Posts Tagged → clinical trials
Sufferers of chronic myeloid leukemia (CML), a rare and tough-to-treat blood cancer, received some good news at the 2011 American Society of Hematology meeting in San Diego this week. On Monday, ARIAD Pharmaceuticals disclosed new results from the Phase 2 PACE trial of its lead drug ponatinib (AP24534). The data (covered by FierceBiotech, Xconomy, and TheStreet), indicate major responses to the drug in ~40% of recipients, even in advanced or refractory (resistant to treatment) CML .
With these numbers in hand, ARIAD enters a tight race, already populated by headliners like Gleevec (imatinib), which in 2001 made a splash as a first-line CML therapy. Drugs such as Gleevec and ponatinib belong to the family of tyrosine kinase (TK) inhibitors, which dock with a mutated protein called Bcr-Abl. This protein (actually a fusion of two distinct proteins via a chromosomal mishap) triggers disease by accelerating blood cell creation, leading to uncontrolled growth and eventually CML.
Since cancers constantly evolve, new mutations in the TK active site had rendered Gleevec ineffective for certain variations of CML. Many of the PACE trial patients had previously tried newer TK inhibitors, such as Sprycel (dasatinib, BMS) and Tasigna (nilotinib, Novartis), and found that their CML had become resistant due to a single amino acid mutation in the kinase active site, which swapped a polar residue (threonine) for a carbon chain (isoleucine). So, ARIAD chemists decided to develop a drug that borrowed the best points from the earlier therapies, but capitalized on this mutation (A pertinent review in Nature Chemical Biology covers early examples of “personalized” cancer drugs developed for disease variants).
So, how did they accomplish this particular act of molecular kung-fu? For that, we hit up the literature and go all the way back to . . . 2010. As explained in a development round-up (J. Med. Chem., 2010, 53, 4701), most approved Bcr-Abl inhibitors share several traits: densely-packed nitrogen heterocycles linked to a toluyl (methyl-phenyl) amide, then a highly polar end group, such as piperazine or imidazole. Since the mutation axed a threonine residue, the hydrogen-bond donor adjacent to the ring in earlier drugs was no longer necessary. So, chemists replaced it with a vinyl group.
A computer analysis designed to achieve better binding and drug-like properties suggested an alkyne linker might fit into the mutated active site even better than a vinyl group, so that’s ultimately what ARIAD installed. The program also suggested moving an exocyclic amino group into the aromatic (forming an uncommon imiadzo-[1,2-b]-pyridazine, green in picture). Borrowing the best stuff from other therapies, ARIAD’s chemists also wove in the “flipped” amide and -CF3 motifs (both blue) from nilotinib, as well as the methylpiperazine (red) from imatinib.
With computational rendering (Cancer Cell, 2009, 16, 401) ARIAD scientists could overlay both imatinib and ponatinib in the mutated enzyme’s active site (see picture, right). Notice that unlike imatinib, ponatinib avoids bumping into isoleucine 315. Ponatinib also gets a little extra binding oomph by poking its CF3 group into a hydrophobic pocket near the bottom of the active site.
Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.
So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects.
Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites.
Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns.
Zafgen, whose science has been the subject of much speculation on the Haystack (see earlier posts), has again found favor with investors, despite a tough climate for obesity drug developers. Last week, the company scored $33 million in Series C venture financing to move its drug ZGN-433 (beloranib hemioxalate) into Phase II trials (We found beloranib’s structure in WHO’s drug information Vol. 22, No. 4). This new cash comes on the heels of some fairly promising (albeit early) data the company presented at the June American Diabetes Association Annual Meeting: in Phase Ib testing, ZGN-433 prompted weight loss without increase in disease biomarkers such as elevated C-reactive protein (an inflammation and hypertension indicator) or heightened LDL “bad” cholesterol .
Despite all that money and early signs of efficacy, plenty of uncertainty remains around the viability of ZGN-433. Zafgen admits that they still don’t know the drug’s exact mode of action in the body. The drug’s claimed target, methionine aminopeptidase (type 2), is known to play a role in clamping off the blood supply to tumors. In obese patients, a much lower dose – roughly 100- to 300-fold, claims the FAQ on the company website – can signal fat tissue to release fatty acids and triglycerides back into the bloodstream; clinical data shows increased levels of breakdown byproducts in blood samples. Further, the drug is currently administered as a twice-weekly subcutaneous injection–not exactly the most user-friendly dosing method.
So what’s so interesting about this drug, from a chemistry perspective? Well, for one thing, it has two epoxide rings that would normally raise red flags for most med chemists as potential alkylating agents. Many biomolecules have nucleophilic (electron-rich and non-hindered) reactive groups that could be trapped this way, leading to DNA mutations or protein misfolding. And that’s not all: the molecule also has an unsaturated Michael acceptor, a ketone connected directly to a double bond, which usually act as sequestering agents for glutathione in cancer models. These three reactive groups together are uncommon in any lead molecule, and the company has not stated if they observe any protein conjugation as a result.
The ultimate goal would be development of an oral variant of their lead structure, although those second-generation compounds appear to be in the discovery/preclinical phase of development. Only time will tell if these drugs will make it to market; FDA rejection of high-profile obesity drugs Qnexa and Lorcaserin still hang over conversations of new weight-loss drugs.
UPDATE: added structure 5:13PM 7/12, added “hemioxalate” to name of ZGN-433.