Veliparib, Abbvie Inc.'s only shot at the oral poly-ADP ribose polymerase (PARP) market, failed two key phase III tests, missing the primary endpoints in studies evaluating the agent in combination with carboplatin and paclitaxel in patients with squamous non-small-cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

Jillian Griffin, spokeswoman at the North Chicago-based company, noted that veliparib is being investigated not only in NSCLC and TNBC but also in BRCA1/2 breast cancer and ovarian cancer, and "we will continue to evaluate veliparib as these studies read out over time." She declined additional comment.

Leerink Partners LLC analyst Geoffrey Porges was quick to bring down the hammer, however.

"While two disappointing trials would not normally completely doom a program, the lack of effect indeed confirms our view that veliparib has limited activity and is not competitive with other products in this class," he wrote in a company update, dropping the probability of success for veliparib to zero and reducing his price target for Abbvie shares (NYSE:ABBV) by $1, to $71.

Raymond James analyst Christopher Raymond was of the same mind, removing veliparib from his model without adjusting his target price of $84.

"We said 2017 is the year of pipeline catalysts; hopefully not this kind of catalyst," Raymond quipped in a company comment. "We have long pointed to this year as pivotal to the story as ABBV looks to diversify away from Humira. While we fully expected success for veliparib, we note that it amounted to just $2 in our sum of parts, and was a minimal contributor to our overall ABBV valuation."

Abbvie's shares were undimmed by the disappointment, gaining 29 cents to close at $63.75.

The randomized, double-blind, multicenter trial in NSCLC examined the efficacy and safety of the veliparib/chemotherapy combination compared to placebo plus chemo in patients with previously untreated metastatic or advanced cancer. The intent-to-treat (ITT) population of 970 patients was stratified by smoking history: those who smoked within the previous 12 months and had more than 100 smoking events in their lifetime; those who had more than 100 smoking events in their lifetime with at least 12 months since the most recent event; and those who had 100 or fewer smoking events in their lifetime.

The primary endpoint was improvement in overall survival (OS) in the cohort of most recent smokers with more than 100 smoking events in their lifetime. Secondary endpoints included improvement in OS in the ITT population along with progression-free survival and overall response in the primary endpoint subgroup and in the ITT population.

The double-blind, multicenter TNBC study randomized 312 patients to veliparib plus the carboplatin/paclitaxel combo, placebo with the combo or placebo plus paclitaxel only, all followed by doxorubicin plus cyclophosphamide. The primary endpoint was complete pathologic response. Secondary endpoints included breast conservation rate, OS and event-free survival.

Abbvie did not report data for any of the endpoints but said it will present detailed results at upcoming medical meetings or publish them in a peer-reviewed journal.

In a statement, Gary Gordon, Abbvie's vice president of oncology clinical development, said the NSCLC and TNBC trials were designed to explore whether a PARP inhibitor could augment chemotherapy in the indications by disrupting the repair of cancer cells – thus, supporting research that suggests a role for PARP inhibitors in cancers associated with DNA repair deficits.

"Unfortunately, these data do not support the use of veliparib in combination with chemotherapy in these patients," Gordon said.

At the 2014 J.P. Morgan Healthcare Conference in San Francisco, 1-year-old Abbvie touted prospects for veliparib, then known as ABT-888, as it prepared to launch the pivotal phase III in TNBC. (See BioWorld Today, Jan. 16, 2014.)

Though findings did not yield the desirable outcome, Abbvie left the door open on veliparib, which continues in phase III studies in previously untreated metastatic squamous NSCLC, HER2-negative or BRCA-associated metastatic breast cancer and metastatic ovarian and related cancer. But in explanation of his decision to pull the asset from his model, Raymond posed a rhetorical question: Are all PARPs created equal?

"We note that little correlation exists between in vitro activity and clinical efficacy in this space," he pointed out. "While some have derided veliparib as a lesser PARP given its in vitro potency profile, the literature simply doesn't support this thesis in our view. However, with two large [phase III] failures, clearly the veliparib bears have some justification to their argument. That said, the clinical rationale for PARP inhibition in NSCLC and TNBC is less clear. Rather, we wonder if this failure is more of a warning that PARP utility may be more limited."

Abbvie had one additional shot against PARP with ABT-767, which it advanced into a phase I study in patients with BRCA1/2 breast, ovarian and other solid tumors, according to Cortellis Clinical Trials Intelligence. The trial, conducted at three sites in the Netherlands, was expected to enroll 75 patients, primarily to evaluate pharmacokinetics. Safety, efficacy and dosing measurements were included as secondary endpoints. Although investigators published a paper last month in Cancer Chemotherapy and Pharmacology explaining the rationale for the pharmacokinetic model, Abbvie has not reported results from the trial and does not list the asset in its oncology pipeline.

Griffin did not comment on the status of ABT-767.

'ONE OF THE BEST PIPELINES IN THE INDUSTRY'

The veliparib setback came the same day that Tesaro Inc. launched the newest PARP inhibitor in the field. Zejula (niraparib) was approved by the FDA last month for maintenance treatment of women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who have complete or partial response to platinum-based chemotherapy – the first PARP inhibitor to gain a nod in the indication. In the phase III NOVA study, Zejula also became the first PARP inhibitor to show a clinically meaningful increase in progression-free survival in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. (See BioWorld Today, March 28, 2017.)

Tesaro, of Waltham, Mass., priced Zejula at a wholesale acquisition cost (WAC) of $9,833 per month, dosed at 200 mg once daily, but the approved starting dose is 300 mg once per day – a distinction that lit up social media when launch plans were disclosed following Wednesday's market close.

Although the starting dose is 300 mg once per day, the FDA-approved label points out that 69 percent of patients are down-dosed either to 200 mg or 100 mg per day, Tesaro spokeswoman Jennifer Davis told BioWorld Today. Patients in the 300-mg cohort will have a monthly WAC of $14,750, she conceded, but those who receive 200 mg will have with a monthly WAC of $9,833 and those in the 100 mg will have a monthly WAC of $4,917.

"Down-dosing occurs over the first one to three months, which is not uncommon for oral anticancer agents as the physician dials in the dose," Davis explained, noting that the median and most common dose in the NOVA trial was 200 mg. "Once a patient doses down, they do not dose back up," she added.

Abbvie's' veliparib phase III trial in fallopian tube, metastatic ovarian and peritoneal cancer continues to recruit and is not expected to read out until 2019, according to Cortellis. Even if Abbvie is unable eventually to compete with Tesaro – or in the PARP inhibitor class, in general – its absence from the category isn't expected to cause the pharma serious harm, suggested Jefferies Group analyst Jeffrey Holford. His model for the company ascribed only $216 million of risk-adjusted revenue from veliparib in squamous NSCLC and TNBC by 2021, representing less than 1 percent of the company's estimated revenues for that year.

"We expect a solid quarter from Humira and Abbvie overall in Q1'17, evidencing the ability to still take price in the U.S. and grow underlying volume despite concerns to the contrary," Holford wrote in a flash note. He cited a "rich set of catalysts in 2017," among them a midyear PDUFA date for the next-generation hepatitis C virus (HCV) regimen, glecaprevir/pibrentasvir (G/P, previously ABT-493/ABT-530) from Abbvie and partner Enanta Pharmaceuticals Inc., of Watertown, Mass.; the read-out of MURANO, the phase III study of Venclexta (venetoclax) in chronic lymphocytic leukemia, an indication where the agent is already conditionally approved; the phase II TRINITY study of Rova-T (rovalpituzumab tesirine) in small-cell lung cancer, scheduled to report in the second half; and phase III read-outs of risankizumab in psoriasis in the second half.

Those data "should help to shift investor focus from Humira onto one of the best pipelines in the industry," Holford maintained.

Indeed, data from EXPEDITION-1, reported Thursday at the International Liver Congress in Amsterdam, suggested the G/P combo was a slam-dunk, with the potential to become a ribavirin-free pan-genotypic therapy in HCV patients with compensated cirrhosis.

Abbvie revealed that G/P achieved 99 percent sustained virologic response at 12 weeks post-treatment, or SVR12, in patients with genotype 1, 2, 4, 5 or 6 chronic HCV infection, even though patients with virus strains associated with resistance or those with a high quantity of the virus in their bloodstream at treatment initiation were not excluded from the study.

G/P is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor, dosed once-daily as three oral tablets.

Most adverse events (AEs) in EXPEDITION-1 were mild, with fatigue and headache as the most common (≥10 percent). No patients in the study experienced ALT elevations equal to or above grade 3, and none discontinued treatment due to AEs. Of the 11 patients (7.5 percent) who experienced serious AEs, none were considered treatment-related.

G/P was granted accelerated assessment by the EMA and priority review by the FDA and Japanese Ministry of Health, Labour and Welfare.

Whether stellar efficacy for the HCV therapy can win market share in a crowded market fighting pricing pressures remains to be seen. The consensus five-year sales forecast for the drug is just $128 million, according to Cortellis Competitive Intelligence.