TG Celebrates High Risk CLL Data - But Cloud Looms From Rival Trial

TG Therapeutics is savoring positive trial data on its investigational TG-1101 in high risk CCL - but that could be soured next year by a little known mid-stage trial of Imbruvica plus Rituxan.

Positive top line data for TG Therapeutics Inc.' Phase III GENUINE study of TG-1101 (ublituximab, a monoclonal antibody that targets CD20) plus Imbruvica (ibrutinib) versus Imbruvica alone in previously treated patients with high-risk r/r CLL were welcomed by analysts and investors alike, ensuring the company's share price almost doubled within a week.

The trial met its primary endpoint of increasing overall response rate. The combination arm had an ORR of 80% compared with 47% in the Imbruvica monotherapy arm.

"We believe this data supports previous data showing that ublituximab is well-tolerated and should reduce the relapse rate," wrote Aegis Capital Corp's Jason Wittes in a March 6 note.

The high risk CLL patient group is currently served by AbbVie Inc. and Johnson & Johnson's Imbruvica, Gilead Sciences Inc.'s Zydelig (idelalisib), bendamustine + rituximab (BR), and increasingly – following its 2016 approval – AbbVie/Roche's BCL-2 inhibitor venetoclax.

"We believe the ublituximab plus ibrutinib combination label will be preferred when treating high-risk r/r CLL patients over venetoclax – the latter being more cumbersome to administer (requiring hospitalization and heavy monitoring) and risky in this patient population, thus rarely used in the community setting," Wittes wrote. "The current standard of care is ibrutinib therapy over Venclexta (venetoclax), given that venetoclax can rescue ibrutinib-treated patients but not vice-versa."

TG is moving full steam ahead to get its product through the regulatory process. In previous discussions with the company, the FDA indicated that a 20% increase in ORR would be clinically significant and sufficient for approval. Following the release of the interim GENUINE results, TG said it was targeting full data presentation at a medical meeting in 1H17 and meeting with the FDA in 2H17 "to discuss the results and filing for accelerated approval."

"The +30% ORR greatly increases the chances of accelerated approval," Wittes said, adding: "Ibrutinib, idelalisib, and venetoclax were approved in a similar manner with a single-arm ORR study (without SPA)."

This is particularly useful as a trial protocol amendment by TG last year invalidated its SPA (special protocol assessment) status at the FDA.

Wittes estimates a BLA filing in the first half of 2018 with launch in 2019, "in line with our prior assumptions, but with a much lower risk profile given [the latest release]."

Potential Cloud

Clouding the therapy's prospects though are data published in 2014 in The Lancet Oncology from a small Phase II trial of a combination of Imbruvica and Rituxan. The single arm, 40-patient study showed encouraging safety and efficacy measured by progression free survival (PFS). The 18-month PFS in all patients was 78%.

According to clinicaltrials.gov, the primary completion date of this study is February 2018.

The sponsors of the trial, the MD Anderson Cancer Center and AbbVie's Pharmacyclics subsidiary, went on to set up a larger follow-up study which is still ongoing. No data from that study have been released yet.

"The data from the early Phase II trial of Imbruvica and Rituxan are definitely promising, but it’s not as robust as the TG study," Datamonitor Healthcare analyst Dominique Fontanilla told Scrip. "It will be interesting to see the data from the larger follow-up study as those results would be more appropriate for a cross-trial comparison with the TG study."

Fontanilla also believes the commercial implications of the Imbruvica+Rituxan trials are difficult to assess as it is unclear whether AbbVie will pursue an official label expansion for the Imbruvica + Rituxan combination in high-risk CLL.

"There is definitely a great need for more targeted therapies and combinations to treat high-risk and relapsed/refractory CLL," she concluded.