2011 nces focus on cancer therapies

The future of the pharma industry increasingly lies in drugs for diseases with smaller patient populations, and those targeted more precisely at specific patient sub-populations. Many of the new chemical entities approved in 2011 were targeted at cancer, diabetes and cardiovascular diseases, as well as bacterial and viral infections

Cancer research at AstraZeneca
Image: AstraZeneca

Last year saw an increase in approval of agents for the treatment of cancers, while new diabetic and infectious disease therapies were also approved. Dr Sarah Houlton looks at 2011’s new chemical entities.

With the days of the big blockbuster drug largely coming to an end, the future of the pharma industry increasingly lies in drugs for diseases with smaller patient populations, and those targeted more precisely at specific patient sub-populations. Many big therapeutic areas are now well-served by effective generics – especially with the expiry of patents on some of the biggest selling drugs like atorvastatin (Lipitor) and clopidogrel (Plavix) – but there is still potential for new medicines in many well-served areas if safer, more effective drugs that act at novel targets can be discovered. Many of the drugs that were approved in 2011 fit squarely into these categories.

As has become the norm, a significant proportion of the new drugs given the green light by EMA last year were for treating various forms of cancer. Melanoma is a particularly difficult form of cancer to treat, because it is aggressive and prone to metastasising before it is spotted. Two new drugs to treat it were approved – Roche’s vemurafenib (Zelboraf) and ipilimumab (Yervoy) from Bristol-Myers Squibb.

Vemurafenib fits directly into the personalised medicine category – it is a protein kinase inhibitor that acts at the BRAF serine-threonine kinase with a mutation at position 600, otherwise known as BRAF V600E. This mutation gives constitutively activated BRAF proteins, which can result in cell proliferation in the absence of those growth factors that would normally be required. It has been approved as monotherapy for melanoma patients with this mutation whose melanoma is unresectable or metastatic – in the absence of the mutation it appears the drug may actually promote tumour growth instead of inhibit it.


The other new melanoma drug, ipilimumab, is a fully human immunoglobulin G1 monoclonal antibody that binds to cytotoxic T-lymphocyte associated antigen 4. This cell-surface molecule is thought to be important in regulating immune responses, and by blocking its activity it gives a sustained active response when attacking cancer cells. Again, it is approved for use in pre-treated metastatic or unresectable melanoma.


A new drug to treat prostate cancer, abiraterone (Zytiga), originated in the labs at Cancer Research UK, was commercialised by BTG and licensed to Cougar Biotechnology, which was then acquired by Johnson & Johnson. It inhibits the enzyme 17 a-hydroxylase C17,20 lyase, or CYP17A1, which is expressed in prostate, adrenal and testicular tumours. It catalyses two reactions involved in the synthesis of dehydroepiandrosterone and androstenedione, both of which are androgen precursors of testosterone. Inhibiting this activity thus reduces the level of circulating testosterone. It has been licensed for use in combination with prednisone or prednisolone in metastatic, castration-resistant prostate cancer in men whose disease has progressed despite being given docetaxel therapy. It was given accelerated approval because of the poor prognosis of the target patient population.

Cabazitaxel (Jevtana) from Sanofi is also designed for patients with hormone refractory metastatic prostate cancer who have been pretreated with docetaxel. The semi-synthetic taxol derivative is, like its parent, a microtubule inhibitor, and again is designed to be given in combination with prednisone or prednisolone.


Another complex natural product-derived molecule, Eisai’s eribulin (Havalin) has been approved to treat breast cancer. It is a fully synthetic macrocyclic ketone analogue of halichondrin B, a molecule first extracted from a marine sponge. It is another form of microtubule inhibitor, and largely binds to high affinity sites at the ends of existing microtubules, rather than preventing them from forming in the first place. This has the effect of blocking mitosis, thus leading to cancer cell death. It has been recommended for use in patients with locally advanced or metastatic breast cancer whose disease has progressed after at least two previous chemotherapy regimens.


A lot of the targets being investigated in cancer are kinases, as they are well understood, and many play roles in the growth and propagation of tumours. Vandetanib (Caprelsa) from AstraZeneca inhibits two of the most common protein kinase targets – vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR). It is also active against the rearranged during transfection, or RET, tyrosine kinase proto-oncogene. In trials, it improved progression-free survival in patients with aggressive and symptomatic medullary thyroid cancer, whose disease was unresectable and either locally advanced or metastatic. This is the first drug on the market designed to treat this form of cancer.

Type II diabetes is reaching epidemic proportions in the developed world, thanks to poor diets and unhealthy lifestyles, and new drugs are still very much needed to treat it as many of the current therapy options have undesirable side-effects, or are not sufficiently effective in the long term.

Two new antidiabetics were approved last year. The first of these, Boehringer Ingelheim’s linagliptin (Trajenta), is an inhibitor of dipeptidyl peptidase IV, or DPP-4 (Scheme 4). It joins three other DPP-4 inhibitors – sitagliptin, vildagliptin and saxagliptin – on the market. Like its rivals, it inhibits this enzyme which degrades the incretin hormones glucagon-like peptide


(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These enzymes increase the biosynthesis and secretion of insulin from pancreatic beta cells in the presence of both normal and elevated glucose levels, and thus by blocking their degradation the release of insulin is encouraged in a glucose-dependent way.

The second novel Type II diabetes treatment is actually a new formulation of an old molecule but, interestingly, it gives a once-weekly treatment option. Byudureon from Amylin and Eli Lilly contains exenatide, the active in Byetta. The peptide hormone was originally isolated from the saliva of the Gila monster, a poisonous lizard from Mexico. To create the long-lasting drug, it was formulated using technology from Alkermes. It is a GLP-1 receptor agonist, thus mimicking the effect of the natural hormone that induces insulin production. Trials showed that this once-weekly formulation gave better results than the twice-daily oral form of the drug.


Despite many cheap options being available for the treatment of hypertension, a new one was approved last year – azilsartan medoxomil (Ipreziv and Edarbi) from Takeda, joining a class in which there are already half a dozen drugs on the market. It is an angiotensin II receptor agonist, and by both potently and selectively blocking this receptor it inhibits the renin – angiotensin – aldosterone system, thus reducing blood pressure.

Clotting is a real problem during elective joint replacement surgery, and thus it is routine to administer an anticlotting drug. In the past, this would probably have been an injectable heparin such as enoxaparin, but now oral therapies are


beginning to become available and another of these was approved last year – apixaban (Eliquis) from Bristol-Myers Squibb and Pfizer. The compound is a direct factor Xa inhibitor, and is indicated for the prevention of venous thromboembolic events in adult patients who have undergone elective hip or knee replacement surgery.

Some therapeutic areas are very underserved by drug treatment, and GlaxoSmithKline’s belimumab (Benlysta) reached the market for one of these – systemic lupus erythmatosis. The drug was developed by Human Genome Scientists from antibodies provided by Cambridge Antibody Technology, and commercialised by GSK. The antibody acts against B-lymphocyte stimulator, a protein that is believed to increase the production of cells that attack healthy tissue, and which is present in elevated levels in patients suffering from lupus. Previous therapies have relied on preventing lupus flare-ups, as the cause of the disease remains unknown, rendering it difficult to identify a target. This is the first new licensed drug for lupus for more than half a century.


Another disease where treatment options are severely limited is multiple sclerosis, and fingolimod (Gilenya) from Novartis is the first orally available drug for the disease. Licensed for the treatment of patients with relapsing remitting multiple sclerosis with high disease activity, it is a sphingosine 1-phosphate receptor modulator, and works by sequestering lymphocytes in the lymph nodes. This has the effect of preventing them from having an autoimmune effect. The starting point for the medicinal chemistry was the immuno-suppressive natural product myriocin, which was isolated from a fermentation broth of the fungus Isaria sinclairii that is used in traditional Chinese medicine.

A novel antiepileptic was also approved. Retigabine (Trobalt) from Valeant Pharmaceuticals and GlaxoSmithKline is an anticonvulsant licensed as an adjunctive treatment for partial onset seizures in adults with epilepsy. Its activity largely derives from its ability to open voltage gated potassium channels in the brain, the first antiepileptic medicine to work via this mechanism.


In the area of infectious diseases there were several new entrants, two of them designed to treat bacterial infections. The first of these, fidaxomicin (Dificlir) from FGK and Optimer Pharmaceuticals, has been shown to eradicate pathogenic Clostridium difficile – one of the bacteria that has recently been causing real problems in a hospital setting due to resistance (Scheme 6). It is the first in a new class of narrow-spectrum macrocyclic antibiotics, and is a fermentation product produced by the actinomycete Dactilo-sporangium aurantiacum. As a non-systemic antibiotic, it is only minimally absorbed into the bloodstream, and it has a limited effect on the microflora in the gut, which may reduce the likelihood of the C. diff infection returning. It is bactericidal and acts by inhibiting RNA synthesis by bacterial RNA polymerase, but importantly for treating resistant bacteria, it acts at a different site on the polymerase than the rifamycins.

The second new antibacterial agent, Astellas’s telavancin (Vibativ), was approved to treat nosocomial pneumonia that is either known or suspected to have been caused by methicillin-resistant Streptococcus aureus, or MRSA. The drug is a synthetic derivative of vancomycin, and thus inhibits bacterial cell wall synthesis in Gram positive bacteria. It is already approved in the US for treatment of complicated skin and skin structure infections, but has not been given this indication in Europe in the first instance. Limiting the application of the drug in this way may prolong its MRSA activity in a hospital setting.



Two new antiviral agents for use in hepatitis C were also approved, and in quick succession. Both boceprevir (Victrelis) from Merck Sharp & Dohme and telaprevir (Incivo) from Janssen-Cilag and Vertex are licensed for use in patients with genotype 1 hepatitis C infection and compensated liver disease, and they are to be given in combination with the standard therapy of interferon and ribavirin.

They can be used either in treatment-naïve patients or those who have previously failed standard therapy. Both drugs are protease inhibitors that bind to the non-structural 3, or NS3, active site on the virus. By directly inhibiting viral replication in infected host cells, administering these drugs can lead to the eradication of the virus in patients with chronic hepatitis C infection.


drug combinations

Combination therapy has become a cornerstone of the treatment of HIV, and another such drug has been approved from Gilead. Eviplera combines three antiviral agents – the nucleoside reverse transcriptase inhibitors emtricitabine and tenofovir disoproxil, and the second generation non-nucleoside reverse transcriptase inhibitor rilpivirine. While all these agents have previously been approved, this new combination is licensed for treatment-naïve patients, and by combining the actives into one pill it should improve compliance.

Another new combination, this time for malaria, is Eurartesim from Sigma-tau, which incorporates dihydroartemisinin and piperaquine phosphate into one pill. Surprisingly, this is the first antimalarial medicine to be approved by EMA’s Committee for Medicinal Products for Human Use, and it is designed for the treatment of uncomplicated Plasmodium falciparum malaria.

Introducing combination therapies has been a real trend in the pharma market in recent years. Not only can it improve patient compliance, but there is also a commercial driver – by combining two molecules into one pill it can extend the patent life of older molecules, with patients being transferred to the combination rather than taking older single agent pills that may already be off patent.

Combinations are particularly popular in the area of cardiovascular and metabolic disease treatment. Rasitrio from Novartis, for example, was approved, which contains its renin inhibitor aliskiren with Pfizer’s off-patent calcium channel blocker amlodipine and the old diuretic hydrochlorothiazide. The medication has the effect of lowering the blood pressure via three different pathways. Similarly, a second combination from Novartis, Rasiamlo, combines the first two of these ingredients. Another cardiovascular combination, Pravafenix from Laboratoires SMB, combines the cholesterol lowering drug pravastatin with the older lipid reducing drug fenofibrate.

A further combination product, Komboglyze, has been licensed by Bristol-Myers Squibb and AstraZeneca, and combines the DPP-4 inhibitor saxagliptin and the older antihyperglycaemic drug metformin, which is thought to act by decreasing hepatic glucose production, reducing intestinal absorption of glucose and improving insulin sensitivity. It is designed for patients whose glucose levels are not being sufficiently well controlled by metformin alone.


At the other end of the spectrum from these well-known actives finding new formulations is tafamidis (Vyndaqel) from Pfizer, which has been given approval despite a lack of comprehensive evidence on the medicine’s efficacy and safety. The agency decided that it was worth the risk as it is the first oral drug for treating transthyretin amyloidosis in patients with symptomatic polyneuropathy – a severe and progressive orphan disease.

First discovered in the labs of the Scripps Institute and developed by FoldRx, a biotech company that was acquired by Pfizer in 2010, the drug works by kinetically stabilising the correctly folded tetrameric form of the protein transthyretin. In patients with this disease, the protein dissociates and aggregates into amyloid fibrils, leading to failure of the autonomic or peripheral nervous system and, ultimately, heart failure. Tafamidis slows the fibril formation process, and thus may have a positive effect in patients with this severe and otherwise untreatable disease.

Diabetes is achieveing epidemic status: two new antidiabetics were approved last year: one of these was linagliptin (Trajenta) from Boehringer Ingelheim
Image: Boehringer Ingelheim GmbH