LONDON – NeuroVive Pharmaceutical AB signed a deal for the development of its two lead mitochondria-sparing programs in China to add to a similar agreement in Europe that should see the two drugs through to commercialization in both markets.

The two products, CicloMulsion for treating heart reperfusion injury following stenting and NeuroStat for traumatic brain injury (TBI), look like a perfect fit with new partner Sihuan Pharmaceutical, which claims it has the largest cardio-cerebral vascular franchise in the rapidly growing Chinese market.

This is the first time that Sihuan, which is listed on the main board of the Hong Kong Stock Exchange, has agreed to a collaboration with an international partner. As a second step in the development of their relationship, NeuroVive and Sihuan are now planning to set up a joint venture to take forward NeuroVive's other earlier-stage mitochondrial-sparing products.

Meanwhile, the name of the European partner has not been disclosed.

Under the agreement with Sihuan, Lund, Sweden-based NeuroVive will receive up-front payments totalling RMB35 million (US$5.6 million) for CicloMulsion and RMB12 million for NeuroStat, and in addition will be entitled to 10 percent of net revenues from the two products for 10 years following launch.

Sihuan will pay for all clinical development and commercialization in China.

"The up-front is not as important as the 10 percent royalty rate, which is a significant achievement for us," Mikael Bronnegard, CEO of NeuroVive, told BioWorld International. According to NeuroVive, the Chinese market for the two products is estimated to reach more than RMB2 billion per annum at its peak. Sihuan has a nationwide distribution network, covering more than 10,000 hospitals and 3,000 distributors. It also has a captive CRM to pick up the clinical development.

It is the huge potential market that makes the agreement "transformational" for NeuroVive, providing validation of its mitochondria-targeted drugs and the prospect of a big day, Bronnegard said.

CicloMulsion and NeuroStat are both formulations of the immune suppressant drug cyclosporine, which works by inhibiting cyclophilin D, an enzyme that is involved in controlling the permeability of the mitochondrial membrane. That inhibition prevents disruption of the membrane when cells are damaged. Sparing mitochondria in the context of cell damage caused by reperfusion injury or TBI preserves cellular energy production and allows normal regenerative processes to proceed to repair and maintain the cell, according to NeuroVive.

In the case of NeuroStat, the product also blocks the intracellular cascade that follows TBI, averting secondary tissue damage.

NeuroVive has been working on developing cyclosporine as a mitochondria-sparing drug since the 1990s, when its protective effect was discovered by chance.

CicloMulsion currently is in a 1,000-patient Phase III trial evaluating its ability to reduce reperfusion injury in patients receiving stents after a myocardial infarction. Sihuan will pick up the data file from that European study and conduct a Phase II/III trial in China based on the same protocol. Bronnegard said that will provide sufficient data to file for regulatory approval in China.

The European trial is about halfway through enrollment, with the last patient expected to join in August 2013 and the study to report in the fourth quarter of 2014. According to Bronnegard, in the Phase II study, "CicloMulsion had a significant effect in limiting reperfusion injury, with the infarcted area reduced by 40 percent." The results were a "trigger for the entire area of mitochondrial protection," he added.

NeuroStat is due to enter a Phase IIa European trial before the end of this year in collaboration with the European Brain Injury Consortium, an academic network. The plan for the development and commercialization of the product in China will be finalized in 2013.

Bronnegard said in an attempt to control the likely heterogeneity of subjects – a factor that has confounded previous TBI trials – the protocol restricts enrollment to patients ages 30 to 60 with a specific type of focal injury of the brain. They will be treated within eight hours of sustaining the injury.

He said he believes NeuroVive also has overcome another problem with previous drugs tested in TBI, which is that the mode of action was uncertain. "Our product has a defined mechanism of action, and hits a well-known target," Bronnegard said.

NeuroVive has a patent on the use of cyclosporine in neurological indications that runs until 2016, and has orphan drug designation in TBI, providing further market exclusivity. The company also is working on a lipid-based formulation designed to cross the blood-brain barrier, for use in treating stroke, which Bronnegard said will be patentable.

Based on its experience, NeuroVive now is looking for second- and third-generation novel cyclophilin D inhibitors, and is in-licensing and testing compounds.