Data on new drugs – including Roche/AbbVie Inc.’s highly potent venetoclax (ABT-199) – released at the American Society of Hematology annual meeting suggest that the revolution in treatment for chronic lymphocytic leukemia spurred by recently approved drugs has only just begun.

Highlights of this year’s ASH meeting, held Dec. 5-8 in Orlando, Fla., included Phase III data that could help expand labeling for two oral drugs approved in recent years – AbbVie Inc./Johnson & Johnson’s BTK inhibitor Imbruvica (ibrutinib) and Gilead Sciences Inc.’s PI3 kinase inhibitor Zydelig (idelalisib) (see related story,[A#00151214006]).

Pipeline drugs with a range of mechanisms of action are on the way to further spur change in the CLL treatment space as well as related hematologic malignancies, including Roche/AbbVie’s BCL-2 inhibitor venetoclax, Acerta Pharmaceuticals’ second-generation BTK inhibitor acalabrutinib (ACP-196) and MorphoSys AG’s CD19 antagonist MOR208 (see table below).

Venetoclax has been impressing ASH attendees in recent years with strong potency, even in hard-to-treat patients with 17p deletions. But potency has been a double-edged sword as the oral agent was also associated with life-threatening tumor lysis syndrome in its early days of development ([A#14131207001]). Sponsors have said that these effects could be managed, but they nevertheless cast a shadow over the drug.

Venetoclax targets the protein B-cell lymphoma 2 (BCL-2), which is often over-expressed in CLL and is associated with cancer resistance.

Results from the pivotal Phase II M13-982 study in 107 relapsed CLL patients with 17p deletions were presented at the ASH meeting as a late-breaker. The drug has breakthrough therapy status for this indication and the sponsors completed a rolling submission to FDA at the end of October.

Dosing was ramped up weekly from 20 mg to 400 mg stepwise, to manage the risk of tumor lysis syndrome.

The objective response rate, judged by independent review, was 79.4%, and in most cases responses lasted for a year. The complete response rate was 7.5%.

Even with the starting dose, the destruction of tumor cells was already evident, said Stephan Stilgenbauer, University of Ulm, Germany.

“This is highlighting the dramatic efficacy of this agent. I am not aware of other chemotherapeutic or therapeutic agents in general that when used at 5% of the target dose are able already to achieve tumor reductions to a significant extent,” Stilgenbauer said during a Dec. 6 press briefing.

Furthermore, 25 of 48 patients assessed had no disease in their bone marrow and 18 of 45 had no minimal residual disease. The normalization of lymphocyte counts is evidence of the efficacy of this agent, Stligenbauer said, adding that the median time to normalization was only 22 days.

The rate of Grade 3/4 adverse events was 76%, including a 40% occurrence of neutropenia. However, Stilgenbauer said that the safety was acceptable compared to frontline chemotherapies and also noted that it was reassuring that infections were uncommon.

Updated results from a Phase I dose-escalation study (M12-175) in relapsed/refractory CLL were published online in the New England Journal of Medicine by the Royal Melbourne Hospital’s Andrew Roberts on Dec. 6.

Most of the patients in that study had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Out of 116 patients, the ORR was 79% and there were complete remissions in 20%, including 5% with no minimal residual disease, investigators reported.

As for safety, tumor lysis syndrome was successfully managed following a previously reported death, though 21 out of 60 patients in an expansion cohort at high risk for this event had to be hospitalized during dosing as a precaution.

“Clinical tumor lysis syndrome occurred in three of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort,” Roberts and colleagues reported.

Investigators reported a 41% rate of Grade 3/4 neutropenia AEs.

In a Dec. 9 note, Leerink Swann analyst Mark Schmidt referred to venetoclax as “the biggest breakthrough in B-cell malignancies, at least in terms of current pipelines.”

The drug has been “in the slow lane” after reports of deaths but sponsors have developed protocols to manage this effect and “still leave patients and physicians with a spectacularly powerful single-agent medicine for these diseases,” the analyst wrote.

The data should support accelerated approval in 2016 and “further disruption in the category,” he concluded.

In an interview at the ASH meeting, Cleveland Clinic specialist Brian Hill said that while venetoclax has seen some myelosuppression effects in trials and has been associated with some cases of tumor lysis syndrome, which will require close monitoring, the drug does not appear to have any record of the atrial fibrillation and bleeding side effects associated with Imbruvica.

"It also has higher remission rates and more [minimal residual disease] negativity than other CLL agents," he added.

Datamonitor analyst Joseph Hedden commented that there is not enough data yet to properly compare venetoclax to Imbruvica, but he noted that the ORRs were similar in the 17p deletion patients.

“Imbruvica has kind of cornered that elderly first-line treatment setting – the [Phase III] RESONATE-2 data were presented and very impressive – so venetoclax would need to do something very significant to move there,” he said.

In the past, Roche has emphasized the attraction of a fixed duration of treatment approach with deep responses, whereas Imbruvica is given indefinitely until progression. Stilgenbauer noted during the press briefing that with continuous therapy over a long time, “even minor side effects can become quite bothersome.”

Data suggest that some people may achieve response rates with venetoclax that allow them to come off therapy and be in remission, Genentech said.

“CLL is a chronic disease and the ultimate goal of treatment is cure or periods of time without treatment,” the company told “The Pink Sheet.”

The company also pointed out that updated data for Gazyva’s pivotal frontline CLL study at the ASH meeting show that patients remain treatment-free for four years on average after a six month course.

Venetoclax is being tested in the Phase III CLL14 study as part of a chemo-free combination with Roche’s anti-CD20 antibody Gazyva (obinutuzumab). In a safety run-in for that trial presented at ASH, the ORR in 12 patients was 100%. Investigators did see tumor lysis syndrome, but only laboratory abnormalities, and none led to discontinuation, Hedden noted.

“All we can really say with this small patient population, with no comparator, is that the efficacy is promising and the combination is well-tolerated,” Hedden commented.

Genentech is open to a variety of combination partners for venetoclax, including pairing with Imbruvica.

Roche and AbbVie/Pharmacyclics have an agreement to evaluate the safety, tolerability and preliminary efficacy of Gazyva in combination with ibrutinib in patients with CLL/SLL, as well as non-Hodgkin lymphoma, Genentech said.

New BTK Inhibitors Challenge Imbruvica

Imbruvica also faces competition from second-generation BTK inhibitors.

Acerta Therapeutics’ ACP-196, licensed from Merck & Co. Inc., in particular looks very promising based on results from a Phase II study in relapsed/refractory CLL, which was presented at the meeting and published in the NEJM on Dec. 7. AstraZeneca is rumored to be offering $5bn for the private Dutch biotech, whose primary asset is the BTK inhibitor.

The trial included 61 patients, 31% of whom had 17p deletions. With median follow-up of about 14 months, the ORR in evaluable patients was 95%, including partial response in 85% and partial response with lymphocytosis in 10%. In those with 17 p deletions, the response rate was 100%, including a partial response rate of 89% and partial response with lymphocytosis in 11%

ACP-196 is given twice daily, whereas Imbruvica is given once daily. Writing in the NEJM, Ohio State’s John Byrd and colleagues said that the twice-daily dosing achieves complete and continuous levels of drug binding to BTK, without increased toxic effects from inhibition of alternative kinases.

“Full target coverage may reduce drug resistance caused by mutations in the BTK enzyme and may also lower the rate of Richter’s transformation,” a progression to a more aggressive lymphoma, Byrd and colleagues reported.

The selective BTK inhibition and short half-life are strong points of differentiation for acalabrutinib, according to the authors. “Thus far, twice daily dosing of ibrutinib has not been pursued and may not be possible owing to the potential for drug accumulation given the ibrutinib half-life of 4 to 13 hours,” they noted.

Most adverse events were Grade 1-2, the most common being headache (43%), diarrhea (39%), and weight gain (26%). No cases of atrial fibrillation or major hemorrhage were reported, despite the long-term follow-up.

Acerta is now testing ACP-196 head-to-head against Imbruvica in a Phase III study in high-risk relapsed CLL, and in a Phase III study in frontline CLL study comparing ACP-196 monotherapy and ACP-196 in combination with Gazyva head-to-head against Gazyva/chlorambucil.

Commenting on the ACP-196 data in a Dec. 8 note, Credit Suisse analyst Vamil Divan said that ACP-196’s 95% ORR was impressive, but that this rate includes a partial response rate of 85% and 10% PR with lymphocytosis.

“This is an important distinction as the initial [Pharmacyclics] Imbruvica trial did not consider a patient to be a PR if they had treatment-related lymphocytosis,” he noted.

Furthermore, looking at the dose being taken forward into Phase III, the ORR, excluding lymphocytosis, was 77%, he pointed out.

BeiGene (Beijing) Co. Ltd. reported a 93% ORR, including partial response with lymphocytosis, and a mild toxicity profile for its BTK inhibitor BGB-3111 in a small study.

Jeffries analyst Jeffrey Holford said in a Dec. 8 note that more long-term data are needed for the new BTK inhibitors and that they were unlikely to displace Imbruvica in a material way before patent expiry.

ASH Data Highlights: Drugs Emerging In CLL
Sponsor & Drug	Target	Trial/Abstract #	Key Efficacy Data	Notable Safety Findings
Roche/AbbVie’s venetoclax (ABT-199)	BCL-2 inhibitor	#LBA-6, pivotal Phase II monotherapy trial (M13-982) of CLL with 17p deletions (n=107)	79.4% ORR, 7% CR; 17% with no minimal residual disease	76% Grade 3/4 AE rate, including neutropenia (40%), anemia (18%), and low platelet count (15%). Tumor lysis syndrome in 5 cases, but with no clinical consequences.
Venetoclax	BCL-2 inhibitor	M12-175 monotherapy study in relapsed CLL, published in NEJM (n=116)	ORR 79%, CR 20%, including 5% with minimal residual disease	83% Grade 3/4 AEs, including neutropenia (41%) and anemia (12%). Tumor lysis syndrome in 3/56 pts in expansion cohort, including one death.
Venetoclax with Roche's Gazyva (obinutuzumab)	BCL-2 inhibitor/anti-CD20	#496 data from safety run-in phase of Phase III study, Gazyva/venetoclax vs. Gazyva/chlorambucil in frontline CLL (n=12)	ORR 92% after 3 cycles, 100% after 6 cycles	Some tumor lysis syndrome reported, but only lab abnormalities that did not lead to discontinuation.
Acerta Therapeutics’ alacabrutinib (ACP-196)	BTK inhibitor	#831 Phase I/II dose ranging study of ACP-196 in relapsed CLL (n=61)	ORR 95%, including 85% PR and 10% PR with lymphocytosis	Most AEs Grade 1-2. No hemorrhage or atrial fibrillation.
BeiGene’s BGB-3111	BTK inhibitor	#832 Phase I study of BGB-311 relapsed CLL (n=14)	93% ORR (includes pts with lymphocytosis), 0 CR	Most AEs Grade 1-2. No hemorrhage or atrial fibrillation.
MorPhoSys’ MOR208	CD-19 antagonist	#2953 Phase II study with Revlimid (lenalidomide), frontline and relapsed CLL (n=11)	3 PRs in naïve patients, 4 PRs in relapsed	Combination well-tolerated.
Merck’s Keytruda (pembrolizumab)	PD-1 inhibitor	#834 Phase II study of Keytruda in relapsed/refractory CLL, including Richter’s transformation (n=12)	3 ORR (21%), 1 CR (7%) – all responses in Richter’s patients	No unexpected side effects.

On-site reporting contributed by Lucie Ellis (lucie.ellis@citeline.com).

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