With positive signs for its stable of cancer drugs, including an imminent filing for the sarcoma candidate ridaforolimus, Ariad Pharmaceuticals Inc. is nearing the turning point from a development to a commercial company.

At the end of June, after the American Society of Clinical Oncology meeting, Ariad’s stock was trading at about $10, almost double the $5.15 price in December 2010 and triple the $3.35 going rate in June 2010.

The trajectory reflects hopes for Ariad’s portfolio, which includes four oncology candidates. Farthest along in development is the mTOR inhibitor and sarcoma candidate ridaforolimus, partnered with Merck & Co. Inc. (Also see "Merck/Ariad Form Billion-Dollar Collaboration To Develop mTOR Inhibitor For Cancers" - Pink Sheet, 12 July, 2007.). Ridaforolimus is nearing the finish line, following the release of full results from the pivotal Phase III SUCCEED study at ASCO.

Ariad is moving forward with other oncologics that it intends to sell itself, with a specialty sales force that will be put in place to co-promote with Merck on ridaforolimus.

Next up is the pan-BCR-ABL inhibitor ponatinib in drug-resistant chronic myelogenous leukemia and Philadelphia-positive acute lymphoblastic leukemia. The company said enrollment in the PACE pivotal trial has ramped up much more quickly than expected and is due to complete by the third quarter. Interim data are now expected by end-2011.

Further back in the pipeline is a once-daily anaplastic lymphoma kinase (ALK) inhibitor in preclinical development for non-small cell lung cancer, which the company envisages as a more potent rival to Pfizer’s twice-daily ALK inhibitor crizotinib, now under FDA review. On June 16, Ariad announced that AP26113 also inhibits the EGFR T790 mutation, which accounts for 50% of cases of resistance to EGFR inhibitors. There are only about 40,000 ALK-positive patients globally. But there are an estimated 125,000 worldwide who carry the EGFR mutation.

The medical need is “huge,” Timothy Clackson, president of R&D, said during a June 17 R&D day: “Adding EGFR activity to ALK activity substantially increases the potential number of patients that can be addressed with ‘113 by up to four-fold.”

Ariad's NSCLC candidate AP26113 inhibits EGFR mutations as well as ALK, expanding its potential beyond Pfizer's crizotinib.

The company is planning to file an IND in June, then start a Phase I/II trial in the third quarter and possibly move into a pivotal study in 2013.

A fourth candidate – AP1903 – is partnered with Bellicum Pharmaceuticals Inc. and is Phase II-ready. Bellicum has it in a Phase I/II trial in castration-resistant prostate cancer as an activating agent used in combination with its therapeutic vaccine BPX-101.

Paving The Way For Ponatinib

Merck confirmed it will submit an NDA for ridaforolimus in the U.S. and also plans to file in Europe sometime this year. Ariad intends to file ponatinib in the U.S. and Europe in the middle of 2012. Both drugs should meet the criteria for priority review with FDA, according to the company.

Through a co-promote option, Ariad will be responsible for up to 20% of the commercialization of ridaforolimus in the U.S., but Merck will foot the bill (Also see "Ariad Opts-in To Co-Promote mTOR With Merck" - Pink Sheet, 18 March, 2011.).

Role in selling ridaforolimus will pave the way for commercial transition.

Ariad will hire its own sales representatives once it gets word from Merck on ridaforolimus commercial plans. The experience will allow Ariad a means of transitioning from a development company to a commercial enterprise. Ariad intends to manage commercialization of ponatinib in the U.S. and probably also in Europe, but is seeking a partner elsewhere.

“The Merck co-promote dovetails in with commercial plans for ponatinib,” Chief Executive Officer Harvey Berger said in an interview.

SUCCEED Results Detailed At ASCO

The ridaforolimus filing will be supported by the pivotal SUCCEED study of the drug as a maintenance treatment after chemotherapy in 711 patients with a variety of sarcomas. The study had been designed with an SPA.

The drug demonstrated a 28% reduction in median PFS (HR 0.72) at 17.7 weeks versus 14.6 weeks. The p-value for this result was less than 0.0001. Ariad argues that the hazard ratio is more telling than the three-week difference in median PFS. Many factors could have influenced the outcome, including the type of prior chemotherapy used and underlying disease, execs said in response to questions from analysts during the R&D day. “Median PFS is absolutely not the parameter to look at,” said Chief Medical Officer Frank Haluska. “You really have to look at a separation of the curve over the entire period of time.”

Will PFS Do The Trick For Ridaforolimus?

The SUCCEED study wasn’t powered for overall survival, but there was a positive trend, the company reported. During the R&D day, execs faced questions about whether the lack of OS benefit on top of a statistically significant benefit for PFS would present a regulatory hurdle.

In mid-2010, Ziopharm Oncology Inc. failed to secure an SPA for a first-line study of its sarcoma treatment Zymafos (palifosfamide) due to disagreement with FDA about the proposed endpoints. The company proceeded without an SPA; the PICASSO 3 trial is using PFS for accelerated approval and will continue, with no crossover, to assess overall survival to support full approval.

Ariad stressed that it has an SPA for ridaforolimus and that PFS is an appropriate endpoint in the maintenance setting. Feedback from FDA suggests that the agency is also interested in the overall consistency of data supporting the application, including subgroup analyses, said Berger. “PFS with a trend in OS” is exactly what the agency is looking for, and overall, the findings are very consistent, he said.

Matthew Alsante, executive director of the Sarcoma Foundation of America, commented that “We consider PFS a meaningful clinical benefit for sarcoma patients.” Alsante noted that there are only about 12,000 new sarcoma cases each year in the U.S. and about 100 different subtypes: “It’s always a challenge with sarcoma or any rare cancer to power a study for survival. The numbers alone make it almost impossible.” Sarcoma represents a significant unmet need, a factor that can go a long way with FDA.

Reimbursement In CML Under Scrutiny

With ponatinib, Ariad is setting its sights on the CML market, which is currently dominated by other BCR-ABL inhibitors backed by big pharmas. Launching ponatinib will give the company the opportunity to “take a leadership role in marketing, selling, distributing and commercializing” a drug, a much bigger opportunity than co-promoting ridaforolimus, according to Berger.

Ariad is touting its resistance profile. In a Phase I study, the drug produced a major cytogenic response in 66% of participants, including all of those with a T315I mutation, which is particularly resistant to existing therapies. And preclinical data suggests resistance could be prevented from emerging in the first place.

Novartis AS’s Gleevec (imatinib), which is set to go generic in the U.S. in 2015, is firmly entrenched in the space and the company’s Tasigna (nilotinib) is being positioned as a successor. Bristol-Myers Squibb Co.’s Sprycel (dasatinib) is another second-generation BCR-ABL inhibitor in the race for market share, but Gleevec continues to hold the lion's share of the field.

The pivotal PACE trial tests ponatinib in patients resistant to existing therapies, but Ariad is also planning to position ponatinib as a first-line drug. A study in first-line CML, which Ariad will use as the confirmatory trial in the NDA, is being planned for mid-2012. If data show that the drug is able to prevent resistance from emerging, the candidate in theory could gain a competitive edge as a first-line option.

Ariad faced questions about reimbursement and commercial challenges in the CML market during its R&D day. Government bodies have push back on pricing in Europe, where the second generation BCR-ABL inhibitors cost about $86,000 compared to $50,000 for Gleevec (Also see "NICE Rejects Leukemia Drugs On Eve Of Conference That Likely Will Debate Cancer Policies, NICE's Future" - Pink Sheet, 6 May, 2011.). In the U.S., the list price for Gleevec is $47,000 versus $99,500 for Sprycel and $91,500 for Tasigna.

CML expert Michael Mauro, Oregon Health & Science University, said there also are issues in the U.S., despite strong data and incorporation of newer drugs into treatment guidelines. “There are still payers in the U.S. that require imatinib [to be used] prior to dasatinib and nilotinib,” he noted.

But second generation BCR-ABL inhibitors are making inroads into first-line CML. According to Kantar Health’s CancerMPact Monthly Drugs and Regimens, Gleevec had a 90% share of first-line CML patients in the U.S. prior to June 2010, when Tasigna received first-line approval. This dropped to 73% in 2011, not a “huge dip in utilization” but demonstration that there has been some movement in the market, said Stephanie Hawthorne, a director at Kantar Health.

Tasigna has claimed most of the first-line gains, according to Kantar, as opposed to Sprycel, which was cleared by FDA for first-line CML in December. It’s possible that more education of clinicians about the clinical significance of the major molecular response endpoint used in Tasigna research could further expand its share in first-line CML, in Hawthorne’s view.

Compared to treatments for other more common cancers, CML drugs are “not on payers’ radar,” in the U.S., commented Terry Tao, also a director at Kantar Health. However, after Gleevec’s patent expires, the more costly next-generation BCR-ABL inhibitors are likely to face more scrutiny from payers. Considering the small patient population, CML is unlikely to become the target of the pathway programs that payers are using to guide care, Tao said ([See Deal]). But the CML drugs may be viewed as interchangeable and could be managed by payers through simple and low-cost step therapy and formulary restriction tools, she said.

It remains to be seen whether a superior resistance profile, if proven, will prove compelling enough to support first-line use of ponatinib over a generic imatinib, or whether physicians will instead opt to reserve ponatinib for resistant cases, Hawthorne commented.

During the R&D day, Haluska said that the development strategy for ponatinib down the line could include additional studies, for example in high-risk patients, to help make the commercial case. But the first priority will be gaining approval, he said.

By Emily Hayes

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