EP Vantage interview – Genmab awaits Arzerra and dara data

The licensing of daratumumab last year marked a turning point for Genmab. Shares in the Danish antibody developer, which touched a nine-year low in 2011, have climbed steadily since Johnson & Johnson bought rights to the multiple myeloma project in a $1bn deal.

There is still some way to go before an entrenched recovery can be declared. Events in the coming months could help bed in that much improved share price – the dara partners are preparing to unveil a “massive” development programme, says Genmab’s chief executive, Jan van de Winkel, while data from four phase III trials conducted with Arzerra, its sole marketed product, are due in the next 12 months.

First in class

The coming months will also bring results from a phase I/II study that combined dara with Revlimid that has been submitted for presentation at this year’s American Society of Hematology meeting. Both events could substantially raise the profile of the project, a monoclonal antibody that targets CD38.

“Janssen thinks [dara] will be very big – they describe it as potentially the new backbone treatment for multiple myeloma in all lines of therapy,” Mr van de Winkel says.

This is a bold claim for a molecule that has so far only been tested in just over 100 patients, clinical trial records show. Analysts who cover J&J have been slow to take notice – consensus for sales in 2018 currently sits at $5m, according to EvaluatePharma, despite dara having breakthrough therapy designation that could potentially win it approval in a very refractory setting in 2016. Analysts at Jefferies, who follow Genmab, however, have pencilled in a 2016 launch and royalties of $34m by 2018. They model for worldwide peak sales of $1.8bn.

Mr van de Winkel describes dara as “the most potent naked antibody I have seen in my 25 years of antibody development”, and points to its five mechanisms of actions and early monotherapy data. He does not expect toxicity issues; although CD38 is expressed in low levels elsewhere, for example on some red blood cells and T-cells, the company has determined that a target cell needs to express a certain threshold of CD38 before dara will hit it.

Growing value

The ultimate potential is still some way from being determined, but, with multiple myeloma a major target for industry right now and much room for improvement in treatment, encouraging data could prompt a swift climb in dara's value. What would also help considerably would be an improvement in the outlook for the company’s already-marketed product, Arzerra, which is sold by its partner GlaxoSmithKline.

A very narrow label and entrenched competition in the shape of Roche’s Rituxan means Arzerra has failed to impress since being launched in 2009 for third-line chronic lymphocytic leukaemia (CLL). Sales totalled $95m last year, and analysts following Glaxo expect $447m in 2018, consensus shows.

The outlook has the potential to improve, Mr van de Winkel argues, as a series of phase III studies read out.

He believes the most important commercially will be a trial testing Arzerra as a maintenance therapy in CLL; nothing is approved in this setting. And he describes a study in relapsed diffuse large B-cell lymphoma (DLBCL) as a “potential sentiment changer”.

While Rituxan plus chemotherapy cures about half of DLBCL cases, patients who do not respond are more difficult and a second round of treatment produces fewer responses. The trial pits Rituxan plus chemo against Arzerra plus chemo in this second-line setting, yielding the first head-to-head data on the two agents.

Mr van de Winkel admits that, in retrospect, more head-to-head studies should have been conducted against Rituxan. “We have had a massive uphill battle in the last few years against a fantastic product in Rituxan.

“But Rituxan is coming off patent in some territories, and Roche is trying to protect that franchise with new products like GA101. And they will want to convince doctors to switch. We have Arzerra data coming at the same time, so I think this opens a window of opportunity.”

Changing world

GA101 (obinutuzumab) is a Rituxan follow-on and is certainly another obstacle in Arzerra’s path. Data released this year from a trial pitting the two against each other in first-line CLL pointed to GA101’s superiority (Roche’s heir to the Rituxan throne ensures succession with regicidal data, July 24, 2013). Front-line Arzerra data released around the same time made for disappointing comparisons, as they appeared to show the Genmab drug also coming up short.

With results from both studies likely to be presented at ASH in December, reactions to these results will be important, as will the swathe of data due to be released on Arzerra in the coming years as Glaxo attempts to establish the product beyond its current niche – a head-to-head against Rituxan in follicular lymphoma will read out in 2016.

But the landscape for CLL is shifting (Therapeutic focus – The tide turns slowly in chronic lymphocytic leukaemia, June 25, 2013). Small molecules like J&J and Pharmacyclics’ BTK inhibitor ibrutinib and Gilead’s PI3K kinase inhibitor idelalisib are drawing closer, and will open up the possibility of new drug combinations.

Mr van de Winkel naturally believes that Arzerra represents the most promising antibody combination, because unlike Rituxan and GA101 its mechanism of action does not rely on antibody-dependent cell-mediated cytotoxicity, which is knocked out by these small molecules.

“We believe we are optimally positioned to do well in this new landscape. It took a long time but now I think we are collecting the data to get a broader label and get more aggressive pick-up,” he says.

This needs to happen for Genmab to continue its revival on the stock market (Genmab basks in Nordic glory, March 22, 2013). The next couple of years will be crucial for Arzerra to prove itself, while the world changes around it.

Drug Setting  ID
Dara + Revlimid Multiple myeloma NCT01615029
Arzerra  1st line CLL NCT00748189
Arzerra  Maintenance CLL NCT01039376
Arzerra  Relapsed CLL NCT00824265
Arzerra  Bulky refractory CLL NCT01313689
Arzerra vs Rituxan Relapsed DLBCL NCT01014208
Arzerra vs Rituxan Follicular lymphoma NCT01200589

To contact the writer of this story email Amy Brown in London at [email protected] or follow @AmyEPVantage on Twitter

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