Pharmaceutical companies navigate through the charted waters of in-licensing, intellectual property transfer, and good, old-fashioned discovery efforts to explore new drug targets for their compounds.
For the pharmaceutical industry, bringing a drug to market is the name of the game. And, although many companies play the acquisition card, there is more than enough activity in their research and development departments to keep innovation alive. So whether a pharmaceutical company discovers a new class of compounds, identifies a new drug target, or strategizes to make a compound first-in-class or best-in-class, innovation is behind every discovery.
Just as Christopher Columbus and his counterparts learned when searching for new lands, new drug targets are difficult to discover. In general, drug targets are discovered in academic labs and then further explored and developed in pharmaceutical labs. However, drug targets have also been discovered in pharmaceutical labs. And, of course, a pharmaceutical company can always in-license a compound and its target from another.
Case in point, Indianapolis-based CoLucid Pharmaceuticals in-licensed their lead compound, COL-144, from Eli Lilly and Company in 2005. James White, PhD, president and CEO of CoLucid was involved in the discovery of the 5HT-1f receptor, the target for which COL-144 is a very selective agonist, while serving as head of Neuroscience R&D at Lilly. White recalls that, “in the beginning, this receptor was actually discovered in a joint collaboration between Synaptic Pharmaceuticals and Eli Lilly and Company.” The object of this collaboration was to clone and screen new human receptors. And, because of Lilly’s broad interest in the serotonergic system, Lilly cloned the 5HT-1f receptor. The screening of compounds against this target resulted in the discovery of a number of potent agonists. These compounds were also very active in Lilly’s animal models of migraine, leading the company to further explore this particular class of molecules. However, initial attempts to produce a first-generation molecule from this class failed due to liver toxicity. “COL-144 really represents the third-generation attempt at this target. And, as far as we know, there really isn’t anyone who has pursued 1f as a target—the rights to the human receptor were exclusively owned by Lilly and Synaptic,” says White. With the acquisition of Synaptic by Lundbeck Pharmaceuticals (Middlesbrough, UK), the patent for 1f now resides between Lilly and Lundbeck; CoLucid is investigating 1f through its in-licensing agreement with Lilly.
Receptors for pain relief
“The reason we are interested in this particular approach is that it could represent a significant improvement over the last real breakthrough in acute migraine, which was the discovery of the triptan drugs,” says White. “But as the molecular biology of the triptans became better understood, it became clear that the efficacy of the triptans was coming through 1b and 1d receptors. Triptans initially were literally designed and screened for their ability to constrict blood vessels across the surface of the brain because, at that time, the theory of migraine headache was that swollen blood vessels were causing the pain. So the hypothesis was that if you could constrict those blood vessels, you could stop a migraine,” says White. However, a major problem with the mechanism of action of triptans is that not only are serotonin 1b (5HT-1b) receptors present on vasculature in the brain, but they are also present on coronary arteries in the heart. “And it was discovered that exposure to triptan drugs could cause vasoconstriction of the coronary arteries. And, in very rare cases, they actually could produce a myocardial infarction,” he explains.
The 5HT-1f receptors are present on the trigeminal nerve and in the trigeminal nerve system, where they can modulate pain signals to higher brain centers. “So the idea was that a 1f agonist might represent a drug that is as [effective], or more effective, than a triptan at stopping migraine pain, but would not have the liability of coronary artery constriction,” says White.
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All 5HT-1 receptors are G-protein-coupled receptors (GPCRs). Unlike other 5HT1 receptors, the 1f subtype is found predominantly in the brain, and is only found post-synaptically. The 1f subtype couples to Gi protein, which leads to inhibition of adenyl cyclase and the opening of potassium channels. This causes neurons to become hyperpolarized, which causes inhibition of the release of neurotransmitters and peptides involved in the genesis and maintenance of migraine pain. The idea is that activating the 1f receptor will reduce migraine pain.
COL-144 is currently in Phase 2 clinical trials. However, at the time it was in-licensed from Lilly, COL-144 had just completed Phase 1 and had a “pretty good” safety profile, making it a very attractive investment opportunity for CoLucid. So why did Lilly license COL-144 to CoLucid? “Lilly was struggling to manage a very large portfolio, and, of course, there’s never enough money to go around for all projects. So they decided that they’d like to leverage other people’s money towards this project,” says White. In 2007, CoLucid conducted a Phase 2 proof-of-concept study of an intravenous formulation of COL-144 in Europe. The result: very good efficacy similar to orally-administered triptans in some aspects, while superior to triptans in other aspects. The most important result: no cardiovascular adverse events.
Currently, CoLucid is transitioning COL-144 from an IV formulation to an oral tablet. “We’ve conducted a Phase 1 escalation study with an oral liquid formulation and found the drug to be very bioavailable, [have] good linear pharmacokinetics of the parent molecule, and no cardiovascular issues,” says White. “Starting next month, we’re actually initiating a crossover study in a large group of patients between the liquid formation and the tablet formulation. And once that is completed, we’ll be starting an outpatient Phase 2 study in 350 patients looking at a broad range of doses with the tablet form of the drug against placebo.”
Battling rheumatoid arthritis
EntreMed, Inc., in Rockville, Md., has an approved investigational new drug application for the use of 2-methoxy-estradiol (2ME2)—an oral, small-molecule metabolite of estradiol for investigation as a new treatment for rheumatoid arthritis. EntreMed has its therapeutic focus in oncology and became interested in 2ME2 for other diseases after establishing its anti-angiogenic activity. Armed with the knowledge that angiogenesis is a component of rheumatoid arthritis pathogenesis, EntreMed, in collaboration with Ernie Brahn, MD, professor of medicine, UCLA Medical Center, Los Angeles, began pre-clinical studies on the compound. According to Entremed representatives, the company has done a considerable amount of preclinical pharmacology work looking at 2ME2 in five different rheumatoid arthritis models. They found that in all five models, regardless of the nuances of each, 2ME2 demonstrated anti-arthritic activity, as well as anti-inflammatory and anti-angiogenic activity.
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The anti-angiogenic mechanism of 2ME2 is complex. 2ME2 inhibits tubulin, which is known to inhibit HIF-1 (also known as hypoxia-inducible factor 1 alpha), a target associated with angiogenesis. Acting on these targets may be one of the ways 2ME2 inhibits angiogenesis. Results from a number of EntreMed studies suggest that 2ME2 also has anti-inflammatory activity by inhibiting the production of inflammatory cytokines like IL-6, IL-1, IL-17, TNF-a—cytokines that are important in the pathogenesis of rheumatoid arthritis.
According to Brahn, 2ME2 is acting by a new mechanism of action. “From a targeting point of view, several growth factors for angiogenesis seem to be markedly inhibited—particularly basic fibroblast growth factor (which was inhibited in about 83% of our animal systems), as well as vascular endothelial growth factor [VEGF],” says Brahn. “[2ME2] lends itself to a very different mechanism of action as opposed to attacking cytokines or marked inhibitors of the immune system. [2ME2] also lends itself to combination therapies because it has a completely different mechanism of action and does not appear to be primarily an immunomodulatory agent at the preclinical stage we’ve looked at.” All work on 2ME2 was performed at EntreMed or through collaborations and the drug candidate is currently at the clinical stage. The company has completed a Phase 1 study in healthy subjects and intends to seek partnering opportunities for 2ME2 in rheumatoid arthritis.
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The bravehearted
Back in the 1960s, before antibiotic resistance and methicillin-resistant Staphylococcus aureus was discovered, most pharmaceutical companies considered microbiology and antibiotic development dead issues. With the emergence of antibiotic resistance, however, antibiotic development is very much alive, but only in a handful of pharmaceutical companies.
One of those companies, Optimer Pharmaceuticals (San Diego, Calif.), has a carbohydrate chemistry-based drug discovery platform, which can add carbohydrate groups onto many different antibiotics—including macrolide and ketolide backbones—in an effort to improve the efficacy and pharmacokinetic profile of those molecules. The company’s therapeutic focus is anti-infectives. Specifically, they design carbohydrate-derivatized molecules to treat infections caused by multi-drug resistant Gram-negative (e.g. Pseudomonas sp.) and Gram-positive bacteria (e.g. Multi-drug-resistant Staphylococcus aureus) that represent significant unmet medical needs. Optimer screens their compound libraries against the isolated target and against resistant strains of bacteria, in parallel.
Optimer’s leading compound, OPT-80, is one of two compounds currently in late-stage clinical development. The macrocyclic compound is an 18-membered ring with a narrow anti-microbial spectrum for Gram-positive bacteria, including anaerobes. For example, according to Michael Chang, PhD, CEO of Optimer, OPT-80 has strong activity and selectivity against Clostridia sp. “When we first looked at this class of compounds, we saw that they somewhat resembled macrolides. Macrolides are mainly 14- to 15-membered ring systems with other tethers hanging off of that,” says Chang. “So we thought these new 18-membered rings would be another generation of the macrolides but with a similar mechanism—binding to a region of bacterial ribosomal RNA and interfering with protein synthesis.” But OPT-80 turned out to be part of a newly-discovered class of molecules with a novel mechanism of action compared to the macrolides, targeting the bacterial enzyme RNA polymerase and not the ribosomal RNA. “For RNA polymerase, most of the drugs that came out interfere with elongation of the RNA chain at the active site of RNA polymerase. This one is very different: it may bind allosterically,” Chang explains.
Optimer currently believes that OPT-80’s MOA is through inhibition of RNA polymerase activity at very early stages of transcription and at a site distinct from the binding site of other known antimicrobials. This belief is based on their unpublished data, which showed that OPT-80 interfered with RNA polymerase assembly or through allosteric interactions, and thereby altered RNA polymerase-DNA template interactions. “We think … that it binds to [an RNA polymerase] subunit and interferes with its assembly,” says Chang. “And that may be the first case I know of where a small molecule interferes with protein-protein interaction and actually becomes a drug.” Not many pharmaceutical companies are doing antibiotic research today, which gives Optimer an edge and an interesting niche.
In summary, discovering new drug targets is, and will always be, like discovering new lands. However, with more recently-added tools, such as microarrays, and emerging biomarker discovery programs at pharmaceutical companies, the discovery of new drug targets is getting a bit easier. In addition, business transactions, collaborations, and intellectual property transfer practices all play their own role in the massive growth of drug target discovery research. Hopefully, this trend will continue.
Published in Drug Discovery & Development magazine: Vol. 12, No. 1, January, 2009, pp. 12-16.
Filed Under: Drug Discovery
