Abbvie's Parp runs out of puff

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Abbvie chose to pursue a high-risk strategy with veliparib in an attempt to gain ground in a competitive space. Failure in two critical phase III trials suggests that the strategy has backfired.

The appearance yesterday of one of these studies in the mistakenly released Asco abstract headlines suggests that Abbvie had known for some time that the triple-negative breast cancer trial was a dud; veliparib has also flunked in squamous lung cancer, it said last night. These setbacks look fatal for what was one of the company’s biggest oncology hopes (see table below).

Still, the muted share price reaction today suggests that, despite veliparib’s prominence in Abbvie’s pipeline, investors had little faith. With an NPV of $4.2bn, the project ranks as the company’s fourth most valuable R&D asset and second most valuable cancer agent, according to EvaluatePharma’s consensus of sellside analysts. This is equivalent to 4% of the company’s market value; Abbvie shares were little changed in early trade today.

Adding benefit

The group's novel pivotal strategy was designed to prove that veliparib could provide extra benefit to chemotherapy agents.

Parp inhibitors work by disabling tumour cells' ability to repair damaged DNA; so far developers have exploited the fact that BRCA1/2-mutated cells have DNA repair mechanisms that are already impaired. However, Abbvie was testing whether these mechanisms could also become more important when DNA-damaging chemotherapy, particularly using the platinum-based products, was used.

Expectations around the project were low anyway, based on a perception of a poor profile compared with others in the Parp class. And Abbvie was already on the back foot as the leading agents Lynparza and Zejula, from Astrazeneca and Tesaro respectively, had already generated very impressive pivotal readouts in ovarian cancer – the former set a benchmark in breast cancer a couple of months ago (Lyparza sets Parp inhibitors a new target, February 17, 2017)

In fact, Lynparza’s success in breast cancer could well derail veliparib’s hopes here. The Brocade-3 study is one of three remaining phase III trials to read out, with data due in the first half of next year, in patients with Her2-negative, BRCA-associated, metastatic breast cancer.

Abbvie's phase III Parp programme
Indication/setting   Pts   Trial ID  Data/outcome
Neoadjuvant, early stage triple-negative breast cancer 624  NCT02032277  Failed
HER2-negative, BRCA-associated breast cancer (Brocade-3) 500 NCT02163694  May-18
Tx-naïve, squamous NSCLC  975  NCT02106546  Failed
1L, non-squamous NSCLC, current or former smokers  525  NCT02264990  Nov-17 
Continuation maintenance Tx, ovarian cancer  1100  NCT02470585  Jan-19 

Tesaro last month scrapped a similar trial called Bravo, after finding that patients in the chemotherapy control arm were understandably reluctant to continue treatment without a Parp inhibitor. By the looks of its Clinicaltrials.gov entry, last year Abbvie raised the enrolment target in Brocade-3 from 270 to 500, but unless it can rely on recruitment in regions where Parp inhibitors are not available this trial is surely vulnerable to the same fate.

The remaining two ongoing phase III trials are in non-squamous NSCLC and ovarian cancer, in a maintenance setting. While the latter is arguably the safest tumour type in which to test a Parp inhibitor, lung cancer is an unproven use in which only Abbvie has been bold enough to venture.

Even here the signs were never encouraging – a phase II trial of veliparib plus chemo in 158 patients failed to show any statistical improvement on either PFS or OS. The company was encouraged to push on into two larger studies on the basis of a numerical survival benefit and signs of greater efficacy in current smokers. The failure of the squamous trial suggests that lung cancer is also a dead end.

Picking winners

Doubts around the potency of veliparib mean that this compound was perhaps never the best test of Abbvie’s chemotherapy combination hypothesis. Either way, veliparib must surely now be written off.

Investors must now wait for a more important oncology readout from the company, on Rova-T. This antibody-drug conjugate targets DLL3 – a potentially registrational study called Trinity in third-line small cell lung cancer is due to yield data in the second half of the year.

Rova-T was bought with Stemcentryx for an eye-watering $5.8bn last year. Investors must hope that the company is better at picking winners when looking outside its labs.

Project Trial ID
veliparib PII lung cancer  NCT01560104
niraparib  Bravo  NCT01905592
Rova-t Trinity  NCT02674568

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @ByAmyBrown on Twitter

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