Shares of Sangamo Therapeutics lost about one-third of their value yesterday after the company released interim results from a pair of Phase I/II trials assessing two of its zinc-finger nuclease (ZFN) genome-editing candidates for two types of mucopolysaccharidosis (MPS). The studies showed favorable safety profiles and some expression of key enzymes, though not as much efficacy as the company had hoped.

“It’s working and it’s not sufficient for a clinical benefit,” Sangamo CEO Sandy Macrae told analysts on a conference call yesterday.

Investors responded to the clinical trial results with a stock selloff that sent Sangamo shares plunging 31% yesterday, to $8.31 from $12.02. Shares slipped further in trading this morning, to $8.01 as of 10:36 a.m.

Sangamo released interim data from its CHAMPIONS trial (NCT03041324), assessing its SB-913 for mucopolysaccharidosis type II (MPS II), also called Hunter syndrome; and its EMPOWERS trial (NCT02702115), evaluating in MPS I (also called Hurler syndrome) the company’s SB-318.

In the same pair of announcements, Sangamo noted that it has also developed second-generation, “potentially more potent” ZFN constructs designed to increase editing efficiency that have already generated favorable preclinical data.

The second-generation ZFNs are already being manufactured and are expected to be ready for clinical use later this year, according to the company.

SB-913 uses ZFN-based genome editing to insert a normal functioning copy of the IDS gene under control of the strong albumin promoter in the patient’s liver. This approach is designed to enable the liver to produce and secrete active IDS into the bloodstream to be taken up by other tissues, according to Sangamo.

CHAMPIONS is an open-label clinical study designed to assess the safety, tolerability, and preliminary efficacy of SB-913 in up to nine adult males with MPS II. Three doses of SB-913 were assessed in six patients—two in each cohort—with an additional three patients receiving the high dose in an expanded cohort. The first patient was dosed in November 2017.

“Small” increases in enzyme activity

“Small” increases in IDS enzyme activity compared to baseline were recorded in the two patients receiving the mid-dose and in one patient receiving the high-dose, Sangamo said. At 24 weeks the measurements remained within the expected range for baseline values (<10 nmol/hour/mL) versus the normal range, estimated at greater than 82 nmol/hour/mL).

Sangamo said plasma IDS activity in the second high-dose cohort patient rose to approximately 50 nmol/hour/mL by week 6 following SB-913 administration. The plasma IDS activity levels subsequently decreased following development of a mild transaminitis—a known risk of AAV-based therapies—due to a suspected immune response in the patients, who was hospitalized on Day 121 for an incarcerated umbilical hernia considered unrelated to the study drug. As of the most recent observation, the company added, the patient’s plasma IDS activity measured 14 nmol/hour/mL, above the baseline value but below normal range.

“More data are needed to understand whether the small increases in IDS enzyme activity observed can translate into improved outcomes in MPS II patients treated with this first generation of SB-913,” Joseph Muenzer, MD, PhD, a professor of pediatrics and genetics at the University of North Carolina School of Medicine in Chapel Hill and a lead study investigator, said in a statement. “I look forward to reviewing additional data later this year from the five patients who have received the high dose of SB-913.”

Baseline urine glycosaminoglycan (GAG) measurements for all six cohort patients were in a range considered at or slightly above normal, except for heparan sulfate which was elevated in all patients at baseline. At 24 weeks, urine GAG results did not show a meaningful change.

Sangamo said clinical relevance of the changes observed following SB-913 administration will be assessed as clinical data and patient outcomes are analyzed following a trial of withdrawal from enzyme replacement therapy (ERT).

As of yesterday, two mid-dose and one high-dose patients had begun ERT withdrawal—though one of the mid-dose patients was recommended to resume ERT approximately three months later due to fatigue and increasing GAGs. Analyses from ERT withdrawals will be available later in 2019, the company said.

EMPOWERS interim results

SB-318 uses ZFN-based genome editing to insert a normal copy of the alpha-L-iduronidase (IDUA) gene into a precise location in the DNA of liver cells—an approach that Sangamo says is designed to enable the liver to produce and secrete active IDUA into the bloodstream to be taken up by other tissues.

EMPOWERS is designed to evaluate the safety and tolerability of ascending doses of SB-318 in patients with mild MPS I receiving weekly ERT. One patient has been dosed with 1e13 vector genomes per kilogram body weight (vg/kg) of SB-318 and two patients have been dosed with 5e13 vg/kg of SB-318. None of the three enrolled patients have received a bone marrow transplant.

According to Sangamo, EMPOWERS results suggested a dose-dependent increase in leukocyte IDUA activity, with activity levels rising above baseline and in the normal range of 6.0 to 71.4 nmol/hr/mg. Plasma IDUA activity was unchanged from baseline in all three patients.

Baseline urine GAG measurements for the three patients in the EMPOWERS study were in a range considered to be at or slightly above normal. In the limited duration data set available at the time of the WORLDSymposium presentation, urine GAG measurements showed no meaningful change.

Sangamo said clinical relevance of the changes seen in patients treated with SB-318 will be assessed as clinical data and patient outcomes are analyzed following a trial of withdrawal from ERT, which is expected later this year. The company also expects to report analyses of liver biopsies later this year.

At the same time, Sangamo also highlighted its second-generation ZFNs, which it said have shown to regulators three potential advantages for clinical use:

  • A 5- to 30-fold improvement in efficiency and potency due to structural changes
  • The ability to function equally well in the patients who have a single nucleotide polymorphism (SNP) in the target locus in the albumin gene (approximately 20% of the population)
  • Improved specificity

Additional data from Sangamo’s in vivo genome editing programs will be assessed before potential integration plans for the second-generation ZFNs are finalized, the company added.



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