Chief Commercial and Strategy Officer Elizabeth Jeffords told BioWorld that the endpoints in Alkahest Inc.'s just-begun phase II trial with human plasma fraction GRF-6021 will not only test how well patients bounce back from hip or knee arthroplasty but "could absolutely support the work in cognitive and neurodegenerative indications as well," where data rolled out earlier this month.

The randomized, placebo-controlled pilot study, called AKST6021-211, is designed to evaluate the effect on intracellular signaling in immune cells, "particularly around the leukocytes and what happens with those," Jeffords said. Patients will be dosed on the day before surgery, the day of and the day after. Alkahest aims to enroll about 45 subjects, taking peeks at recovery and relevant biological mechanisms of action along the way.

The leukocyte scrutiny will be done with "elegant mass spectrometry" methods from Stanford University, she said, whereas recovery measures include the Surgical Recovery Scale and the Western Ontario and McMaster Universities Osteoarthritis Index, or WOMAC. "It's going to be a fascinating study for us."

About two weeks ago, Alkahest unveiled tantalizing phase II data in Alzheimer's disease (AD) with plasma fraction GRF-6019, a different version of the same drug deployed in the arthroplasty therapy. The study tested the safety, tolerability and potential therapeutic effects of multiple doses in patients with mild to moderate AD over six months. Subjects were randomized and treated intravenously with 100 mL or 250 mL of GRF-6019 for five consecutive days during the first week and again for five consecutive days during the 13th week, with a treatment-free interval of 12 weeks following each dose. GRF-6019 proved safe and well-tolerated. Secondary endpoints showed that those on the drug had no decline in cognition, as measured by the 11-item Alzheimer's Disease Assessment Scale–Cognitive Subscale and the Mini-Mental State Examination, and negligible drop in function by the AD Cooperative Study Activities of Daily Living scale 23-item version and the Clinical Dementia Rating scale Sum-of-Boxes score. The findings showed a maintenance of cognitive and functional status over a period of six months in a population "where you would really expect to see change," Jeffords noted. "Of course, there's a lot more work to be done. We need to do randomized, controlled studies, which will be next."

The company also has a phase II study recruiting in severe AD. "This is more of a long shot," she conceded, but any benefit shown in the notoriously tough patient segment "could be profound." Another phase II is investigating Parkinson's disease with cognitive impairment.

Alkahest's work is part of what co-founder and Chairman Tony Wyss-Coray of Stanford calls "the molecularization of plasma," helped along by recent advances in mass spectrometry, array technologies and single-molecule analyses.

CEO Karoly Nikolich said his firm is "now applying [those methods] to very high-quality samples," thanks to a partnership with Grifols SA, of Barcelona, Spain, one of the top three plasma outfits in the world. "We have the luxury of being the leaders in this" research, Nikolich said, though other firms are "popping up in the space." Although it's a truism that age is the main risk factor in all neurodegenerative diseases, "not many companies have actually approached it from the aging side," he said. "The literature is unfortunately full of weakly founded publications. The quality of plasma samples, the way they are collected, the way they are handled, the way they are frozen, thawed – the standard operating procedures that underlie [research with plasma fractions] – are extremely important." All of the neurodegenerative diseases likely have multifactorial backgrounds, and there's a "tremendous drive" to discover the prodromal factors in play. "Only about 4 to 5 percent of AD patients are genetic," he pointed out. "The rest are sporadic, meaning that we don't know." Likely to blame is a "myriad of factors" including lifestyle and nutrition, but "there is a growing recognition that it is simply age." As the years pass, humans lose the good proteins and the bad ones increase. "We are killing ourselves gradually" by existing longer, he said, and Alkahest is hunting for fixes.

Small-molecule in pipeline, too

Preclinical efforts were undertaken by Wyss-Coray. "The first one was to connect a young mouse and an old mouse," Nikolich said. "In the brain of the old mouse, he actually saw regenerative processes taking place, including synthesis of new synaptic proteins, creation of new neurons in the brain." The "connecting" was done by way of parabiosis, a method developed in the 1700s that involves making horizontal cuts on the sides of mice and suturing them together. "They live a semi-normal life" as two-headed, eight-legged creatures, he said. Improvements seen in the old mice were verified in experiments that, rather than sewing rodents together, used infusion; thus researchers determined "it was a soluble agent in plasma that mediated this [beneficial] activity," he said. With GRF-6019 and GRF-6021, containing 400 to 500 proteins, "we know precisely who is in there, and now we have started fractionating further" to sharpen the focus.

Jeffords likened the research to investigations in oncology, saying that Alkahest has found "checkpoint proteins that impact a number of signaling pathways," and a new candidate is slated to enter the clinic shortly.

CEO Nikolich said the firm has a "comfortable runway" through 2021 for its lab work. "We are on the course toward financing," he added. "The current environment is very conducive. The space we operate in is of great generational interest and socioeconomic interest. Depending on how successful we are in our financing, we will be moving forward toward further growth." Alkahest lists about 85 employees now and could have about 100 by the end of the year, he said.

There's more than plasma fractions in the pipeline. In late July, the company said its phase IIa trial with AKST-4290, an orally administered small-molecule CCR3 inhibitor, met the primary endpoint of achieving an increase in best corrected visual acuity in patients with refractory wet or neovascular age-related macular degeneration. The drug was found safe and well-tolerated, meeting the secondary endpoint of the trial, in results presented during an oral presentation at the American Society of Retina Specialists meeting in Chicago.

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