Preliminary overall survival results from a phase III melanoma study of Amgen’s T-Vec look promising for the oncolytic virus project, but with Asco inundated with positive data on numerous novel agents the actual market potential of T-Vec is becoming harder to gauge.
Melanoma is one of the hottest topics at this year’s Asco, and with this the bar for success is rising. Promising flesh is being put on the bones of T-Vec data first released in March, but the result risks losing relevance considering novel agents like Bristol-Myers Squibb’s Yervoy and the promise of combinations with other immunotherapies and targeted therapies.
The doubts were framed in a stinging criticism at Asco on Saturday from Dr Kim Margolin, of the Seattle Cancer Care Alliance, who said, “T-Vec is a complex approach, and isn’t really practical. [It] isn’t really quite ready for prime time.”
Amgen has a lot riding on the project, which it gained through its 2011 acquisition of BioVex for around $1bn. T-Vec comprises an HSV1 virus into which genes encoding GM-CSF have been inserted, and is thus thought have a dual effect, causing direct lysis like other oncolytic viruses, as well as initiating an immune response by virtue of the action of GM-CSF.
Preliminary data in March showed a durable response rate – the primary efficacy measure of the phase III Optim study – in the T-Vec arm of 16% versus 2% for GM-CSF. But it was overall survival, a secondary endpoint, that was seen as the single most important data point (Will Amgen's success be infectious for oncolytic viruses?, March 20, 2013).
Asco saw the first time these overall survival results were presented, and although the dataset is still immature the signs are promising. The Kaplan-Meier curve shows a good separation, and a hazard ratio of 0.79 has been reported, with a p value of 0.07.
The lead Optim investigator, Dr Robert Andtbacka of the University of Utah School of Medicine, said overall survival data were “not yet significant but [were] trending towards significance”. A final analysis is about six months away, and this might be the trigger for a filing.
ISI Group’s Mark Schoenebaum said the result was clearly encouraging, but cautioned that Yervoy had outstanding overall survival data, with a 30% reduction in risk of death. Moreover, Yervoy’s combination with novel agents to increase efficacy and reduce toxicity poses a considerable threat.
And Dr Margolin’s doubts suggest more fundamental problems. Apart from citing the as-yet unproven survival effect she questioned the use of GM-CSF as a comparator, and speculated that a more realistic approach might be to combine T-Vec with novel treatments. Interestingly, clinicaltrials.gov already shows an ongoing phase I/II study adding T-Vec on top of Yervoy.
Her reference to T-Vec’s lack of practicality relates to its need to be injected directly into tumours – a point with particular relevance to Virttu Biologics, a private UK company far earlier in developing an oncolytic virus. At Asco Virttu boasted the receipt of clearance to start IV dosing in a 15-patient US sarcoma trial in which the first two patient cohorts had been treated intratumourally.
Like T-Vec, Virttu’s approach, called Seprehvir, is based on HSV1. The virus has a single gene deletion, but unlike T-Vec it does not contain any insertions. Virttu’s chief executive, Steven Powell, says the company has been making quiet progress over 13 years, but needed a management change to be converted “from a research to a development story”.
Seprehvir is also in a phase I/II UK trial in mesothelioma, and has completed early studies in glioma, melanoma and squamous head and neck cancer. Mr Powell says a phase I/II trial in liver cancer might begin around the end of 2013.
“The clever thing about [Seprehvir] is the simplicity,” he told EP Vantage. “It’s a straight, potent, lytic agent and is very easy to manufacture in high yields.” Mr Powell says early signs of synergistic activity point the way to using Seprehvir in combination – for instance with sorafenib or tyrosine kinase inhibitors.
Virttu has raised just £12m so far, all from a single investor, and has no venture capital funds on board. “Our strategy is a big pharma partnership,” says the chief executive.
This is why he is convinced that Amgen’s move on BioVex has a highly positive read-across, giving this space a big company validation despite the obvious doubts that surround such a novel approach. At the time of BioVex’s acquisition “most companies didn’t know Virttu existed”.
There is of course more in this space than just Amgen (see table below). Mr Powell says he has been encouraged by news of oncolytic virus projects owned by Jennerex Biotherapeutics/Transgene, and Oncolytics Biotech, which he views as having generated a “wave of positive clinical data” with Reolysin.
Still, one thing that Oncolytics has shown is that far more focus is needed; the company has run a confusingly designed phase III study in head and neck cancer, altering its design part-way through – a move that embarrassingly caused the trial to lose its pivotal status.
Despite this the sellside seems ecstatic. EvaluatePharma’s consensus estimates still call for a 2014 launch of Reolysin – impossible given that the REO 018 trial is no longer pivotal – and forecast a barely credible $1.1bn of 2018 revenue.
Much of this enthusiasm might be the result of Amgen’s move on BioVex, which has clearly stimulated a surge of work in oncolytic viruses. But the area still needs validation, and as far as melanoma goes the goalposts might be shifting just a little too fast.
|Clinical-stage oncolytic virus projects|
|Project||Company||Virus used||Product encoded||Status|
|Oncorine||Shanghai Sunway Biotech||Adenovirus||–||Marketed (China)|
|Reolysin||Oncolytics Biotech||Reovirus||–||Phase III (non-pivotal)|
|Pexa-Vec||Jennerex/ Transgene||Vaccinia||GM-CSF||Phase II|
|GL-ONC1||Genelux||Vaccinia||Green fluorescent protein||Phase II|
|NTX-010||Neotropix||Seneca Valley virus||–||Failed Phase II|
|ParvOryx||Oryx||Parvovirus H-1||–||Phase II|
|NDV-HUJ||TheraVir Management||Avian paramyxovirus type-1||–||Phase II|
|Seprehvir||Virttu Biologics||HSV1||–||Phase I/II|
|JX-929||Jennerex||Vaccinia||Prodrug-activating enzyme||Phase I|
|CGTG-102||Oncos Therapeutics||Adenovirus||–||Phase I|