Antibiotic development increased, but still insufficient

Antibiotic development increased, but still insufficient

While the pipeline of new antibiotics has improved over the past six years, momentum in the development of new infection-fighting agents remains inadequate and could take a significant downturn without new incentives, a report released in Clinical Infectious Diseases shows. This report, an update of progress toward the Infectious Diseases Society of America’s 10 x ’20 initiative to see FDA approval of 10 new systemic antibacterial agents by 2020, follows a 2013 report on the status of the antibacterial drug pipeline.
While the numbers of antibiotics annually approved for marketing in the US has increased following a decline in the previous decade, the authors found, the most recently approved drugs represent modifications to existing classes, rather than innovative approaches. With some momentum propelled by antibiotic incentives enacted in the last few years as well as by increased funding for NIAID and BARDA, the report finds that unmet needs persist, with far too few treatment options available for multidrug resistant infections. At the same time, while larger pharmaceutical companies continue to leave the field, the small companies that are responsible for most of the antibiotic innovation are struggling to stay in business, the authors note.
« Pharmaceutical sponsor and investor disengagement continues to worsen, such that the prognosis for a sustainable antibiotic R&D infrastructure will be bleak in the absence of further economic incentives for antibiotic development. In the meantime, clinicians must protect currently available antibacterial drugs through robust antibiotic stewardship and infection prevention.» Highlighting needs for additional incentives to stabilize the antibiotic market and fuel the development of drugs needed to address current and future threats, as well as for improved oversight and stewardship to protect the effectiveness of existing drugs, the authors call for increased regulatory, governmental, industry, and scientific support and collaboration.

(The Infectious Diseases Society of America’s 10 × ’20 Initiative (Ten New Systemic Antibacterial Agents FDA-approved by 2020): Is 20 × ’20 a Possibility? George H Talbot, Amanda Jezek, Barbara E Murray, Ronald N Jones, Richard H Ebright, Gerard J Nau, Keith A Rodvold, Jason G NewlandHelen, W Boucher, Infectious Diseases Society of America – https://doi.org/10.1093/cid/ciz089)

(February 6, 2019)

Antibiotic development increased, but still insufficient

The 2018 Nobel Prize in Physiology or Medicine has been jointly awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. During the 1990s, in his laboratory at the University of California, Berkeley, James P. Allison studied the T-cell protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. He had developed an antibody that could bind to CTLA-4 and block its function and now set out to investigate if CTLA-4 blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells. Allison and co-workers performed a first experiment at the end of 1994 that showed that mice with cancer had been cured by treatment with the antibodies that inhibit the brake and unlock antitumor T-cell activity.

In 1992, Tasuku Honjo discovered PD-1, another protein expressed on the surface of T-cells. Experiments performed over many years in his laboratory at Kyoto University showed that PD-1, similar to CTLA-4, functions as a T-cell brake, but operates by a different mechanism. In animal experiments, PD-1 blockade was also shown to be a promising strategy in the fight against cancer, as demonstrated by Honjo and other groups. This paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer.

Figure: Upper left: Activation of T cells requires that the T-cell receptor binds to structures on other immune cells recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA- 4 functions as a brake on T cells that inhibits the function of the accelerator. Lower left: Antibodies (green) against CTLA-4 block the function of the brake leading to activation of T cells and attack on cancer cells.Upper right: PD-1 is another T-cell brake that inhibits T-cell activation. Lower right: Antibodies against PD-1 inhibit the function of the brake leading to activation of T cells and highly efficient attack on cancer cells.

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Antibiotic development increased, but still insufficient