Non-exclusive deals, like Monday’s between Kyowa Hakko Kirin and Pfizer, are all the rage in cancer immunotherapy as companies try everything possible to discover more potent and less toxic combinations, whatever their business origins might be.
So the more surprising aspect of the tie-up is that it includes mogamulizumab, a drug that has been marketed in Japan for over two years for a haematological cancer. It had also been licensed to and abandoned by Amgen, but after that disappointment in April it has been given two big pharma endorsements in the space of two months.
It is possible that Pfizer had specifically sought a project that blocks CCR4, and Kyowa’s was the most advanced, and thus most obvious, choice. AstraZeneca and Affitech have very early work ongoing here, but beyond this the industry involvement in CCR4 blocking is thin on the ground.
Under the alliance Pfizer and Kyowa will co-fund a trial of mogamulizumab in combination with PF-05082566, a CD137 MAb that the US company had co-discovered with MorphoSys. This phase Ib study, run by Pfizer, will evaluate safety and tolerability in patients with solid tumours.
Kyowa struck a very similar non-exclusive tie-up in July with AstraZeneca, seeking to study two mogamulizumab combinations, one with the UK firm’s anti-PD-L1 MAb MEDI4736, and the other with its anti-CTLA4 MAb tremelimumab.
Among the vast proliferation of immuno-oncology combinations MEDI4736 is already in more advanced trials with tremelimumab, while Pfizer’s PF-05082566 is being studied with Roche’s Rituxan (Latest immuno-oncology deal brings big pharma endorsement, March 18, 2014).
CCR4, not to be confused with CXCR4, is a chemokine receptor also known as CD194. It is expressed on certain immune system cells, and its activation is thought to help malignant cells evade an immune response.
It is also thought to be over-expressed on various malignant T-cells, so its blocking could in itself have a dual antitumour action. And a combo with PF-05082566 could logically be assumed to result in increased potency, since the Pfizer project stimulates signalling through CD137 (4-1BB), a tumour necrosis factor receptor.
The most prominent CD137 project is Bristol-Myers Squibb’s urelumab, which is in three recruiting phase I monotherapy studies.
It is noteworthy that Astra was active in the CCR4 mechanism before it struck the Kyowa alliance. Through a deal done last December with Cancer Research UK Astra’s CCR4-blocking small molecule AZD2098 is being repurposed for use against renal cancer; this had originally been in development for asthma.
Mogamulizumab is easily the most advanced anti-CCR4 agent, having been launched in Japan in 2012 as Poteligio for the treatment of relapsed or refractory CCR4-positive adult T-cell leukaemia-lymphoma. The indication was later expanded to two other lymphomas, but sales have been negligible – $11m in 2013 and $15m expected by analysts this year.
Kyowa is continuing to develop it as a monotherapy for the Western markets. Amgen had acquired exclusive Western rights – though in non-oncology indications – in 2008, but terminated the deal six months ago. It appears that the US firm had conducted clinical studies targeting mogamulizumab at patients with asthma.
A final point of interest is that the Amgen legacy company Immunex had an early-stage MAb targeting CD137, but this is presumed now to be discontinued.
Did Amgen miss a trick by not considering the potential of mogamulizumab in oncology, with or without an appropriate combination molecule? This is the cautious early bet that Astra and Pfizer have just made.