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.
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)|
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|
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|
|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.|