Elios’ Phase IIb Melanoma Data Are Promising, But Present Tricky Issues For Phase III Vaccine Study

SCRIP, July 17, 2019 – By Joseph Haas

Executive Summary

The biotech’s personalized vaccine shows it can reduce the risk of melanoma recurrence by 50% in the per-treatment population, but Phase III will need to demonstrate a similar benefit in an intent-to-treat population.

Elios Therapeutics plans to advance its personalized vaccine for stage III and stage IV melanoma into Phase III – with a partner or on its own – following the release of Phase IIb top-line data that showed the vaccine can reduce the risk of disease recurrence by roughly 50% in patients who completed a full series of treatment.

Austin, TX-based Elios unveiled the data on 17 July, noting that in a per treatment (PT) population of 98 patients, a 29% recurrence rate was seen in the treatment arm compared to 56% in the placebo arm. Overall, the study enrolled 144 patients and in this intent-to-treat (ITT) population, including patients who never received the vaccine or did not complete an 18-month course of therapy, the recurrence rate was 54% for the treatment arm versus 66% for placebo.

The PT arm met statistical significance in the study’s primary endpoint of disease-free survival (DFS), while the ITT data were clinically meaningful, but not statistically significant.

This creates a “math problem” for Elios in designing the planned pivotal Phase III study of the candidate, known as the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine, CEO Buddy Long told Scrip. An autologous cell therapy, the vaccine is produced from the patient’s own tumor and blood cells in a process that takes about two weeks from resection to injection, he said, much shorter than the three months or so typical of other autologous cell therapies.

In the study, patients whose melanoma recurred on standard-of-care (SOC) therapy were randomized to the vaccine or placebo. Treatment was initiated within three months of SOC completion, with patients scheduled to receive TLPLDC at months zero, one, two, six, 12 and 18. Evaluation of the primary endpoint of DFS at 24 months was performed in both the ITT and PT populations as co-primary analyses due to the high early recurrence rate often seen in advance melanoma patients, the company explained.

“I don’t think we’re going to get approval on PT; we’re going to get approval on ITT,” Long said. “When you evaluate a therapy, you have to look at the people who actually got it – but with the benefit that we’ve seen in the ITT, showing a statistical benefit on that is a math problem now. We don’t have a clinical or scientific problem, we need to power a study that appropriately is going to show the statistical value of that benefit that we’ve already seen in the ITT population.”

Single Focus Of Taking TLPLDC To A Development Partner

Elios was founded in 2014 as a subsidiary of Orbis Health Solutions with a singular focus on TLPLDC in melanoma. The company began with a strategy of producing Phase IIb data that would entice a big pharma or other deep-pocketed partner to fund a Phase III program. (Also see “Cancer Immunotherapy Reaches A Tipping Point” – Scrip, 22 Oct, 2014.)

Long said now that his company – a direct subsidiary of Perseus Holdings USA, which is affiliated with Orbis – has the data in hand, it will plan to go ahead into Phase III with or without a partner. But he also conceded that the fastest path to bringing TLPLDC to patients is through a partnership.

“We’re not waiting on a partner,” Long said. “We are completely capable of taking this to the finish line on our own and so we are initiating a crossover phase from a fundraising standpoint, selecting banks in the next couple of weeks, and kicking that off in the next 60 days to run full steam ahead as a standalone product. Any company has to have that posture – we can’t count on the right partner being ready at the right time.”

To date, Elios has had what Long calls “coming attractions” talks with potential partners, but also has had to deal with a recent lack of enthusiasm for the cancer vaccine concept.

In melanoma, Biomedtracker lists seven vaccine candidates in clinical development for melanoma, including TLPLDC. The most advanced are Polynoma LLC’s seviprotimut in Phase III, KAEL-GemVax’s telomerase peptide vaccine GV1001 in Phase II, and Vaccinogen Inc.’s OncoVax in Phase I/II for melanoma and Phase III for colorectal cancer. GV1001 also was investigated in non-small cell lung and pancreatic cancers as well as hepatocellular carcinoma, but those efforts are suspended.

“The bottom line for everyone has been ‘we love the team, love the technology, love the concept, but we’ve got to see a positive clinical benefit in one indication,’” Long noted. “Whatever we do in the immunotherapy space, the bottom line is fundamentally there needs to be a post-immune response that can create an army of tumor-reactive T cells that can not only function as a monotherapy but also combine with other therapies out there that do anything with T cells.”

In addition to its monotherapy study, Elios has been running an open-label trial for patients’ whose melanoma recurs in which they can go on TLPLDC monotherapy or combination therapy with any SOC agent. It also is running a Phase I/II study testing the vaccine with the physician’s choice of checkpoint inhibitor therapy, but Long says the most important thing Elios can do is demonstrate TLPLDC’s efficacy as a monotherapy.

“One thing that is lacking in combination trials is there’s theoretical synergistic benefit, but a lot of times it hasn’t been proven in a rigorously scientific fashion that you have single-agent efficacy that would translate into theoretical, practical benefit in a combination,” he said.

Safety Profile Could Be Ideal For Combination Therapy

However, monotherapy efficacy plus the vaccine’s safety profile might position TLPLDC for combination with a wide range of therapies.

In the Phase IIb monotherapy study, about one-third of patients reported an adverse event, mostly grade 1 or 2 events. By contrast, typical cancer studies often have AE rates of 80% to 90%, sometimes even 100%, with 70%-80% of AEs deemed treatment-related. In potential combination regimens, TLPLDC’s safety profile mean patients can add its benefits with little or no physical cost, Long asserted.

“We don’t create a systemic immune response, we create a cellular immune response,” he explained. The autologous process creates a therapy that delivers a patient’s complete repertoire of tumor antigens to the immune system, yielding a dual innate and adaptive immune response that triggers the immune system to recognize, seek and destroy antigen-containing cells, the company says.

Because the vaccine expresses pathogen related to the patient’s own molecular profile at the cellular level, this enable the immune system sees the antigen as a pathogen, Long said. “The actual presentation of the antigen does not carry any of the autoimmune or other immunological side effects,” he added.

Manufacturing of the personalized vaccine can occur in roughly 48 hours by taking advantage of the process in which monocytic cells turn into dendritic cells, the exec said. “There’s a certain point in time where [the transforming cells] become extremely phagocytic and the delivery mechanism we have takes tumor antigen and captures it in a particle that is phagocytized into the cytotoxic dendritic cell,” he continued.

Down the road, Elios believes its vaccine technology can be applied to a broad range of solid tumors, but the work in recurrent advanced melanoma comes first, Long said.