How Does Your Pipeline Grow?

08 November 2004 00:01  [Source: ICB Americas]

Pharma industry executives share their views on their company’s most promising candidates. Patricia Van Arnum reports.

As 2005 nears to a close, big pharma is once again under scrutiny for a lack of product innovation. Through the first nine months of 2004, only 16 new molecular entities (NMEs) were approved by the Food and Drug Administration (FDA), with less than half of them coming from big pharma. However, drug industry executives point to positive signs from their late-stage pipelines.

Of the 16 approved NMEs, only six came from big pharma: Boehringer Ingel-heim’s Spiriva (tiotropium), Eli Lilly’s Alimta (pemetrexed), Eli Lilly’s Cymbalta (duloxetine), Aventis’ Ketek (telithromycin), Aventis’ Apidra (insulin glulisine) and Amgen’s Sensipar (cinacalet).

As they did last year, most drug approvals came from smaller drug companies. They include ChiRhoClin’s human secretin, Bertek Pharmaceuticals’ Apokyn (apomorphine), Presutti Laboratories’ Tindamax (tinidazole), Pharmion’s Vidaza (azacitidine), Salix Pharmaceuticals’ Xi-faxan (rifaximin), Indevus’s Sanctura (trospium), Lipha’s Campral (acamprosate), Nutritional Restart’s NutreStore (L-glutamine), and two products by Pharma Hameln—pentetate calcium trisodium and pentetate zinc trisodium.

Two big name biotech companies—Genentech and ImClone Systems—secured biologic license approvals (BLAs) for Avastin (bevacizumab) and Erbitux (cetuximab), respectively. The third BLA came from Palatin Technologies’ NeutroSpec (technetium 99m Tc fanolesomab).

Pfizer Advances Pipeline

Although Pfizer Inc., the largest glo-bal pharmaceutical company, has not had any NMEs approved thus far in 2004, the drug giant continues to benefit from strong sales. The company’s five top-selling drugs—Lipitor (atorvastatin), Nor-vasc (amlodipine), Zoloft (sertraline), Celebrex (celecoxib) and Neurontin (gabapentin)—accounted for slightly more than half of Pfizer’s human health pharmaceutical sales through the first nine months of 2004, with each delivering sales of at least $2 billion. Meanwhile, Viagra (sildenafil citrate) and Zithromax (azithromycin) each have passed the $1 billion sales mark this year, and Zyrtec (cetirizine) is nearing the $1 billion mark with US sales of $938 million through the first nine months.

Pfizer says it remains on track. “Pfizer’s new product pipeline continues to grow, and our late-stage candidates are progressing well,” says John LaMattina, president of Pfizer Global Research and Development. “We remain on target to submit 20 major US regulatory filings in a five-year period ending in 2006,” he says.

Some important NME developments for Pfizer include a new drug application (NDA) to the FDA for lasofoxifene, a selective estrogen modulator for preventing postmenopausal osteoporosis in August. Pfizer also received priority re-view for Macugen (pegaptanib), a new class of drug for treating neovascular age-related macular degeneration, which the company is developing with Eyetech Pharmaceuticals. The drug garnered a favorable review by an FDA panel in August, and it has received priority review status by the FDA. In September, the European Union accepted the regulatory filing for Macugen. Also, Pfizer’s UK-427-857, a CCR-5 inhibitor for treating HIV diseases, has completed Phase 2 testing and is expected to progress to Phase 3 during this quarter.

Other key drug candidates continuing to advance in late-stage development or under regulatory review from Pfizer include:

• indiplon, with an immediate-release formulation for treating insomnia, in development with Neurocrine Biosciences Inc.

• parecoxib, the injectable prodrug of valdecoxib, for treating acute pain

• Daxas (roflumilast), in co-development with Altana Pharma for treating chronic obstructive pulmonary disease and asthma, now under regulatory review in the European Union;

• Exubera, an inhalable form of insulin for Type 1 and Type 2 diabetes under co-development, co-manufacture, and co-marketing with Sanofi-Aventis, with the participation of Nektar Therapeutics, now under regulatory review in the European Union;

• Sutent, or SU-11248, an angiogenesis inhibitor for treating gastrointestinal stromal tumors, renal carcinoma, and other cancers;

• edotecarin, for colorectal cancer and glioma;

• apravirine, a non-nucleotide reverse transcriptase inhibitor for treatment of HIV;

• varenicline, a mechanistically novel treatment for smoking cessation;

• torcetrapib/Lipitor, for treating heart disease;

• asenapine, for schizophrenia and bipolar disorder, under co-development with Akzo Nobel’s Organon healthcare unit; and

• Zithromax-chloroquine, for treatment of malaria.

Pfizer is also moving along with regulatory filings. It submitted a supplemental NDA in August to incorporate the cardiac-risk reduction results from a recent trial to update the labeling of Norvasc (amlodipine), a calcium channel blocker for treating hypertension, to include the reduction of cardiovascular risk. In August, the company received FDA approval for a new indication for Geodon (ziprasidone) for treating bipolar acute mania and mixed episodes. It also received a successful mutual recognition outcome in the European Union for Inspra (eplerenone), for treating post-MI heart failure.

However, the company received mixed news on Lyrica (pregabalin), a next generation drug to address increasing generic competition for Neurontin (gabapentin). Lyrica received approvable status from the FDA for treating neuropathic pain associated with diabetic neuropathy and herpes zoster, and use as an adjunctive therapy for treating partial seizures, but it received a nonapprovable letter from the FDA for treating generalized anxiety order.

The company also has to deal with the aftermath of the withdrawal of Merck & Company Inc.’s COX-2 inhibitor Vioxx (rofecoxib), which Merck volun-tarily withdrew from the market in September on safety concerns of an in-creased risk of cardiovascular events (including heart attack and stroke) in patients taking the drug.

Pfizer has two COX-2 inhibitors on the market—Celebrex and Bextra (valdecoxib). Last month the company announced it will launch a major clinical trial for Celebrex to eliminate concerns over cardiovascular risk with the product.

The new trial, which is expected to begin in early 2005, will assess the safety of Celebrex when used by osteoarthritis patients at high risk for cardiovascular disease. Pfizer intends to enroll over 4,000 osteoarthritis patients who have had a recent heart attack.

GSK Looks to Overcome Losses To Generic Competition

For GlaxoSmithKline (GSK), the key issue is advancing its pipeline to absorb losses stemming from increased generic competition for its antidepressants Paxil (paroxetine) and Wellbutrin (bupropion). The company posted third quarter sales of £15.0 billion ($27.6 billion) for the first nine months of 2004, a 6 percent decline in local currencies. For the third quarter, excluding the sales of these products, its sales increased 12 percent in the US and 8 percent globally.

“These results confirm GSK’s success in managing to absorb over £1.2 billion of lost sales to generic Paxil IR and Wellburtin SR during the first nine months of the year and keeping overall pharmaceutical sales level,” said GSK CEO JP Garnier, late last month. “This is being driven by the strong performance of our key product growth drivers including Avandia for diabetes and Advair for asthma/COPD, both of which continue to grow very strongly in the US and Europe. As the the impact from Paxil generics now diminishes, we look forward to improved earnings growth in the fourth quarter and 2005.”

The GSK CEO points to several key products in late stage development as potential growth drivers for the company. “Several key NCEs [new chemical entities]—such as lapatinib for cancer, Allermist (698) for rhinitis and Cervarix, a vaccine for cervical cancer—are now in Phase III clinical development and a wave of other exciting compounds for diseases such as pain, HIV and blood disorders are making good process,” says Mr. Garnier.

GSK expects several near-term pro-duct launches. Vesicare (solifenacin suc-cinate) for treating overactive bladder, which GSK will co-promote with Yamanouchi Pharma America, is ex-pected to be approved later this year. An FDA approvable letter was received for diabetes product Avandaryl, a once-daily combination of Avandia and Aven-tis’s Amaryl. Final approval is expect-ed before the end of the year. Requip (ropinirole) is expected to be approved by the FDA for treating restless leg syndrome in the first half of 2005. Boniva (ibandronale), an oral bisphosphonate for treating osteoporosis with a once-monthly dosing regimen, was filed with the FDA in May, and approval is expected in the first half of 2005. Boniva is being co-developed by GSK and Roche.

And Entereg (alvimopan), under US regulatory review, is expected to be approved in the first half of 2005. The drug is already approved in Europe for treating post operative ileus. GSK and Adolor are collaborating on the worldwide development and commercialization of Entereg.

As these drugs near commercialization, GSK expects to make some key filings in the 2004/2005 time frame. It expects to file an NDA for its anticancer treatment lapatinib, a dual kinase inhibitor, in 2005. Trexima (umatriptan and naproxen sodium), which is used to treat migraines, is scheduled to be filed in 2005. Nelarabine, used for treating childhood T-cell leukemia, is scheduled for filing this quarter.

In other NCEs, GSK says it will evaluate higher doses for its antidepressant 353162, a noradrenaline/dopamine reuptake inhibitor, before moving the drug to Phase III trials and has rescheduled advancing the drug into Phase III trials to 2007. It will also evaluate the drug for treating obesity. The company will meet with regulatory authorities regarding its COX-2 inhibitor 406381 before move forwarding with clinical development in light of the recent issues with Merck’s Vioxx.

GSK is also developing what would be the first oral product for treating thrombocytopenia (low blood-platelet levels brought about by chemotherapy, chronic liver disease and other conditions). That drug is about to enter Phase II studies in a variety of indications, and filing has been brought forward from 2007 to 2006.

GSK’s oral CCR5 inhibitor for the treating of HIV, now in Phase II trials, is expected to be filed in 2007.

Merck Is Regrouping

The key issue for Merck is how to regroup following the voluntary withdrawal of its COX-2 inhibitor Vioxx (rofexoxib) in September.

“The voluntary withdrawal of Vioxx, with sales of $2.5 billion last year, represents a significant financial loss for us, but clearly was the right course of action,” said Merck Chairman, president and CEO Raymond V. Gilmartin, late last month. “We look to the strong launch of Vytorin and the five Phase III compounds that we expect to file or launch by the end of 2006 to contribute to the company’s future growth,” says Mr. Gilmartin.

Merck received approval for Vytorin (ezetimibe/simvastatin), its combination therapy for treating high-LDL choles-terol in July. The drug was developed by Merck/Schering Plough Pharmaceu-ticals, a joint venture between Merck and Schering Plough, and consists of the active pharmaceuticals found in Merck’s Zocor (simvastatin) and Schering-Plough’s Zetia (ezetimibe).

Merck hopes to recover with its second-generation drug Arcoxia (etoricoxib). Late last month, the company received an approvable letter from the FDA for treating arthritis and pain. The drug is already approved in Europe, Latin America and Asia.

Merck also plans to file an NDA with the FDA this quarter for muraglitazar, a PPAR agonist for treating Type II diabetes being developed with Bristol-Myers Squibb.

Meanwhile, Merck continues to look to build its pipeline through alliances. In September, it signed a pact (up to $210 million) with Nastech for developing and commercializing Peptide YY3-36 nasal spray, a Phase I product for treating obesity. It also formed a pact with Kyorin Pharmaceutical Co. Ltd. to develop drugs to treat infectious diseases.

In August, Merck agreed to partner with DOV Pharmaceutical Inc. in a deal for developing and commer-cializing triple uptake inhibitors being developed for depression and related disorders. The deal includes a $35 million up-front licensing payment, milestone payments up to $300 million, and an additional $120 million for certain sales objectives.

Other research deals by Merck include one with Pierre Fabre Medica-ments for F50035, an antibody targeted against the insulin-like growth factor (GF-1) receptor. The drug is targeted for treating cancer and is in pre-clinical development. Merck also signed deals this year with Sunesis Pharmaceutical for developing oral drugs to treat viral infections and another pact for developing drugs to treat Alzheimer’s disease. And it signed a new, multi-year deal with Alnylam Pharmaceuticals to develop and commercialize RNAi therapeutics for ocular diseases.

Other Pharma Majors Ramp Up

Bristol-Myers Squibb Company (BMS), which gained approval for its monoclonal antibody Erbitux (cetuximab) for colorectal cancer in combination with irinotecan earlier this year, is looking to expand treatment to other cancers, such as non-small cell lung cancer. BMS also submitted a NDA to the FDA for entecavir, to treat hepatitis B.

Other late-stage BMS compounds include: Abatacept to treat arthritis; DDP4 inhibitor for diabetes; edifoligide for preventing vein-graft failure; ixabepilone and vinflunine, both for treating cancer; LEA 29Y, to prevent solid organ transplant rejection and razaxaban, a factor Xa inhibitor for treating venous thrombosis.

On the alliance front, BMS joined forces with Solvay for developing SLV 319 (an anti-obesity drug) and with Merck and Gilead Sciences for a combination therapy of three HIV drugs—Merck’s Stocrin (efavirenz) and Gilead’s Viread (tenofovir) and Emtriva (emtricitabine).

For its part, AstraZeneca received a setback when the FDA did not grant approval for Exanta (ximelagatran) for stroke prevention.

However, AstraZeneca chief executive Tom McKillop says the company is “well positioned to overcome the recent disappointment of Exanta and to meet the wider challenges facing the industry.”

He points to the potential of the company’s pipeline, which includes 50 percent more drug candidates in Phase I and Phase II trials this year compared to last.

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