Expressed RNAi drug developer Benitec Biopharma this week provided an update on its pipeline, stating that its two lead programs in cancer-associated neuropathic pain and drug-resistant lung cancer have fallen behind schedule as the company further optimizes its therapeutic candidates and deals with delivery-related issues.
Overall, however, Benitec remains largely on track in its efforts to revitalize itself after suffering major setbacks years ago that saw the company nearly close its doors.
Earlier this year, Benitec presented details of its broad portfolio of drug candidates, stating that it expected to have three in clinical trials in 2013. This week, the company indicated that it likely wouldn't have any drug in human testing until 2014.
The first of these is Nervarna, which is designed to inhibit protein kinase C gamma to control neuropathic pain, initially in terminally ill cancer patients.
Following the validation of the target by an independent group of Chinese researchers, Benitec said it has begun in vivo testing of two different RNAi constructs targeting PKC gamma, and aims to complete efficacy and preliminary safety testing this year.
Previously, Benitec CEO Peter French told Gene Silencing News that the company has partnered with Oxford Biomedica to handle manufacturing of the drug's lentivirus vector (GSN 4/5/2012). At the time, he said that he expected unanticipated manufacturing issues to be resolved in time to begin phase I testing of Nervarna, either in the US or the UK, in early 2013.
However, Benitec said that French recently met informally with UK regulators regarding the drug program and, “on the basis of these discussions and in consultation with a European regulatory consultant, the timing for the pain program to enter the clinic have been adjusted to reflect the regulatory requirements in both Europe and the US.”
Benitec now anticipates completing toxicology and biodistribution studies by mid-2013, and starting human testing around the beginning of 2014.
The second candidate in Benitec's pipeline is Tribetarna, a cocktail of shRNAs against three regions of the beta III tubulin gene that is being developed to overcome drug resistance in non-small cell lung cancer patients, and which is delivered directly to the lung using Polyplus Transfection's JetPEI polyethylenimine polymer technology.
Based on positive data in orthotopic mouse models showing that the therapy can specifically knock down its target when delivered via intravenous injection, Benitec said that it is now aiming to validate these findings in “larger groups of animals.”
Despite the promising initial findings, the company noted that the Tribetarna effort is running behind schedule because of difficulties optimizing its expressed RNAi constructs with the JetPEI technology. It also warned that it is likely going to have to design species-specific beta III tubulin constructs in order to conduct requisite toxicology studies, which would further delay the program.
Previously, French had said that Benitec anticipated beginning phase I testing of the drug next year. This week, the firm said that a clinical trial would most likely happen around the end of 2014.
Benitec's third program is in hepatitis B, for which it is developing Hepbarna. In April, French said that the firm expected to soon select an RNAi construct in order to begin in vitro testing this summer, and that it would likely use an adeno-associated viral delivery approach. Phase I testing was slated to begin in mid-2013, he said, most likely in China given the high incidence of the disease in that country.
This week, however, the company said it doesn't expect to file an application with Chinese regulators to begin the clinical trial until the end of 2014.
Benitec's earliest-stage drug candidate is Pabparna, which it is developing to treat a rare form of muscular dystrophy called oculopharyngeal muscular dystrophy — a disorder characterized by weakness in the muscles of the eyelids and throat, resulting in difficulty swallowing and keeping the eyes open.
The company said this week that it has developed expressed RNAi constructs that have, in vitro, triggered around 65 percent silencing of its target, a mutant form of the gene PABPN1. Additionally, early in vivo studies have shown “encouraging levels of normal PABPN1 gene expression in muscles from AAV-delivered gene constructs.”
Benitec said this week that Pabparna could reach phase I testing by 2014 or 2015, in line with previous guidance.
Despite the slight changes to the timing of its pipeline programs, Benitec continues to make significant strides in turning itself around after a period when its future was in question.
Though it was one of the first players in the RNAi space, and had carved out a strong position for itself with an early US patent on its core technology, in 2004 the company embarked on a litigation spree that would result in a protracted and costly legal battle with now-defunct Nucleonics (GSN 4/2/2004).
Rather than take a license to Benitec's patent, No. 6,573,099, Nucleonics fought the case and, as part of its strategy, sought re-examinations of the intellectual property in the US and abroad.
Although the suit was eventually dismissed at Benitec's request, the damage was done. Under the strain of legal bills, the company shuttered its US operations and reorganized as a significantly smaller firm in its native Australia. Meantime, the US Patent and Trademark Office deemed the '099 patent invalid in light of prior art, delivering a devastating blow to Benitec's efforts to find desperately needed funding.
In 2010, the company's fortunes began to reverse when it pulled in $6 million from an investment group and the USPTO backtracked on its initial ruling and reinstated the '099 patent in full (GSN 11/11/2010). Less than a year later, Benitec raised another $8.5 million, giving it the resources to build out its in-house pipeline.