SCRIP Intelligence: WORLD Symposium Notebook: New Data In Lysosomal Diseases And A Push For Earlier Testing

By Mandy Jackson


Executive Summary

The WORLD Symposium Feb. 13 to 16 in San Diego offered everything from basic research through late-stage clinical data in lysosomal diseases, including ArmaGen’s blood-brain barrier-crossing treatment for Hurler syndrome and updates from ongoing development programs from rare disease specialists, such as Genzyme, Amicus and Protalix.

The WORLD Symposium from Feb. 13 to 16 in San Diego brought together academic researchers and biopharmaceutical companies to share emerging research in lysosomal diseases, including next-generation enzyme replacement therapies, gene therapies and tests that identify patients before debilitating effects of the diseases kick in.

Researchers, clinicians and biopharma company scientists presented a range of basic research, preclinical data and clinical trial results for Gaucher, Fabry and Farber diseases, Hunter and Hurler syndromes, and other rare and ultra-rare lysosomal diseases. ArmaGen Technologies Inc., Shire PLC, Sanofi’s Genzyme business unit, BioMarin Pharmaceutical Inc. and Amicus Therapeutics Inc. presented data, set up shop in the exhibit hall and sponsored topical seminars, showing how far research has come since the grassroots-organized WORLD (We’re Organizing Research on Lysosomal Diseases) Symposium began 13 years ago, while the array of very early disease and therapeutic candidate research served as a reminder of how far the field has to go for many patients.


Crossing The Blood-Brain Barrier

One of the biggest challenges for many lysosomal diseases – even those with commercially successful treatments – is getting enzyme replacement therapies (ERTs) and other treatments across the blood-brain barrier. Existing therapies often successfully treat or halt progression of somatic symptoms, but don’t have an effect on neurological aspects of the diseases.

ArmaGen presented interim results from its ongoing Phase II clinical trial for AGT-181 in Hurler and Hurler-Scheie syndrome (mucopolysaccharidosis type I or MPS I) that showed improvements in somatic and cognitive symptoms in pediatric patients. Hurler syndrome, caused by a lack of the enzyme iduronidase, affects the brain and spinal cord, leading to joint stiffness, loss of physical function and airway obstruction as well as developmental delays and mental decline, among other symptoms.

AGT-181 is an ERT consisting of re-engineered iduronidase as a fusion protein with an immunoglobulin G (IgG) antibody targeting the insulin receptor. ArmaGen’s “Trojan horse” technology uses the body’s natural system for transporting large molecules across the blood-brain barrier; AGT-181 binds to the receptor that transports insulin into the brain.

Data were presented on Feb. 16 at the WORLD Symposium for the first five patients (age two and older) enrolled in the Phase II study. Results through 26 weeks of treatment showed neurological and cognitive gains for four of the children and stabilization of those symptoms for the fifth child.

ArmaGen CEO Mathias Schmidt described the cognitive changes in an interview with Scrip as “remarkable” given the children’s condition at baseline and the patients’ poor prognosis. For instance, a nine-year-old boy severely affected by Hurler syndrome started the study with the cognitive ability of a 16-week-old baby and improved to a nine-month-old child’s cognitive ability at week 26 with significant functional gains as well.

A six-year-old boy doubled his cognitive ability; a 15-year-old gained conceptual thinking and the ability to manipulate his clenched hands; and a three-year-old boy who did not improve after a stem cell transplant at six months old stabilized after treatment with AGT-181.

ArmaGen described AGT-181’s impact on somatic symptoms as similar to existing ERTs – stabilization of urinary glycosaminoglycan (GAG) levels and stabilization or reduction in liver and/or spleen volume. In terms of safety, there were two infusion site reactions and two hypoglycemic events, which were described as transient and well-controlled by glucose administration.

Enrollment in the Phase II study is complete at 13 patients, including two who dropped out due to the travel burden of getting to the clinical trial site. ArmaGen expects to receive final data in July and may report the full results in August.

“We’re already planning very aggressively our Phase III strategy,” Schmidt said. “We have various approaches, because MPS I is a very heterogeneous disease, so we may have more than one small Phase III study.”


Hunter Candidates

ArmaGen has a second product candidate in the clinic in partnership with Shire – AGT-182 for Hunter Syndrome (MPS II). (Also see ” ‘In transition’ Shire strikes deal for follow-on Hunter syndrome product ” – Scrip, 23 Jul, 2014.) Phase I studies in adults are wrapping up and a Phase II program is being planned by Shire, which will take over clinical trial responsibilities for proof-of-concept studies.

Shire also has SHP609, an intrathecal version of its marketed Hunter syndrome ERT Elaprase (idursulfase), under investigation in a Phase III clinical trial with data expected in the fourth quarter of 2017. (Also see “Shire’s Sales, R&D Heads Shed Light On The Post-Baxalta Road Ahead” – Scrip, 14 Feb, 2017.) The rare disease and specialty pharma company presented results at the WORLD Symposium for both Elaprase and SHP609 as well as observational data about Hunter and Gaucher disease.

ArmaGen has raised $70m to date, including a $17m Series A venture capital round in Dec. 2012; the rest is from Shire, other corporate partners and government grants. (Also see “ArmaGen taps Big Pharma interest in ‘Trojan horse’ tech to get drugs into brain ” – Scrip, 3 Dec, 2012.) Schmidt said ArmaGen is talking to potential Series B investors about funding ongoing clinical studies and advancing preclinical programs.


Earlier Diagnosis To Prevent Irreversible Damage

Lysosomal diseases often go undiagnosed until after patients exhibit severe symptoms that cause damage which cannot be undone, so efforts to develop diagnostic tools and implement earlier screening are important to clinicians and biopharma companies.

Shire already works with various academic and other partners to offer early diagnosis and free testing, Vice President and Head of Genetic Diseases Hartmann Wellhoefer told Scrip in an interview at the WORLD Symposium.

Fabry disease, for instance, typically is diagnosed when patients already are on dialysis for kidney damage rather than during the period when patients experience non-specific pain and gastrointestinal issues; in children, hearing loss and behavioral issues are a concern. Patients with Hunter disease experience bone structure issues and joint damage that could be prevented, as least in part, by earlier treatment.

Amicus hosted a seminar on Feb. 15 to discuss personalized medicine in lysosomal diseases, which highlighted the difficulty of early diagnosis in diseases for which the early symptoms aren’t an obvious indication of a particular rare disease.

That’s where Ana Jovanovic, a consultant in adult inherited metabolic disorders who works in the Mark Holland Metabolic Unit at the Salford Royal NHS Foundation Trust in Salford, UK, noted that the traditional path to diagnosis requires “a high degree of clinical suspicion” on the part of the treating physician.

Precision medicine – targeted and often personalized treatments based on patient- or subgroup-specific disease targets – is difficult in lysosomal diseases, Jovanovic said, because biomarkers haven’t been identified in many diseases and the patient populations are heterogeneous with varying degrees of disease and symptom severity.

Amicus Vice President and Head of Global Regulatory Affairs Andrew Mulberg noted that a lack of natural history data in many lysosomal diseases also makes personalized medicines and other therapeutic approaches difficult. Data aren’t available to compare with biopharma clinical trial results and show that a drug can slow the progression of a disease.

Marc Patterson – a neurology, pediatrics and medical genetics professor who chairs the Division of Child and Adolescent Neurology at the Mayo Clinic in Rochester, Minnesota – said that’s why disease-specific organizations should organize patient registries if they haven’t already. The information could identify biomarkers and other data to support the development of new diagnostics and treatment options.

Mulberg agreed, noting that “non-proprietary, non-pharma-related natural history data is important,” because “we’re all then looking at the same apples” rather than comparing apples to oranges.


Other Data At WORLD Symposium

Biopharma companies presented data from a mix of preclinical, early clinical and post-marketing studies at the WORLD Symposium. Some highlights for therapies still in development were:

  • Phase Ib data for Sanofi/Genzyme’s breakthrough therapy-designated olipudase alfa to treat acid sphingomyelinase deficiency (ASMD or Niemann-Pick type B) showed effects on non-neurological symptoms in adults treated for 30 months. (Also see “FDA deems Sanofi/Genzyme drug olipudase alfa ‘breakthrough'” – Scrip, 5 Jun, 2015.)
  • BioMarin’s and Sanofi/Genzyme’s intrathecal version of Aldurazyme (laronidase) for the treatment of cognitive decline in Hurler syndrome (MPS I) appeared to be safe in an open label study conducted between 2009 and 2015.
  • BioMarin’s Brineura (cerliponase alfa) significantly reduced the rate of motor and language decline for children with CLN2 disease, a form of Batten disease, who were enrolled in a long-term study compared to a control group; a biologic license application for the ERT is under review by the US FDA. (Also see “10 Approvals To Watch For In Early 2017” – Scrip, 3 Feb, 2017.)
  • A Phase III retrospective analysis showed a correlation between the reduction in disease substrate and reduction in diarrhea for Fabry disease patients treated with migalastat. Amicus will initiate a study in 2017 to confirm the gastrointestinal benefit of the pharmacological chaperone – data that are needed to seek FDA approval. (Also see “J.P. Morgan Notebook Day 2: Bristol Humbled By Competition, Sanofi’s Sarilumab Ready For Review, Justifying Spinraza’s Price And More” – Scrip, 11 Jan, 2017.)
  • Updated and long-term Phase I/II results for PRX-102, a plant-derived alpha-GAL-a enzyme, showed continued benefit for Fabry disease patients; Protalix BioTherapeutics Inc. initiated a Phase III clinical trial in October. (Also see “PIPELINE WATCH: Phase III Trials Start In Atypical HUS, Fabry Disease And Colorectal Cancer” – Scrip, 28 Oct, 2016.)
  • Abeona Therapeutics Inc. presented additional data from the first dosing cohort of its Phase I/II clinical trial testing the gene therapy ABO-102 in Sanfilippo syndrome type A (MPS IIIA), which showed continued positive effects with some fluctuations; enrollment in the second cohort is under way. A Biomedtracker analysis noted that longer-term data and results from higher doses are needed to confirm what looks to be an encouraging effect on Sanfilippo type A. (Also see ” Video Interview: Abeona Breaking Into Rare Diseases ” – Scrip, 12 Feb, 2016.)

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