Signals

The FDA outdid itself last year, granting first-time approvals to 43 new biotech-derived medicines and 36 supplemental indications for drugs and biologics developed by specialty and big pharma companies as well as biotech firms. Some of those newly approved therapies represent significant breakthroughs, too. For instance, adults suffering from diabetes no longer have to submit themselves to painful injections thanks to Pfizer’s Exubera, an inhaled powder formulation of recombinant insulin. As well, for the first time in history, women and girls have access to a vaccine, Merck’s Gardasil, that’s 100 percent effective in preventing cervical cancer. Elderly patients suffering from wet age-related macular degeneration no longer have to fear blindness, now that Genentech’s Lucentis is on the market. Importantly, this therapy not only halts disease progression but also improves vision – an unheard-of benefit ‘til now. Indeed, 2006 was a year full of “firsts” for the FDA – including its approval of the recombinant human growth hormone Omnitrope, considered by many to be the very first bio-generic to pass muster in the U.S.

By Jennifer Van Brunt

Biotechnology and specialty pharma companies were spectacularly successful in their bids to gain regulatory approval for new drugs and biologics in 2006. And the major pharmaceutical houses, most of which are now vested in targeted therapies (small molecule drugs as well as monoclonal antibodies), reaped substantial rewards for new biotech-derived medicines as well.

Indeed, the FDA granted first-time approvals to 31 new drugs and 12 new biologics in 2006 (43 in all), easily topping earlier records. (The tables below provide details on these medicines.) In 2005, for instance, the agency gave the nod to 29 new therapies – 11 biologics and 18 drugs. In 2004, 27 new medicines (only five of which were biologics) won FDA’s stamp of approval, and in 2003, 25 therapies won first-time approvals (with eight of them classed as biologics).

Many of 2006’s first-time approvals went to eagerly anticipated therapies that epitomize the power of cutting-edge drug discovery and development technologies. Chief among those is Exubera, a rapid-acting recombinant human insulin (developed by Pfizer Inc. and Nektar Therapeutics Inc.) prescribed for treating Types I and II diabetes in adults. Doesn’t sound very special, does it? Well, the biological component may be common, but its means of delivery is totally new. For the first time, diabetics can inhale their medicine rather than inject it day after day.

Analysts and physicians alike were pleased in June when the FDA approved Genentech Inc.’s anti-angiogenesis monoclonal antibody Lucentis for treating wet age-related macular degeneration (AMD). Importantly, this biologic is not only able to maintain vision in AMD patients but it also improves vision – a huge advantage over earlier products, including the anti-VEGF inhibitor Macugen, which was approved in December 2004 and is marketed by Pfizer and OSI Pharmaceuticals Inc. However, Genentech’s cancer therapy Avastin is essentially identical to Lucentis, and costs considerably less when used for AMD. Doctors are taking advantage of this price differential, too, creating a sticky situation in which two of Genentech’s therapies are pitted against each other.

New Milestones

We witnessed a number of significant regulatory events in 2006. For one, the troubled multiple sclerosis therapy Tysabri, a humanized monoclonal antibody developed by Biogen Idec Inc. and Elan Corp. plc, is back on the market. The product, which inhibits the adhesion molecule alpha-4-beta-1 integrin, was re-approved in June but now 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 in February 2005, a mere two months after it garnered FDA’s approval. This re-approval was a bold step for the FDA, coming as it did in the midst of a drug-safety “crisis” (including for Vioxx and Iressa) that inflamed legislators on Capitol Hill and landed the FDA in the hot seat.

Another milestone in 2006 centered on Amgen Inc.’s new cancer therapy Vectibix. Approved in September for treating epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer in patients who have failed standard chemotherapy, Vectibix is the first fully human antibody approved in this indication as well as the first to significantly improve progression-free survival.

Biotech And 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.


But the notable event actually concerns the simultaneous approval of a diagnostic test, Dako A/S’ EGFR pharmDx, which can be used to assess patient eligibility for treatment with Vectibix. In fact, patients enrolled in Vectibix clinical studies were tested for immunohistochemical evidence of EGFR expression with this assay. As well, Dako’s EGFR pharmDx assay was approved in 2004 to aid in identifying colorectal cancer patients eligible for treatment with ImClone Systems Inc.’s Erbitux (an anti-EGFR chimeric antibody cleared for use in these patients in February 2004). It was also used in clinical trials of AstraZeneca plc’s cancer drug Iressa. Personalized medicine has been slow to catch on, but Dako’s assays give a big boost to the practice of matching patient and drug.

Broad Horizons

Biologic therapies for treating cancer and inflammatory diseases, especially, have come into their own in the last decade or so – largely because sponsoring companies have continued to expand product franchises by adding new indications on a more-or-less regular basis.

In 2006, the FDA approved 36 supplemental NDAs and BLAs – including for 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 and in November as a therapy capable of inhibiting structural joint damage and improving physical function in patients with psoriatic arthritis.

And in late February 2007, Humira gained approval for treating moderate-to-severe Crohn’s disease – the seventh indication for this therapy, which was first approved in December 2002 for treating rheumatoid arthritis (RA) in patients who had inadequate responses to DMARDs. Patients taking Humira will have an easier time of it, too, as a delivery device for self-administration of the injected biologic – Humira Pen – was approved for use in June 2006.

ImClone Systems’ 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, garnered in February 2004).

Indeed, add-on approvals for biologics far exceeded those granted to drugs in 2006. Other biologics that tacked on extra indications last year include (but are not limited to):

Aranesp: Amgen’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. So, too, will the Aranesp prefilled autoinjector, which was launched in September 2006.

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. And Avastin is now approved for use in lung cancer, too: In October 2006, the FDA approved its use in combination with platinum-based chemotherapy as a first-line treatment for advanced non-squamous non-small cell lung cancer.

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. And in September, Remicade was approved for treating chronic severe plaque psoriasis.

Rituxan: This monoclonal antibody-based therapy, developed by Biogen Idec and Genentech, garnered four additional approvals last year, two in February and two in September. 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 (NHL). It can also be used as a first-line therapy in treatment-naïve NHL patients and as a follow-on to chemotherapy in NHL patients with stable disease as well as those who responded to the chemotherapy. 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.

Herceptin: Genentech’s popular breast cancer therapy was approved in November 2006 for use with standard adjuvant therapy in patients with early-stage, HER-2 positive breast cancer. The humanized monoclonal antibody garnered its first FDA approval in September 1998 to treat HER-2 over-expressing metastatic breast cancer. It can be used with chemotherapy or as a stand-alone therapy.

Betaseron: Originally marketed by Schering AG (which has merged with Bayer to form Bayer Schering Pharma AG) and developer Chiron Corp. (which has since been acquired by Novartis AG), this recombinant beta-interferon garnered its first FDA approval as a therapy for multiple sclerosis in July 1993. In 2003, the FDA approved expanded labeling that allows the product’s use to reduce the frequency of clinical exacerbations in patients with relapsing MS; it also approved a prefilled diluent syringe, making it easier for patients to prepare their medication. And in October 2006, Betaseron’s label was expanded to include its use in patients whose first clinical episode is suggestive of multiple sclerosis.

Small Molecules Shine

Although fewer drugs than biologics per se garnered additional approvals in 2006 (14 vs. 22), some of these added significant new therapeutic indications, including:

Byetta: Developed by Amylin Pharmaceuticals Inc. and Eli Lilly and Co., this synthetic peptide won its second approval in December – as an add-on therapy to thiazolidinediones in patients with Type II diabetes who are not achieving acceptable blood sugar control. Its first approval, in April 2005, was also for use as an adjunctive therapy, this time to improve blood

sugar control in patients with Type II diabetes who have not achieved adequate control on metformin and/or a sulfonylurea.

Cubicin: Cubist Pharmaceuticals Inc.’s injectable antibiotic Cubicin (daptomycin) won approval in May as a once-daily therapy for Staphylococcus aureus bloodstream infections, including right-sided endocarditis. The drug received its first approval in September 2003 as a once-daily treatment for complicated skin and skin structure infections caused by Gram-positive organisms.

Revlimid: Celgene Corp.’s thalidomide analog Revlimid is rapidly gaining momentum. The drug garnered its first FDA approval – for treating patients with transfusion-dependent anemia due to myelodysplastic syndrome (MDS) associated with a deletion 5q cytogenetic abnormality -- in the waning days of 2005. In June 2006, Revlimid received its second approval – for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. It’s also being tested in other hematological malignancies.

Thalomid: In May 2006, Celgene’s other thalidomide-based drug Thalomid also garnered approval for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. It was first approved in July 1998 for treating a leprosy-related condition called erythema nodosum leprosum (ENL). But since multiple myeloma is the second most common blood cancer in the U.S., sales of Revlimid and Thalomid are destined to break the billion-dollar barrier in short order. (Sales of the two products in 2006 amounted to $754 million.)

Velcade: Millennium Pharmaceuticals Inc.’s small molecule proteasome inhibitor won its second approval in December, and is now indicated for treating patients with mantle cell lymphoma (an aggressive form of NHL) who have received at least one prior therapy. The drug was first approved in May 2003 for treating relapsed and refractory multiple myeloma. Interestingly, both approvals were issued on the basis of Phase II clinical data.

Gleevec: Novartis’ blockbuster cancer therapy Gleevec continues to garner new approvals. Initially approved in May 2001 for treating patients with advanced stages of chronic myeloid leukemia (CML), Gleevec has since won U.S. approval for use in all stages of CML and gastrointestinal stromal tumors. In October 2006, the rationally designed tyrosine kinase inhibitor won FDA’s simultaneous blessing for five rare, life-threatening disorders, including the solid tumor cancer dermatofibrosarcoma protuberans and four blood diseases (myelodysplastic/myeloproliferative disease and aggressive systemic mastocytosis, among others). According to Novartis, the October approval marked the first time that a regulatory authority has ever simultaneously approved one targeted medicine for so many disorders.

That may be true, but the multiple Gleevec approvals came on the heels of two other ground-breaking moves by the FDA: In January 2006, the agency 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) is a small molecule drug that inhibits multiple tyrosine kinases. The FDA approved Sutent for treating advanced kidney cancer and for treating gastrointestinal stromal tumors (GIST, or stomach cancer) in patients whose disease has progressed or who are not able to tolerate Gleevec.

Biotech And 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.


The FDA repeated this performance in June, when it 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 in 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.

Fighting Infection

There was lots of activity on the antiviral front, too – especially where it concerns vaccines. Pharma heavyweight Merck & Co. Inc. took center stage here: In 2006, it garnered FDA approval for not one but three vaccines. Gardasil grabbed headlines when it was approved in June for preventing human papillomavirus-caused cervical cancer and genital warts. The FDA approved Gardasil’s use in girls and women aged 9 to 26 years, and the Centers for Disease Control and Prevention quickly recommended a similar age group, emphasizing that girls 11-12 years of age should routinely receive the vaccine.

Needless to say, we have witnessed numerous debates on whether these vaccinations against a sexually transmitted virus should be mandated by law, and to whom they should actually be given. Religious groups and parental organizations have been especially vocal, and in late February 2007 the intense publicity led Merck to end its lobbying of state legislatures to require mandatory inoculation of schoolgirls. But the pharma is still promoting use of the vaccine through education efforts.

Merck also garnered FDA approval in May for Zostavax, its vaccine for preventing shingles (herpes zoster) in individuals 60 years of age and older, and in February for Rotateq, a vaccine intended to prevent rotavirus-caused gastroenteritis in young infants.

Biotech And 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.

GlaxoSmithKline plc’s new flu vaccine FluLaval (developed by Canadian firm ID Biomedical Corp., which GSK acquired in December 2005) was approved in time for last year’s flu season: The FDA cleared the preventive vaccine in October for immunizing adults 18 years of age and older.

A number of antiviral drugs got the nod, too – including Novartis’ Famvir: In July it was approved as a single-day treatment for recurrent genital herpes or recurrent cold sores in immunocompetent patients. Famvir was already approved for treating recurrent herpes infections in HIV-infected patients and for treating acute shingles.

Other antivirals approved in 2006 included Atripla, HepaGam, Prezista, and Tyseka. These drugs and others winning first-time approvals are detailed in the tables in this article.

Biotech And 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.


And, lest we forget, the FDA broke new ground in one other important arena in May 2006 when it approved Sandoz’ Omnitrope, a recombinant human growth hormone that many consider to be the very first U.S.-approved bio-generic (although the agency calls it a follow-on protein product). This distinction is not merely a matter of semantics, either, and raises issues that will be subjected to considerable debate in the months to come. (For details, see the Signals articles, “The Bio-Generic Regulatory Debate” and “Gearing Up For Bio-Generics.” Omnitrope’s approval is not included in the tables in this article.)

Waiting In Line

While Omnitrope was the first approved bio-generic, several more have been waiting for FDA action for nearly as long (Sandoz submitted the ANDA for Omnitrope in July 2003). Nastech Pharmaceutical Company Inc., for one, has developed a so-called generic calcitonin-salmon nasal spray for osteoporosis, which was specifically developed to be similar to Novartis’ branded product Miacalcin. The company submitted an abbreviated NDA to the FDA’s Office of Generic Drugs in December 2003. Despite a citizen’s petition in September 2005 asking that the FDA not approve the application, the product is still under review. In July 2006, the agency issued an approvable letter for the nasal spray but worried that the calcitonin itself might interact with chlorobutanol, the preservative used in the product’s formulation, to render the spray immunogenic. Nastech addressed this concern in a letter to the FDA in late September 2006, but the agency wants still more information, which Nastech expects to submit in the first half of this year.

Canadian company Cangene Corp. and its partner the Apotex Group are developing several products they describe as “follow-on” biologics. The NDA for one of them, a recombinant human growth hormone called Accretropin, was accepted by the FDA for filing in July 2006. The companies submitted the application under section 505(b) of the Food, Drug and Cosmetic Act, which allows for the approval of new or improved formulations of previously approved products by referring to studies supporting the original approvals. The FDA was unusually swift in its review of this application: In mid-March 2007, it issued an approvable letter for the product, requesting additional data regarding the manufacturing process. Importantly, the agency did not require further clinical trials.)

Not surprisingly, Barr Laboratories Inc. submitted an ANDA for a generic version of Celgene’s Thalomid for treating ENL in September 2006. That application covered 200 mg. capsules; in December Barr amended the application to cover 50 mg. and 100 mg. capsules, as well. Celgene, naturally, intends to fight Barr and will soon file a complaint for patent infringement.

As always, a few NDAs and BLAs have been waiting in regulatory limbo for years and years as the sponsoring company and the FDA try to resolve their differences. Genelabs Technologies Inc., for instance, has yet to win approval for its lupus drug Prestara, the subject of a rolling NDA whose submission was complete in September 2000. When the FDA issued an approvable letter in August 2002, it asked the company to conduct a confirmatory Phase III trial designed to ascertain whether the drug, a synthetic adrenal hormone, can limit the loss of bone mineral density (BMD) in women with lupus who are taking glucocorticoids. The drug failed to meet the primary endpoint (BMD) in this trial as well as two others. Thus, the company switched gears to focus on a different endpoint – the treatment of the signs and symptoms of lupus. The FDA said it would help Genelabs design a Phase III trial to this end, a process that is still not complete.

La Jolla Pharmaceutical Inc. is also developing a drug for lupus -- Riquent, a toleragen that binds to B cells and reduces levels of antibodies to double-stranded DNA. The NDA was submitted in December 2003; the company is still conducting an international, pivotal Phase III trial to demonstrate the drug’s clinical benefit in preventing or delaying renal flares in lupus patients with renal disease.

Northfield Laboratories Inc., which filed a BLA for its oxygen-carrying blood substitute PolyHeme in August 2001, is another company that’s still caught in the regulatory trap. It’s conducted a number of clinical trials, including one that uses the product to treat severely injured trauma patients before they reach a hospital. Preliminary results of the pivotal Phase III trial announced in December 2006 demonstrated a discrepancy in the data, unfortunately, which the company intends correcting before statistical analyses are finalized.

While 92 NDAs, BLAs, and supplemental applications are in some stage of regulatory review, the agency has already approved a few products in 2007. These include MedImmune Inc.’s new formulation of FluMist, its intranasal flu vaccine. Approved in January 2007, this product is now available as a refrigerator-stable (rather than frozen) vaccine for preventing flu in people 5-49 years of age. The company is still waiting for the FDA to approve the new formulation for use in children 6-59 months of age.

As we mentioned earlier, the anti-TNF antibody Humira won approval in February for treating Crohn’s disease. And Shire plc’s drug Lialda (a once-daily, sustained release formulation of mesalamine) was approved in January for the induction of remission in patients with active, mild-to-moderate ulcerative colitis.

Shire got lucky again in February, when the agency approved Vyvanse, an amphetamine derivative developed by its partner and soon-to-be subsidiary New River Pharmaceuticals Inc. for treating attention deficit hyperactivity disorder in children 6-12 years of age.

And the FDA approved Pharmion Corp.’s sNDA for Vidaza in January 2007. The drug, a DNA demethylating agent, is now approved for IV administration to patients suffering from myelodysplastic syndromes. It was approved for subcutaneous administration in May 2004.

Five approvals since the beginning of the year is not a great start – especially since only two of them were first-time approvals. However, numerous FDA action dates are coming up in the next few months, which could yield a basketful of new drugs and biologics.

To make any comments on this article, or to ask a question of the author, please contact the publisher. If you would like to submit an article, please contact the editors.

The opinions expressed in the articles published in this section do not necessarily reflect those of Pharmalicensing or UTEK Corporation. No actions including proposals to or agreements with other companies should be taken by any reader without obtaining specific business or legal advice. Neither the publisher nor the authors accept any liability for any actions or activities undertaken by any reader or other third party as a consequence of these articles or for any errors or omissions therein.