Clavis making hay while sun shines on cancer candidate

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The decision by Clavis Pharma to raise NKr163m ($27m) on the markets this week is no doubt due to the impressive doubling in the company’s shares over the last four months. Increasing interest in the US around a pancreatic drug it licensed to Clovis Oncology has a lot to do with the recent surge.

Alongside sharing a very similar name, the future commercial success of both companies firmly rests on the success or failure of CP-4126, or CO-101, which is due to report important phase II data during the fourth quarter of the year, an important event on the horizon. Although early stage the drug, which was licensed from Clavis in 2009 for up to $380m, is attracting attention for its novel approach to treating a subset of pancreatic cancer patients that could lead to a new standard of care in this notoriously hard to treat malignancy (Clavis calls on experience of newcomer Clovis in cancer deal, 24th November 2009).

Limited options

Pancreatic cancer has one of the poorest outcomes in terms of survival. Often by the time the disease has been diagnosed tumours have spread and patient do not live much beyond 6-9 months. Currently the standard of care for inoperable pancreatic cancer is gemcitabine, the generic name for Gemzar.

Many sufferers do not respond to the drug. Patients' varying ability to transport the chemotherapy agent into cancer cells is believed to be the reason.

To kill cancer cells gemcitabine needs to be moved by specific membrane transporters on the surface of cells - human equilibrative nucleoside transporter 1 (hENT1) has been shown to be the dominant transporter for gemcitabine. This means that patients whose tumours have low hENT1 expression are potentially resistant to gemcitabine therapy meaning that they receive little or no benefit from the drug.

It is estimated that between 50%-65% of patients have low hENT1 expression, providing a reason why the outcome for the cancer is so poor.

New way in

Norway-based Clavis believes it has got round this issue of hENT1 and the lack of efficacy with gemcitabine with CP-4126, a version of gemcitabine that has conjugated lipids attached to it. This means the drug can cross the cellular membrane much more easily, regardless of hENT1 expression.

Phase II trials of the drug have certainly shown good results; low hENT1 patients treated with CP-4126 lived for median 9.1 months versus 3.3 months for those treated with gemcitabine. But it should be remembered that this trial only consisted of 21 patients.

The big test for the drug will be the results of the first line phase IIb Leap trial, which has enrolled 360 patients and will see them either receive CP-4126 or gemcitabine. It is hoped that the drug will demonstrate a survival benefit in patients with low levels of hENT1 expression, proving a definitive link between amounts of the transporter molecule and the increased benefit of CP-4126.

Planning for the future

In what should help negotiations with regulators Colorado-based Clovis has also come up with a companion diagnostic for the drug, which identifies patients with low hENT1 levels. Should the test be validated by a finding of a survival benefit, CP-4126 could well become an important treatment option for these sufferers.

Leap is due to report results in the fourth quarter and if successful will be the basis for an accelerated filing of the drug, which could see it come onto the market in early 2014.

At present there are few estimates for peak sales of CP-4126, but JP Morgan have pencilled in sales of $506m by 2019. Analysts at Leerink Swann believe these could be exceeded and peak sales hit $1bn given that two thirds of pancreatic cancer patients could benefit from the drug.

Caution needed

Given the lack of treatment options for pancreatic cancer patients it would be easy to get carried away betting on the future success of CP-4126. But the drug is still very much early stage and while there does appear to be link between hENT1 and the effectiveness of gemcitabine, it could equally be that more aggressive tumours have lower hENT1 expression.

Also while the drug has show an acceptable safety profile to date, with GI events being one of the biggest side effects, very few patients have actually been exposed to the drug. The larger Leap trial and any subsequent trials that dose patients for longer could potentially see safety signals crop up.

So while CP-4126 is certainly exciting and could make the fortunes of both Clavis and Clovis, there is still a long way to go with this drug. With few future catalysts on the horizon Clavis has been sensible getting its cash call in now.

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