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Abstract

Industry Wire

Advanced Cell Technology (ACT) (Santa Monica, CA, USA) announced it received approval from FDA to pursue clinical testing of an embryonic stem cell (ESC) therapy for dry age-related macular dystrophy, a blinding condition in older individuals that affects millions in the western world. This news comes only a month after its approval of an ESC clinical trial for the rare blinding genetic disorder Stargardt Retinitis Pigmentosa. In parallel to the US, the company seeks regulatory clearance from the European agencies. ACT recently secured US$ 25 million in funding through a subsidiary of Socius Capital Group. This move makes ACT, according to the company, virtually debt-free. And with approximately $15 million cash on hand, this will allow ACT to progress its other clinical programs. (lhv)

Johnson & Johnson (J&J) (New Brunswick, NJ, U.S.) is in the final stages of acquiring the Dutch Vaccine maker Crucell (Leiden, The Netherlands). In December, J&J announced a formal bid for the purchase of the remainder of Crucell. J&J already had a 17.9& stake in Crucell and is now offering 24.75 euro per share to a total amount of 1.75 billion euro or $2.3 billion. (lhv)

Oxford Biomedica (Oxford, UK) saw its stock drop more than 30& after it announced an open stock offer for an additional GBP 20 million in funding mid-December. The gene therapy firm with proprietary equine lentivirus technology seeks funds to further its plans for a UK-based manufacturing facility and its ProSavin Parkinson's program. A promising update on ProSavin's ongoing Phase I=II clinical trial was unable to raise the stock price substantially. The drop in share price is attributed to the fact that the public offering is at a substantial discount and the current market conditions in the biotech arena. (lhv)

Clinical Trial Wire

Positive Results Seen in Clinical Gene Therapy Trial for Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency disorder caused by mutations in the WAS gene; the disease is characterized by recurrent infections, eczema, autoimmunity and a bleeding diathesis caused by thrombocytopenia and platelet dysfunction. WAS protein (WASP) is a cytosolic protein expressed on all hematopoietic cell lineages and is essential for normal antibody function, T-cell responses, and platelet production. About 300 mutations have been found throughout the WAS gene and can include base pair substitutions, insertions, and deletions. Allogeneic hematopoietic stem cell (HSC) transplantation is the only currently available curative therapy, although this approach may be associated with considerable risk of death or complications. HSC gene therapy has been pursued as a potential alternative treatment modality for WAS.

A new study from an international consortium of researchers, spearheaded by Dr. Christopher Klein of Hannover Medical School in Germany, now reports positive results from an HSC gene therapy clinical trial for WAS¹. The authors transplanted genetically modified autologous CD34+ HSCs into two boys with WAS. The cells were transduced with WASP-expressing retroviral vectors. Transplantation of these cells led to marked improvements in platelet count, T cell proliferation, T cell diversity, total and specific antibody production, natural killer (NK) cell synapse formation and resolution of clinical signs including hemorrhagic diathesis, eczema, autoimmunity, and infections.

Recent gene therapy trials for hematopoietic diseases, all of which were performed using gammaretroviral vectors, have been marred by the occurrence of leukemia and myelodysplasia due to insertional oncogenesis (IO). Klein and colleagues, as part of their study, performed detailed analysis of retroviral insertion sites (RIS) in the two boys with WAS. The authors show that clonal dominance does occur, though not persistently, for the timeframe analyzed, and that insertions into sites previously implicated in myeloid and T lymphoid clonal dominance or oncogenesis are frequently detectable.

According to Dr. Sung-Yun Pai of Children's Hospital Boston, “this article is the first to report successful correction of the clinical and laboratory manifestations of Wiskott-Aldrich syndrome (WAS) using gene transfer in autologous CD34+ hematopoietic stem cells².” Nonetheless, according to Dr. Pai, it will be important to compare RIS, safety and efficacy outcomes “between this trial and future trials using next generation vectors with added safety features (i.e., self-inactivating gammaretroviral vectors, lentiviral vectors, and vectors containing endogenous or cellular promoters).” Moreover, according to Dr. Pai, it will be important to examine why “gammaretroviral gene therapy for some diseases (X-SCID and CGD) has resulted in IO, while others (ADA-SCID) have not.” (sk)

References

Boztug

, Schmidt

, Schwarzer

, Banerjee

, Díez

, Dewey

, Böhm

, Nowrouzi

, Ball

, Glimm

, Naundorf

, Kühlcke

, Blasczyk

, Kondratenko

, Maródi

, Orange

, von

Kalle C

, Klein

. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med, 2010 Nov 11 363,20:1918–1927.

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Evaluation of. Boztug

et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med, 2010 Nov 11 363,20:1918–1927. doi:10.1056/NEJMoa1003548]Faculty of 1000, 08 Dec 2010. F1000.com/6643956.

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Regulatory Wire

Highlights of FDA's Workshop on Gene and Cell Therapy Clinical Trials in Pediatric Populations

There are currently 113 active cell and gene therapy clinical trials involving pediatric populations. Nineteen of these trials are “first in man” protocols. According to OCTGT's Clinical Branch Chief, Dr. Wilson Bryan, the current trials are evenly divided by treatment indication for oncology and medicine. 60% of active protocols involve cell therapy, 27% are for gene therapy, 4% are for combination therapies, with the remaining 9% rounded out by miscellaneous therapies such as engineered tissues¹. The number of pediatric protocols submitted to the FDA's Office of Cellular, Tissue and Gene Therapies (OCTGT) has markedly increased over the past years. Given the rising popularity of clinical trials in pediatric populations, OCTGT recently held a one day public workshop to gather information from Institutional Review Boards (IRBs), gene and cellular therapy clinical researchers, and other stakeholders regarding best practices related to cell and gene therapy clinical trials in pediatric populations, as well as challenges and considerations in the review of these clinical trials.

One of the major challenges of clinical trials for pediatric populations is funding. As Dr. Christopher Breuer, Director of Tissue Engineering at Yale University, noted at the workshop, because cell and gene therapy for pediatric disorders are of relatively low prevalence, (i.e., not a big market share), it is hard to get companies interested. Therefore, most trials are being developed at academicmedical centers. “Yet, the very long timeline to obtain multiple awards for funding the successive stages and the redundant regulatory reviews present nearly insurmountable hurdles to progress².” To address this major challenge, Dr. Breuer recommended that “granting agencies develop integrated milestone-driven funding mechanisms for the stages to translate from preclinical at the bench to the bedside, pharm/tox clinical regulatory studies, product production and then the trial.”

Another major hurdle is the multiple regulatory steps involved in bringing a gene or cell therapy to the clinic. According to Dr. Ronald Crystal, Professor and Department Chairman of Genetic Medicine at Weill Cornell Medical College, although the regulatory agencies and monitoring groups play an important role in that [they] protect us [investigators] as well as patients, it [the regulatory process] is a huge burden on the academic groups².” Specifically, Dr. Crystal noted that “multi-institutional and multinational review of protocols leads to divergent evolution and non-harmonized protocols that weaken the scientific strength of the study.” Dr. Crystal stated that, “a recommendation would be to harmonize reviews when possible like institutional review boards (IRBs) at multiple institutions maybe if there is some mechanism for them to talk through things in parallel rather than in series and coordinating the review process to accelerate progress and improve quality of shared data.”

Dr. Celia Witten, Director of OCTGT, concluded the workshop by saying “that it's clear that there's a need for studies in these very small populations which are many of the pediatric studies. The challenges are considerable. It requires a great commitment on the part of the PIs to get these studies done. There are issues relating to the populations, the IRBs, informed consent, and from the perspective of the investigators.” Dr. Witten noted that “we'll be taking these lessons back to FDA and considering what else we might be able to do².”

References

Bryan

Wilson

. FDA IND Review: Regulations and Challenges Power Point presentation, presented at Public Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations on. November 2, 2010. http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm224217.htm

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Transcript for Public Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations. Presented at the U.S. Food and Drug Administration Public Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations. Bethesda: Maryland, November 2, 2010. http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm236681.htm

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