Gene Therapy Briefs

Abstract

Voyager Therapeutics (www.voyagertherapeutics.com) was launched February 12 by Third Rock Ventures (http://thirdrockventures.com/) with $45 million in Series A financing. The gene therapy company will focus on developing one-time treatments for fatal and debilitating diseases of the central nervous system using its adeno-associated virus (AAV) vector platform and on innovating and investing in areas such as vector optimization and engineering, dosing techniques, and process development and production.

“We believe the time is right for gene therapy, and we have assembled the expertise, technology and strategies to convert the promise of AAV gene therapy into meaningful treatments for patients,” Mark Levin, interim CEO of Voyager and partner at Third Rock, said in a statement (Voyager, 2014).

Voyager's four founders include:

• Krystof Bankiewicz, MD, PhD, the Kinetics Foundation chair in Translational Research and professor in residence of neurological surgery and neurology at the University of California, San Francisco (UCSF; www.ucsf.edu/);

• Guangping Gao, PhD, director of the University of Massachusetts Medical School (UMMS; www.umassmed.edu) Gene Therapy Center & Vector Core, scientific director of the UMMS-China Program Office, and professor of microbiology and physiology systems and Penelope Booth Rockwell professor in biomedical research at UMMS;

• Mark Kay, MD, PhD, head of the Division of Human Gene Therapy and professor in the Departments of Pediatrics and Genetics at Stanford University School of Medicine (http://med.stanford.edu), an original founding member of the American Society of Gene and Cell Therapy, and currently the editor of Human Gene Therapy; and

• Phillip Zamore, PhD, Howard Hughes Medical Institute investigator, the Gretchen Stone Cook chair of biomedical sciences at UMMS, professor of biochemistry and molecular pharmacology, and codirector of the RNA Therapeutics Institute at UMMS.

Voyager said it will launch with multiple clinical and preclinical product programs for CNS diseases, including a Parkinson's disease program in an ongoing Phase Ib study with collaborators at UCSF, as well as preclinical programs for a monogenic form of amyotrophic lateral sclerosis and Friedreich's ataxia.

Voyager has entered into licensing and other agreements with UMMS, UCSF, and Stanford University for technology and data, including rights to intellectual property related to expressed RNAi technology discovered at UMMS, clinical data related to the Parkinson's disease program from UCSF, and certain rights to AAV intellectual property developed at Stanford. Voyager has also entered into a broad strategic collaboration with UMMS, with the goal of accelerating its research and development efforts.

The company is also building relationships with patient education and research foundations such as the Friedreich's Ataxia Research Alliance (FARA) and The Michael J. Fox Foundation for Parkinson's Research, which partly funds Dr. Bankiewicz's work with AAV gene therapy.

BioMarin Pharmaceutical (www.bmrn.com) won FDA approval for VIMIZIM (elosulfase alfa) for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome), the company stated on February 14. VIMIZIM is the first treatment approved for the disease, which affects an estimated 3,000 patients in the developed world—including 800 in the United States (BioMarin, 2014a; U.S. Food and Drug Administration, 2014).

Six days after the FDA's approval, BioMarin received a positive opinion for its marketing authorization application for the drug from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP). The European Commission is expected to render a final decision in the second quarter (BioMarin, 2014b).

VIMIZIM is an enzyme replacement treatment for Morquio A syndrome, which occurs as a result of a deficiency of activity in N-acetylgalactosamine-6-sulfate sulfatase (GALNS), an enzyme involved in the metabolism of glycosaminoglycan (GAG). VIMIZIM is intended to replace the missing enzyme and stop pervasive and progressive accumulation of GAGs, which leads to significant deaths and clinical impairments resulting in diminished functional capacity, impaired quality of life, and early mortality.

FDA cited safety and efficacy data from a clinical trial involving 176 participants with Morquio A syndrome, ranging in age from 5 to 57 years. Participants treated with VIMIZIM showed greater improvement in a 6-minute walk test than participants treated with placebo. On average, patients treated with VIMIZIM in the trial walked 22.5 meters farther in 6 minutes compared to the patients who received placebo (U.S. Food and Drug Administration, 2014).

VIMIZIM was granted priority review by FDA, an expedited review of drugs for serious diseases or conditions that, according to the agency, may offer major advances in treatment. The drug was also the first to receive the Rare Pediatric Disease Priority Review Voucher—a provision that aims to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Before the FDA's approval, patients with Morquio A syndrome had no approved drug treatment options.

“We are thrilled that patients with Morquio A syndrome will have access to this potentially life-changing therapy and appreciate BioMarin's commitment to the MPS community and the individuals and their families who are affected by these devastating conditions,” Barbara Wedehase, MSW, CGC, executive director of the National MPS Society, said in a statement. “This approval provides the community with a therapy and with hope” (BioMarin, 2014a).

Chimeric antigen receptor T cell (CAR-T) therapy has recently been at the center of a scramble by companies seeking to commercialize their versions of the technology, as well as additional promising clinical results.

Cellectis (www.cellectis.com) said February 17 it will work with Servier (www.servier.com) to develop and commercialize product candidates targeting leukemia and solid tumors, beginning with Cellectis's lead product candidate, UCART19, in which engineered allogeneic CD19 T cells treat various types of leukemias and lymphomas.

The agreement also includes research, development, and potential commercialization of five other product candidates targeting solid tumors. Cellectis will oversee R&D of unspecified product candidates through the end of Phase I.

Servier may exercise an exclusive worldwide option for a license on each product candidate developed under the agreement. Upon exercising each option, Servier will be responsible for taking over clinical development, registration, and commercialization of each product.

In return, Servier agreed to pay Cellectis $10 million upfront and up to $140 million for each of the six product candidates potentially developed, spread over various milestones in the development and commercialization phases. Servier will also pay Cellectis royalties on the sales of commercialized products (Servier, 2014).

Servier teamed up with Cellectis after publishing data it said showed UCART19 “eradicated” human leukemia cells transferred into mice. The Servier–Cellectis alliance creates an alternative to the two companies already competing to develop their own CAR-T-based therapies.

A day after the Cellectis–Servier collaboration was announced, researchers at Memorial Sloan-Kettering Cancer Center published results in Science Translational Medicine showing that 88% of leukemia patients achieved complete remissions following T cell treatment (Memorial Sloan-Kettering Cancer Center; www.mskcc.org). In the study—which MSKCC said was the largest clinical study ever conducted to date of patients with advanced leukemia—16 patients with relapsed Adult B cell acute lymphoblastic leukemia (B-ALL) were given an infusion of their own genetically modified immune cells, which were “re-educated” to recognize and destroy cancer cells containing the protein CD19.

While overall complete response rate for all patients was 88%, those with detectable disease prior to treatment had a complete response rate of 78%, far exceeding that of salvage chemotherapy alone (Davila et al., 2014). “These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” said Michel Sadelain, MD, PhD, director of MSKCC's Center for Cell Engineering and a senior author of the study with Renier Brentjens, MD, PhD, MSKCC's director of cellular therapeutics (MSKCC, 2014).

Drs. Sadelain and Brentjens cohold a U.S. patent covering the technology used to create the modified T cells in this study. The technology was licensed in December 2013 to Juno Therapeutics (http://junotherapeutics.com/), which along with St. Jude Children's Research Hospital (www.stjude.org) are allied in a lawsuit over CAR technology with the University of Pennsylvania (UPenn; www.upenn.edu).

St. Jude contends that UPenn wrongly used material covered by U.S. patent no. 8,399,645 and two earlier material transfer agreements (MTAs) in the development of its own chimeric T cell receptor. UPenn has asked the court to declare it had not infringed the patent or the two MTAs and that the patent was invalid. A settlement conference held March 5 failed to resolve the lawsuit, which is pending in U.S. District Court for the Eastern District of Pennsylvania (Dalzell, 2014).

Novartis (www.novartis.com) is awaiting a court decision on a motion to join the lawsuit on the side of UPenn, with which it has partnered to expand the use of personalized T cell therapy; Juno has said it will oppose the motion. Novartis contributed $20 million toward a Center for Advanced Cellular Therapies at UPenn, with joint R&D focused on discovery, development, and manufacturing of adoptive T cell immunotherapies.

American Society of Gene and Cell Therapy (ASGCT; www.asgct.org) will devote a daylong conference to the growth of commercial gene and cell therapy companies, a day before beginning its 17th Annual Meeting in Washington, D.C., on May 21–24 (American Society of Gene and Cell Therapy, 2014).

ASGCT's Commercialization of Gene and Cell Therapy Products Program will begin with welcoming remarks and a statement of objectives by program cochairs Rachel Salzman, DVM, chief scientific officer of The Stop ALD Foundation, and James M. Wilson, MD, PhD, director of the Gene Therapy Program at the Perelman School of Medicine, University of Pennsylvania, and editor-in-chief of Human Gene Therapy. Malcolm Brenner, MD, PhD, director of the Center for Cell and Gene Therapy, Baylor College of Medicine, will offer introductory remarks designed to provide context and general background highlighting maturation of the gene and cell therapy field, accompanied by robust private sector investment.

Drs. Brenner and Wilson will chair a panel discussion focused on gene therapy as a disruptive technology and the commercialization challenges that accompany paradigm shifts. Panelists include Rahul Kapoor, MD, assistant professor at the Wharton School, University of Pennsylvania; Nicolas Koebel, global commercial lead at GlaxoSmithKline; Jeff Walsh, chief operation officer at bluebird bio; Rich Gregory, head of Sanofi's Genzyme R&D Center; and, pending at deadline, Gregory MacMichael, global head of advanced therapies for Novartis.

Following individual presentations, the panel will engage in a discussion of topics set to include the need for accompanying innovative infrastructure, the importance of sustainability and scale-up, the importance of sticker-shock associated with new therapy costs, and the need or lack thereof for tools to educate payers, patients, and pharma on pay-as-you-go, pay-for-performance, and program portability.

Emil Kakkis, MD, PhD, chief executive officer of Ultragenyx Pharmaceutical, will chair a discussion titled “Regulatory Strategy in Gene and Cell Therapy Development.” His panelists will include Dr. Brenner and Jörn Aldag, CEO of uniQure.

Brendan Lee, MD, PhD, professor and investigator of Baylor College of Medicine and investigator at Howard Hughes Medical Institute, will chair a discussion of pricing and reimbursement. Dr. Lee's panel will feature Douglas Paul, PharmD, PhD, MS, vice president and partner of Medical Marketing Economics, LLC; Troyen Brennan, MD, executive vice president and chief medical officer of CVS Caremark; Louis Jacques, MD, director of Coverage and Analysis Group Center for Clinical Standards & Quality Center for Medicare & Medicaid Services; and Jay Matthews, PhD, associate director of clinical research at Merck.

Drs. Salzman and Wilson will chair the program's remaining two panel discussions. The first, “Finding the Value: Business Cases and R&D Models,” will include presentations by Aldag and Fulvio Mavilio, PhD, scientific director at Genethon; pending at deadline was Carole Greve-Philips, senior vice president of business at Spark Therapeutics, LLC.

The second, “The rubber meets the road; applying today's learnings toward maximizing success,” is the program's concluding panel and will feature Aldag and Drs. Paul, Brennan, Jacques, Matthews, and Kakkis. They will address gap analysis, the precompetitive space, and the next steps toward providing and advancing solutions that benefit all stakeholders.

References

American Society of Gene and Cell Therapy (2014). Commercialization of gene and cell therapy products program. Available at www.asgct.org/meetings-educational-programs/asgct-annual-meetings/2014-annual-meeting/attendee/program-submission/commercialization-workshop-schedule (accessed Feb. 6, 2014 ).

BioMarin Pharmaceutical (2014a). BioMarin announces FDA approval for VIMIZIM™ (elosulfase alfa) for the treatment of patients with Morquio A Syndrome. Available at http://investors.bmrn.com/releasedetail.cfm?ReleaseID=825970 (accessed March 6, 2014 ).

BioMarin Pharmaceutical (2014b). BioMarin receives positive opinion from the CHMP in the European Union for VIMIZIM™ (elosulfase alfa) for Morquio A Syndrome. Available at http://investors.bmrn.com/releasedetail.cfm?ReleaseID=827132 (accessed March 6, 2014 ).

Dalzell

Stewart

(2014). Order filed March 5, 2014, in Trustees of the University of Pennsylvania, plaintiff, v. St. Jude's Children's Research Hospital, defendant, and Juno Therapeutics, intervenor. U.S. District Court, Eastern District of Pennsylvania. Available via PACER at https://ecf.paed.uscourts.gov/doc1/153113436130 (accessed March 7, 2014 ).

Davila

M.L.

, Riviere

, Wang

, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med., 6, 224–225. Available at http://stm.sciencemag.org/content/6/224/224ra25 (accessed March 7, 2014 ).

Memorial Sloan-Kettering Cancer Center (2014). Cell therapy shows remarkable ability to eradicate cancer in clinical study. Available at www.mskcc.org/pressroom/press/cell-therapy-shows-remarkable-ability-eradicate-clinical-study (accessed March 7, 2014 ).

Servier (2014). Cellectis and Servier announce collaboration in allogeneic cell therapy: UCART19 to treat leukemia and 5 product candidates targeting solid tumors. Available at www.servier.com/content/cellectis-and-servier-announce-collaboration-allogeneic-cell-therapy-ucart19-treat-leukemia (accessed March 6, 2014 ).

U.S. Food and Drug Administration (2014). FDA approves Vimizim to treat rare congenital enzyme disorder. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm386008.htm (accessed March 6, 2014 ).

Voyager Therapeutics (2014). Third Rock Ventures launches Voyager Therapeutics with $45 million series A to develop life-changing gene therapies for CNS disorders. Available at www.voyagertherapeutics.com/pdfs/Voyager_02.11.14.pdf (accessed March 3, 2014 ).