Fresh off presentations this month at the American Society of Clinical Oncology in Chicago and the European Hematology Association in Stockholm that confirmed continued progress in its late-stage pipeline, TG Therapeutics Inc. struck a deal to collaborate on the development and commercialization of a preclinical anti-CD47/anti-CD19 bispecific antibody discovered by Novimmune SA. The companies will jointly advance the fully human IgG1, known as TG-1801 (previously NI-1701), on a global basis with a focus on hematologic B-cell malignancies.
Designed to target and deplete B cells via multiple mechanisms, TG-1801 is the lead candidate to emerge from Novimmune's kappa-lambda body format, which allows for the preservation of favorable properties in a conventional monoclonal antibody (MAb) while adding bispecific functionalities. A mechanism unique to this bispecific is the selective blockage of CD47, sometimes called the "don't eat me" signal for the body's phagocytic cells, in the effector arm, while binding to CD19 with high affinity to target tumor cells selectively.
TG, of New York, is set to make undisclosed up-front and milestone payments based on early development as it assumes responsibility for advancing the asset through the end of phase II studies. At that point, the companies will share development and commercialization costs. Each partner maintained an exclusive option that may be exercised at specific development inflection points for TG to license the rights to TG-1801. Should that occur, Novimmune will be eligible for additional payments of up to $185 million based on prespecified clinical, regulatory and commercial milestones, as well as tiered royalties on net sales.
The arrangement represented Plan B for privately held Novimmune, which initially planned to advance NI-1701 in-house "because we think it has great promise," observed Adrian Mills, chief business officer. But providence, in the form of a potential first approval by year-end, intervened, and the Geneva-based company shuffled its priorities.
"We have another asset that's going through a BLA review at the moment," Mills told BioWorld. "We're a small biotech company based in Switzerland. We don't have the capacity to drive all of our assets as fast as we would like. It began to make sense for us to look for a partner."
That near-commercial asset is emapalumab (NI-0501), a wholly owned candidate that inhibits interferon-gamma (IFN-gamma), which is produced by natural killer and natural killer T cells as well as by CD4-positive and CD8-positive cytotoxic T-lymphocyte cells in response to specific pathogens. Although both the innate and adaptive immune systems use the cytokine to fight viral and intracellular bacterial infections, abnormally high levels of IFN-gamma are associated with autoinflammatory and autoimmune diseases that include lupus, insulin-dependent diabetes, arthritis and hemophagocytic lymphohistiocytosis (HLH). Novimmune hopes to gain FDA approval for emapalumab to treat HLH, a rare disease that is fatal in about 50 percent of cases. In 2016, Novimmune raised CHF60 million (US$62 million) to fund the pivotal program. (See BioWorld Today, May 12, 2016.)
Last month, the FDA granted the BLA priority review, setting a Nov. 20 PDUFA date for a decision on the asset, which was previously granted breakthrough therapy and rare pediatric disease designations by the agency and PRIME eligibility by the EMA. Novimmune plans to submit a marketing authorization application for emapalumab in HLH by year-end.
"Our top priority is moving this asset to market quickly, because that can generate revenues in the short term," Mills said, and the company is considering multiple commercialization options. "We are talking to a number of partners, because it's obviously a very attractive asset. It's also for a very rare disease, which is served by a limited pool of hospitals that treat that disease, so it's an ideal asset for a small company."
'More targeted and much safer approach'
Novimmune had been in conversation about its fully human bispecific technology with TG as well as Fortress Biotech – where TG's president, CEO and executive chair, Michael Weiss, also serves as executive vice chair of strategic development – for about 18 months, Mills said, although the deal came together in a fraction of that time. TG was impressed with Novimmune's platform, and the Swiss biopharma was swayed by TG's prowess in clinical trials and specialization in B-cell malignancies.
"They're ideally positioned to take TG-1801 through the clinic as rapidly as possible, and we're looking forward to seeing it perform there," he said.
Initial trials are expected to begin late this year or in early 2019.
TG-1801 is designed to target and deplete B cells while avoiding the general toxicity concerns associated with other agents that target the CD47 pathway, Mills pointed out. Co-targeting of CD19 also allows the agent to retain its IgG1 Fc functionality, providing a secondary mechanism of antitumor activity through the induction of antibody-dependent cellular cytotoxicity, or ADCC.
In December 2016, Novimmune presented preclinical data at the American Society of Hematology annual meeting in San Diego from a syngeneic re-challenge A20 murine B-cell lymphoma model. Combined administration of NI-1701 with cyclophosphamide resulted in long-lasting antitumor response, with all mice showing a reduction in tumor volume. In Cynomolgus monkeys, NI-1701 (300 mg/kg to 100 mg/kg I.V.), both as single and multiple doses, generated positive kinetics of elimination data up to 100 mg/kg without altering hematological parameters. In a NOD/SCID murine model subcutaneously implanted with Raji cells, NI-1701 potentiated the tumoricidal activity of macrophages by redirecting the tumor cell environment to an antitumor M1-like phenotype and diminishing the presence of granulocytic-inhibitory myeloid-derived suppressor cells.
Novimmune now has the opportunity to watch and learn as the asset moves through the clinic without spending its own cash. With its other six disclosed programs already partnered, the company fully intends to apply the lessons learned from TG-1801 to other fully human bispecifics.
"We can use the CD47 arm in many different types of cancer," Mills said. "We just need a different targeting arm."
Having the ability to block the CD47 immune checkpoint gives the Novimmune asset distinct therapeutic advantages, he said. On the one hand, cancer cells sometimes trick the immune system to back away by overexpressing the "don't eat me" signal produced by CD47. On the other, effective CD47 targeting also requires that healthy cells don't have their signal switched off – a problem that can arise with less specific approaches, such as MAbs and alpha fragments, Mills said. For example, CD47 is heavily expressed on red blood cells, so imprecise targeting can result in anemia and related problems.
"We're hoping that we have both a more targeted and much safer approach than others," he said.
And there aren't many others out there, according to Cortellis Competitive Intelligence. Forty Seven Inc. has advanced its humanized anti-CD47 antibody, Hu5F9-G4, developed in conjunction with Stanford University and Oxford University, into phase II combination studies with Rituxan (rituximab, Roche Holding AG/Biogen Inc.) in non-Hodgkin lymphoma and with Erbitux (cetuximab, Eli Lilly and Co.) in colorectal cancer after reporting promising preclinical data last year in pediatric brain tumors. (See BioWorld Today, March 16, 2017.)
Phase I studies are underway for INBRX-103 (CC-90002), a CD47 MAb from Inhibrx LP partnered with Celgene Corp.; SRF-231, an anti-CD47 MAb from Surface Oncology Inc. partnered with Novartis AG; ALX-148, a fusion protein developed by Alexo Therapeutics Inc.; and TTI-621 and TTI-622, SIRP-alpha Fc fusion proteins from Trillium Therapeutics Inc. (See BioWorld Today, June 28, 2012, and Jan. 12, 2016.)
Twenty-one additional CD47-targeting assets are in discovery, including TG-1801/NI-1701 and a second Novimmune asset, NI-1801, a bispecific that uses the innate immune system to destroy mesothelin-positive solid tumors. Novimmune is the only company to combine a CD19 modulator with a CD47 antagonist or mesothelin modulator.
In TG, the company thinks it's found "a great partner on B cells," Mills said. "This is just one of many bispecifics we can make. We're working on a number of targets, and we have a platform that's very flexible for making fully human bispecific molecules. We think these are going to become the standard format for the future."
On Wednesday, TG's shares (NASDAQ:TGTX) closed at $14.60 for a gain of 65 cents.