Some of the world’s greatest discoveries, from antibiotics to X-rays to the birth of our universe, have come from persistently and patiently following hints nature has left behind; and those hints are often hiding in plain sight. But even small insights in seemingly unrelated areas can combine to reveal powerful theoretical and scientific truths.
The discovery of the protein Bruton’s tyrosine kinase (BTK) is one that has just such a history. In 1993, patients with a rare inherited genetic disorder, called X-linked agammaglobulinemia (XLA), were found to have a defective form of BTK1. This defect essentially leaves people with XLA incapable of producing B-cells, immune cells critical to the formation of antibodies that protect us against foreign pathogens, germs and particles. Without this immunological defense mechanism, people with XLA are at severe risk of infection and require lifelong treatment with antibody replacement therapy.
But behind this debilitating condition lies a genetic clue and a fundamental truth about the nature of BTK: without it, B-cells can’t differentiate and mature. Harnessed in the right way, this insight could be beneficial in an entirely different setting – inflammatory diseases where B-cells and other immune cells are believed to run amok.
“It’s a case where the genetics of human disease have revealed something profound about how our immune systems are wired,” says Wendy Young, Ph.D., Vice President, Discovery Chemistry. “And the drug discovery implications are far reaching, particularly for diseases associated with the overproduction of inflammatory signals like in rheumatoid arthritis, lupus and urticaria.”
The identification of BTK as a key activator of B-cells and eventually, other immune cell types called, myeloid cells, suggests that specifically shutting down or inhibiting this protein may quell overactive immune cells that contribute to such chronic conditions.
The road from this insight to developing a medicine that’s appropriate for rheumatoid arthritis (RA) or lupus, however, is not so simple.
“We’ve been studying B-cell diseases for many years at Genentech and BTK for over ten,” says Young. “We’ve always believed strongly in the biological rationale to target BTK, but finding the right molecule has not been easy.”
One key factor is the way a molecule binds to BTK. There are two general types of small molecule medicines: those that permanently (“covalently”) bind to their target, and those that bind reversibly (“non-covalently”).
“There were a lot of researchers and clinicians studying BTK, but we knew there was an unmet need out there for patients and wanted to do something different. As chemists we believe that discovering reversible molecules is the right course even if it’s more challenging, because this strategy can add an additional element of safety to the molecule,” noted Young.
We’ve always believed strongly in the biological rationale to target BTK, but finding the right molecule has not been easy.
Genentech scientists had to consider countless other criteria as well. An ideal BTK inhibitor should be sufficiently potent but also remarkably specific, which can be a tall order given there are hundreds of kinases in the body and many of them look incredibly similar. In addition, the best approach for a chronic condition like RA or lupus might be different than in other diseases.
“We didn’t stop until we found a molecule with the right combination of potency – meaning it could be given at low doses – and stability so it wouldn’t be metabolized by the body too quickly,” says Young. “It took nearly seven years, but we finally found a investigational molecule that may offer a targeted approach to modulate B-cells and myeloid cells.”
A Measure of Success
In order to put a BTK inhibitor or any other potential new medicine to the test, researchers need to first decide how to measure if the treatment is working in patients. These measurements are known as clinical endpoints. And in diseases like lupus, it’s more challenging than you might think.
RA and lupus both occur when our immune systems begin attacking our own organs and tissues. RA manifests most commonly as inflammation in the joints, causing swelling, tenderness and stiffness. The disease is characterized by a number of immune signals, including an increase in circulating “autoantibodies” produced by B-cells and by the production of inflammatory cytokine proteins by myeloid cells. Both of these molecular signals trigger a chain of immunological events that target our otherwise healthy tissue and contribute to joint inflammation.
The complex physiology confounds not only how lupus is diagnosed but also how it’s treated and even the basics of how to effectively evaluate whether treatments are working in the clinic.
Similarly, in lupus, the overproduction of autoantibodies and cytokines drives inflammation. But the physiological manifestations of lupus are more complex than RA.
No two cases of lupus are exactly alike. It can affect different tissues and organs, including the joints, skin, blood vessels, heart and even the brain. The physical symptoms can range from joint and chest pain, to skin rashes or lesions, to more serious complications in vital organs like the kidneys.
“The complex physiology confounds not only how lupus is diagnosed, but also how it’s treated and even the basics of how to effectively evaluate whether treatments are working in the clinic,” says Jorge Tavel, M.D., Group Medical Director for Early Clinical Development at Genentech.
In fact, the fundamental challenge of measuring whether new investigational medicines are improving outcomes for people with lupus has been one of the primary barriers to the development of new therapies. In over 60 years, there has only been one new medicine approved specifically for the treatment of lupus by the Food and Drug Administration2.
But new efforts attempt to combine a wide range of assessments, including neurological, musculoskeletal and hematological functions, into singular endpoints for clinical trials in lupus. This means that researchers sometimes account for nearly 100 different physical and organ-specific measurements when assessing responses to therapies.
“We’re not just measuring one outcome. We’re making a global assessment of how a new investigational treatment can potentially improve a person’s overall health,” says Udo Klein, Ph.D., Project Team Leader. “It’s what makes this disease so challenging because it always manifests in different ways in different people. But having these complex endpoints provides a standardized index for measuring response across different patients and therapies.”
A New Molecular Frontier
Further insights may come from deepening our understanding of immunological diseases at the molecular level. Measuring biomarkers that are indicative of the underlying causes of disease and the mechanism of BTK inhibition could be valuable for assessing the efficacy of treatment as well as potentially identifying the people most likely to benefit from a medicine like a BTK inhibitor. Identifying predictive biomarkers in RA and lupus for BTK inhibition has been notoriously difficult because of the complexity of these conditions, but we’re making progress.
“These types of diseases aren’t associated with diseased cells, like tumors in cancer,” says Mike Townsend, Associate Director, Biomarker Discovery in Research. “RA and lupus are systemic diseases, requiring samples to be measured from clinically accessible sites such as blood.”
This poses a number of distinct challenges. For one, systemic biomarkers can be complex and it’s not always clear how to determine where a cutoff should be drawn to define a subpopulation, with a specific disease type. Diseases like RA and lupus may also require an examination of multiple cellular and molecular biomarkers in order to classify disease and disease subtypes because there isn’t just one pathogenic driver.
“It’s truly a new frontier for immunological diseases,” says Heleen Scheerens, PhD, Senior Director, OMNI-Biomarker Development in Development Sciences. “We’re seeing that there are certain biomarkers associated with particular types of inflammation, and this may lead to new ways of personalizing therapy or measuring treatment efficacy earlier than was ever possible before.”
“To think that there’s only been one new treatment approved for lupus in over half a century is pretty astounding considering the overall pace of medical innovation in that time,” says Tavel. “But it’s reflective of the challenges the disease poses and the fact that there’s a huge unmet need for people with lupus.”
It’s been a long and winding road with many challenges and obstacles, but the vision of making life better for people with debilitating conditions like RA and lupus has continued to drive scientists and clinicians in this quest.
As Young puts it, “If you believe in a target, and believe in a molecule, then the approach of never giving up is always the right choice.”
Read more about these important findings in the following papers from Genentech scientists:
Nature Chemical Biology. Specific BTK inhibition suppresses B cell- and myeloid cell-mediated arthritis
ACS Medicinal Chemistry Letters. Discovery of Potent and Selective Tricycle-containing Bruton’s Tyrosine Kinase Inhibitors with Improved Drug-like Properties
Journal of Pharmacological and Experimental Therapeutics. BTK Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats
Bioorganic and Medicinal Chemistry Letters. Discovery of Highly Potent and Selective Bruton’s Tyrosine Kinase Inhibitors: Pyridazinone Analogs with Improved Metabolic Stability
Bioorganic and Medicinal Chemistry Letters. Potent and Selective BTK Inhibitors: Discovery of GDC-0834