Many of our current antiviral, antibacterial and anti-tumour medications are comprised of combinations of two or three active substances, selected on the basis that these combinations slow down emergence of drug resistance. We are currently witnessing a rapid expansion of disease indications for which exploratory drug combos are being tested, as well as of the rationales for combining drugs. In this article, we examine the drivers behind this trend and the inherent caveats and complexities of drug combo development.
This article was authored by Willem Broekaert from V-Bio Ventures.
A long history of combining approved drugs
The value of using combinations of approved drugs has long been recognized in antibiotic treatments. Already in 1948, a controlled clinical trial established that a combination of para-aminosalicylic acid and streptomycin results in better control of tuberculosis and less antibiotic resistant bacteria compared to treatment with each drug alone. A quadruple combo of antibiotics (isoniazid, rifampicin, pyrazinamide and ethambutol) is today part of the standard tuberculosis treatment regimen. With the rising threat of antimicrobial resistance, drug combinations are being used to try to slow the widespread emergence of antibiotic-resistant bacterial strains.
Combinations of approved drugs are also being used in other disease areas. The underlying rationale is that a combination of selected medicines, each acting on a different molecular circuit, simultaneously pulls multiple strings. This, in turn, ideally results in both improved efficacy and less side effects, due to lower doses of the active substances being used. Drug combinations can either be administered as separate drugs or as fixed-dose combinations formulated in one pill, with the latter option ensuring better patient compliance.
Although identification of effective drug combos was largely based on patient experience in the past, modern methods have moved one step ahead and started testing new combinations in rigorous clinical trials.
These days, most patients with severe hypertension use at least two different antihypertensive drugs. A full quarter of patients even take a triple combination. For antihypertensive drug combos, figuring out which approved drug classes made effective combos was historically based on empirical observations by individual clinicians. Large-scale studies have been run a posteriori to confirm or disprove proposed combinations. Current hypertension guidelines reflect these studies by, for instance, advocating for combinations of angiotensin-converting enzyme inhibitors with calcium antagonists (for safe and effective hypertension management), while advising against combinations of beta-adrenergic blockers with non-dihydropyridine calcium antagonists (due a greater risk for certain cardiac events). Although identification of effective drug combos was largely based on patient experience in the past, modern methods have moved one step ahead and started testing new combinations in rigorous clinical trials.
Trialling combos of investigational drugs
Until recently, drug combinations were mainly applied in those fields where underlying disease mechanisms are relatively simple. The development of antivirals, for example, revolves around a handful of viral protein targets that are markedly different from host cell proteins. For instance, the anti-HIV drug Biktarvy combines two compounds that inhibit viral reverse transcriptase and one that blocks viral integrase
However, for multifactorial diseases with a complex pathophysiology, the number of contributing biological pathways increase dramatically, as do the number of cell types, tissues or organs involved. With modern technology we have been able to deepen our understanding of these mechanistic circuits at the genomic, proteomic and metabolomic level. Combined with computational modelling approaches, it has now become possible to investigate hypothesis-driven drug synergies, rather than relying on empiric combinations.
An example of this is in non-alcoholic steatohepatitis (NASH), a complex disease which involves concurrent excess fat deposition, inflammation, and fibrosis in the liver. Similarly, neurodegenerative diseases like Alzheimer’s disease feature synaptic transmission loss, inflammation and cell degeneration in an interplay between neurons and glial cells. Any successful therapies for these multifactorial diseases will have to act on all pathways simultaneously. Unfortunately, single compound drugs capable of selectively modulating multiple defined pathways are unlikely to exist. However, combinations of selective drugs could potentially do the job.
Exploring investigational drug combos is inherently more complex than combining approved drugs… Nevertheless, many such studies are currently taking place, with the benefits of successful combinations deemed worth the trouble.
In a vast range of disease areas, including immuno-oncology, autoimmunity, pain, neurodegenerative and metabolic diseases, trials are underway to examine combinations of investigational drugs with either approved drugs or even other investigational compounds. An example of the latter is a seven arm Phase II trial in NASH run by Gilead, with different two-by-two combinations of an investigational farnesoid X Receptor agonist, an Acetyl-CoA carboxylase inhibitor and an ASK1 kinase inhibitor. Regulators require a compelling biological rationale for any proposed combination treatment, backed up by a set of nonclinical data and clinical data on both the monotherapies and combination therapies. Obviously, exploring investigational drug combos is inherently more complex than combining approved drugs, since clinical data for the individual drugs are lacking at the outset of the study. Nevertheless, many such studies are currently taking place, with the benefits of successful combinations deemed worth the trouble.
The many challenges with combination therapies
To develop combination therapies, substantial nonclinical data need to be gathered. These data need to demonstrate not only the synergistic effects of the drugs, but also the absence of synergistic toxicities and untoward drug-drug interactions. Part of the challenge is the availability of animal models: these studies require models that replicate all the pathological cues of the human disease that the drugs combo is supposed to act upon. Additionally, the dynamic range of the animal models needs be large enough to discriminate between single compounds that work well and which combinations (if any) work even better. Better models will need to be developed to fully meet these needs.
We at V-Bio Ventures believe that high-risk trials of investigational drug combos are here to stay, despite the likely significant failure rates, because the long-term outcome will be significantly better therapies for patients.
A next hurdle arises at the clinical stage. Phase I studies of combination therapies tend to be lengthy and expensive, particularly for combinations of investigational drugs. Establishing toxicity thresholds requires dose escalations for both drugs and, as moving to the next dose can only be done sequentially, this can take a lot of time. When one of the drugs is already approved, then this component can be maintained at its safe and effective dose, or one dose level below, which obviously speeds up such studies. Phase II studies require creative adaptive trial designs, as they have to show the efficacy of each individual agent, as well as improved efficacy of the combo, on an appropriate endpoint. Only once the efficacy of the combo versus the single drugs has been established in a Phase IIb study, negotiation with the regulators will determine if a Phase III study can begin with just the combo at the selected dose. The whole clinical process is magnitudes more complex than a normal clinical trial for a single compound, which is already a challenging undertaking in itself.
Read this previous BioVox article to learn how business models shaped our current drug development trends.
Our thoughts on drug combos
The attempts of the biotech industry to evaluate combination therapies, even before single drugs have been approved, are testimony to their strong commitment to find effective solutions for hard-to-treat diseases. Some may judge that such endeavors as premature and therefore a waste of resources. We at V-Bio Ventures believe that high-risk trials of investigational drug combos are here to stay, despite the likely significant failure rates, because the long-term outcome will be significantly better therapies for patients.
