These are my totally subjective picks for the best pharmaceutical (including biopharmaceutical/biologics) innovations this past year. Only drugs eligible for sale in the US or EU after January 1st, 2007 are eligible.
1. The number one innovation is a tie: Maraviroc (Selzentry, Pfizer (PFE)) and Raltegravir (Isentress, Merck (MRK)). Two NMEs that attack HIV-1 via novel mechansims tie for first place in this year’s best-of list, despite the relatively modest fanfare that greeted their arrivals.
Maraviroc is the first in a class of drugs called chemokine (C-C motif) receptor 5 [CCR5] co-receptor antagonists that are designed to interfere with white blood cell entry of HIV via CCR5. CCR5 is likely the most physiologically important co-receptor during natural infection, and at least 50% to 60% of treatment-experienced infected patients harbor CCR5-using viruses. When added to optimized therapy in clinically advanced patients, Maraviroc led to virologic responses in roughly twice as many patients relative to placebo.
Raltegravir is the first in a class of antiretroviral agents known as HIV-integrase strand transfer inhibitor (HIV-1 INSTII) that are designed to slow HIV-1 progression by blocking the integrase enzyme required for viral insertion into human DNA. It is approved for clinically advanced patients with evidence of viral replication and multi-drug resistant HIV-1. Like Maraviroc, Raltegavir was tested as add-on to optimized therapy and resulted in similar virologic response rates relative to placebo.
However, Merck has the PR advantage over Pfizer. Here’s a representative quote for Isentress, courtesy of SFGate.com: “This drug looks more potent than virtually anything we have ever seen.” (UCSF Professor Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology). I found no similar effusiveness over Selzentry, but rest assured that both drugs represent welcome advances in AIDS treatment and deserve to share top innovation honors this year.
2. Lapatinib (Tykerb, Glaxosmithkline (GSK)). Lapatinib is a small molecule, orally-active tyrosine kinase inhibitor [TKI] that targets both erbB1 [EGF] and erbB2 (Her2/neu) receptors. Its dual mode of action distinguishes it from other marketed small-molecule TKIs, such as gefitinib (Iressa) and erlotinib (Tarceva), which target just EGFR, and the monoclonal antibody trastuzumab (Herceptin), which targets just Her2/neu. In theory, dual TK inhibition might diminish drug resistance arising from single TK inhibition. In practice, we just don’t know.
The pivotal trial tested Lapatinib combination therapy with capecitibine versus capecitabine alone in women whose Her2/neu-overexpressing breast cancer had progressed after therapy with Taxanes, Anthracycline, and Herceptin. I’ve read several different reports of the results of this study, probably because the interim results were published in the NEJM, and updated results were used by FDA to support approval. Furthermore, FDA relied both on the investigator-reported and independent assessments of TTP.
The bottom line is that Lapatinib did NOT “nearly double” TTP, as you might have read; rather, addition of Lapatinib increased TTP by 33-40% over capecitabine alone and had no effect on survival. Still, Lapatinib represents the best option for women with Her2-overexpressing breast cancer whose disease has progressed despite chemotherapy and Herceptin and holds promise for earlier disease stages as well.
3. Eculizumab (Soliris, Alexion (ALXN)). Eculizumab is a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation. It is the first complement activation inhibitor approved for human use and is also the first drug indicated for Paroxsymal Nocturnal Hemoglobinuria [PNH], a rare, complement-mediated disease characterized by red blood cell destruction.
Eculizumab was approved for its ability to stabilize hemoglobin (49% versus 0% with placebo) and reduce transfusion requirements (mean 3 U versus 11 U with placebo) in PNH. Eculizumab represents a tremendous clinical advance for PNH and represents clinical proof-of-concept for inhibition of complement activation generally. Its downside is its exorbitant cost of nearly $400k per year.
4. Ixabepilone (Ixempra, Bemis (BMS)). Ixabepilone is the first approved epothilone analog. Epothilones are microtubule inhibitors found naturally in a myxobacterium. BMS developed ixabepilone first as treatment for advanced breast cancer, testing it as monotherapy and in combination with capecitabine.
Both indications were approved in the US, with ixabepilone demonstrating improved progression-free survival in the combination therapy study (5.7 vs. 4.1 months) and objective tumor response (median response time of 6 months in up to 18% of subjects) as monotherapy. Ixabepilone and other epothilones are currently being studied for other advanced cancers, including hormone-refractory prostate cancer.
5. Temsirolimus (Torisel, Wyeth (WYE)). A metabolic parent of Wyeth’s immunosuppresant sirolimus (Rapamune), Temsirolimus is an mTOR inhibitor that arrests the cell cycle at G1 in kindey tumor cells in vitro. In its pivotal studies in previously untreated advanced renal cancer, temsirolimus improved overall and progression-free survival versus interferon-alpha alone (10.9 vs. 7.3 months and 5.5 vs. 3.1 months, respectively). More mTOR inhibitors will follow in the footsteps of temsirolimus in the years ahead, and, along with PI3/Akt inhibitors, should be important advances in the treatment of a wide variety of cancers.
6. Aliskerin (Tekturna/Rasilez, Novartis(NVS)). Aliskerin, the first approved renin inhibitor, is probably best known for the story of its development, which I won’t recount here. Aliskerin inhibits the renin-angiotensin-aldosterone axis without increasing bradykinin, circumventing bradykinin-induced cough and angioedema that is a problem with inhibitors of downstream RAAS effectors. We can’t have too many useful treatments for hypertension and heart failure.
7. Ambrisentan (Letairis, Gilead (GILD)). Ambrisentan is the second approved Endothelin A receptor antagonist following Bosentan (Tracleer, Actelion, which is also an Endothelin B antagonist) for treatment of pulmonary artery hypertension [PAH]. Both are oral therapies. So, what puts Ambrisentan on this list?
It’s more convenient (once-daily versus twice) and has the potential for fewer drug interactions (Tracleer induces 3A4 and 2C9, reducing the plasma concentration of sildenafil, used to treat PAH). It’s also shown to be safe in patients who have discontinued Tracleer due to elevated hepatic enzymes. Neither Ambrisentan nor Bosentan has powerful efficacy, however, and there have been no head-to-head studies.
Honorable Mention: Protein C Concentrate (Ceprotin, Baxter (BAX)). Baxter studied nearly every patient with severe inherited Protein C deficiency during the long development of Ceprotin.