The Bizarre Little Battle over Pixantrone

One of the poorest-performing biotech companies of all time is gaining traction with European regulatory agencies regarding a drug designed to treat some patients with lymphoma. The U.S. FDA remains thoroughly unconvinced of the drug's efficacy. Who's right and who's wrong?

Seattle's own Cell Therapeutics Inc (CTI) has earned a green light from the UK's National Institute for Health and Care Excellence (NICE) to peddle the chemotherapeutic agent pixantrone (Pixurvi) in England. Before that the company scored a similar coup with the regulatory agency repping the European Union.

According to CTI:

1. Pixantrone is labeled as a third or fourth line treatment for patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Currently there is no consensus third or fourth line therapy for these patients beyond a clinical trial or palliative care. That means exactly what you think it means.
2. Pixantrone has the cancer-killing efficacy of an anthracycline without the cardiotoxic side effects of anthracyclines.
3. The results of the company's Phase III PIX301 ("EXTEND") trial demonstrated both of these assertions.

The EXTEND Trial

The EXTEND trial began in 2003 when CTI presented its full phase III trial design for pixantrone to the US Food and Drug Administration, and left with a Special Protocol Assessment (SPA) to conduct the trial. The SPA called for an enrollment of 320 patients with aggressive B-cell NHL who had failed two prior therapies.

They would be split into two arms: half would receive pixantrone, and the other half would receive one of a handful of other, older chemotherapeutic drugs.

Four years later, as CTI prepared to bring their data to the FDA, they informed the agency that they halted enrollment at 140 because they failed to enroll any more patients. Also, CTI had skipped out on an agreed-upon interim analysis of the trial data.

In other words, they had invalidated the SPA.

This was of little concern to CTI, a company that for 20 years had spent $1.5 billion making its executive suite wealthy without providing the public with much of anything in the way of therapeutic drugs.

In 2009 they presented their findings from EXTEND to the FDA seeking the kind of market approval they have since gained in Europe and the UK. The total number of patients enrolled in the pixantrone arm was 70, but ultimately only 68 patients received the drug.

Of those 70 patients:

• 50 discontinued treatment before completing all six cycles
• 19 were from Eastern Europe
• 19 were from Western Europe
• Four were from the United States

According to CTI, data from the EXTEND trial showed that the overall response rate of patients who received pixantrone was 37 percent; put another way, 26 patients out of 70 showed some clinical response to the drug.

Eleven percent, or eight patients, had a complete response to pixantrone. How long this lasted is anybody's guess.

The FDA Responds

The FDA's Oncologic Drugs Advisory Committee released its assessment of EXTEND in 2010. They unanimously recommended that the FDA decline CTI's application for market approval, and some months later the FDA did just that, they said no. Among the reasons:

• Pixantrone was unacceptably ineffective.
• CTI had invalidated the SPA.
• Pixantrone was far more cardiotoxic than it was alleged to be. (As it turns out, it was deemed to be less cardiotoxic in preclinical trials – in mice. In humans it was indeed very bad for the heart.)
• On reviewing the raw data, the FDA determined that at least 24 enrolled patients did not actually have aggressive disease in the first place.

On reading the Committee's review of the EXTEND trial, you get the impression that CTI's presentation was amateurish at best, pieced together at the last minute, like a huge end-of-semester project that you only started working on the night before it was due.

The FDA said that CTI would need to conduct another phase III trial, this time enrolling 350 patients, before it would consider the drug for the US market. In rejecting the application, Dr. Richard Pazdur, head of the cancer drugs office at the FDA, was especially critical of CTI over pixantrone and the EXTEND trial data, adding that it was unclear if the drug had any anti-cancer effect at all because the sample size- 70 people- was far too small to say yes or no with any certainty.

CTI appealed this ruling, but in the meantime sought approval in Europe and the UK.

Despite being presented with the same awful, woefully pathetic data, both the European Commission and the UK have given it a conditional thumbs up.

They Can't Both Be Right

Which brings me to this paragraph, from the 6 January 2014 Wall Street Journal, following NICE's green light (the bold highlight is from me):

Professor Finbarr E. Cotter, Professor of Haematology and Chair of Experimental Haematology, Centre for Haemato-Oncology, Barts Cancer Institute, and representative for the British Society for Haematology (BSH) commented, "The availability of PIXUVRI means physicians will be able to extend an approved salvage regimen to those patients that fail second- or third-line therapy. The data from the pivotal EXTEND Phase 3 trial of PIXUVRI clearly indicate that this drug is effective in heavily pretreated patients with relapsed or refractory aggressive NHL.

Pazdur says the EXTEND data indicates nothing conclusive. Cotter says it indicates that the drug is "clearly ... effective."

Both are experts. I concede that both know better than me. Who's right? They can't both be right.

There is no other available treatment option for this patient population. Does that mean that the first substandard product that comes along should be approved? Historically, cancer drugs under Pazdur that meet an unmet need like this have cruised through the FDA's approval process like it was buttered down.

The fact that they said no, for me, speaks far louder than anything Cotter or any other expert might assert.

Read the ODAC's FDA briefing document here and judge for yourself.