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As DART misses bull's-eye, Acceleron Pharma's focus turns squarely to luspatercept

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By Marie Powers
News Editor

Acceleron Pharma Inc. found itself in an enviable position considering the phase II DART study of dalantercept plus Inlyta (axitinib, Pfizer Inc.) missed its primary endpoint in advanced renal cell carcinoma (RCC). Instead of rocking the company's shares (NASDAQ:XLRN), the trial failure and decision to halt development of dalantercept seemed to allay concerns that the asset was a distraction from the company's lead program, luspatercept, partnered with Celgene Corp.

Although shares of Cambridge, Mass.-based Acceleron were off sharply before the opening bell, the stock opened only modestly lower Tuesday and quickly rose into the plus column as analysts – who mostly had written off the oncology agent – shrugged at the news. Shares gained $1.41, or 5 percent, to close at $29.64.

Dalantercept is a protein therapeutic that inhibits angiogenesis by preventing BMP9, a protein in the transforming growth factor-beta (TGF-beta) superfamily, from interacting with activin receptor-like kinase 1, or ALK1, a cell-surface receptor found on proliferating vascular endothelial cells. DART was designed to assess whether dalantercept in combination with the anti-VEGF axitinib would show statistically significant improvement in progression-free survival (PFS) over placebo plus axitinib in advanced RCC patients whose disease progressed on prior anti-VEGF therapy.

Median PFS for dalantercept plus axitinib was 6.8 months vs. 5.6 months for placebo plus axitinib, confirming that the study drug did not decrease the rate of disease progression or death (HR 1.11, two-sided 95 percent CI [0.71, 1.73], one-sided "p" value 0.67). In the key secondary endpoint of PFS for patients who received two or more prior systemic cancer therapies, median PFS for dalantercept plus axitinib was 8.1 months vs. seven months for placebo plus axitinib (HR 0.78, two-sided 95 percent CI [0.33, 1.87], one-sided "p" value 0.29). The confirmed objective response rate (ORR) for dalantercept plus axitinib was 19 percent vs. 25 percent for the placebo arm (p=0.43, Cochran-Mantel-Haenszel test).

In terms of safety, based on 119 all-treated set (ATS) patients, the frequency of grade 3 or higher adverse events (AEs) regardless of causality was similar in the treatment (59 percent) and placebo (64 percent) arms. The frequency of serious AEs of any grade regardless of causality also was similar in the dalantercept (29 percent) vs. placebo (26 percent) arms. Acceleron said AEs associated with dalantercept were consistent with those previously observed.

DART enrolled 131 patients with advanced RCC, with efficacy and safety data based on the ATS of 119 randomized patients who received any study drug at the time of database cutoff. In the ATS, 58 patients were randomized to the treatment arm and 61 to placebo.

In a statement, Habib Dable, Acceleron's president and CEO, said the company was halting development of the compound based on the DART efficacy findings. Through a spokesman, the company declined additional comment.

'No read-through to the rest of the pipeline'

The CEO might have given analysts a bit of a foreshadowing about the fate of dalantercept last month. Speaking at the UBS Global Healthcare Conference, Dable was almost entirely focused on prospects for luspatercept, Acceleron's candidate to treat chronic anemia associated with rare blood disorders, turning "very, very quickly" toward the end of his remarks to dalantercept in second-line RCC, an opportunity that he described as "extremely exciting but extremely competitive." Dable characterized his outlook on dalantercept as "cautiously optimistic," adding, "Independent of the results, there is no pivot in strategy. We will partner this drug if it is indeed successful. And dalantercept will not be the anchor for our future oncology business at Acceleron."

Alrighty then.

J.P. Morgan analyst Whitney Ijem was one who read between the lines.

"We did not include this program in our model, and this news doesn't impact our thesis or valuation," she wrote in a company note. "Dalantercept acted via a different mechanism vs. XLRN's lead product luspatercept (partnered with CELG) as well as XLRN's earlier pipeline programs. As such, we see no read-through to the rest of the pipeline."

Ijem predicted "significant potential" for luspatercept in the lead indications of beta-thalassemia and myelodysplastic syndromes (MDS), "though the lack of significant catalysts in 2017 keeps us on the sidelines for now," she added.

Piper Jaffray analyst Edward Tenthoff agreed that most eyes are on luspatercept, with phase III MEDALIST MDS and BELIEVE beta-thalassemia data, due the middle of next year, as the primary driver. Acceleron and Celgene plan to begin a third phase III luspatercept trial in lower-risk MDS early next year, Tenthoff pointed out, "and we expect new phase II luspatercept studies in non-transfusion-dependent beta-thal and myelofibrosis" by the end of this year, he wrote.

Tenthoff maintained his "overweight" rating on Acceleron's shares but lowered his price target to $32 from $37 on the dalantercept miss.

The company took a bigger hit in Leerink Partners LLC's model. Analyst Geoffrey Porges, while acknowledging that dalantercept's demise "was largely expected given tepid comments from management in recent interactions," nevertheless noted that "as the company's only late-stage wholly owned program, it did carry significant value in our model." Porges dropped Acceleron's price target to $36 from $54 but observed, "We do not believe the stock will lose a similar 30 percent of value in line with our price target update," since most models already accounted for the candidate's failure.

"While disappointing, the discontinuation of dalantercept should not come as a great shock to investors," Porges wrote.

Termination of the dalantercept program does put more pressure on Acceleron to succeed with luspatercept, designed to promote production of healthy red blood cells by targeting and regulating specific TGF-beta proteins in late-stage red blood cell differentiation and maturation. The company sealed its partnership with Celgene in 2011, when the big biotech paid $25 million up front and agreed to $217 million more in potential milestones as part of the collaboration. (See BioWorld Today, Aug. 4, 2011.)

Celgene, of Summit, N.J., subsequently invested in Acceleron's 2013 IPO, which grossed $96.26 million, including overallotments, and participated in the company's 2014 public offering, which raised $120 million. (See BioWorld Today, Aug. 8, 2013, and Jan. 24, 2014.)

Acceleron also has a wholly owned neuromuscular candidate, ACE-083, designed to bind to and inhibit select proteins in the TGF-beta protein superfamily, such as activins and myostatin, that reduce muscle growth. That program has advanced into phase II studies in the lead indication of facioscapulohumeral muscular dystrophy, or FSHD, and in Charcot-Marie-Tooth disease, according to Cortellis Clinical Trials Intelligence.

A 2010 rare disease partnership between Acceleron and Shire plc, then based in Basingstoke, U.K., also involved rare muscle disorders, including ACE-031 (ramatercept), a GDF-8 antagonist then in phase II to treat Duchenne muscular dystrophy. In 2013, Shire halted development of ACE-031 and returned the program to Acceleron, which shelved the asset, according to Cortellis. Months before Acceleron filed for its IPO, Shire pulled out of the potential $498 million deal between the companies. (See BioWorld Today, Sept. 10, 2010.)