Cell Therapeutics & pixantrone: Putting the B.O. in biotech

They put the B.O. in biotech, and they're back—Seattle's own Cell Therapeutics Inc (CTI).

Two decades in business and nothing—and I mean nothing—to show for it. Well, in that time they have spent $1.5 billion, which is something of an achievement.

And yet after discussions with the FDA, it appears they will be taking another shot at getting their lead oncology drug candidate, pixantrone (Pixurvi) to market with yet another phase III trial.

CTI pitches pixantrone as a potential third-line (sorry, now it's second- to fourth-line) treatment option for patients with aggressive, relapsed or refractory diffuse large B-cell lymphoma who have failed two previous therapies. They hype pixantrone as having all the efficacy of an anthracycline but without the cardiotoxicity (a claim flatly refuted by experts at the FDA).

Recall last year around this time: CTI had submitted the results of the first pivotal phase III trial of pixantrone, known as the EXTEND trial, or PIX301, seeking market approval. Instead, they got rejected and then bitch-slapped by Richard Pazdur, the head of the FDA's oncology drug office.

Little surprise they have appealed the decision. In the meantime, they will be recruiting for the the so-called PIX-R trial, which will compare pixantrone + Rituxan to gemcitabine (Gemzar) + Rituxan. Gemzar is not FDA-approved to treat any type of lymphoma, but there is some evidence of its potential in this setting [1, 2].

CTI in hot water

Legal problems have hounded them, especially in the past decade. In 2008 they paid $5.1 million to a financial management company in a civil action claiming breach of contract. They paid another firm cash and stock to settle another breach of contract claim.

In 2007 they reached a settlement agreement with the US Attorney's Office, which had launched an investigation into CTI's unsavory marketing and promotion practices as they pertained to the drug Trisenox (arsenic trioxide), a form of the well-known poison arsenic, indicated for patients with relapsed or refractory acute promyelocytic leukemia.

The scheme by CTI to generate sales of Trisenox included paying illegal kickbacks to high-prescribing physicians and taking them on all sorts of fun getaways.

CTI did not admit guilt, but they did pay $10.6 million to settle the lawsuit. That may have put a few bucks back into Medicare coffers, but it was little help for the patient population highlighted in the box below.

ZEVALIN

The best, most innovative and effective treatment they ever had in their portfolio was the radioimmunotherapy treatment ZEVALIN for the treatment of indolent NHLs like follicular lymphoma. They owned half of Zevalin for maybe a year before getting rid of it, likely because it wasn't profitable enough.

CTI also probably learned pretty quickly that Zevalin is not easy or convenient to administer, and it has to be sourced out to specific treatment centers and nuclear medicine departments. Apparently too much hassle.

The EXTEND bomb

So here's how the EXTEND trial went down:

-- In 2004, CTI and the FDA agree on an SPA for pixantrone's EXTEND trial, contingent in part on a patient enrollment of 320 (a Special Protocol Assessment (SPA) is an agreement of sorts between the FDA and a drug company saying that the FDA has approved of the company's clinical trial design, endpoints, details like enrollment number, etc.)

-- In June 2005, the EXTEND trial (#NCT00088530, aka PIX301) goes live at ClinicalTrials.gov.

-- After 45 arduous months, CTI concludes that patient recruitment is a bitch!

-- On August 30 2007, CTI makes multiple minor changes to the study's page at ClinicalTrials.gov. This web site archives all such changes, revealing that one change made by CTI is to the expected enrollment number: It was 320. Now the entire line has vanished.

-- In March of 2008 they finally notify the FDA that enrollment has been halted at 140, just 44% of 320 [NB:When Pazdur and the FDA analyzed the raw EXTEND data, they determined that over two dozen trial participants did not actually have an aggressive cancer in the first place]

In halting enrollment, they had effectively invalidated the SPA—something they neglected to tell their shareholders—which is why they got hit with a class action lawsuit concerning pixantrone which alleges that company principals like CEO James Bianco committed securities fraud and in sum ripped them off by lying about important milestones in the drug's development. Not surprisingly, principles like Bianco have financial rewards attached to seeing certain products like pixantrone reach various stages of the approval process

Pixantrone, take two

Personally I think we can do without pixantrone, especially since CTI has never managed to show that it has any true efficacy beyond the pre-clinical setting, and especially since they would likely have to charge an astronomical price to have any hope of making any money—and the end result for a good 80-90% of the people who take it will be the same result if they never took it at all, except they would spend the last few months of their lives enduring the worst side effects chemotherapy has to offer.

You know, after 45 months CTI managed to recruit just 140 patients to the EXTEND trial.

What makes them or anyone think they'll find 350 for PIX-R?

By Ross Bonander