2020-10-25| M&AR&D

Retrophin Acquires Orphan Technologies to Develop Potential, Effective Cure for Rare Disease

by Judy Ya-Hsuan Lin
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By Judy Ya-Hsuan Lin

On October 22nd, San Diego-based Retrophin announced they would acquire Lexington, MA-based Orphan Technologies with an upfront payment of $90 million in cash and an additional milestone payment up to $427 million for a potential classical homocystinuria (HCU) treatment OT-58. Both companies dedicate their resources to improving the quality of lives of patients suffering from rare disorders. The transaction is anticipated to close in the fourth quarter of 2020.

Frank Glavin, Chief Executive Officer of Orphan Technologies, said, “we are now at an ideal juncture to pair the therapeutic promise of OT-58 with Retrophin’s late-stage development and commercial capabilities in rare diseases. I believe that with this new stewardship, we increase the potential for OT-58 to become an impactful new treatment option for patients.”


Homocystinuria – A Rare Disease

Classical HCU is a rare metabolic disorder characterized by elevated levels of plasma homocysteine that leads to life-threatening thrombotic events, including heart attacks and stroke, developmental delay, as well as skeletal and ophthalmologic complications. It is caused by the deficiency of a naturally occurring enzyme cystathionine beta-synthase (CBS) responsible for maintaining concentrations of methionine and cysteine in the body. Such a deficiency limits normal metabolism from taking place and thus triggers increased levels of homocysteine.

According to Jefferies analyst Maury Raycroft, an estimated 3500 HCU patients are diagnosed in both the U.S. and Europe. Additionally, this estimation is much higher if newborns’ testing is included, according to a paper published in May in the journal Molecular Genetics and Metabolism. Current treatments include heavy dietary restrictions and supplemental intake of vitamin B6 and betaine. Still, these options are unfortunately ineffective in lowering homocysteine levels because it is really challenging to keep track of the amount ingested every day.


OT-58 – A Potential Cure for HCU

The development of OT-58 becomes very significant in filling the current unmet need, as it has demonstrated up to a 90% reduction of homocysteine levels in plasma and tissues. One good news for OT-58 is that it has been granted Rare Pediatric Disease and Fast Track designations by the USFDA and Orphan Drug designation in both the U.S. and Europe.

After explaining that existing treatments do not serve as a viable option, Eric Dube, Ph.D., Chief Executive Officer of Retrophin, expressed his optimism toward the new treatment.

“OT-58 has demonstrated an ability to meaningfully reduce homocysteine levels in preclinical models and has the potential to ultimately become the first disease-modifying therapy for HCU. This promising, novel development candidate fits directly with our mission to identify, develop, and deliver life-changing therapies to people living with a rare disease and brings exciting growth potential to Retrophin,” he said.

Incorporated in the use of a modified version of the human CBS enzyme, OT-58 is a PEGylated, recombinant enzyme replacement therapy to suppress the cause of classical HCU. OT-58 showed its effectiveness in removing homocysteine to help extend survival rate, reduce osteoporosis, and repair ocular structure during the preclinical trial, so it will move on to a Phase 1/2 dose-escalation study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics, and other clinical effects in patients with classical HCU.


Competition & Future Efforts

The collaboration of Retrophin and Orphan Tech is not the only entity that contributes to solutions for HCU; Austin, Texas-based Aeglea Biotherapeutics Inc. is also developing a recombinant human enzyme ACN-00177 and is ready to enroll 16-20 patients for the Phase 1/2 clinical study. In contrast, Retrophin has not yet been scheduled when, in 2021 the study would be launched.

Besides the peer competition, Retrophin should dig deeper into correlations between the homocysteine level and the occurrence of derivative adverse events because only a few publications discussed such. In other words, Retrophin has to define what levels of homocysteine should be considered toxic because the presence of homocysteine could assist in lowering the rates of cardiovascular adverse events or lens dislocations. As evidence has shown, patients with less than 120 micromolar concentrations (well above the normal) of homocysteine are less likely to have those adverse events than those with even fewer concentrations. Therefore, Retrophin should focus more on finding the balance rather than complete elimination.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related article: Potential Treatment for Osteogenesis Imperfecta Receives FDA’s “Rare Pediatric Disease Designation”



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