• Sustainability
  • DE&I
  • Pandemic
  • Finance
  • Legal
  • Technology
  • Regulatory
  • Global
  • Pricing
  • Strategy
  • R&D/Clinical Trials
  • Opinion
  • Executive Roundtable
  • Sales & Marketing
  • Executive Profiles
  • Leadership
  • Market Access
  • Patient Engagement
  • Supply Chain
  • Industry Trends

Magic Molecules


Pharmaceutical Executive

Pharmaceutical ExecutivePharmaceutical Executive-12-01-2004

Pharm Exec's Pipeline Report is packed with 25 of the year's most eye-catching experimental drugs. What's their secret? No smoke or mirrors-just innovative science, therapeutic value, and good business sense.

Science fiction writer Arthur C. Clarke's Third Law states: "Any sufficiently advanced technology is indistinguishable from magic." Paul Ehrlich, the Nobel Prize-winning pharmaceutical pioneer, used to say, "We must learn to shoot microbes with magic bullets." This year's 25 Most Attention-Getting Investigational Compounds (MAGIC), are all products of advanced technology—"bullets" that may well appear magical some day. But there are no tricks involved. Chosen by pharmaceutical analysts and consultants asked to name the late-stage products that caught their notice (candidates had to be beyond Phase II but not yet launched, and new uses for known products were counted as new), they embody the hopes and hard work of countless people.

Keeping in mind the effort, the uncertainty, the inevitable twists and turns and ups and downs, it might be said that every molecule tells a story. Here then, out of hundreds swimming upstream through the pipeline against all odds, are 25.

Acomplia [rimonabant]

from Sanofi-Aventis

The most popular selection in the MAGIC 25, Acomplia (rimonabant) has been dubbed the antimunchie drug because, as a cannabinoid CB1 receptor antagonist, it blocks sites "believed to mediate hunger responses when individuals smoke marijuana," says 2Value analyst Marc Samet, PhD. This mechanism has produced "promising clinical data for two indications—obesity and smoking—both large consumer-friendly spaces," says Mara Goldstein, pharmaceutical analyst for CIBC World Markets. What's more, subjects in a recently reported two-year trial not only lost an average of 19 pounds, their cardiovascular profiles improved. And patients who stayed on the drug tended to maintain their weight loss, while those who went off it gained theirs back. Says David Moskowitz, an analyst with Friedman, Billings, Ramsey:"There may be some nervousness in the wake of fen-phen, but there is clearly a need for a way to reduce weight safely, especially since abdominal fat is an important indicator of cardiovascular risk."

Acomplia is "not an extraordinary breakthrough," in the view of David Goldstein, MD, PhD, formerly with Eli Lilly and now a consultant and a member of the board of the American Society for Clinical Pharmacology and Therapeutics. But it is "a novel mechanism that will add to physicians' arsenals and allow them to try multiple treatments for obesity." Although, he adds, the efficacy of these combinations "has not been tested." He expects "marginally better results from Acomplia compared with other recent products," and thinks it will "probably get off to a hot start—people are hungry for something new." But then "reality will set in: It won't make people thin." Goldstein also foresees three potential problems: "Studies show an increase in infections in year one, possibly involving immune modulator CB2. Cannabinoids are analgesics, so those taking painkillers along with Acomplia may find their effects blunted. Finally, there are hints that Acomplia may be accompanied by an increase in anxiety and depression."

Acomplia may appear formidable, but analysts warn that it is entering a crowded smoking cessation market and is also up against several well-entrenched statins.

A New Drug Application (NDA) for an obesity indication is expected to be filed as early as next year.

Exenatide [synthetic exendin-4]

from Amylin Pharmaceuticals/Eli Lilly

Called by analyst Moskowitz "an effective new molecule" for the treatment of Type 2 (noninsulin dependent, adult onset) diabetes, Exenatide was discovered in a protein found in the toxic saliva of the beaded lizard, a close relative of the Gila monster. Exenatide is the first in a new class of drugs called incretin mimetics. A glucagon-like peptide-1 (GLP-1) agonist, it stimulates insulin secretion to improve blood glucose control. But, Moskowitz says, "Unlike insulin, it does so without incurring the risk of hypoglycemia [low blood sugar]." In addition to that, Exenatide appears to promote weight loss—which would in many cases lessen the severity of diabetes—something insulin impedes. Exenatide has been found effective for Type 2 diabetics not taking insulin who have had no success with current oral medications.

There is one possible drawback, Moskowitz says: "As a twice-daily injectable, its growth could be slowed by resistance to the delivery system." There is also competition coming. Novo Nordisk has its own GLP-1 agonist Liraglutide (NN-2211) in Phase II, and Merck and Novartis are working on oral agents with a similar mechanism of action (MOA). An NDA was filed in June and was accepted for review by FDA in September. A decision is anticipated by the end of first quarter 2005.


from Neurocrine Biosciences/Pfizer

A treatment for insomnia, a condition that affects 40 percent of US adults, indiplon is a second-generation nonbenzodiazepine sedative hypnotic that functions as a GABAA receptor agonist. Its mechanism of action is similar to Sanofi-Aventis' best-selling Ambien (zolpidem), Jones Pharma's Sonata (zaleplon), and Sepracor's forthcoming Estorra (eszopiclone). But indiplon, perhaps because of its tendency to bind selectively with the alpha-1 subunit, believed to be the specific subsite responsible for promoting sleep, has shown little, if any, residual hangover effects or evidence of withdrawal or rebound insomnia. In addition to its clean side-effect profile, indiplon's biggest advantage may be Neurocrine Biosciences' choice of marketing partner: Pfizer. The two are collaborating on clinical development and promotion in the United States. Pfizer has exclusive rights to market and develop indiplon elsewhere. An NDA for indiplon IR (immediate release) was filed in October and one for a modified release formulation last month. A decision is likely in the middle of 2005.


from Ligand/Pfizer

One of three carryovers from last year's Pipeline Report—it topped the list—lasofoxifene is a potent, non-steroidal, tissue-selective estrogen receptor modulator (SERM) being tested for the prevention of postmenopausal osteoporosis and breast cancer. Unlike estrogen, which inhibits bone loss but raises the risk of uterine cancer, it shows signs of being an anti-cancer agent. Discovered by Ligand and Pfizer, the drug is being developed by Pfizer under license in accordance with the resolution of a contract dispute.

An NDA was submitted in October for postmenopausal osteoporosis, and a product launch is forecast for 2006-2007. Phase III trials are under way to test its effectiveness in reducing the risk of breast cancer, vertebral fractures, and cardiovascular disease.

Lipitor/torcetrapib [atorvastatin/torcetrapib]

from Pfizer

Acombination of Lipitor (atorvastatin) and torcetrapib is "the first major therapy to adopt a dual approach to lipid-profile management," says Albert Rauch, PhD, an analyst with A.G. Edwards & Sons. The former lowers LDL ("bad" cholesterol), and the latter is expected to raise HDL ("good" cholesterol). It "could set a new standard in the $20 billion cholesterol reducer market and add years of exclusivity to Lipitor," says Mara Goldstein. Moskowitz thinks it has the potential to be bigger than Lipitor alone, as well as expand the market beyond $20 billion. "Initially, it will enhance Pfizer's revenues, then after Lipitor's patent expires in 2011, it will stabilize them,"she says. "Pfizer could have the cholesterol lowering market to itself."

Pharmaceutical Executive Pipeline Report

Torcetrapib "inhibits cholesteryl ester transferase protein (CETP), an enzyme responsible for LDL-mediated control of cholesterol synthesis," Samet explains. Now in a massive Phase III study—the largest clinical trial ever—torcetrapib, in combination with Lipitor, boosted HDL by 60-100 percent. But this, Samet points out, "required twice-daily dosing, which may slow the launch of a combination pill." However, he adds, "There are few drugs near the market that can significantly elevate HDL, which provides a unique marketing advantage for Pfizer's franchise." Winton Gibbons, an analyst at William Blair & Co. agrees: "The marketing advantage is all Pfizer's. Roche has no statin with which to package JTT-705, the HDL-raising drug it in-licensed from Japan Tobacco—though it could conceivably make a deal for one." What's more, he says, "Results of Phase II tests showed that Lipitor and torcetrapib had genuine synergy: Patients' lipid profiles were better when the drugs were taken together than when taken alone." Finally, Gibbon says, "Lipitor already has a broad claim to prevent cardiovascular disease in its original label, while Roche will have to earn it at considerable expense and over time." An NDA filing is expected before 2006.

PTK 787 [vatalanib]

from Schering AG/Novartis

Vatalanib is an anti-angiogenic RTK (receptor tyrosine kinase) inhibitor. It disrupts intercellular communication through a well-known signaling pathway that has been implicated in the way cancer cells create new blood vessels from existing ones (angiogenesis). In particular, like Genentech's Avastin (bevacizumab), it blocks the vascular endothelial growth factor (VEGF) receptors, and so deprives certain tumors of the blood supply they need to grow. However, Avastin is taken intravenously, while PTK 787 is formulated as a pill. Phase III trials are ongoing. An NDA filing may be expected before the end of 2005.


from Eli Lilly

Ruboxistaurin, "the first treatment to address the microvascular complications of diabetes affecting the nerves, eyes, and kidneys," according to Rauch, "answers a huge unmet medical need." Six Phase III trials are under way. So far, initial clinical data has been positive for a variety of diabetic complications.

Ruboxistaurin is a protein kinase C beta (PKC beta) inhibitor. Numerous studies to date have highlighted diabetic activation of PKC as a mechanism leading to the development of serious microvascular complications.

Ruboxistaurin promises to map entirely new medical terrain. A recent study on diabetic neuropathy from Decision Resources predicts that its launch will shift the market from pain control to disease modification.

Tysabri [natalizumab]

from Biogen Idec/Elan

In late November, Tysabri (natalizumab), the drug formerly known as Antegren, received approval for the prevention of multiple sclerosis (MS) relapses. That's also when it was renamed at FDA's request. An NDA had been filed on the basis of first-year results in two ongoing two-year Phase III trials in which Tysabri monotherapy reduced the rate of relapses by 66 percent compared with placebo—twice as effective as current drugs tested in other trials (which may void comparison).

A humanized monoclonal antibody with the potential to also treat rheumatoid arthritis (RA) and Crohn's disease, Tysabri is the first alpha4-integrin antagonist in a new class of compounds known as selective adhesion molecule inhibitors, offering a new option to patients who have not responded to existing treatments. It appears to work by blocking alpha4beta1 integrin-mediated leukocyte migration across the blood-brain barrier and into inflamed tissue.

Tysabri requires only a monthly dose in contrast to existing MS drugs, such as the US market leader, Biogen's own Avonex (interferon beta-1a), which requires a weekly self-injection. But Tysabri must be infused intravenously. Its adoption, therefore, depends as much on logistics as on medicine. Biogen must not only persuade patients to go where they can undergo the one-hour procedure but also provide enough suitable locations. Estimates say there are only half the infusion sites needed.

Biogen also has the delicate task of introducing Tysabri without cannibalizing sales of Avonex, which reached $1.2 billion last year, accounting for two-thirds of Biogen's total revenue. That may be why it has chosen to price Tysabri at a premium, a $23,500 annualized cost, 30-40 percent more than most other therapies. It is also testing to see if its two MS drugs work best in combination—perhaps the optimal outcome from its perspective.

Therapeutic Advance

CDP-870 [certolizumab pegol]

from UCB Pharma

Originally codeveloped by Celltech (now UCB Pharma) and Pharmacia (now Pfizer), CDP-870 reverted to UCB last year, when Pfizer terminated its rights after Celltech (as it was then called) declined to renegotiate terms.

A third-generation, antitumor-necrosis factor-alpha (TNF-a) antibody fragment (FAb), the drug represents a new approach to immunosuppression. The idea of the drug is to "shoot" the messenger, blocking the action of TNF-a, a cytokine that normally functions as a signal in the body's immune system to create inflammation. When overproduced, however, the result is often an inflammatory disease. Phase III studies show that CDP-870 significantly improves the quality of life for rheumatoid arthritis sufferers.

One of its virtues is that it binds to TNF-a with high affinity. Another is the absence, thus far, of any sign of immunogenicity, meaning that it fails to provoke an autoimmune attack. Its production process, using fermented E. coli, is also a competitive edge. It costs just 5-10 percent of the alternative technique using mammalian cell cultures. In addition, the FAbs are modified by pegylation. Molecules of polyethylene glycol (PEG) are attached to improve their pharmacokinetics, prolonging their half-life to 12-15 days, thereby lowering the drug's dosing frequency. This potential for a once-a-month injections is what Sena Lund, senior analyst at Cathay Financial, says "should be its key advantage over established products."

Entereg [alvimopan]

from Adolor/GlaxoSmithKline

Mu-opioid antagonist Entereg "could be very big," says David Goldstein, "because it stays in the gastrointestinal tract." Plus, the fact that it is not absorbed, he says, makes it "totally safe."

Initially submitted for postoperative ileus and accepted for review this quarter, Entereg "eliminates anesthesia-induced nausea," according to Goldstein, "so you can feed patients and get them out of the hospital a day earlier." It has other uses as well, including reversing the constipation that opioids tend to promote. But, because it stays in the gut, "It doesn't affect the opioid's analgesic—or, in the case of methadone and certain other drugs, its psychomimetic—effects." It may also be used for treating irritable bowel syndrome and idiopathic constipation.

HPV vaccine

from Merck

Merck's vaccine for human papillomavirus (HPV), the most common sexually transmitted disease, Rauch believes "could eliminate cervical cancer," which kills 4,000 women in the United States and nearly 250,000 worldwide every year. It is also, Moskowitz says, "very important for the prevention of genital warts in men and women." A regulatory filing is expected in the second half of 2005.

Lucentis AMD [ranibizumab]

from Genentech/Novartis

Age-related macular degeneration (AMD)—the leading cause of blindness in Americans over 50—is a problem that grows as the population grays. Every year, 200,000 cases crop up in the United States, and half a billion are diagnosed around the world. By 2025, 11 million people could be affected. Today, 6-10 percent develop wet AMD, characterized by the growth of abnormal blood vessels. Just one in four, those with certain subtypes, can be treated. Lucentis, Samet notes, is one of "many products targeting VEGF-mediated angiogenesis by a variety of novel molecular techniques, including monoclonal antibodies and iRNA." But it is just one of two expected to be monotherapies for all subtypes of wet AMD. The other is Macugen (next).

Lucentis is injected directly into an anesthetized eyeball. Because it is a fragment of a larger anti-VEGF antibody, it can deeply penetrate to better block the growth of new blood vessels and stem leakage from existing ones. Two Phase III trials are ongoing. Data are expected in the first half of next year, and a filing is possible before year's end.

Macugen [pegaptanib]

from Pfizer/Eyetech

Macugen is like Lucentis in attempting "to inhibit VEGF-mediated vascularization within the retina leading to leaky blood vessels," Samet says. Unlike Lucentis, Macugen is an oligonucleotide molecule or aptamer. But both work to block the protein that effects blood vessel growth.

There seems to be no doubt that Macugen has broader application than the standard treatment, QLT's Visudyne (verteporfin). There also appears to be little question that it is well tolerated and safe. What remains at issue is whether it is more effective than Visudyne. Another question is its comparative convenience. Like Lucentis, Macugen requires intraocular injection. Visudyne is administered via a subcutaneous injection, then stimulated by a cold laser. Macugen has been given priority review status by regulatory authorities in the US and Canada. Approval could come soon enough for a first-quarter launch in 2005.

RotaTeq [rotavirusvaccine]

from Merck

Rotaviruses, a major cause of gastroenteritis, generate 500,000 doctor visits and 50,000 hospital stays in the United States every year, Moskowitz says. Elsewhere they are far deadlier: diarrheal infection is one of the top five causes of death worldwide. Wyeth's rotavirus vaccine, RotaShield, was withdrawn five years ago after a severe side effect (intussusception, a potentially fatal telescoping of the intestine) appeared in 20 out of 1 million US infants within one month of vaccination. Moskowitz says Wyeth's vaccine was derived from the Rhesus monkey, whereas Merck's has a bovine source. Now in a Phase III safety study of 30,000 infants, RotaTeq has shown no serious side effects to date. The company expects to file a Biologics License Application (BLA) next year.

Varivax [varicella zoster virus vaccine]

from Merck

A more potent formulation of Merck's chicken pox vaccine, Varivax, now in Phase III, could become the first product to prevent shingles, the recrudescence of the childhood ailment in adults. More than 35,000 volunteers over the age of 60—a population especially particularly vulnerable to shingles—are participating. Results thus far have been encouraging. Varivax is also being tested for postherpetic neuralgia (PHN), a condition that afflicts 20 percent of shingles sufferers. Often more painful than the original illness, PHN can persist for months or years, compared with shingles itself, which lasts a few weeks.

Zometa [zoledronic acid]

from Novartis

Zoledronic acid, a new-generation bisphosphonate that has become the standard treatment for malignant hypercalcemia, is being studied as an intravenously administered medication. Zolendronic acid addresses the structural damage wrought by RA and not just the symptoms, as many current treatments do. Studies show it reduces bone erosion in RA patients. A regulatory filing is anticipated by 2006.

Biomedical Breakthrough

CTLA4Ig [abatacept]

from Bristol-Myers Squibb

Abatacept, the first biologic discovered in-house by Bristol-Myers Squibb, is a genetically engineered fusion protein that would be the first in a new class of agents—selective T-cell costimulation modulators—for rheumatoid arthritis. Abatacept prevents the proliferation of T-cells and has been shown to work in patients who have not been helped by methotrexate or TNF antagonists. Jim Kelly, an analyst with Goldman Sachs, says it's going to be used "both when people fail with the current injectable agents and in their stead." Several Phase III trials are under way, including one testing abatacept for juvenile RA. The FDA granted abatacept fast-track status. A BLA is anticipated this year.


from Bristol-Myers Squibb/Merck

Muraglitazar is the first dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist. No other compound simultaneously stimulates both alpha and gamma PPARs. That means the drug is capable of both lipid and glucose alterations. Rauch thinks it could also be the first therapy to address metabolic syndrome, a major risk factor for cardiovascular complications reaching epidemic proportions. In one study involving 4,500 patients with Type 2 diabetes, muraglitazar significantly improved blood glucose, triglyceride, and HDL cholesterol levels. Says Kelly: "The key issue is not just to demonstrate that it raises good cholesterol but that doing so has a clinical benefit—leads to positive clinical outcomes—something that has not yet been proved." BMS and Merck plan to publish full Phase III data next year.


from GlaxoSmithKline

Nelarabine, a nucleoside analogue that kills cancer cells by accumulating in T-cells, has fast-track status for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in patients who have not responded to at least two other chemotherapy regimens. Viren Mehta, principal of New York-based Mehta Partners, is confident that nelarabine will eventually be approved to fight other forms of cancer. It may also be useful for treating other types of T-cell malignancies, such as Sézary syndrome.

Rituxan [rituximab]

from Genentech/Biogen Idec/Roche

Rituxan presents "a novel approach to treating autoimmune diseases," Gibbons says. Currently on the market for the treatment of non-Hodgkins lymphoma and other carcinomas, it works, he says, "by binding to a receptor on B-cells, effectively eliminating them." This is significant, Gibbons says, because "a lot of autoimmune diseases have been thought to be diseases of the T-cell and were treated by TNF drugs like Remicade [infliximab]. But it turns out that B-cells are also involved." So far, the data through Phase II on Rituxan look good, he says. Phase III trials have begun.

Rituxan has a few built-in marketing advantages too, Gibbons adds. "Even if it doesn't work better than existing drugs, it works differently and so may find support for being used in tandem with them. Also, people with autoimmune diseases tend to have an elevated risk of lymphoma to which Remicade and other similar drugs may possibly contribute. Even if this is not the case, however, Rituxan stands out because it is a treatment for lymphoma and so almost certainly won't worsen this risk, and may even possibly improve it—although that has not been tested."

SB 480848

from GlaxoSmithKline

SB 480848 has not yet entered Phase III and is still at least four years from approval. But Mara Goldstein nominated it because it is a lipoprotein-associated phospholipase A2 (LpPLA2) inhibitor, and elevated levels of inflammatory markers such as LpPLA2 "have been shown to indicate an increased risk of coronary artery disease," she says. In fact, they appear to do a better job of predicting stroke than cholesterol does. LpPLA2is now thought to play a critical role in transforming LDL cholesterol into plaque and triggering the inflammation that eventually produces clots. Attacking this enzyme may hinder the development of atherosclerosis.

Sutent [SU 11248]

from Pfizer

Sutent combats cancer in two ways at once. An orally administered angiogenesis inhibitor, it also acts as a multi-targeted tyrosine kinase inhibitor for solid tumors. Thus, it seems capable of not only preventing tumors from increasing their blood supply but also interfering with several of the kinase pathways essential for their survival. According to Mara Goldstein, "Data released this year show an increase in objective response rates and time to progression in patients with renal cell carcinoma or gastrointestinal stromal tumors (GIST)." What's more, Kelly says, the drug's "been shown to be effective with cases that Novartis' Gleevec [imatinib] can't handle."

Thymitaq [nolatrexed]

Eximias Pharmaceutical

Thymitaq is a novel thymidilate synthetase inhibitor that, Samet says, "does not require facilitated uptake into cells." What's more, its MOA, inhibition of DNA synthesis, "makes it potentially applicable to a wide range of tumors," and "its unique molecular structure may reduce the resistance many cytotoxic chemotherapeutics face."

Thymitaq is one of two drugs in Phase III trials for hepatocellular carcinoma (HCC), a disease closely associated with hepatitis C, which infects 4 million Americans annually. Studies show that it increases survival time in nonresectable HCC patients by up to144 percent. "Orphan disease status for this condition would provide a quick path to market," says Samet.

UK 427857

from Pfizer

Gibbons says people who are HIV- positive but don't develop AIDS have a version of the CCR-5 receptor that works to their advantage. UK 427857 "blocks those receptors so HIV can't use them to affect T-cells, stopping or slowing the progress of AIDS." Drugs with a similar method of action (MOA) are in development, including a preclinical compound from Sangamo BioSciences. But with UK 427857 moving to Phase III this quarter, it may become the first to advance that far.

Velcade [bortezomib]

rom Millennium/Johnson & Johnson (Ortho Biotech)

Velcade, recently approved for the treatment of multiple myeloma, has a "unique MOA that is potentially applicable to a wide variety of cancers," says Samet. It works by blocking proteasomes, which he describes as "the garbage dump of cells," to induce apoptosis (cell death). One problem: "The potential for fatal overdose is significant. Proteasome activity is an intracellular pathway tightly connected to protein function and viability. Nonspecific proteasome inhibition has no antidote, unlike other cytotoxic antimetabolites." Samet believes the extent to which Velcade's therapeutic index can remain high will play a big part in its success as an anticancer agent. It is currently in late-stage development for lung, prostate, renal, and colorectal tumors.

SOURCE: The R&D Insight (RDI) database, generously provided by the Adis division of Wolters Kluwer Health. NOTE: Data were not available for all products. Adis ratings assess therapeutic impact. A score of 80–100 means "potential major advance"; 60–79, "important benefits compared to existing therapies and some modest benefits"; and 45–59, "equivalent efficacy." Probability of success—defined as obtaining the anticipated approvals—and global peak sales were extracted from RDI but generated by Lehman Bros.

Related Videos
Related Content