Pfizer set to cycle into phase III breast cancer trial

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Highly positive data with Pfizer’s PD-0332991 in a phase II breast cancer study have given a new lease of life to the once vaunted pharmacological approach of halting cancer by arresting the cell cycle.

The molecule, a first-in-class inhibitor of cyclin-dependent kinase 4/6, significantly extended progression-free survival when added on top of Femara in a large subset of patients, and is set to enter a phase III study next year. The move could give this approach a boost, and one immediate beneficiary – the tiny cell cycle specialist Cyclacel – closed up 19% yesterday. EvaluatePharma identifies just three other similarly acting projects in development (see table below).

While PD-0332991 is still too early for analysts to include it in their models, some have already made bullish noises: UBS sees it generating $300m in risk-adjusted 2020 sales, while ISI Group’s Mark Schoenebaum said at 50% penetration and a $25,000 annual price the drug would sell $1.25bn in the US alone.

50-70% subgroup

Its phase I/II trial, whose updated results have been presented at the San Antonio Breast Cancer Symposium, was in first-line, locally advanced or metastatic oestrogen receptor-positive, Her2-negative disease, a subtype thought to account for 50-70% of all US breast cancers.

Novartis’s Femara is the standard of care in this setting, and patients taking this alone had median PFS of 7.5 months. In contrast, those on Femara plus PD-0332991 survived without disease progression for a median 26.1 months, which hit statistical significance with p<0.001.

In patients with measurable disease overall response rate improved from 31% to 45%, also statistically favouring PD-0332991, and notable safety signals included neutropenia and leukopenia, which analysts think are manageable. Overall survival data were not disclosed.

The project targets cyclin-dependent kinases (CDKs), an important group of enzymes involved in driving cells’ transition from quiescence through growth to proliferation. In certain cancers the expression of these enzymes is aberrant, and conversely, inhibiting them can trigger cell death.

Academic research has suggested that CDK inhibition could be a useful way of targeting certain cancers, and in particular selective targeting of CDK4/6 has been reported to be preferentially effective in oestrogen receptor-positive breast cancer.

While numerous CDK subtype inhibitors have been studied there have been many failures and discontinuations, and the current industry pipeline of agents specifically targeting CDK4 numbers just four.

Cyclin-dependent kinase 4 inhibitors in clinical development
Product Company Mechanism Phase
PD-0332991 Pfizer/Onyx Pharmaceuticals CDK 4 & 6 inhibitor Phase II
LY2835219 Eli Lilly CDK 4 & 6 inhibitor Phase II
LEE011 Novartis/Astex Pharmaceuticals CDK 4 & 6 inhibitor Phase I
P1446 Piramal Healthcare CDK 4 inhibitor Phase I

Cyclacel, a company founded on the premise of cell cycle biology, has several general cyclin-dependent kinase inhibitors in the early pipeline (Event – Cyclacel seeking return on investment during crucial period, June 19, 2008). But its slow progress has caused it to fall distinctly out of favour, and its stock has lost 98% of its value since gaining a Nasdaq listing in 2005 via a reverse takeover.

1995 deal

Interestingly, PD-0332991 is the result of a 1995 research alliance between Onyx Pharmaceuticals and Warner-Lambert, a company subsequently bought by Pfizer. Given the early stage at which the deal was struck Onyx stands to gain little beyond "high single-digit” royalties from the molecule, and entry into phase II triggered a milestone payment of just $1m.

Pfizer now intends to start a phase III study in the same oestrogen receptor-positive, Her2-negative population, and clinicaltrials.gov already lists this as a 450-patient trial due to start next February. If nothing else this should raise the profile of a project that – rather like Lilly’s ramucirumab – has flown under many investors’ radar.

Certainly, Pfizer has more important pipeline catalysts, including Eliquis, which faces a new FDA action date of March 17, and Prevnar 13, whose huge phase IV Capita study reads out next year.

But overall survival data and entry into phase III should prompt the addition of PD-0332991 to most analysts’ models and, given its present zero pipeline value, upgrades should ensue.

Study Detail Trial ID
Phase II/III 450 patients, due to start Feb 2013 NCT01740427
Phase I/II 177 patients, data presented Dec 5 NCT00721409

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter.

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