Biotech Tracker News - Xolair BLA Re-Submitted
December 19, 2002 Genentech (NYSE: DNA), and Novartis (NYSE: NVS) submitted an amended BLA to the FDA for Xolair (omalizumab) for the treatment of moderate to severe allergic asthma in adults and adolescents. Genentech and Novartis are developing Xolair with Tanox (NASDAQ: TNOX).  In a July 2001 Complete Response Letter, the FDA requested more analyses regarding animal and human efficacy as well as human pharmacokinetic profiles especially in terms of absorption and elimination characteristics. Revised clinical data are from study of more than 6,000 patients, of whom approximately 4,000 have received Xolair. The data include safety profiles derived from a recently completed investigation enrolling 1,899 patients.  New data is also expected to be submitted to the European Medical Evaluations Agency (EMEA) “at the end of 2003,” and Xolair’s European marketing application is expected to be submitted in the first half of 2004.  Xolair, an anti-IgE monoclonal antibody, was approved for marketing in Australia last July. We are impressed with Xolair’s magnitude of treatment effect as demonstrated in multiple U.S. and European peer-reviewed publications. Some key results include:  August 2001 electronic issue of the journal Pediatrics: Xolair reduces the need for corticosteroids and minimizes asthma exacerbations in atopic (“allergic”) asthmatic children. Endpoints of school days lost and unscheduled asthma-related medical visits were significantly fewer in Xolair treated children versus their placebo-treated counterparts. The frequency and severity of adverse events were similar between Xolair and placebo, and there were no serious treatment-related adverse events.  August 2001 issue of the Journal of Allergy and Clinical Immunology: Xolair both reduces the frequency of asthma exacerbations and decreases use of inhaled corticosteroid and rescue medication when added to standard asthma therapy. Moreover, Xolair had an adverse effect profile similar to that of placebo. This publication provided confirmation of analogous results for adults published and presented in multiple medical society forums.  December 19, 2001 issue of The Journal of the American Medical Association (JAMA): Xolair significantly reduces symptoms of seasonal allergic rhinitis (hay fever) in patients between the ages of 12 and 75 years old who had at least a 2-year history of moderate to severe ragweed-induced allergic rhinitis and baseline IgE levels between 30 IU/mL and 700 IU/mL. Xolair provided a linear dose-response relationship for average daily nasal symptom severity scores. Recipients of Xolair 300 mg demonstrated minimal change in weekly nasal symptom severity scores during the entire pollen season, indicating that their seasonal increase in hay fever symptoms was largely eliminated. Rhinitis-specific quality of life scores were consistently better in recipients of Xolair 300 mg compared with placebo. The linear dose-response relationship accompanied by a reassuring adverse effect profile indicates that increasing the dose provides increased symptom relief for patients with more severe symptoms. Furthermore, the finding that this relationship mirrored the relationship between dose and the proportion of patients with declining IgE levels suggests that the mechanism of Xolair action is responsible for the strong treatment effect. The ability of the maximum dose to provide people with protection against the typical increase in symptoms as the hay fever season progresses is obviously of great value.  An accompanying commentary by Dr. Marshall Plaut of the National Institute of Allergy and Infectious Diseases stressed that many children with allergic rhinitis go on to develop asthma within 2 to 5 years, and that "it will be important for future research to evaluate whether (Xolair) blocks the onset of asthma." If this proves to be the case, then not only will Xolair be used for the treatment of asthma and hay fever, but also for the prevention of asthma in those predisposed by virtue of their having hay fever.  Xolair treatment effect profiles against other IgE-mediated disorders such as atopic dermatitis and food allergies are also being studied. In multiple studies, Xolair has demonstrated an unequivocally clinically important treatment effect, and thus far has demonstrated a reassuring safety profile in both adults and children. The potential blockbuster, a key driver of the monoclonal antibody sector, has a considerably greater than average probability of gaining FDA approval. ALLHAT Studies will Impact Use of Non-Thiazides More than Use of Statins  December 19, 2002  Two large-scale studies published in this week’s Journal of the American Medical Association (JAMA) have captured considerable attention in the general public. The studies highlight a trend to compare drugs that target similar patient populations. The null hypotheses of these studies are often that older, less expensive drugs are just as good as newer, more expensive drugs. In some cases, this hypothesis will be rejected, supporting the more innovative product. In other cases, this hypothesis will be validated and that validation will be subject to further analytic scrutiny in order characterize its validity as internal, external, or both. The degree of external validity (for which internal validity is a prerequisite) is the degree of generalizability, and characterizes the extent to which the findings can or should be applied to the practice of medicine on a population basis.  Studies like the two JAMA studies will become more frequent given the increasing demand for improved resource allocation in the health care and biomedical industries. Studies like these will be a source of pressure on the pharmaceutical and biotechnology industries as they struggle to meet the demands of providing innovative medicines that impact disease more favorably than their predecessors. Analysis of studies like these require high-profile critical appraisal in order to project their impact on utilization, reimbursement, and sales trends.  Both JAMA studies are out of investigation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial cohort. The first study’s conclusion is that cheap, old, Thiazide-type diuretics (“water pills”) are just as effective as newer antihypertensives such as calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors. Dr. Jackson T. Wright Jr., vice-chairman of the ALLHAT steering committee, went so far as to say that, “They are unsurpassed at lowering blood pressure and reducing the clinical complications of hypertension. Furthermore, they are well tolerated by patients and they cost less.”  The second study’s conclusion is that pravastatin (Bristol-Myers Squibb’s Pravachol) does not provide vastly superior clinical outcomes compared to “usual care” for patients with high cholesterol. However, Dr. Jeffrey L. Probstfield, steering committee director for the second study, said, “As a physician whose clinical activities focus on those with high lipids, particularly high cholesterol, my final recommendation is to continue to take and prescribe cholesterol-lowering drugs, particularly statins… this will reduce the rate of coronary heart disease and deaths.” On balance, the first study is likely to have a more significant impact on the use of non-thiazides for hypertension than the second study will have on the use of statins. ALLHAT: Thiazides for the initial therapy of hypertension, a 4-year study 42,418 men and women 55 years of age or older with hypertension and at least one other risk factor for coronary heart disease were randomized to receive chlorthalidone (12.5 mg to 25 mg/day of a thiazide, sold as Hygroton from Novartis and Thalitone from King), amlodipine (2.5 mg to 10 mg/day of a calcium channel blocker sold as Lotrel from Novartis and Norvasc from Pfizer) or lisinopril (10 mg to 40 mg/day of an ACE inhibitor sold as formulations from Merck and AstraZeneca). An alpha-adrenergic blocker was also a part of this study, but that arm was stopped in March 2000 because recipients experienced 25% more cardiovascular events and were twice as likely to be hospitalized for heart failure compared to thiazide recipients. Mean follow-up time was 4.9 years.  No significant differences in outcomes were seen between the amlodipine and chlorthalidone arms for the endpoints of: fatal coronary heart disease (CHD) or non-fatal myocardial infarction (MI, heart attack)  all-cause mortality  combined CHD, stroke  combined CVD, angina, coronary revascularization, peripheral arterial disease, cancer or end-stage renal disease (ESRD).  Moreover, the amlodipine group also had a 38% greater risk of heart failure.  No significant differences in outcomes were seen between the lisinopril and chlorthalidone arms for the endpoints of:  fatal CHD or non-fatal MI  all-cause mortality  combined CHD, peripheral arterial disease, cancer or ESRD.  The lisinopril group had a 15% higher risk of stroke and a 10% higher risk of combined cardiovascular disease.  The generalizability of the results is enhanced by earlier findings of no significant differences in CHD and stroke rates observed between chlorthalidone- and amlodipine-based intervention. Earlier investigation also support the increased heart failure rate for amlodipine recipients. The lower heart failure incidence for thiazide diuretics is also well-substantiated.  Dr. Lawrence J. Appel, of Johns Hopkins University hit the nail on the head in terms of payor perception, for this specific clinical scenario, in an accompanying editorial indicating that, “ALLHAT results...are particularly noteworthy, because there is no cost-quality tradeoff; the most effective therapy was also the least expensive…it is unclear why physicians should implement an ACE inhibitor-based strategy that commonly leads to use of two drugs (ACE inhibitor and diuretic) when monotherapy with a thiazide diuretic can effectively reduce blood pressure and prevent blood pressure-related cardiovascular outcomes.” ALLHAT: Pravastatin for cholesterol management, an 8-year study Investigators evaluated 10,355 patients, 55 years of age or older, with low-density lipoprotein (LDL, “bad” cholesterol) levels of 120 mg/dL to 890 mg/dL and triglycerides levels lower than 350 mg/dL. Study subjects were randomized to receive Pravastatin 40 mg per day or “usual care.” Mean follow-up was 4.8 years. At the fourth year, Pravastatin was found to do what it was supposed to do. Total cholesterol was down 17.2% for pravastatin recipients versus 7.6% with “usual care.” LDL was down 27.7% versus 11.0% for Pravastatin and “usual care” recipients, respectively. However, the primary endpoint of all-cause mortality did not differ significantly between the two treatment groups. Similar rates of both cardiovascular death and 6-year incident cancer were observed. Overall CHD and stroke were somewhat lower in the pravastatin group.  The study observations that appear to diminish the generalizability of the observations, and thus the impact on use, reimbursement, and sales patterns were:  smaller than expected difference in total cholesterol levels between groups  nonblinded study design  protocol switching by year 6 70.3% of those randomized to pravisatatin were still taking 40 mg of the agent  28.5% of the usual care group was actually receiving a lipid-lower drug, 26.1% a statin.  An accompanying editorial by Dr. Richard C. Pasternak of Massachusetts General Hospital and Harvard Medical School highlights these aspects of protocol switching. Dr. Pasternak writes, “Did all of those randomly selected actually have testing, or could those returning for testing have been more motivated to be tested because of their concurrent adherence to therapy? If adherent patients were more likely to return for LDL testing, the differential could be even smaller than the 16.7% reported, further explaining the similar outcomes.”  Given the suspect generalizability and understanding that numerous investigations demonstrate poor compliance with statins, Dr. Pasternak felt that the results of ALLHAT, “point to the need for improved adherence and understanding reasons for nonadherence,” cautioning doctors to read and appraise these results with extreme care.  Thiazides are sold by Novartis, Merck, Pfizer, Parke-Davis, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Wyeth, Bertek, Boehringer Ingelheim, Watson, Schwarz, Lederle, Mylan, Geneva, Endo Generics, Par, Roxane, King, Wallace, Celltech, and Monarch. Statins are sold by Pfizer, Merck, Novartis, and Bristol-Myers Squibb. AstraZeneca’s Crestor has been approved in Holland and is being reviewed for approval in many other worldwide markets.
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