By Jennifer Van Brunt, Editor

The FDA has already approved some very important new therapies this year – and more are on the way. For instance, physicians are now able to prescribe a vaccine for the prevention of cervical cancer, the second most common cause of death in women worldwide. The agency also broke new ground when it granted approval to not one, but two targeted cancer drugs – each of which was approved for two indications simultaneously. And adults suffering from diabetes can now use Exubera to inhale their insulin rather than continue often painful injections. As well, elderly individuals who are losing their sight to wet macular degeneration can now take Lucentis, which not only halts this process but also actually improves vision. Moreover, as you'll discover, already approved medicines such as Avastin, Humira and Remicade continue to prove their value in new disease settings, underscoring the power of today's targeted therapies, whether they are biological or chemical in nature.

This year could mark another high point in the biotech and pharmaceutical sector's impact on the practice of medicine. Already, the FDA has granted first-time approvals to nine biologics and 22 drugs – and by New Year's Eve, another three or so could be added to the list.

Many of the brand new therapies are the long-awaited fruits of cutting-edge technologies – methods that now allow researchers to devise precisely targeted small molecule drugs and monoclonal antibodies to fight cancer, inflammatory diseases, and other ailments.

New vaccines made a big splash this year, too – especially Merck & Co. Inc.'s Gardasil for preventing cervical cancer. Merck's contribution didn't end there, though: Its shingles vaccine Zostavax and Rotateq, its vaccine for gastroenteritis in infants, also won FDA approval this year. (See the tables that follow for details of first-time approvals in 2006.)

As well, already popular biological medicines for fighting arthritis and cancer continued to prove their worth in additional indications: By mid-September, Avastin, Erbitux, Humira, Remicade and Rituxan had all earned additional approvals, which we shall discuss later.

And, perhaps most dramatically, the FDA re-approved the troubled multiple sclerosis therapy Tysabri, developed by Biogen Idec Inc. and Elan Corp. plc – which this time comes with enhanced safety warnings and a risk management plan that addresses the chance of patients contracting progressive multifocal leukoencephalopathy (PML), the rare but deadly brain infection that caused the withdrawal of Tysabri from the market last year.

First prize
Of particular note, the FDA pulled a first by approving an oncology drug for two indications simultaneously. Sutent, which originated in the labs of biotech company Sugen Inc. (which was acquired by Pharmacia & Upjohn in 1999 and is now a unit of Pfizer Inc.), is a small molecule drug that inhibits multiple tyrosine kinases. In January 2006, the FDA approved Sutent for treating advanced kidney cancer and for treating gastro-intestinal stromal tumors (GIST, or stomach cancer) in patients whose disease has progressed or who are not able to tolerate Novartis AG's blockbuster Gleevec, a small molecule tyrosine kinase inhibitor that has been on the market since mid-2001.

More good news followed: In June, the agency approved a second new oncology drug for two separate indications. In this case, Bristol-Myers Squibb Co.'s Sprycel got the go-ahead for use in adults with all phases of CML and for use in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Here, too, physicians can now prescribe the small molecule drug, which also inhibits multiple tyrosine kinases, for use in patients who have become resistant to or intolerant of Gleevec.

Gleevec was the first approved oncology drug in this class of targeted compounds: It worked so well against chronic myelogenous leukemia (CML) that the FDA's initial approval came in a mere 2.5 months and that approval was based on data from three Phase II trials. (Gleevec has since been approved for use in pediatric patients with Philadelphia chromosome-positive CML, for use in patients newly diagnosed with CML, and for treating advanced GIST.)

Biotech & Biotech-related therapeutics approved in 2006

*Includes first-time approval in the U.S. for drugs, biologics and vaccines developed by biotechnology and specialty pharma companies as well as biotech-derived products developed by pharmaceutical companies (through Sept. 15, 2006. Cephalon Inc.'s Fentora, a medicine for managing breakthrough pain in cancer patients, was approved on Sept. 25, 2006 and Amgen Inc.'s colorectal cancer therapy Vectibix was approved on Sept. 27, 2006.)

Sutent and Sprycel also sped through the regulatory approval process, garnering the FDA's stamp of approval in five and six months, respectively. That speedy success highlights an important aspect of targeted drug development which is now coming to the fore: When a drug's molecular target is known, and a particular cancer develops resistance to that drug, then it should be possible to identify the mutation responsible for the resistance. (Known mechanisms of resistance to Gleevec include mutations in Bcr-Abl tyrosine kinase, the activation of alternate signaling pathways via Src kinases, and the overexpression of genes for multidrug resistance.) Once that knowledge is in hand, one can test a different compound that blocks those mutations, for instance, or binds to the mutant proteins in new ways. No more educated guesswork (well… almost none).

Other exciting therapies that received FDA approval this year include Genentech Inc.'s much heralded anti-angiogenesis monoclonal Lucentis, which is able not only to maintain but also to improve vision in patients with wet age-related macular degeneration (AMD). It took a mere six months for this product to navigate the regulatory maze.

And adults suffering from Type I or Type II diabetes finally have a new way to take their medicine: In January, the FDA approved the very first inhaleable form of recombinant insulin, developed by pharma giant Pfizer and biotech Nektar Therapeutics Inc., which supplied the powdered insulin and the inhalers. It took the agency slightly longer – 13 months – to approve this product, called Exubera, but that's still a comparatively rapid pace.

Bumper crop
At the other end of the spectrum, we find a number of new medicines that struggled for years to win the agency's seal of approval. Chief among these is Ranexa, a partial fatty acid oxidation inhibitor developed by CV Therapeutics Inc. Although Ranexa is the first new pharmaceutical approach for treating chronic angina in more than 20 years, it still took the FDA about 37 months to clear it for marketing – and even so, the drug should only be used in patients who have not achieved an adequate response with other anti-anginal drugs.

Some newly approved medicines lingered even longer in regulatory limbo: It took the FDA 47 months to approve Daytrana, a once-daily patch developed by Shire plc and Noven Pharmaceuticals Inc. for treating attention deficit hyperactivity disorder in children aged 6-12 years.

And Barrier Therapeutics Inc., a dermatology firm that was spun out of Johnson & Johnson in May 2002 with a portfolio of clinical-stage products, found that its heritage did not guarantee smooth sailing with the FDA: It took 90 months to win marketing approval for its diaper dermatitis product Vusion. On the other hand, the company's new product Xolegel, which is used to treat seborrheic dermatitis in immunocompetent individuals, received the agency's blessing in a mere 10 months.

As we mentioned earlier, companies developing hot new therapies for cancer and inflammatory diseases, especially, have continued to expand their franchises by adding new indications on a more-or-less regular basis. So far this year, the FDA has approved 25 supplemental NDAs and BLAs – including the anti-tumor necrosis factor antibody Humira. Developed by Cambridge Antibody Technology Group plc and Abbott Laboratories, Humira garnered approval in July as a therapy for ankylosing spondylitis. This marks the fifth indication for this therapy, which was first approved in December 2002 for treating rheumatoid arthritis (RA) in patients who had inadequate responses to DMARDs.

ImClone Systems Inc.'s anti-EGFr monoclonal therapy Erbitux won an additional approval in March 2006, enabling its use in head and neck cancer as well as metastatic colorectal cancer (the first approved indication).

The biologics are proving their worth, all right, and many others have already received add-on approvals this year, including:

• Aranesp: Amgen Inc.'s second-generation EPO can now be administered to cancer patients suffering from chemotherapy-induced anemia once every three weeks instead of weekly. The new dosing regimen, approved in March, is intended to ease the burden for patients and healthcare professionals.
• Avastin: Genentech won another approval for its anti-VEGF cancer therapy in June. Avastin (plus chemotherapy) can now be used in metastatic colorectal cancer patients who have received a prior therapeutic regimen (second-line therapy). It is already approved as a first-line treatment in these patients.
• Remicade: Developed by Centocor, a Johnson & Johnson company, this anti-TNF antibody was approved in May as a treatment for children with active Crohn's disease. In August, the FDA expanded Remicade's psoriatic arthritis indication to include its ability to inhibit the progression of structural damage and improve physical function in patients with this disease.
• Rituxan: This monoclonal antibody-based therapy, developed by Biogen Idec and Genentech, has garnered two additional approvals this year, both in February. Rituxan, which targets the CD20 antigen on the surface of B cells, is now approved as a first-line therapy in patients with diffuse large B-cell, CD20-positive non-Hodgkin's lymphoma. Interestingly, this successful cancer drug is also approved for treating rheumatoid arthritis in patients who have not had an adequate response to the anti-TNF therapies, a crossover indication that could open the door to new therapeutic areas.

On the vine

So, how is 2006 stacking up? Well, in 2005, the FDA granted first-time approvals to 29 new therapies -- 11 biologics and 18 drugs. That was a slight improvement over the previous two years: In 2004, the agency approved 27 new medicines (only five of which were biologics); in 2003, 25 therapies reaped first-time approvals (with eight of them classed as biologics).

If everything runs smoothly over the next few months, we could end up with about 10 new biologics and 24 new drugs in 2006 (34 all told). That's a better record than we've seen in some time, obviously, and all the more surprising because the FDA has experienced another unsettling year without a permanent director at the helm.

New products that could very well get the green light shortly include Nuvo Research Inc.'s topical non-steroidal anti-inflammatory osteoarthritis drug Pennsaid. At the end of September, the FDA approved Amgen's Vectibix (panitumumab), an anti-EGFr (epidermal growth factor receptor) monoclonal therapy for third-line treatment of metastatic colorectal cancer that it co-developed with Abgenix Inc. (which Amgen acquired in April 2006).

Moreover, Encysive Pharmaceuticals Inc.'s small molecule drug Thelin (a selective endothelin A receptor antagonist) is on the verge of receiving approval as a once-daily oral treatment for patients with pulmonary arterial hypertension. It's already been approved in the EU; U.S. approval hangs on the resolution of one outstanding item, which has not been disclosed.

Biotech & Biotech-related therapeutics approved in 2006

*Includes first-time approval in the U.S. for drugs, biologics and vaccines developed by biotechnology and specialty pharma companies as well as biotech-derived products developed by pharmaceutical companies (through Sept. 15, 2006. Cephalon Inc.'s Fentora, a medicine for managing breakthrough pain in cancer patients, was approved on Sept. 25, 2006 and Amgen Inc.'s colorectal cancer therapy Vectibix was approved on Sept. 27, 2006.)

As well, the sponsors of the increasingly popular biologic therapies keep on expanding their horizons. By the end of the year, a handful could garner additional approvals -- including Genentech's monoclonal antibody Herceptin, which is under review as an adjuvant therapy for treating patients with early-stage, HER-2 positive breast cancer. The big biotech's monoclonal therapy Avastin could also be approved as a first-line treatment for non small-cell lung cancer this year, although its approval for use as a first-line therapy for metastatic breast cancer isn't expected until sometime next year.

And Johnson & Johnson's monoclonal antibody Remicade is pending approval as a treatment for plaque psoriasis, the sixth distinct disease for which it has proven effective.

Aside from those pending approvals mentioned above, investors and patients are also eagerly awaiting the green light for Sanofi-Aventis' weight-loss drug Acomplia, a CB1 endocannabinoid receptor antagonist; Roche's anemia drug contender CERA (continuous erythropoiesis receptor activator); MedImmune Inc.'s new, refrigerator-stable formulation of its flu vaccine FluMist; and Dendreon Corp.'s prostate cancer vaccine Provenge – among others.

Of course, there are many more drugs and biologics still wending their way through the FDA's regulatory maze. As of mid-September, a total of 90 experimental therapies were under some stage of regulatory review – from newly submitted BLAs and NDAs to applications that have been tossed back and forth between the agency and the drug sponsor for years already.

Sour grapes

In part, extended review times mirror the decision by the agency – or one of its advisory committees – that the clinical data submitted in support of a BLA or NDA do not, in fact, support approval.

But we've also noticed that whenever the agency is director-less, the regulatory approval process tends to bog down as key employees stall for more time. Loathe to make important decisions, they instead delay approvals or ask for more data from sponsoring companies. Sometimes it's hard to distinguish real deficiencies from delaying tactics.

The FDA has had a permanent director for just 18 months during President Bush's tenure – and that situation throws a monkey wrench into the works. A year ago, FDA commissioner Lester Crawford (who had only been in that office a few months) quit his post in the midst of several controversies, and since then the acting commissioner slot has been filled by the head of the National Cancer Institute, Andrew von Eschenbach. Last week a Senate committee voted to make von Eschenbach the permanent commissioner, but delays are still likely as various politicians use the situation to advance their own agendas.

This year, for instance, even the almighty Genentech felt the FDA's displeasure: In September, the agency requested a substantial update on the efficacy and safety of Avastin, when used with chemotherapy, as a first-line treatment for metastatic breast cancer. According to the company's press release, "The FDA has communicated to Genentech that they now expect the information from this cooperative group trial [conducted by the Eastern Cooperative Oncology Group under a CRADA between Genentech and the NCI] to be audited and summarized in a manner typically used for a company-sponsored trial. This expectation is different from the understanding Genentech had when the sBLA was submitted [May 2006] and will require the re-collection of information from ECOG study sites." The bottom line: Genentech predicts it won't be able to re-submit its application to the FDA until mid-2007.

*Includes first-time approval in the U.S. for drugs, biologics and vaccines developed by biotechnology and specialty pharma companies as well as biotech-derived products developed by pharmaceutical companies (through Sept. 15, 2006. Cephalon Inc.'s Fentora, a medicine for managing breakthrough pain in cancer patients, was approved on Sept. 25, 2006 and Amgen Inc.'s colorectal cancer therapy Vectibix was approved on Sept. 27, 2006.)

As well, there seems to be a trend at the FDA to require that when an experimental drug is tested against the standard of care, it is shown to be superior to that standard rather than non-inferior. That means a big strategic shift for companies following this path. Recently, Oscient Pharmaceuticals Inc.'s supplemental NDA for its anti-infective drug Factive was subjected to this test. In mid-September, FDA's Anti-Infective Drugs Advisory Committee voted that the data from the non-inferiority trials of Factive as a five-day treatment for acute bacterial sinusitis were not sufficient to demonstrate efficacy and that they did not support the approval of this drug in this indication. Reportedly, the committee's chairman (as well as other reviewers and consumer group representatives) called for a superiority trial to demonstrate Factive's benefit in this disease setting.

Bad apples

Meanwhile, many experimental therapies fail in mid-stream – and smart sponsors usually heed the warning and drop development of the product rather than try and push it through despite the odds. Examples abound, but we'll cite a few of the more recent events.

For instance, when an independent data monitoring committee (DMC) recommended in August that Inspire Pharmaceuticals Inc. terminate its Phase II trial on INS50589 Antiplatelet for use in cardiopulmonary bypass procedures, the company quickly complied. The DMC's planned interim analysis picked up a range of bleeding complications in the enrolled patients, though no deaths had been reported. Inspire is conducting its own analysis of the data, but it's not likely it will take up the trials again.

Over the summer, SGX Pharmaceuticals Inc. stopped a Phase II/III trial of Troxatyl when its DMC determined that the study response rates were unlikely to provide evidence of a treatment benefit for Troxatyl, a cytidine analog, as a third-line therapy for patients with acute myelogenous leukemia. The San Diego firm is analyzing the data, and may pursue the drug's development in other indications in the future.

In a dramatic announcement in mid-July, Valentis Inc. said that it is considering selling the company after its lead drug failed in a mid-stage trial. VLTS 934, a non-ionic copolymer which was being tested as a treatment for peripheral arterial disease, did not show a statistically significant benefit over placebo in a Phase IIb trial. Within a month, the Burlingame, CA firm had reduced its staff by 60 percent and identified a buyer for certain biomanufacturing rights and intellectual property.

In a similar move, Therion Biologics Corp. announced in late June that its cancer vaccine PANVAC-VF failed to meet its primary efficacy endpoint of improving overall survival in a Phase III trial of patients with advanced pancreatic cancer. The privately held company not only dropped its plans to file a BLA for this product, but also announced that its investors were going to sell the company. And so, another cancer vaccine – as well as another cancer vaccine firm -- bites the dust.

It seems a shame for any company to be so beholden to its lead product that a failure in the clinic precipitates a failure for the business per se – but every year a few biotech firms find themselves trapped in this insoluble predicament.

Importantly, many technologies, scientific know-how and even product candidates manage to avoid total death in this situation, as other struggling companies reach out to acquire abruptly discarded assets they hope to turn into future products – and profits. The short history of the biotech industry reveals that this approach can work – but it's still not a sure bet.

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