by 2020.

Esbriet had $70.2 million in revenues for 2013, InterMune announced Jan. 9, up from $26.2 million in 2012.

New Options In The Works

InterMune is currently working on new formulations of the drug to decrease the pill burden. Currently the drug is dosed three times a day with up to three tablets taken at each time period.

The company is also working on developing a pirfenidone analog that it says is at least 10 times more potent than pirfenidone. The company said it could be dosed once or twice a day, and in animals the GI profile of the drug was meaningfully better and the fibrosis activity seems to be much more impressive than pirfenidone. It plans to put the drug into the clinic sometime next year.