From Promise to Payoff - Pharmaceutical Executive


From Promise to Payoff

Pharmaceutical Executive


A novel approach shakes up the established order

When patients come to even after a minor surgery, their safety and comfort depend in part on the timely reversal of the effects of muscle relaxants used in anesthesia. Indeed they can't check out of the hospital until the muscle relaxants administered by the anesthesiologist wear off. Several issues come into play, from a patient's discomfort or fear at feeling paralysis to the hospital down time involved. Patients want to feel better and leave. Hospitals need their beds.

Sugammedex (Bridion) is a selective relaxant binding agent developed by Organon Biosciences to reverse the neuromuscular blockade that follows surgery done under muscle relaxants such as rocuronium bromide and vecuronium bromide. (Organon was acquired by Schering-Plough in 2007.) Current agents that reverse the effects of muscle relaxants include neostigmine, which is eight or nine times slower than suggamedex, according to its maker, Merck/Schering. "It's the first new drug for 30 years and anesthesiologists are excited for it," says Deutsche Bank's Barbara Ryan.


Pfizer may have a big blockbuster at last

A potential treatment for rheumatoid arthritis (RA), Pfizer's oral immunosuppressant, CP 690550, goes to the root of the disease, according to Deutsch Bank's Barbara Ryan. This small-molecule compound would be cheaper than many competing biological therapies as well as an advance in convenience over anti-RA injectibles, such as tumor-necrosis-factor inhibitors.

CP 690550 is a Janus kinase 3, or JAK-3, inhibitor—and the first to make it into late-stage development. JAK-3 is an enzyme that governs the passage of cytokines, cellular proteins released to signal other cells, from the outer wall of the receiving cell across the cell membrane. This pathway plays a role in governing immune responses and inflammation, which are important elements of flare-ups in RA, MS, and other immune disorders.

A Phase III trial, due to be complete in 2012, is enrolling 750 patients with moderate to severe RA. They will add two different doses of CP690550 to their weekly methotrexate therapy (the standard of care) vs. a methotrexate-only group, according to WoltersKluwer.

In a smaller study in Japan, researchers found that at least half of patients receiving a variety of doses of CP 690550 with methotrexate reached the endpoint of ACR 20 (a 20 percent improvement in tender and swollen joint counts) at week 12—a statistically significant faster rate than patients on only methotrexate, according to Pfizer. Efficacy was better at higher doses. "If the safety and efficacy hold up," says Ryan, "it could certainly be worth billions of dollars, given the size of the current market."

Canakinumab, an injectible monoclonal antibody that Novartis launched as Ilaris this year for cryopyrin associated periodic syndromes (CAPS)—a rare form of chronic recurring inflammation—is also being tested in Phase III against rheumatoid arthritis and in Phase II against gout. Patients with early RA receive IV canakinumab or placebo plus oral methotrexate. "The drug was launched for a minor indication," says Miller Tabak's Funtleyder. "It would have a big impact if it is approved for RA or gout."

Canakinumab looks to be more effective against acute flare-ups of gout than triamcinolone acetonide, a commonly used antihistamine. In a Phase II trial with 191 patients contra-indicated or refractory to NSAIDs, pain relief came in one day rather than two, and the intensity of pain declined more under canakinumab, according to WoltersKluwer. More important, the probability of recurrent gout flare-ups was 3.7 percent with canakinumab vs. 45 percent with the antihistamine.


A new class for an exploding epidemic—and a Januvia rival, finally!

In a space crowded with "me-too" products aiming at a rapidly expanding patient population, one new class of drugs stands out. The SGLT2 inhibitor dapagliflozin is a joint project by Bristol-Myers Squibb and AstraZeneca, with BMS controlling the US rights and AZ the rest. An oral drug, dapagliflozin tackles two problems plaguing insulin-dependent patients: weight gain and hypoglycemia.

"It's a good add-on option for patients whose condition is not being controlled with current therapies," says Christine Helliwell, an analyst at Decision Resources. "We think this is going to be the next blockbuster diabetes class."

The sodium glucose transporter protein (SGLT2) governs glucose reabsorption in the kidneys, helping retain glucose for the body's energy requirements. For patients with diabetes, retaining glucose via the SGLT2 pathway contributes to high blood sugar levels; blocking SGLT2 leads to the excretion of glucose in the urine, preventing it from being turned into fat by insulin. Although there are side effect concerns, including urinary tract and genital infection, preliminary Phase III data released in October remain encouraging, Helliwell says. The adverse events were mild to moderate and did not result in patients quitting the study, according to WoltersKluwer.

Nine different companies have SGLT2 inhibitors in Phase I or II, but only Sanofi-Aventis and Boehringer Ingelheim are likely to have the sales force to market a drug of this size without a partner. The rest are small pharmas or biotechs; they are looking at in-licensing or even takeovers by Big Pharmas, should dapagliflozin do well.

But new diabetes agents face an uphill battle at FDA—especially regarding cardiovascular signals—following questions raised about safety standards sparked in 2007 by the controversy over heart attack risk associated with GSK's Avandia. "I think the evolution of new agents has been fairly clear over the last decade, but the bar going forward is a pole vault," Barclays Capital analyst Tony Butler told Reuters.

Meanwhile, Merck's first-in-class DPP-4 inhibitor, sitagliptin (Januvia), is about to get some competition after taking the Type II diabetes market by storm over the past three years. The WoltersKluwer site lists nearly two dozen compounds in this class that are making their way through the pipeline. The drugs inhibit the enzyme dipeptidyl peptidase 4 (DPP-4), which breaks down the gastrointestinal hormones released in response to a meal, which in turn stimulates the secretion of insulin and suppresses the release of glucagon, the hormone that tells the liver to convert glycogen to glucose. Blocking this enzyme prevents the body from overcompensating in either direction by overproducing insulin or glucagon.

The next DPP-4 inhibitor to reach the US market, according to Helliwell, will be saxagliptin, which Bristol-Myers Squibb plans to launch under the name Onglyza late in 2010, following its FDA approval in July.

"It looks clinically very similar to Januvia," Helliwell says, "So it really is going to come down to marketing." Given the expected strong marketing push behind the drug, and the trailblazing effects of Januvia, Helliwell forecasts another blockbuster.

Finally, Helliwell likes the chances of Vivus' Qnexa, a novel phentermine/topiramate combination (both drugs are already on the market). "It's really the only drug that can hit the benchmark of 10 percent weight loss in a large portion of patients," Helliwell says. "For diabetes, it also significantly reduces the HbA1C, so you can see why physicians would be interested in prescribing a drug like that for patients for whom serious weight loss would be a significant benefit."


Two new candidates against the growing threat of MRSA

Any new drug to treat MRSA (methicillin-resistant Staphylococcus aureus) must be measured against vancomycin, a cheap, effective drug that works against the scourge of hospitals and, more recently, the general community. No matter how often a MRSA strain mutates, it has failed to become resistant to the 50-year-old workhorse, vancomycin.

Despite success in head-to-head trials against vancomycin, Pfizer withdrew its NDA and its European MAA for dalbavancin last year. Discussions with regulators convinced Pfizer to put its new glycopeptide antibiotic through an additional Phase III trial for complex, MRSA-related skin infections. The drug remains a strong candidate, however, not least because its once-a-week IV dosing is a significant promoter of patient compliance.

Ceftaroline fosamil, by Takeda and Forest Labs, promises to kill not only gram-positive bacteria like MRSA but gram-negative organisms as well. Formulated as a pro-drug to increase its water solubility, the new compound is a cephalosporin, a family of drugs including penicillin that kill bacteria by interfering with cell wall synthesis. Doctors have trusted this family of drugs for decades, but until recently none had been found that were effective against MRSA.


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