Therapeutic focus – Cachexia research enlivened by cancer asset chase
Red-hot interest in oncology has spilled over into supportive care assets with Aveo Oncology signing over its pre-clinical cachexia treatment AV-380 to Novartis for $15m and more than $300m in milestones.
At least nine candidates stand ahead of the Aveo project, including Novartis’s own bimagrumab, but AV-380 has a competitive advantage in its novel approach: it blocks growth differentiation factor 15 (GDF-15). Modulation of appetite and muscle-building hormones is the leading approach to this condition, although other programmes that Novartis has pursued recognise its complexity (see table below).
Novartis is the big pharma group that appears to have focused most clearly on cachexia. It also has tested bimagrumab, an antibody that acts on activin receptor type IIb, to help improve muscle mass, although so far the Swiss group has only advanced that project into phase III in the separate disorder inclusion body myositis.
Maintenance of body weight is troublesome enough for cancer patients as chemotherapy causes nausea and vomiting. For example, one treatment for these conditions, Tesaro’s rolapitant is due an FDA decision by early September, and Heron Therapeutics may be close behind with Sustol.
However, separately from the vomiting is tissue wasting that can result from treatment as well as from changes in metabolism induced by the disease, such as modifying the synthesis of amino acids and fats and altering the body’s response to insulin. It is blamed for 20-40% of cancer-related deaths.
|Selected cancer cachexia projects|
|WW Indication Status (Current)||Product||Generic Name||Company||Pharmacological Class|
|Phase III||Anamorelin||anamorelin hydrochloride||Helsinn Group||Ghrelin agonist|
|Phase II||Jakafi/Jakavi||ruxolitinib phosphate||Novartis/Incyte||Janus kinase (JAK)-1/2 inhibitor|
|Bimagrumab||bimagrumab||Novartis/MorphoSys||Anti-activin receptor type IIB (ActRIIB) MAb|
|APD209||formoterol fumarate; megestrol acetate||Acacia Pharma||Beta 2 adrenoreceptor agonist & progestogen agonist|
|MT-102||n/a||Numedicus/PsiOxus Therapeutics||Anabolic catabolic transforming agent|
|Macrilen||macimorelin acetate||Æterna Zentaris||Growth hormone secretagogue/ghrelin receptor agonist|
|Phase I||LGD-4033||n/a||Ligand Pharmaceuticals||Selective androgen receptor modulator|
|GSK2881078||n/a||GlaxoSmithKline||Selective androgen receptor modulator|
|PF-06260414||n/a||Pfizer||Selective androgen receptor modulator|
|Pre-clinical||AV-380||n/a||Novartis/Aveo Oncology||Anti-growth differentiation factor 15 (GDF15) MAb|
Helsinn Group has taken a leading position in cancer supportive care, and as such has the most advanced candidate in anamorelin (Interview – Oncology advances leave a niche for Helsinn, November 25, 2014). As an agonist of ghrelin, it acts to stimulate appetite. Given the complexity of the condition, it would seem to have only limited potential, although the Romana 1 and 2 studies returned significant improvements in lean body mass when compared to a placebo, even if there were hypoglycaemia side effects (Esmo – Cachexia progress at last, but watch the diabetes, September 27, 2014).
Anamorelin’s results have set a modest benchmark for others to try to beat, and Novartis appears to be game.
More than just gastrointestinal
The deal struck with Aveo shines a light on the inflammatory aspects of the disease.The drug's target GDF-15 is a cytokine elevated in patients with cachexia, and Aveo says inhibition of this protein in pre-clinical models has resulted in a switch from tissue breakdown to synthesis. Novartis is assuming development and commericalisation costs, and has promised $311m in milestones as well as royalties up to the low double digits.
Its decision to in-license AV-380 may be a signal that it will not be taking bimagrumab into phase III in cancer cachexia. That antibody, in-licensed from MorphoSys, targets the activin type IIb receptor, a regulator of muscle growth.
Separately, Jakafi, the Janus kinase 1/2 inhibitor to which Novartis has licensed ex-US rights from Incyte, is being tested in a Swiss-based investigator-led trial in cachexia.
The remaining pipeline consists primarily of hormone modulation projects. The selective androgen receptor modulator approach took a knock when enobosarm failed in this setting, but GlaxoSmithKline, Pfizer and Ligand Pharmaceuticals all have live projects (Cachexia drug failure falls heavily on GTx, August 20, 2013).
Acacia Pharma looks uniquely focused in the supportive care space, and its beta 2 adrenoreceptor agonist and progestogen agonist APD209 had progressed as far as phase II, but the UK group looks like it has placed more emphasis on its surgery nausea project APD421 (Acacia Pharma mulls path ahead after phase III success, October 8, 2014).
With a greater understanding of both the disease mechanisms and its effects on both mortality and quality of life, cachexia seems like an area ripe for more activity. Helsinn has set the pace and Novartis is looking to catch up – others may soon join the race.