Upcoming events – Rare disease data for Sangamo and Strongbridge

Results of a phase I/II trial in Hunter syndrome will have implications for Gliead, and a Cushing's candidate will be watched for side-effects.

Welcome to your weekly digest of approaching regulatory and clinical readouts. The genome editing company Sangamo is due to report early data with SB-913 in Hunter syndrome, a rare lysosomal storage disease for which Shire's market-leading enzyme-replacement therapy cannot cross the blood brain barrier, potentially giving Sangamo an advantage.

And by mid-year Strongbridge Biopharma will report pivotal data in Cushing’s disease. The company’s Recorlev is an enantiomer of ketoconazole, which is used off label in the US but is associated with liver toxicity, so safety will be a key point to watch.

Sangamo’s hunt

Hunter syndrome, also known as mucopolysaccharidosis type II, is caused by mutations in the gene encoding iduronate-2-sulfatase (IDS), which is needed to break down glycosaminoglycans. The condition primarily affects males, and manifests as developmental delay, decreased mobility and cognitive decline.

Sangamo’s SB-913 uses zinc finger nuclease genome editing, using an AAV vector, to insert a corrective IDS gene into a precise location in the DNA.

The phase I/II Champions trial is testing three doses of SB-913 and aims to recruit nine adult males in total; so far four patients have been dosed across the first two cohorts, with initial data due by late summer.

Champions trial doses
Dose (vector genomes/kg)
Cohort 1 5x1012
Cohort 2 1x1013
Cohort 3 5x1013

The primary endpoint is safety at three years. Secondaries include IDS activity in the plasma, urine glycosaminoglycan levels and AAV clearance in plasma, saliva, urine, stool and semen. In February the company reported encouraging safety data from two patients given the lowest dose, and shares climbed 12.5%.

Patients in the trial can continue to take enzyme-replacement therapies, such as Shire’s Elaprase, which has been shown to improve walking distance but cannot cross the blood-brain barrier, so cognition is unaffected. Shire has reformulated this product into SHP609, delivered via the spinal cord, but this has failed to slow cognitive decline in a phase II/III trial (Snippet roundup: Approvals for Merck/Pfizer and Biom Up, but Shire disappoints, December 22, 2017).

With so few options available the zinc finger approach will be watched with interest, especially since Gilead recently paid $150m to develop cell therapies using Sangamo’s technology.

Mucopolysaccharidosis type II pipeline
Status Project Pharma class Delivery Company 2024eindication sales ($m) Clinical trial/notes
Marketed Elaprase IDS enzyme-replacement therapy IV, weekly Shire/Sanofi 889 -
Marketed (S Korea only) Hunterase IDS enzyme-replacement therapy IV, weekly GC Pharma - -
Phase III SHP609 IDS enzyme-replacement therapy Intrathecal, monthly Shire - Ph II/III (NCT02055118) failed to hit cognitive endpoint in Dec 2017 
Phase II JR-141 IDS enzyme-replacement therapy IV, weekly JCR Pharmaceuticals 46 Ph I/II Japan trial (NCT03128593) showed crossover into the blood brain barrier Dec 2017
Phase II SB-913 IDS gene therapy Single IV delivery Sangamo Therapeutics 21 Champions (NCT03041324) data due late summer 2018
Phase I SHP631 Anti-insulin receptor MAb-iduronidase conjugate IV, weekly Shire/Armagen - Ph I trial (NCT02262338) recruiting according to clinicaltrials.gov, little news since 2016
Source: EvaluatePharma.

Safety watch

Topline results are due mid-year for Strongbridge Biopharma’s Recorlev in the phase III Sonics study in 94 adult Cushing’s disease patients.

Cushing’s is due to overproduction of the stress hormone cortisol, and can cause diabetes, weight gain, hair loss, osteoporosis and high blood pressure; this leaves sufferers prone to heart disease.

About three quarters of cases are caused by a benign tumour in the pituitary gland. First-line therapy is surgical removal of the gland and/or radiotherapy, but many patients do not respond, and around half relapse.

The Sonics study has an initial titration phase, with patients given 150mg increments of Recorlev up to 600mg twice daily, until normal levels of urinary free cortisol (UFC) are achieved; the dose is maintained for six months, followed by a further six months' treatment.

The primary endpoint is responder rate, defined as normalised UFC without a dose increase. Biomarkers of Cushing’s such as HbA1c, blood pressure, lipid profile, C-reactive protein and BMI are also being measured. The trial is powered for a responder rate of around 25%, which the company believes would be considered clinically important if improvements in comorbidities of Cushing’s are also seen.

If the trial succeeds Strongbridge plans to file Recorlev using the shortened 505(b)(2) pathway.

The biggest issue surrounding Recorlev will be safety, as it is an enantiomer of ketoconazole, which has been associated with liver toxicities. In the US ketoconazole has a black box warning for use in fungal infections, its approved indication. In Europe it was taken off the market for fungal use but has since been approved in Cushing’s, with strict monitoring, owing to the significant unmet need. 

Novartis’s Signifor is the leading Cushing’s therapy, with sales expected to reach $384m by 2024, according to consensus from EvaluatePharma. Signifor was approved for Cushing’s in the US in 2012, but one of its major side effects is rapid onset of hyperglycaemia – one of the disease’s main symptoms. Alternative options would be welcomed.

Phase III trials of Recorlev 
Study Trial ID Note
Sonics NCT01838551 Data due late summer
Logics NCT03277690 Randomised withdrawal trial. Data due Q1 2019
Note: Both trials will form part of the US approval submission.

To contact the writer of this story email Joanne Fagg in London at [email protected] or follow @ByJoFagg on Twitter

Share This Article