CTI’s Pixuvri Flops Again At British NICE, As Discount Fails To Impress

Despite a sizeable price cut, uncertainty surrounding CTI’s non-Hodgkin’s lymphoma therapy Pixuvri has landed it with a second NICE rejection.

NICE’s second rejection of CTI BioPharma Corp.’s Pixuvri (pixantrone) for non-Hodgkin’s lymphoma, coming on the back of a presumably meaningful discount, represents a kick in the teeth for the Seattle-based drug manufacturer. While it is not the end of the road for Pixuvri in the U.K. – there is a third evaluation round to come – it is hard to see how the company can claw its way back into NICE’s good books without providing additional evidence of clinical effectiveness.

This interim decision from NICE might also go some way to silencing those critics who perpetually denigrate the health technology assessor for focusing too much on price rather than therapeutic value. The discount offered by CTI did in fact bring the cost-effectiveness of the drug into the range that NICE traditionally finds acceptable, but the reimbursement watchdog refuses to budge from its position that the drug remains shrouded in uncertainty.

NICE is not discounting Pixuvri’s potential. It accepted that there was “limited and non-robust evidence” to show Pixuvri was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive B cell non-Hodgkin’s lymphoma.

Results from the PIX301 study that CTI submitted to NICE as evidence included a high proportion of patients who would be eligible for treatment under the terms of the European marketing authorization, but it was the intention-to-treat population of PIX301 that was not appropriate for evaluation and decision-making.

NICE therefore reiterated its concerns from the last evaluation of Pixuvri in April in which it commented that PIX301 was inadequately powered to detect a difference between treatment groups in the intention-to-treat population, because it had accrued less than half of the planned 320 patients (Also see "CTI Finds Pixuvri’s Conditional Authorization Is Not Enough To Win NICE Approval" - Pink Sheet, 11 Apr, 2013.). Considerable uncertainty over the validity and robustness of the results therefore remained.

FDA was equally disparaging about the trial design back in March 2010 and CTI subsequently withdrew its NDA for the drug prior to an FDA advisory committee review (Also see "Cell Therapeutics Should Consider Different Trial Design For Pixuvri, FDA's Pazdur Says" - Pink Sheet, 22 Mar, 2010.).

It’s All About Rituximab

There is, meanwhile, another troubling issue for Pixuvri – although it must not be viewed in isolation. A subgroup analysis showed a reduced benefit of Pixuvri in patients who had previously received Roche’s MabThera (rituximab). Complete or unconfirmed complete response rates were higher in the pixantrone arm than in the comparator arm – 20% compared with 11% – but this difference was not statistically significant, NICE’s Expert Review Group noted.

The problem for CTI is that rituximab is an integral part of standard first-line treatment in the NHS and is also often used as a second-line treatment, so Pixuvri’s reduced benefit will not apply to isolated cases. However – at least in this area – some things may be running in Pixuvri’s favor.

Firstly, reduced benefit has been noticed in other drugs in clinical development and is not specific to pixantrone. Secondly, NICE acknowledged comments received in response to its consultation that the complete response rates with pixantrone in PIX301 were among the highest reported to date in trials for patients with diffuse large B cell lymphoma who had previously received MabThera.

Finally – and perhaps most importantly – is the fact that Pixuvri has a conditional marketing authorization from the European Medicines Agency, granted in May 2012, as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (Also see "Pixuvri’s Conditional EU Approval Could Herald The Rise Of Staggered Approval" - Pink Sheet, 15 May, 2012.). This can be translated into a full marketing authorization once CTI has completed a study to further investigate the effects of using Pixuvri in patients who had received prior treatment with MabThera.

Full marketing authorization will depend on positive results from the Phase III PIX306 trial, a randomized trial investigating pixantrone plus rituximab versus gemcitabine with rituximab in patients with relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have previously received a rituximab-containing regimen.

So much is riding on this trial that CTI has to get the right results if Pixuvri is to get reimbursement across Europe. Not only has it failed to do so in the U.K. to date, but it also flopped in Germany, where the joint federal committee (G-BA) also cited the rituximab issue as being a major hurdle for CTI to overcome (Also see "Germany’s G-BA Finds No Added Benefit For CTI’s Pixuvri, Exposing Price" - Pink Sheet, 20 May, 2013.).

How Low Is Too Low?

At least one thing is going in the right direction for the company, though. NICE estimated that the incremental cost-effectiveness ratios were probably around £30,700 ($49,000) per quality-adjusted life-year gained, marginally above the traditional £30,000 ($47,900) per QALY threshold.

However, NICE’s guide to the methods of technology appraisal (2008) says that if the most plausible ICER is greater than £20,000 ($32,000) per QALY gained, judgments about a product’s effective use of NHS resources should address any uncertainty around the ICER. This is where Pixuvri fell down and why the rituximab trial is so vital to its resurrection.

Consultees, including CTI, healthcare professionals and members of the public, have until Nov. 4, 2013, to comment on the draft guidance. A third Appraisal Committee meeting is expected to be held on November 13, 2013, where subject to approval, CTI said that it hopes the Committee will consider an ‘enhanced’ patient access scheme to demonstrate the cost effectiveness of pixantrone for use by the NHS in the UK.

“We look forward to collaborating with NICE during the final stage of the process as we seek to bring this new approved therapy to patients in the UK with aggressive non-Hodgkin lymphoma in the 3rd line salvage setting,” said James A. Bianco, President and CEO of CTI.

The company has not yet elaborated on what “enhanced” may signify, but it can be assumed that another price cut is on the cards.

The question remains how plausible it is for CTI to make another sizeable cut – taking the ICER per QALY close to the £20,000 ($32,000) mark – that will be appreciated by NICE and rewarded with the reimbursement watchdog’s willingness to overlook the manifest uncertainties before the completion of the rituximab trial.