Ceftobiprol
	Alitretinoin
	Isavuconazol
	Early-stage Projects

 

Ceftobiprole

“Cephalosporin antibiotics play a central role in the empirical treatment of bacterial infections in the hospital but have lacked MRSA coverage. With increasing prevalence of MRSA, there is a growing medical need for new drugs. The novel cephalosporin ceftobiprole can prolong the usefulness of this important drug class.” Joseph S. Solomkin, M.D. Professor of Surgery & Director of Research, Division of Trauma and Critical Care University of Cincinnati, USA

Ceftobiprole belongs to a well accepted class of antibacterial agents known as cephalosporins that are used to treat serious life-threatening infections caused by Gram-negative and Gram-positive bacteria. Ceftobiprole is an investigational drug at pre-registration stage for potential first line empiric use to treat the increasing number of patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections.

Key Achievements in 2007

Positive Phase III Data Reported for Ceftobiprole in the Treatment of Severe Skin Infections and Severe Pneumonia in the Hospital Setting...

Three pivotal phase III clinical studies were completed in 2007 demonstrating positive non-inferiority results as compared to standard treatment. These data provide the basis for initial regulatory filings for complicated severe skin and soft tissue infections (cSSSI) and planned follow-on filings for pneumonia including both, hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) requiring hospitalization. Pneumonia and severe skin infections account for a significant proportion of bacterial infections treated in hospitals.

The second phase III study for severe skin infections including diabetic foot infections was reported early 2007 and demonstrated clinical cure rates of 91% for ceftobiprole versus 90% for a two-drug combination therapy of ceftazidime plus vancomycin. Response rates for confirmed MRSA infections were 90% versus 86%. In addition, response rates in diabetic patients with difficult-to-treat foot infections were 86% for ceftobiprole compared to 82% for the two-drug combination therapy.

The Phase III CAP study of patients requiring hospitalization met the primary endpoint of non-inferiority versus the study comparators. The clinical cure rate was 86% for ceftobiprole and 87% for the drug comparator arm of ceftriaxone with or without with linezolid.

The HAP phase III study compared clinical outcomes following the treatment with either ceftobiprole monotherapy or combination therapy of ceftazidime plus linezolid and met the primary endpoint of non-inferiority versus combination therapy. Overall, 69% of patients were cured with ceftobiprole compared to 72% of patients treated with combination therapy. The HAP study also allowed inclusion of ventilator-associated pneumonia (VAP) patients. Cure rates in the smaller VAP patient subset were lower for ceftobiprole treated patients and non-inferiority was not established in these patients.

...and International Regulatory Filings

The first regulatory dossiers for ceftobiprole were submitted and accepted for review by the regulatory authorities in the US, Canada, the EU and in Switzerland, the latter under an accelerated review process. Regulatory filings for ceftobiprole for the treatment of pneumonias are planned as subsequent additional indications.

In preparation of the potential launch of ceftobiprole, supply has been prepared by Basilea's partner Johnson & Johnson. Basilea experts continued to provide their extensive know-how in drug analytics and state-of-the-art technology.

Ceftobiprole's Competitive Profile

Clinical data demonstrate that ceftobiprole, as a single agent, may be as effective as commonly used combination therapy in treating a range of today's serious Gram-negative and Gram-positive infections with excellent activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). Ceftobiprole is expected to have a good safety profile and a low potential to select for resistance.

Commercial Potential

 

 

Alitretinoin

“In two clinical phase III trials, alitretinoin was found to be effective in treating severe chronic hand eczema in patients failing on topical treatments. Patients responsive to initial treatment with alitretinoin can also benefit from additional treatment courses after eventual disease recurrence.” Thomas L. Diepgen, M.D. Professor of Clinical Social Medicine Ruprecht-Karls University, Heidelberg, Germany

Chronic Hand Eczema results in significant patient disability and has profound occupational, medical and social consequences. Alitretinoin is the first drug candidate to be developed specifically for patients whose chronic hand eczema is refractory to topical treatments, including high-potency steroids.

Key Achievements in 2007

Positive Phase III Results in The Largest Therapeutic Trials Ever Performed in Chronic Hand Eczema…

This year we reported positive results from two phase III trials. Our BACH trial (Benefit of Alitretinoin in Chronic Hand eczema) successfully met its primary objective demonstrating that alitretinoin was effective in patients suffering from severe and refractory chronic hand eczema (CHE), as determined by the stringent endpoint of clear and almost clear hands. This randomized double-blind phase III pivotal study, the largest therapeutic trial ever performed in CHE, showed a response rate of 48% in the 30mg and of 28% in the 10mg alitretinoin group, while the placebo response was 17%.

The second pivotal re-treatment trial demonstrated that patients responsive to initial treatment with alitretinoin can also benefit from additional treatment courses after eventual disease recurrence and that patients with initially partial response benefited from an extended treatment period. Response rates following re-treatment were 80% for the alitretinoin 30mg group and 48% for the 10mg group demonstrating that alitretinoin can effectively treat the disease in a subsequent treatment cycle. The same study included a second patient group who had either no or an incomplete response following on initial six months treatment, and who received an extended treatment of alitretinoin for up to an additional six months. Forty-seven percent (47%) of these patients also met the clinical end point and achieved a full clinical response.

In all clinical studies to date alitretinoin was generally well tolerated. The most frequent adverse events were headache and blood lipid elevation. These were dose-dependent and reversible. Alitretinoin is a teratogen. Pregnancy prevention measures were therefore in place for all women of child-bearing potential who received alitretinoin in clinical trials. The post-treatment contraceptive period was four weeks as alitretinoin levels return to endogenous levels within days after discontinuation of therapy.

The data of the two pivotal trials including almost 2000 patients and healthy volunteers treated with alitretinoin formed the basis of a Marketing Authorization Application (MAA) submitted under the decentralized procedure to various EU member states and was filed with the Swiss and the Canadian health authorities.

Basilea completed a consultation meeting with the US health authority (FDA) to determine the additional requirements for a New Drug Application and in-line with expectations, plans to conduct a clinical program to confirm the relevance of the existing data in US populations.

…and Regulatory Filings for Alitretinoin in Europe and Canada

The commercial supply chain, warehousing and distribution logistics were established to support the potential launch in Europe, Switzerland and Canada. Commercial supplies were manufactured including validation campaigns for the active pharmaceutical ingredient and the bulk capsules.

Alitretinoin’s Competitive Profile

In a number of countries hand eczema is the most frequently reported occupational disease with high socio-economic costs to the healthcare and social system. Alitretinoin is the first pharmaceutical product to be developed specifically for patients whose chronic hand eczema (CHE) is refractory to topical treatments, including high-potency steroids. In clinical trials with alitretinoin, a significant proportion of patients who suffered from moderate and severe hand eczema for many years had disease clearance following a treatment period of between three and twelve months. The short drug elimination period may enable pregnancy prevention measures, which are necessary during therapy, to be discontinued one month after the end of therapy.

Commercial Potential

Severe refractory chronic hand eczema (CHE) is a relapsing disorder for which no approved treatment currently exists. This debilitating disease prevents patients from using their hands normally and requires frequent treatment interventions over time. Hand eczema is a common skin disease and is often chronic and relapsing. It is estimated to affect up to 10% of the general population. The more severe, chronic form of the condition is thought to affect up to 7% of these patients, many of whom do not respond, or no longer respond to topical corticosteroids. Basilea estimates there are at least one million patients in Europe and North America with refractory severe CHE for which currently no approved, effective pharmaceutical treatment is available. The social impact and economic burden related to severe chronic hand eczema are significant in the US and Europe. On basis of the positive clinical results reported to-date, alitretinoin has the potential to become the first product available to treat patients who suffer from severe CHE refractory to topical corticosteroids.

 

 

Isavuconazole

“The ongoing randomized double-blind isavuconazole phase III studies will expand our knowledge on the available primary treatments for candidemia and invasive aspergillosis. Isavuconazole has the potential to become a valuable member of our antifungal armamentarium if shown to be effective and well tolerated.” Kieren A. Marr, M.D. Adjunct Professor of Medicine Oregon Health and Science University, Portland, USA

Our second anti-infective, isavuconazole, is an investigational antifungal drug that is positioned to address the limit­ed treatment options and high mortality associated with severe invasive fungal infections in immunocompromised patients. Isavuconazole has the potential to become the best-in-class azole for invasive fungal infections with its extended spectrum of efficacy. It is available as an intravenous injectable form that can be given to patients with normal as well as impaired renal function. Its oral form is highly bioavailable, allowing convenient switching from intravenous to oral applications, and is suitable for daily or less frequent dosing.

Key Achievements in 2007

State-of-the-art Phase III Program Ongoing…

Isavuconazole, as both the intravenous and oral dose form, is currently in phase III clinical development for the treatment of severe invasive fungal infections where mortality rates are high despite existing therapies. Our front-line treatment trial for invasive aspergillosis versus voriconazole, the current leading broad-spectrum azole, will be the first double-blind registration study in this setting. In our candidemia trial we test the drug as front line therapy in patients with candida infections against caspofungin, the current leading treatment for invasive candida infections.We expect these studies to take two to three years to complete.

The ongoing phase III program will be complemented with an additional study for the treatment of aspergillosis in renally impaired patients and for the treatment of rare yeast and mold infections in patients who require salvage therapy.

Isavuconazole’s Competitive Profile

The FDA has granted fast track status to isavuconazole due to its unique profile. Isavuconazole has both, a broader anti-fungal spectrum, more reliable absorption compared to the current generation of azoles, and therefore has the potential to become the best-in-class azole. Patients may be given either injectable or oral dosage forms and isavuconazole offers the convenience of once-daily or even once-weekly dosing. Within the azole class, isavuconazole has demonstrated a good clinical safety profile to date and a lower potential for drug-drug interactions. The injectable form, unlike for the leading azoles, can potentially be given to patients with poor kidney function.

Commercial Potential

Basilea’s second anti-infective product for the hospital market, isavuconazole, fully complements our antibiotic ceftobiprole. Both products address significant challenges of severe hospital infections in the areas of cancer, transplantation and AIDS with their associated high mortality rates. Isavuconazole will target seriously ill patients who typically incur high daily hospital treatment costs.

…to Address Key Limitations of Current Antifungal Therapies

Isavuconazole may address key limitations of current therapies, most importantly gaps in the antifungal spectrum, the lack of early adequate dosing with reliable drug exposure, patient limitations due to underlying co-morbidities and concomitant medications, unwanted side effects and inconvenient dosing. Expected improvements in the safety profile over current standard treatments may allow preferential administration of isavuconazole as best-in-class azole in a wide patient population.

 

Early-stage Projects

Combating Resistance

The rapid and global emergence of pathogenic bacteria resistant to current antibiotic therapy as well as the frequent development of resistant tumors upon chemotherapy of cancer patients are both alarming developments which lead to high mortality/morbidity of patients as well as pose an enormous financial burden on health-care systems. Basilea’s research group focuses its discovery efforts on these areas of drug-resistance, thereby supporting the company’s long-term vision of building a strong and sustainable business in fields of high medical need. In the area of anti-infectives, Basilea research is working on new antibiotic therapies against particularly dangerous resistant bacteria as well as on application routes allowing different treatment modalities. In oncology, approaches focus on novel structural classes with no cross-resistance to existing drugs as well as on inhibitors of oncogenic mutant proteins.

Antibiotics Targeting Resistant Gram-negative Bacteria

There is a significant and growing market opportunity for anti-infective therapy of multi-resistant Gram-negative pathogens. Infections by Gram-negative bacteria cause approximately half of the hospital acquired infections in the U.S. and Europe and can be associated with high mortality. The death rates associated with these infections range from 25% to 60% in certain infections, such as ventilator-associated pneumonia. The incidence of antibiotic-resistant Gram-negative bacteria has risen substantially in the last five-year period across many geographic regions and this has been linked to higher mortality, prolonged periods of hospitalization and increased health-care costs. Four Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii) have been highlighted by the Infectious Disease Society of America (IDSA) because of the particularly high rapid rise of resistance, which is making these organisms more difficult to treat. The most common illnesses caused by such Gram-negative pathogens are complicated urin­ary tract infections, intra-abdominal infections and pneumonia. Basilea is responding to the increased concern among clinicians over the threat posed by Gram-negative bacteria by making significant efforts to bring forward novel drugs for empiric use against serious Gram-negative infections. Basilea has filed a number of patents in this key research area during the last twelve months covering its two most advanced antibiotic research programs with activity against a broad range of Gram-negative bacteria. The most advanced pre-clinical development candidate, BAL30376, is uniquely active in vitro against multi-resistant strains of P. aeruginosa and A. baumannii, as well as K. pneumoniae.

Antibiotics Targeting Resistant Gram-positive Bacteria

Basilea is currently testing a novel series of antifolates with potent in vitro activity against various staphylococci with different resistance characteristics. These include methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-intermediate Staphylococcus aureus (VISA), trimethoprim-resistant coagulase-negative staphylococci resistance as well as vancomycin-resistant strains of enterococci. The compounds have shown intravenous and oral efficacy in animal models of infection.

Macrolide Antibiotics: Antibacterials and Anti-Inflammatories

Macrolide antibiotics form a well-known class of drugs and their use over many decades provides a clear understanding of their safety and efficacy. Basilea has discovered a number of novel molecules possessing both antibacterial and anti-inflammatory activity. Out of this series a class of compounds has been identified which shows excellent activity against sensitive and antibiotic-resistant bacteria associated with acne. The most advanced member of this class, BAL19403, has successfully completed initial proof-of-concept testing as a topical formulation for moderate inflammatory acne.

Drug Resistance: Beyond Microbes to Cancer

Basilea’s current pipeline of antibiotic and antifungal development products target severely ill, often immunocompromised patients including cancer patients who are at risk of bacterial or fungal infection because of their weakened immune system. Aligning with our focus on hospital/specialty products and patients with high medical needs, Basilea has identified novel proprietary compound classes that exhibit potent in vitro and in vivo activity against a broad panel of tumor cell lines.

Drug resistance is not only a problem in the field of anti-infectives, but is also frequently encountered in oncology. In many cases, this resistance is due to cellular transporters that remove drugs from cancer cells, thus rendering them ineffective. Basilea’s cell death inducer BAL27862 is a novel tubulin-interacting agent with a unique mode of action that overcomes P-glycoprotein pump-related resistance. Its activity against a broad panel of tumor types and the potential for intravenous and oral administration make BAL27862 a promising preclinical candidate for the treatment of cancer patients no longer responding to prior chemotherapy.