"There are many forms of graft vs. host disease [GVHD], many types, so there will not be one solution for all of them," Gil Efron, deputy CEO and chief financial officer of Kamada Ltd., told BioWorld Today, but the Ness Ziona, Israel-based firm may have a fix for major unmet need.

The orphan indication-geared company expects to reach profitability this year. Having proven the anti-inflammatory value of its alpha-1 antitrypsin (AAT, purified from human plasma) by way of the marketed product Glassia for AAT-deficient patients with emphysema, Kamada has begun testing intravenous (I.V.) AAT as an immunomodulator. The compound, partnered with Shire plc, of Dublin, probably has "many therapeutic roles," Efron said. A phase II/III trial is underway in the U.S. in patients with the product called G1-AAT for acute GVHD, which can manifest in the gastrointestinal (GI) system, the liver, or on the skin, and can even affect the lungs. "The most severe patients are those with the gut symptoms, so we are treating GI patients," he said.

A graft-vs.-host reaction refers to the over-activation of a patients' new, modified immune system after an allogeneic hematopoietic stem cell transplantation (HSCT), a procedure that uses the donor's immune system to fight diseases such as acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. The study with G1-AAT is estimated to enroll as many as 168 adult subjects who've received an HSCT, with the mandating disease in remission at the time and with newly diagnosed, acute GVHD evident, including lower GI involvement; other organ systems may be affected or not. Treatment with methylprednisolone/systemic steroids must have been started within 72 hours prior to the first dose of study treatment after enrollment, the protocol says.

AAT is "naturally occurring in humans so we're using something that should have a very good safety profile" and it does, Efron said. Research began with GVHD patients who were refractory to high-dose steroids, the standard of care (SOC). "Usually these patients are grade 3 and grade 4 of the disease," he said, the worst grades. "We had a proof-of-concept study on these patients, and out of 12 patients in the first two cohorts, eight responded to the treatment – four had partial response and four had complete response." For the phase II/III experiment, Kamada and Shire chose to "engage earlier in the treatment of the disease," so the experiment is "not only in steroid-refractory. It's all patients who have GVHD," with G1-AAT given along with SOC. "It's really a question of how the development will [proceed], but right now we are treating on top of standard of care," he said. Data are due around 2020. "We'll probably have interim data earlier, after we complete the first part of the study," he said. "We expect that toward the end of this year or maybe the beginning of next year."

Shire owns rights to the product in the U.S., Canada, Australia and New Zealand. "We're planning to develop [the compound in] GVHD independently in Europe," Efron said, and the company will ask for a clinical trial authorization, or CTA, there in the second half of the year in order to conduct its own phase II/III experiment. "We had scientific advice from the EMA," he said, as well as "positive feedback."

Phase II/III work also is ongoing with G1-AAT in type 1 diabetes, and results are expected in the first half of this year. A phase II study investigating the compound in the prevention of lung-transplant rejection. Kamada and Shire hope the treatment can do the job across the board. For type 1 diabetes, the benefit could be in G1-AAT's "ability to halt the progression of the autoimmune attack on the beta cells," Efron said. "In GVHD, it's [the capacity] to have an impact on the immune system of the graft that attacks the host following the bone-marrow transplant." In preventing lung-transplant rejection, "the idea is similar to GVHD. In GVHD, it's the graft immune system that attacks the host. In lung transplant, it's the host that attacks the new solid organ. We're trying to reduce the level of rejection." Lung transplant represents a strong market because about "33 percent of lung transplants do not survive after one year, and 50 percent after five years," he said. "We started the clinical study in a very large lung-transplantation center in Israel last year. It should take us a few years to complete, because the treatment period is about two years," so the readout will likely come in late 2019.

'transformative' year: Analyst

There's also an inhaled version of AAT for people who are deficient in the protein. A would-be pivotal phase II/III clinical trial was completed in Europe and Canada. Though the primary endpoint of the study (time to first exacerbation) was not met, updated results showed clinically and statistically significant improvements in lung function and complementary efficacy in the severity of the first exacerbation, Kamada said, with safety data remaining supportive and consistent with the firm's previous inhaled AAT studies. Better news came in August, when a phase II trial in the U.S. with the inhaled version using the Eflow device from Pari Gmbh, of Starnberg, Germany, hit its endpoint. The product, tested at two dose levels (80 mg/day or 160 mg/day) vs. placebo, turned up a significant increase in endothelial lining fluid (ELF) AAT antigenic level compared to the placebo group [median increase 4551 nM, p-value<0.0005 (80 mg/day, n=12), and 13454 nM, p-value<0.002 (160mg/day, n=12)]. These results are more than twice the increase of ELF antigenic AAT level (+2600 nM) that appeared in Kamada's I.V. AAT pivotal study (60mg/kg/week). Antigenic AAT represents the total amount of AAT in the lung, both active and inactive. The company submitted a marketing authorization application to the EMA, and gatekeepers are due to decide around mid-year. In the second half of this year, an IND for the inhaled version will go to regulators in the U.S., where Kamada's recently completed "day 120" responses to European regulators will help steer talks with the FDA. (See BioWorld Today, May 19, 2014.)

Kamada recorded positive cash flow last year, when (in October) the company extended the contract with Shire for manufacturing Glassia supply for the fourth time since the deal was signed in 2010. Minimum revenue for Glassia in the lengthened pact for the years 2017 to 2020 will reach about $237 million during the period and may be expanded to $288 million. Kamada will now continue to produce Glassia through 2020 for Shire, after which Shire may produce the product at its facility and pay Kamada established royalty rates. "We are already generating a significant amount of revenue," Efron said, and the company is on track to record $100 million in sales this year. "We are in a good position to execute [our] plans," he said. (See BioWorld Today, Aug. 25, 2010.)

Jefferies analyst Raj Denhoy said the $100 million Glassia sales mark "looks achievable," as does profitability. Fourth-quarter 2016 sales landed "directly in line with the $24.3 million we modeled," he added in a research report in February, predicting this year could be "transformative from a regulatory standpoint" for Kamada. "Shire's $237 million in guaranteed U.S. revenue provides a solid base to the story with the only question lingering of if and when Shire will bring manufacturing capabilities in-house," he said. H.C. Wainwright analyst Andrew Fein was optimistic, too. "This steady uptrend of Glassia revenue should provide investors a relatively de-risked entry point with eyes towards the numerous pipeline programs with catalysts on tap for the year," he said in a Feb. 7 research report.

Earlier this month, Lifesci Capital analysts attended a key opinion leader event focused on GVHD, which featured talks by Joachim Deeg of the Fred Hutchinson Cancer Research Center and David Gelmont, who recently served as senior medical director at Shire and acts as clinical advisor for Kamada's GVHD program. Deeg pointed out that about half of patients who undergo HSCT will develop acute GVHD and need treatment, and about 70 percent of these will respond to high-dose steroids. "This leaves approximately 15 percent of the patients undergoing allogenic HSCT with persistent GVHD, and Deeg noted that there is no standard treatment for second-line therapy," Lifesci analyst Jerry Isaacson wrote. "About 13,100 individuals worldwide develop acute GVHD and will require therapy with steroids. We note that this is the population being targeted in Kamada's phase II/III studies with G1-AAT. The company has also mentioned the potential of G1-AAT as a prophylactic therapy, which could expand the market opportunity to include a greater number of allogenic HSCT procedures."

Also in the GVHD game with AAT is Melbourne, Australia-based CSL Ltd. unit CSL Behring. A pilot phase II study sponsored by the University of Michigan Cancer Center with CSL collaborating, along with The Leukemia and Lymphoma Society, is testing Zemaira – approved by the FDA in 2003 for AAT-deficient people with emphysema – in steroid-refractory GVHD. The trial is expected to enroll about 40 patients and end in June 2019.