Abstract
“This study represents a unique direct gene therapy clinical trial in the oral cavity for a nonmalignant condition and one of the few times that gene transfer has been used to treat a quality-of-life disorder,” the coauthors wrote.
The study's lead author is Bruce Baum, D.M.D., Ph.D., a recently retired National Institute of Dental and Craniofacial Research (NIDCR) scientist. His interest in helping head-and-neck cancer survivors dates to the early 1980s, at which time he was attending patients in the NIDCR's Dry Mouth Clinic; many of the patients had head-and-neck cancer and had received radiation therapy to shrink their tumors. Although effective in treating cancer, the radiation inadvertently damaged nearby salivary glands, compromising their ability to secrete saliva into the mouth
In the early 1990s, as the first gene therapy studies entered research clinics, Baum drew a napkin sketch of the procedure he had in mind, and then joined colleagues in spending 15 years on research, finding in animal studies that the transferred aquaporin-1 gene, once expressed, will create new water channels in the impermeable salivary gland cells and allow water to flow through them.
A phase 1 protocol was launched, and the first patients treated, in 2008. Scientists gave 11 head-and-neck cancer survivors a single-dose injection of aquaporin-1 directly into one of their two parotid salivary glands. The gene was packaged in a disabled, nonreplicating adenovirus that served as the vector to deliver the gene into cells lining the salivary gland.
Five participants had increased levels of saliva secretion, and a renewed sense of moisture and lubrication in their mouths, within 42 days. Of the six who did not benefit from gene therapy, none had serious side effects. The most common side effect was a transient and relatively minor immune response against the disabled adenovirus.
“It is time to evaluate a different vector to deliver the aquaporin-1 gene,” Dr. Baum said in a statement, adding: “These data will serve as stepping stones for other scientists to improve on this first attempt in the years ahead.”
AGTC said the funding will allow it to continue developing its phase 2 program in α1-antitrypsin deficiency (Alpha-1). The vector being used in this program is the same as that used in the uniQure product, Glybera, which was the first gene therapy product approved for sale in the Western Hemisphere. The funding will also allow AGTC to initiate full development of potential treatments for two orphan hereditary ophthalmological conditions: achromatopsia (ACHM) and X-linked retinoschisis (XLRS).
“Based on encouraging clinical results from AGTC and others, we concluded that a large set of genetically defined diseases could be cured using AGTC's proprietary vectors and manufacturing technologies,” Ed Hurwitz, General Partner of Alta Partners, said in a statement. “The Series B financing is designed to move several of AGTC's programs through proof of concept as well as to allow the company to leverage its manufacturing and development infrastructure with partners to accelerate a broad portfolio of curative products.”
About 22,000 patients in the United States and Europe suffer from ACHM, caused by mutations in a group of genes that render the cone cells concentrated in the central retina nonfunctional. Some 35,000 patients in the United States and Europe have XLRS, a leading cause of juvenile macular degeneration in males, in which mutations in the RS1 gene cause the layers of the central retina to split.
AGTC has developed for ACHM and XLRS conditions a potential treatment that uses an adeno-associated virus to deliver healthy copies of genes to human cells. A single treatment is expected to halt ACHM, for example, for several years, perhaps a lifetime.
A European Patent Office decision granted Cardium rights to patents covering its gene therapy approach, while in the United States, the U.S. Court of Appeals for the Federal Circuit affirmed Cardium ownership of three patents challenged by Boston Scientific.
“The resolution of these important reviews of our gene therapy patents, and the consistent decisions in our favor including rulings by the U.S. Courts of Appeal, underscore the value of our patent portfolio, which we believe reflects a breakthrough approach to the treatment of coronary heart disease,” Tyler M. Dylan-Hyde, Ph.D., J.D., Cardium's chief business officer and general counsel, said in a statement.
The statement also trumpeted research showing that Cardium's new technique for adenovector gene delivery in the heart can be used to dramatically boost adenovector delivery.
In a study published in Human Gene Therapy Methods, a sister journal to Human Gene Therapy published by Mary Ann Liebert Inc. (Shi et al., 2012), Cardium's use of transient cardiac ischemia was found to dramatically enhance gene delivery and transfection efficiency after one-time intracoronary administration of adenovector in mammalian hearts. Two consecutive but brief periods of coronary artery occlusion combined with coadministration of nitroglycerin increased both adenovector presence (measured by PCR) and transgene expression (assessed by luciferase activity) by more than 100-fold in the heart, compared with prior intracoronary artery delivery methods.
Enhancing uptake, even in patients with less severe forms of disease and ischemia, would be expected to reduce response variability and allow for the potential treatment of patients with a broader range of associated coronary artery disease. Cardium said it is using that insight in new treatment protocols for its recently launched clinical study ASPIRE (Efficacy and Safety of Ad5FGF-4 for Myocardial Ischemia in Patients with Stable Angina Due to Coronary Artery Disease), with the goal of enhancing nonsurgical, catheter-based delivery of Generx to the heart.
Cardium also said it successfully transferred an improved manufacturing process to SAFC, the custom manufacturing and services business unit of Sigma-Aldrich, resulting in much higher yields. Generx's long-term product stability has been established at a minimum of 6 years, making it possible to manufacture product in large, cost-effective batch sizes.
As part of the approval, uniQure agreed that patients will receive treatment with Glybera through dedicated centers of excellence and by specially trained doctors. uniQure also agreed to build a patient registry to improve understanding of the disease and the effects of treatment with Glybera. The marketing authorization covers all 27 E.U. member states.
uniQure said it is preparing to apply for regulatory approval in the United States, Canada, and other markets. Glybera has orphan drug designation in the European Union and the United States.
“The final approval of Glybera from the EC marks a major step forward in making gene therapies available not only for LPLD but also for a large number of rare diseases with a very high unmet medical need,” Jörn Aldag, CEO of uniQure, said in a statement. The company has development programs for Glybera in acute intermittent porphyria, Sanfilippo syndrome type B, hemophilia B, and Parkinson's disease.
Over the summer, uniQure acquired Glybera's original developer,
Alnylam will pay $30 million to Tekmira to secure rights to manufacture its own LNP-based products in the future, either on its own or through a third party. Alnylam said in a statement it will use that capability to advance its ALN-TTR02 drug candidate—which targets the transthyretin (TTR) gene to treat TTR-mediated amyloidosis (ATTR) into phase 3 clinical trials that the company expects will start by the end of 2013.
ALN-TTR02 is the subject of a phase 2 clinical trial in Europe, with more locations to be added, evaluating safety, tolerability, and potential clinical activity of multiple once-monthly doses of the drug in patients with ATTR.
In addition, Tekmira will receive $35 million to buy down its milestone and royalty payments owed by Alnylam for ALN-TTR02 and two of its other drug candidates: ALN-VSP for liver cancers and potentially other solid tumors with liver involvement, and ALN-PCS for high levels of cholesterol in the blood. Tekmira is also eligible for up to $10 million in milestone payments tied to advancement of ALN-VSP and ALN-TTR02.
The two companies also agreed to resolve Alnylam's interference lawsuit against Tekmira for use of Alnylam's U.S. Patent No. 7718629 directed to a small interfering RNA (siRNA) component in ALN-VSP. In return, Tekmira and a company formed in 2009 by both parties in the suits, AlCana Technologies, will drop claims and counterclaims in lawsuits filed in Massachusetts and British Columbia. Alnylam and Tekmira also agreed to submit future disputes over the next 3 years to binding arbitration, as well as not to sue each other in the future on matters related to the just-settled litigation, or else be liable for damages.
Alnylam said it will take a $65 million charge against fourth-quarter operating expenses to reflect the settlement and resulting restructuring of licensing agreements with Tekmira. In revised guidance to investors, Alnylam said it will finish this year with more than $215 million cash.
“The companies have created clarity around the overall patent estate for LNP-based products, while ensuring Alnylam's full access to use this technology for our products in the future,” Barry Greene, Alnylam's president and COO, said in a statement.
Mark J. Murray, Ph.D., Tekmira's president and CEO, said in a separate statement: “With our cash runway now extending into 2015, we are excited about our plans to aggressively advance multiple products into human clinical trials.”
In the Tekmira statement, issued with the company's third-quarter 2012 results, Dr. Murray noted that Tekmira expects its lead oncology drug TKM-PLK1 will enter a phase 2 trial next year, in 2013, and that it can advance its TKM-Ebola vaccine in collaboration with the U.S. Department of Defense's Transformational Medical Technologies program, through which Tekmira won a $120 million commitment earlier this year to develop an RNAi drug using its LNP technology.