Bringing Together

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The setbacks were many over the 40 years of development. OKT3g1(Ala-Ala) was developed in 1986. They came down to three core issues: five different companies with varying degrees of commitment, poor clinical trial design, and lack of a champion in the industry.

The drug started as a collaboration with Ortho Pharmaceutical/J&J, built on the background of OKT3. The work involved two scientists, Bob Zivin and Linda Jolliffe, with humanization by John Adair at Celltech. Unfortunately, Ortho decided to give up monoclonal antibodies as therapeutics. Even after they acquired Centocor, there was no interest in moving forward.

This cost us 10 years, although I was able to get access to the drug and make product for early phase I studies and phase II trials supported by the Immune Tolerance Network, with support from NIAID and JDRF. Kevan Herold was essential, as he conducted the clinical trial.

We then licensed the drug to MacroGenics. They were very engaged and motivated to develop it. In partnership with Lilly, MacroGenics started a phase III trial in stage 3, or recent-onset, type 1 diabetes. At the same time, a second company, Tolerx, was developing a similar Fc receptor non-binding, low-toxicity anti-CD3 monoclonal antibody.

The competition led to a large, complex clinical trial that required 300 sites and 500 patients in multiple arms, including sites and patients in India and Eastern Europe. The trial failed to meet its primary endpoint, and Lilly immediately terminated the partnership. However, further post-hoc analysis suggested that the primary endpoint was met if the analysis was limited to US patients.

At that point, MacroGenics agreed to out-license teplizumab to another company or a new company. But, not being a business development person, I found it very difficult.

By a stroke of luck, I met Leni Ramos, a previous chief medical officer at the Immune Tolerance Network, in New Orleans. She was at a meeting with members of her leadership team from a new company, Provention Bio. I suggested they might be interested in teplizumab. After multiple meetings and a meeting of the minds with the CEO at MacroGenics, teplizumab was licensed to Provention Bio.

In the process of replicating the phase III trial, data became available from a stage 2, "prevention" trial conducted by TrialNet, a consortium supported by NIDDK. The results showed that teplizumab could delay disease onset in high-risk stage 2 patients for two to three years. These data led to the approval of teplizumab in November 2022, some 35 years after development.

More recently, the results of the stage 3 new-onset trial led to a label expansion for this population, making the drug available to more people with early-stage disease or a recent diagnosis.¹

As for the next wave, this was the first disease-modifying immunotherapy for type 1 diabetes. In many ways, it has opened the floodgates. Approaches include novel anti-CD3 monoclonal antibodies, in one case given intranasally; antigen-based peptide therapies; antibodies against novel targets such as CD40L; and potentially tolerogenic cell therapies, including CAR- and TCR-Tregs and CD19 CAR-T cells.

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Treg cell therapies are a new field, and there are many areas where these therapies can be improved to provide greater access. This includes the potential for allogeneic therapies, assuming the immunogenicity issue can be resolved; more efficient manufacturing using automation and shorter or more efficient culture conditions; and even the potential for in vivo gene therapy, using novel approaches to ensure that expression of the target receptor, CARs or TCRs, is limited to Tregs.

Vie Ventures is committed to supporting companies in the autoimmune and inflammatory space, including startups and companies with drug candidates that need resources to tackle autoimmunity. One key aspect is that we look for innovative therapies that tackle core pathobiological pathways likely to be shared by multiple autoimmune diseases, not unlike anti-CD3, Tregs and similar approaches. Tolerance remains the Holy Grail for these treatments, but Vie is not restricted to tolerogenic approaches.

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Multiple autoimmune diseases are in the mix for early intervention, given recent data identifying patients with disease before major clinical manifestations. These include rheumatoid arthritis, celiac disease, autoimmune Addison's disease, systemic lupus erythematosus, systemic sclerosis and autoimmune thyroid disease.

A: The chemical biology mindset has contributed meaningful in-roads to the discovery of new molecules working in new ways, in many cases on historically intractable targets. Molecular glues, which remain a focus of my research, leverage large protein interfaces adjacent to binding sites to complete molecular recognition events, allowing the engagement of protein targets that would otherwise not be “druggable”. This has been particularly exciting in the field of gene control, which for years was the focus of my scholarship as an investigator. Gene control proteins, in particular transcription factors, frequently possess intrinsically disordered regions that rare adopt coherent secondary structures. High entropic penalties and absent binding sites continue to challenge the drug hunter. Beyond small molecules, approaches to deliver large biomolecules into cells remains a grand challenge, which we and others are working on to this day.

A: Artificial Intelligence is proving to be a powerful catalyst for biomedical discovery research and therapeutic development, with a growing number of high-impact applications. Protein structure prediction accelerates both de novo discovery of active large molecules, as well as their optimization for drug-like properties. Document authoring decreases the time to regulatory filing. Pattern recognition identifies new target pathways in complex genomic and phenotypic datasets. Forecasting and clustering optimize clinical trial enrollment. Together, these and other tools cut through complexity, improve decision-making and ultimately improve the probability of success. Most exciting to me at this moment is the systematic application of agentic workstreams to critical phases of pharmaceutical science, and business. AI is an instrument best played by a disciplinary expert, who has accepted the invitation to approach their work in a new way. While there remains some distracting hype around AI across sectors, there is no question that AI is emerging as a powerful adjacency for biomedicine – which we call convergent innovation.

A: In this post-genomic era, biomedicine is best practiced by hypothesis-testing. Where available, incisive prototype drugs paired with predictive pre-clinical models can expedite therapeutic translation. The experience of creating, characterizing, studying and sharing the BET bromodomain inhibitor, JQ1, provided a powerful learning. Open access to chemical probes opens up a field of study and accelerates medical progress. In the few years following the publication of JQ1, hundreds of laboratories worked with the molecule to learn about the biology of BRD4 in cancer, heart disease, fibrosis, inflammation, fertility, and most importantly the fundamental role of BRD4 in gene control (transcription elongation). In this way, JQ1 powerfully accelerated scientific discovery, bringing BRD4 biology into view in many disparate fields of study. Years later, scientists have used JQ1 as a work-horse of protein degradation, since our publication of the chemical solution to protein degradation and the molecule dBET1. Others have used JQ1 to recruit BRD4 to oncogenic transcription factors, such as the Androgen Receptor (at Halda, now J&J). JQ1-derived therapeutics are presently in advanced stages of clinical investigation as cancer therapies and for cardiovascular disease. I am hopeful that patients will benefit from the learnings of this remarkable molecule.