Sarepta Therapeutics Inc.'s potential licensing deal with Paris-based Lysogene SA drew more attention to the already hot space of gene therapy for lysosomal storage disorders (LSDs), the news coming just a week after Amicus Therapeutics Inc. – eager to guard its franchises in Pompe and Fabry disease – signed a pact with Perelman School of Medicine at the University of Pennsylvania (Penn) to pursue gene therapy treatments for those two conditions as well as CDKL5 deficiency and an additional rare metabolic disorder that was not disclosed.

At the center of the agreement between Cambridge, Mass.-based Sarepta and Lysogene is LYS-SAF302 to treat mucopolysaccharidosis IIIA (MPS IIIA). Under the terms, Lysogene will complete the pivotal trial, set to begin in the fourth quarter of this year. Sarepta hangs onto exclusive commercial rights to LYS-SAF302 in the U.S. and all territories outside of Europe, while Lysogene has rights in Europe, with Sarepta responsible for global manufacturing and supply to Lysogene.

This year, Sarepta will make committed cash payments to Lysogene totaling €22 million (US$26 million) plus the purchase of Lysogene equity for €2.2 million. In 2019, Sarepta will pay Lysogene up to €16 million more. Total payouts from Sarepta to Lysogene if all milestones are met would total about €108 million plus royalties, the companies said. Also, Sarepta gains option rights to an additional central nervous system (CNS)-targeted gene therapy candidate. The company could not be reached.

MPS III is divided into types IIIA, IIIB, IIIC and IIID, each distinguished by its genetic cause. The different types of MPS III have similar signs and symptoms, although the features of MPS IIIA typically appear earlier in life and progress more rapidly. People with MPS III usually live into adolescence or early adulthood, according to the NIH's National Library of Medicine. Also known as Sanfilippo syndrome, MPS III is a progressive disorder that primarily affects the brain and CNS, though other body systems can also be involved. Affected children often first show delayed speech and behavior problems. They may become restless, destructive, anxious or aggressive, and some exhibit features of autism spectrum disorder. In general, the physical features of MPS III are less pronounced than those of other types of MPS.

News flow from Sarepta lately has been steady. This month, the company entered a long-term manufacturing partnership with Paragon Bioservices Inc., of Baltimore, adding access to more commercial manufacturing capacity for its microdystrophin Duchenne muscular dystrophy (DMD) gene therapy program, as well as a manufacturing platform for future gene therapy programs, such as limb-girdle muscular dystrophy. The company offered encouraging DMD biomarker data from its phase I/IIa study at the World Muscle Meeting in Mendoza, Argentina, in the four patients that have been dosed with Sarepta's AAVrh74 microdystrophin gene therapy.

Sarepta recently inked an exclusive agreement for Nationwide Children's Hospital's gene therapy candidate, neurotrophin 3 (NT-3), to treat Charcot-Marie-Tooth (CMT) neuropathies, including CMT type IA. CMT is a group of hereditary, degenerative nerve diseases that can affect motor skills, resulting in muscle weakness, and limiting patients' ability to walk or use their hands. It's the most common inherited neuromuscular disorder, affecting more than 2.8 million people worldwide. CMT IA is most often caused by an extra copy of the PMP22 gene and affects about 50,000 patients in the U.S. Sarepta plans to enter the clinic next year with NT-3. No treatment options are approved.

In a report last Friday, BTIG analyst Timothy Chiang said "the recent drop in [Sarepta's] share price creates a potential buying opportunity," and he maintained a 12-month price target of $190. The stock (NASDAQ:SRPT) closed Monday at $131.34, up 84 cents.

Amicus 'relatively on par'

Cranbury, N.J.-based Amicus' tie-up with Penn makes a good marriage, said Leerink analyst Joseph Schwartz. "Importantly, partnering with a prominent gene therapy leader like James Wilson should be a significant leverageable advantage going forward and boost the company's odds of success as they can marry Wilson's gene therapy expertise with Amicus' biologics expertise," he wrote in a report about a week ago. Amicus markets Galafold (migalastat) for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data.

In Pompe disease, Amicus is using investigational biologics and Chaperone-Advanced Replacement Therapy to develop AT-GAA, which consists of recombinant human acid alpha-glucosidase enzyme with an optimized carbohydrate structure (designated ATB-200), administered with a small-molecule pharmacological chaperone (designated AT-2221).

At least four companies are known to be advancing gene therapies in Pompe: Sarepta, which signed a deal in early August with Alachua, Fla.-based Lacerta Therapeutics Inc.; Audentes Therapeutics Inc., of San Francisco; Philadelphia-based Spark Therapeutics Inc.; Avrobio Inc., of Cambridge, Mass. In Fabry disease, there's just one and it's in the hands of Avrobio, which at the start of the month disclosed findings on the first participants in an investigator-sponsored phase I study and company-sponsored phase II of ex vivo lentiviral gene therapy AVR-RD-01. The company said two phase I patients showed alpha-galactosidase-A (AGA) enzyme activity above the diagnostic range for classic Fabry disease at 18 months and six months, respectively, after receiving AVR-RD-01, and patient one was no longer receiving enzyme replacement therapy (ERT). At three months, the first participant in the phase II effort – an ERT-naïve patient – also showed evidence of AGA enzyme activity. But the enzyme activity did not show a steady state, failing to reach a plateau at 18 months. (See BioWorld, Oct. 2, 2018.)

Amicus' management "has repeatedly reminded us of their unwavering commitment to revolutionize treatments for both LSDs, going so far as to 'obsolete' their technologies," Schwartz noted, and the deal with Penn "is consistent with this core belief. Furthermore, with all the gene therapy assets in preclinical stages of development, Amicus can remain relatively on par with other developers, particularly given its already promising agent, AT-GAA, [which] can capture significant market share in the near-to-medium term," in his view. The Penn contract "tackled investors' long-standing concern surrounding the Fabry and Pompe" efforts, he said.

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