Per the annual pre-holiday tradition, abstracts poured out Thursday morning precisely one month prior to the start of the American Society of Hematology (ASH) annual meeting in San Diego. As usual, analysts and investors reacted quickly to the summaries, and many were less than enthused.
Headliners such as Bluebird Bio Inc. and Spark Therapeutics Inc. saw shares tumble in midday trading, and small- and mid-cap companies such as Trillium Therapeutics Inc. (NASDAQ:TRIL) and Achillion Pharmaceuticals Inc. (NASDAQ:ACHN) were drawn into the fray. Although many of the stock movers had ASH in common, underlying differences also emerged.
For one, ASH abstracts got tangled up with third-quarter earnings, magnifying the importance of seemingly small disappointments. Such was the case for Achillion, of New Haven, Conn., which provided an update of the ongoing phase I multiple ascending-dose (MAD) study of its factor D inhibitor, ACH-4471, in healthy volunteers as part of its earnings release. Although the therapy was generally well-tolerated across three dose groups (200 mg, 500 mg or 800 mg every 12 hours), with no treatment-related severe adverse events, two cases of self-limited alanine aminotransferase (ALT) elevations (grade 3 and 4) were observed following treatment in the middle and high dose groups. Neither subject showed signs or symptoms of hepatic decompensation. In both cases, ALT levels subsequently returned to normal without intervention, and no treatment-associated fever or infections were observed.
In terms of efficacy, Achillion said strong complement inhibition was observed in the three dose cohorts completed to date. Still, the company's stock plummeted 28.5 percent Thursday to close at $4.32 for a loss of $1.72.
At ASH, Achillion plans to report updated data on ACH-4471, including findings that patients with paroxysmal nocturnal hemoglobinuria encountered no increased risk of pathogen-induced hemolytic breakthrough when treated with a complement alternative pathway inhibitor.
In a flash note and follow-on earnings report on Achillion, Leerink Partners LLC analyst Joseph Schwartz conceded that "investors are understandably focused on the well-being of this program, which we continue to view as high-risk/high-return. That said, it is unclear whether there may have been other confounding sources of ALT rises in these patients, which is important to consider given the potential for these assays to be triggered by things such as alcohol or other health conditions."
Although investors were, perhaps, expressing "dismay" that MAD data will not be included in the company's ASH presentations, as previously guided, the "stock reaction [looks] overblown to us," Schwartz added.
In terms of the ALT elevations, Achillion confirmed that "both cases were deemed by investigators to be not related to study drug, and occurred three and five days after cessation of treatment, when very little drug was present in the plasma according to the [pharmacokinetic] data," he wrote. "Since study subjects were housed for 14 days before being released back into the real world, we continue to wonder whether alcohol may have confounded things."
Trillium shares also took it on the chin, falling to a one-year low of $6.62 before closing at $6.85 for a loss of $7.75, or 53.1 percent, after the Mississauga, Ontario-based company issued a press release citing three poster presentations at ASH, including interim data from the dose-escalation phase Ia study of TTI-621 in patients with lymphoma. A day earlier, Trillium disclosed that it was advancing TTI-621, a SIRPa-IgG1 Fc fusion protein, from dose escalation into a phase Ib cohort expansion.
The letdown, disclosed in the phase I TTI-621 ASH abstract, was that the higher, 0.3 mg/kg-dose was associated with reversible, dose-limiting toxicity (DLT) in two of five patients, including one with G3 elevated ALT/aspartate aminotransferase (AST) and G4 platelet count and a second with G4 platelet count who was transfused. "Dosing at 0.2 mg/kg is now being explored," according to the abstract.
Leerink analyst Michael Schmidt was unfazed.
"While early DLTs are in our view generally a major concern for the prospects of any drug, at the end of the day viability of a therapeutic candidate is a function of its therapeutic window," he wrote in a flash note after the stock's drubbing. "And while no clinical activity was observed in this early study, [management] noted observation of pharmacodynamics markers which [suggested] on-target activity. In this context, we think results from upcoming dose-expansion cohorts, including combinations, should be of interest."
Schmidt added, "We continue to think CD47 holds promise as an emerging immuno-oncology target, although clear clinical proof of concept is still outstanding, highlighting the early development stage of TRIL's lead product candidate."
'Where Lentiglobin works, it really works'
Much of the Street's attention flew to matinee companies such as Bluebird, of Cambridge, Mass., which disclosed third-quarter financials after Wednesday's market close. The company will present data at ASH on phase I/II studies of its lentiviral-based gene therapy, Lentiglobin, in transfusion-dependent beta-thalassemia (TDT) and severe sickle cell disease (SCD). In September, Bluebird opened its first phase III study of Lentiglobin with the global, multicenter HGB-207 study in patients with TDT with non-β0/β0 genotypes. (See BioWorld Today, Sept. 9, 2016.)
ASH abstract data revealed, unsurprisingly, that patients with TDT and non-β0/β0 genotypes who previously achieved transfusion-independence remained transfusion-free at longer term follow-up, while TDT patients with the β0/β0 genotype did not, though they required fewer transfusions. The findings were directly in line with Bluebird's 2015 ASH abstracts, which caught investors by surprise last year and sent the company's shares tumbling 22 percent at the time. (See BioWorld Today, Nov. 6, 2015.)
The fallout was only modestly lower this year. Bluebird's shares (NASDAQ:BLUE) sank as much as 20 percent early before regaining some ground to close at $41.30 for a loss of $5.10, or 11 percent.
"Overall, the latest results were in line with our expectations, which leave us surprised by the sharp sell-off this morning," J.P. Morgan analyst Cory Kasimov wrote about Bluebird's ASH abstracts. "Some investors were clearly expecting more from the SCD program, but we believe those expectations were misplaced going back to last year's ASH and more recently at the company's R&D Day. The key takeaway, in our view, is that where Lentiglobin works, it really works and it appears durable (and safe)."
Other analysts had similar views.
"The three datasets based on the old manufacturing process and suboptimal conditioning regimen showed in-line expectation for hemoglobin expression and clinical benefits, in our view," Gena Wang, of Jefferies, wrote in a flash note. "We continue to expect improved process to provide potential clinical benefit in SCD (initial data likely ASH 2017) and see the sell-off as an especially good buying [opportunity]."
Despite the general sentiment that Lentiglobin treatment of SCD still has a long way to go, "overlooked in the abstract release is the durability of HbAT87Q production and transfusion-independence in bet-thal patients, in our view," observed Piper Jaffray analyst Joshua Schimmer in a hot comment. In TDT patients with non-β0/β0 genotypes treated for at least six months, median hemoglobin levels of 4.7 g/dL were achieved and maintained in those treated for at least 12 months, while those with the more severe β0/β0 phenotype reduced their transfusion requirements by a median of 60 percent.
"The profile of Lentiglobin continues to be well-tolerated, and we continue to see a clear path forward" that includes the potential for more severe TDT patients to become transfusion-independent, he added.
In hemophilia B, Spark Therapeutics and partner Pfizer Inc., of New York, offered a peek at abstract data from the first seven participants in the phase I/II trial of SPK-9001, a bioengineered adeno-associated virus capsid that expresses a codon-optimized high-activity human factor IX (FIX) variant. Four of the seven reached greater than 12 weeks post-vector administration at the time of abstract submission. Those four showed consistent and sustained factor IX (FIX) activity levels, with a mean greater than 30 percent of normal, with no sustained elevation in liver enzyme levels, extending the findings in three patients reported by Philadelphia-based Spark earlier this year. (See BioWorld Today, May 20, 2016.)
However, one participant, less than 12 weeks post-administration, showed an immune response accompanied by a drop in FIX activity level and was placed on a tapering course of corticosteroids. The companies indicated the single participant did not have any bleeds or require replacement factor, and no other participant required the use of corticosteroids.
Still, the episode was sufficient to dent shares of Spark (NASDAQ:ONCE), which fell more than 25 percent Thursday before partly rebounding to close at $40.51 for a loss of $6.45, or 13.7 percent.
Despite the single immune response, "SPK-9001 continues to look like a functional cure in the patients, in our opinion," Cowen and Co. analyst Phil Nadeau wrote in an earnings update. The ASH abstract indicated that SPK-9001 was well-tolerated, he pointed out, with no liver enzyme elevations above 1.5 times the upper limit of normal.
Nadeau panned investors for dropping the company's shares "as if SPK-9001 has encountered a fatal flaw," he wrote. "We think this is an overreaction."
J.P. Morgan's Kasimov was a bit more understanding about investor sentiment. He called the ASH abstract and Spark's third-quarter update "incrementally negative." That said, "the extent of the sell-off seems overdone," Kasimov agreed, maintaining that Spark appears "well-positioned in the emerging gene therapy space."
The ASH meeting opens Dec. 3.