Celator Shines At ASCO, Highlights Upside For Jazz

With proof of concept for its CombiPlex platform in the form of Phase III results for Vyxeos in acute myeloid leukemia, the $1.5bn purchase price paid by Jazz bought more than a promising late-stage asset.

The presentation of stellar full results for its nano-engineered Vyxeos at the American Society of Clinical Oncology meeting has been the icing on the cake for Celator Pharmaceuticals Inc., which has had a rapid rise in the past few months, culminating in its acquisition by Jazz Pharmaceuticals PLC just ahead of the cancer conference.

Jazz swooped in on May 31 with a cash offer of $30.25 per share – a huge increase over where it had been trading, even reflecting the gains Celator saw with the announcement of topline findings for the high-risk acute myeloid leukemia trial in March (when it shot up 400%).

The release of the final results at ASCO on June 4 provide definitive support that Vyxeos, a nano-scale co-formulation of cytarabine and daunorubicin, should replace the standard "7+3" regimen of the two chemotherapies as standard of care for high-risk AML.

They also validate the ability of Celator's CombiPlex technology to reformulate drugs not just for a safety advantage, but to improve their efficacy.

"Historically drug delivery vehicles like liposomes and nanoparticles [such as Celgene's Abraxane (nab-paclitaxel)] have been used to shift the exposure away from healthy tissue and toward the tumor tissue, which results in lower toxicity and allows the administration of slightly more drug," Lawrence Meyer, the company's founder and president, explained in an interview at ASCO. "While those provided improvements, they've been incremental – better but not markedly better."

Celator has come up with a platform for developing combinations of drugs at fixed ratios, identified for optimal synergistic anti-tumor activity, that are encapsulated in a nano-scale liposome to maintain the ratio after administration.

"We're actually giving less drug but because we have the synergistic ratio encapsulated within the nanoscale delivery vehicle, we're improving the clinical benefit of that drug combination," CEO Scott Jackson added. Traditional oncology drug development has been based on the idea of giving more drug to get better cell kill, up to a maximum tolerated dose. "But what that fails to take into consideration is the ratio of the drugs may be an important factor. And that's where the ComboPlex technology comes in."

"In some instances you can actually be administering more drug and get less efficacy. The concept of more is not always better," Meyer said.

With preclinical modeling and computational work, Celator was able to determine the ideal ratio of daunorubicin and cytarabine – 5:1 – which is synergistic without any antagonism.

"The technology is really broadly applicable," Jackson noted. Celator has shown preclinically that it works with chemo plus a targeted agent or with two targeted agents. The firm has been able to mix and match up to three agents and maintain the ratio and pharmacokinetics.

"We think that the proof of concept with the Phase III trial really sets the stage so that we can now look at the potential for R&D collaborations or internal development of new combinations." Jackson said.

Celator has had its own plans to move forward, though future planning will now go through Jazz. The logical next steps are to move into other AML populations, and other blood cancers, like high-risk myelodysplastic syndromes and acute lymphoblastic leukemia. There are investigator-initiated trials in these areas. (Also see "Ten Programs To Watch Out For At ASCO" - Scrip, 20 May, 2016.)

Changing The Standard Of Care In AML

There have been multiple attempts to modify the 7+3 regimen over time, including modifying the schedule and adding targeted therapies, University of Chicago's Richard Larson said in discussing the presentation of the Vyxeos data. "Although Phase II trials have looked promising, with rare exception Phase III trials did not validate a marked improvement," he noted. "Adding agents adds toxicity and may actually shorten survival."

Overall survival is poor even with current treatment, Celator notes, with a five-year survival rate of less than 10% in patients over 60. The rate is even lower in high-risk (secondary) AML.

That context made the Vyxeos results all the more striking. The Phase III trial, conducted in partnership with the Leukemia & Lymphoma Society, compared Vyxeos to the conventional daunorubicin and cytarabine regimen as first-line treatment in 309 older patients with high-risk AML.

Overall survival was significantly greater (HR 0.69), with median survival of 9.6 months versus 6 months for the 7+3 arm. There was a more modest but still significant benefit in terms of event-free survival (2.5 months vs. 1.3 months), and a modest decrease in early mortality at 30 days (5.9% vs. 10.6%) and 60 days (13.7% vs. 21.2%), lead investigator Jeffrey Lancet, Moffit Cancer Center, reported at ASCO. More Vyxeos patients went on to a stem cell transplant (34% vs. 25%) and Vyxeos patients had significantly improved survival post-transplant.

The most common adverse events were related to fever and infection, as expected in this group, the investigator noted. There was a seven day delay in recovery of neutrophils, but that did not have any impact on early death, Lancet added.

Lancet also noted that there was drug exposure up to seven days after dosing, which Celator's Meyer attributed to the stability of the liposomes. Rather than being quickly eliminated out of the blood, "they circulate for a long time, which allows the accumulation in the bone marrow," he explained. But the liposomal formulation means there isn't exposure in heart, muscle or kidney tissue or the resulting toxicity.

"That may be the price you pay," the exec said, but he pointed out it didn't turn into a difference in safety in the trial.

FDA granted CPX-351 breakthrough designation in May based on the Phase III data, and Celator anticipates filing the NDA by the end of the third quarter. Jackson also expects the Jazz acquisition to accelerate the European filing, which had been slated for Q1 2017, pending finding a partner.

Manufacturing is a multi-step process, "more involved than a simple ad mixture of some water soluble agent," Meyer noted, but Celator has already scaled up and ran the Phase III trial with commercial product, produced at Baxter in Germany.