Perspectives

Home , Edobacomab, Nebacumab, Palivizumab

PERSPECTIVES

or anti-infective drugs — for example, OUTLOOK cytomegalovirus, hepatitis B virus, human immunodeficiency virus (HIV) and human Anti-infective monoclonal antibodies: rhinovirus infections, and sepsis. The original mAb production method perils and promise of development — the fusion of mouse lymphocyte and myeloma cells — provided murine mAbs. These products were often immunogenic6, Janice M. Reichert and Matthew C. Dewitz and so human mAbs were preferred as therapeutics. Of the eleven anti-infective mAbs in Abstract | So far, most monoclonal antibodies have been developed for treating clinical study in the 1980s, seven (64%) were cancer or immunological diseases. However, the global spread of infections such as human, and only four (36%) were murine West Nile and corona viruses, and the need to address the potential threat of products. At the time, human mAbs were bioterrorism, has boosted public interest in, and government support of, counter - derived from human B-lymphocytes. measures for infectious diseases. The attractive features of monoclonal antibodies, As naturally infected patients were the such as high specificity and effective recruitment of the immune system, would source of these cells, only a limited number of pathogens could be targeted. seem to make them excellent candidates as anti-infective agents. Here, we analyse The early hybridoma methods lent them- trends in the development and approval of anti-infective monoclonal antibodies, selves to preparation of immunoglobulin and discuss factors that influence their success. M (IgM) mAbs as well as the more versatile IgG products5. Of the eleven mAbs, four (36%) were IgM antibodies. However, IgM Over the past decade, monoclonal anti- Study of Drug Development collected data antibodies are composed of five monomers, bodies (mAbs) have become a thriving class for commercially sponsored anti-infective with four protein chains comprising each of therapeutics, with 18 having received mAbs at the preclinical and clinical stages monomer, and so have limited utility as regulatory approval, and more than 150 now of development (see BOX 1 for inclusion therapeutics because of their large size. IgM in clinical development. The majority of criteria). Probabilities of success were calcu- antibodies are largely confined to the circu- such agents have been developed for treating lated for products that entered clinical study latory system, and so these products were cancer and immune disorders owing, at least in the 1980s and the 1990s. Vaccines and studied in the 1980s primarily as treatments in part, to the well-defined unmet medical anti-infective drugs are potential market for bloodstream bacterial infections (that is, needs and markets in these areas. competitors, so we compared the anti- sepsis). In contrast, the majority (86%) of However, mAbs have also been inves- infective mAbs in clinical development with the IgG mAbs were studied as treatments for tigated for their potential as anti-infective marketed and pipeline vaccines and antiviral infections. agents, although with limited success so infective drugs and assessed overlap between The overall approval success rate for far; of the 18 mAbs approved by the US target organisms. anti-infective mAbs studied in the 1980s was FDA, only one is an anti-infective agent. zero. Of the eleven products that entered Nevertheless, numerous candidates are Nascent technology: 1980s clinical study, five products (45%) pro- undergoing preclinical and clinical study, The technology for the production of mAbs gressed to Phase II, three (60%) progressed and ample medical needs exist for targeted was developed in the late 1970s. Although to Phase III and two (67%) advanced to FDA anti-infective treatments. With careful selec- more than 70 therapeutic mAbs entered review, but neither application was approved. tion of indications and mAb characteristics clinical study in the 1980s, only 11 were The two products reviewed by the FDA (such as specificity, avidity and isotype), anti-infective products. The concept of mAbs were edobacomab (XOMEN-E5; XOMA) opportunities exist for the development of as ‘magic bullets’ capable of homing in on and nebacumab (Centoxin; Centocor), safe and efficacious anti-infective mAbs that specific targets caught the imagination of both IgM antibodies studied as treatments would complement the arsenal of vaccines scientists, businesspeople and the public, for Gram-negative septicaemia. Additional and anti-infective drugs. Some caution but in practice the idea was most commonly efficacy testing was requested during the is advisable because, despite an increase applied to cancer therapeutics. A ‘war on FDA review of edobacomab, but the product in government funding for development, cancer’ had been declared in 1971, but effica- did not meet the endpoint (improvement the markets for countermeasures to many cious oncology products were still very much of short-term survival) in an additional pathogens have not yet been clearly defined. in demand a decade later. Nevertheless, a study7. Development of nebacumab was As part of ongoing efforts to track number of companies explored the judicious terminated due to excess mortality in sepsis trends in the development and approval of use of anti-infective mAbs in areas in which patients who were treated but later diag- therapeutic mAbs1–4, Tufts Center for the medical need was as yet unmet by vaccines nosed without Gram-negative bacteraemia8.

Box 1 | Analysis criteria diseases entered clinical study. Most are at early stages of development, with 11 (50%) at Since it was founded in 1976, Tufts Center for the Study of Drug Development has collected data Phase I and nine (41%) at Phase II. Only two on the clinical development and approval of therapeutics and vaccines. Data for monoclonal (9%) have entered Phase III studies (TABLE 1). antibodies (mAbs) were collected by survey of pharmaceutical and biotechnology firms, from The average length of the clinical develop- company web sites and from public documents (for example, press releases and annual reports). Commercially available databases (IDdb3, IMS R&D Focus and PharmaProjects) were accessed to ment phase for FDA-approved mAbs was verify the status of products. Products in Phase I/II were assigned to Phase II and products in 6.5 years, so it is not surprising that these Phase II/III were assigned to Phase III. Data were updated with all changes noted through June 2005. products are still undergoing evaluation. The mAb data set comprised a total of 355 therapeutic products that entered clinical study Success rates cannot be calculated for anti- sponsored by commercial firms between 1980 and mid-2005. Products either originated at the infective mAbs comprising the current 2000s sponsoring company or were licensed from a commercial, government or academic source. Of the cohort because all of the agents are still under 355 mAbs, 46 (13%) were identified as anti-infective agents. The clinical status of the products was clinical study. Predictions based on success as follows: 11 were in Phase I, 12 were in Phase II, two were in Phase III, one was approved in the rates for the 1990s cohort suggest that two US and other countries, and 20 were discontinued. Status of anti-infective mAbs in preclinical or three of the products might be approved. development sponsored by commercial firms was assessed during June 2005. However, due to the small size of the 1990s Approval success calculations were based on products with a known fate (US approval or discontinuation). Percent completion was defined as the percent of products with a known fate cohort, this result must be considered an esti- in a given cohort. Phase-transition probabilities were calculated as follows: the number of mate. In addition, a number of factors might products that completed a given phase and entered the next was divided by the difference improve success rates for the 2000s cohort, between the number of products that entered the phase and those that were still in the phase which includes more human mAbs and a at the time of the calculation. Transitions occurring between phases of clinical studies number of mAbs with fast-track designation. conducted worldwide were included. Genetically engineered human mAbs comprise the majority (59%) of the 22 anti- infective products and might have higher Nebacumab was approved in a number of respectively (FIG. 1). Only one anti-infective probabilities of success compared with countries outside the US, and then voluntarily mAb studied in the 1990s, palivizumab chimeric or humanized products. Accurate withdrawn from these markets. (Synagis; MedImmune), was reviewed by the assessment of success rates is not yet possible FDA; it was approved in June 1998 as a treat- because few human mAbs in any therapeutic Limited success: 1990s ment for respiratory syncytial virus infection category have completed the development Technological advances opened new oppor- in high-risk paediatric patients. process. Only one is FDA-approved so far: tunities in the 1990s when genetically engi- We have previously published phase- adalimumab (Humira; Abbott), which neered mAbs such as chimeric, humanized transition probabilities for humanized received approval on 31 December 2002, and bispecific products began entering the mAbs stratified by time and therapeutic as a treatment for rheumatoid arthritis. clinic in large numbers. Phage-display and category4. Humanized mAbs comprise 50% Four mAbs in the current 2000s cohort transgenic mouse technologies made human of the US-approved mAbs and are the most have FDA fast-track designations as mAbs readily available for development. abundant of the three main varieties of mAbs treatments for bacterial (Bacillus anthracis, More than 140 therapeutic mAbs entered (chimeric, humanized and human) in clinical Staphylococcus) and viral infections clinical study during the 1990s, double the study. Phase-transition probabilities for anti- number studied in the 1980s. However, infective mAbs developed in the 1990s fell perhaps because of the high-profile product short of benchmarks set by humanized mAbs 100 terminations of the previous decade, only 13 in clinical study during a similar period, as 90 89 88 mAbs were studied as anti-infective agents. well as most of those for oncological and 80 80 80 73 76 Anti-infective mAb development in the immunological diseases (FIG. 1). The prob- 70 69 1990s was focused on the antiviral therapeu- lematic step for the anti-infective mAbs was 60 60 53 tics, which comprised 77% of the total. Study successful completion of Phase III. Of the 50 50 43 of anti-HIV mAbs intensified: only one anti- three non-murine anti-infective mAbs that 40 33 HIV mAb was studied in the 1980s, whereas entered Phase III, only one (palivizumab) 30 six of these products were in the clinic in the was successful, whereas two were terminated 20 1990s. The variety of the specificities was in Phase III due to lack of efficacy. (%) probability Transition 10 not large though: four (67%) mAbs targeted 0 regions of HIV glycoprotein 120. Clinical monoclonal pipeline: 2000–2005 Phase I–II Phase II–III Phase III The overall approval success rate Industry focus on mAb products has intensi- to approval* Clinical phase transition calculated for anti-infective mAbs studied fied further in the 2000s. More than 130 in the 1990s was 10%; three mAbs remain at therapeutic mAbs entered clinical study Anti-infective, non-murine mAbs, 1990–1999 (n = 11) Phase II of clinical study. The rate increased between January 2000 and June 2005. If Humanized mAbs, 1988–1997 (n = 46) slightly (to 11%) when the two murine this pace continues, the total for the decade Oncological humanized mAbs, all (n = 46) products were removed from the analysis. could approach 240 products. However, as Immunological humanized mAbs, all (n = 34) Clinical phase-transition probabilities (the was the case in the two previous decades, Figure 1 | Clinical phase-transition probabilities probability of moving from one clinical anti-infective mAbs still comprise a for monoclonal antibodies (mAbs). *Review to phase to the next) were 73%, 50% and 33% small percentage of the total products in approval transitions were 100% for all cohorts, so for transitions from Phase I to II, Phase II development to date. In the first 5.5 years of transition probabilities for Phase III to FDA review to III, and Phase III to US approval, the 2000s, 22 mAb treatments for infectious and FDA review to approval were combined.

Table 1 | Anti-infective monoclonal antibodies in Phase III studies or US-approved

Company name Generic name or specificity Trade name US status Indication NeuTec Anti-MRSA AUROGRAB Phase III MRSA infection MedImmune Anti-RSV NUMAX Phase III RSV infection in high risk infants MedImmune Palivizumab Synagis Approved June 1998 RSV infection in high risk infants See analysis criteria box for methodology. MRSA, methicillin-resistant Staphylococcus aureus; RSV, respiratory syncytial virus.

(hepatitis C, HIV). Available only since 1997, transmitted person-to-person. Of the pre- Although in theory prevention of infec- fast-track designation is intended to facilitate clinical products, eight (73%) were targeted tion would be desirable compared with treat- the development of medicinal products that to a Category A, B or C pathogen (TABLE 2). ment, a vaccine is currently marketed in the might be improvements over the existing Nearly half the products were potential treat- US for only one of the relevant pathogens therapies available for patients with serious ments for either anthrax (Category A; three — anthrax. The anthrax vaccine is not con- or life-threatening diseases. Companies mAbs) or West Nile virus (Category B; two venient — six doses must be administered sponsoring fast-track products are eligible mAbs) infection. By contrast, only six (24%) over an 18-month interval — and is recom- for frequent and timely interactions with of the mAbs currently in clinical studies and mended only for persons thought to be at FDA. Fast-track product applications are none of the now discontinued mAbs were risk of exposure. eligible for ‘rolling review’, in which sec- directed towards pathogens on the priority Vaccines are in development for all of the tions can be filed over time. Although these pathogens list. five target organisms, though all are in early benefits will obviously not affect the overall The early research and screening groups stage clinical studies. Eight vaccines are in safety or efficacy of the products, they might contain the most speculative products Phase I and four vaccines are in Phase II improve the quality of the clinical develop- and programmes. A total of 21 potential studies for hepatitis C, B. anthracis, pathogenic ment programme and marketing applica- products from 17 companies were identi- E. coli or Staphylococcus infections. At least tion, increase the speed of the FDA review fied in early research. Though not present 16 HIV vaccines are currently in early clinical and decrease the likelihood of a termination in the preclinical group, mAb therapeutics studies sponsored at least in part by compa- for commercial reasons. for HIV and hepatitis B and C infection nies. Non-profit institutions and government reappear in the early research group. Only agencies worldwide have been involved in Potential clinical candidates four mAbs for priority pathogens were the development of many HIV vaccines10 and We examined company preclinical pipelines included — one each for anthrax, rabies, the extent of commercial involvement in the to assess the number of anti-infective mAbs severe acute respiratory syndrome (SARS) development of some is unclear. As is well that might enter the clinic in the remainder and variola infection. The screening group known, none of the HIV vaccines have as yet of the decade. Products and company pro- comprised anti-infective mAb programmes shown a great deal of promise. grammes were assigned to three categories: from 15 companies. Screening programmes Anti-infective drugs are marketed as the ‘preclinical’ category comprising discrete, for mAbs targeted to HIV, hepatitis A, B treatments for all five pathogens. However, clearly defined mAbs that had been tested and C, as well as four priority pathogens many drugs for the viral pathogens are not in animals; the ‘early research’ category — Clostridium botulinum, Ebola virus, exceptionally effective because they inhibit comprising single mAbs or groups of several SARS-associated corona virus and variola but do not cure infection, and some cause mAbs that had in vitro data (for example, virus — were identified. Targets for five serious side effects. The antibacterial drug target organism neutralization data); and the programmes were not disclosed. It remains ciprofloxacin (Bayer) is efficacious for ‘screening’ category comprising mAb library to be seen whether any of these programmes mild cases of cutaneous anthrax, though generation and screening programmes. will generate clinical candidates. it is not as effective against the inhaled Preclinical mAb products and pro- pathogen. Infections with pathogenic grammes sponsored solely by government Competitive pressure E. coli can be managed with supportive care, and academic institutions were excluded. Companies developing anti-infective mAbs though development of haemolytic uremic Because discoveries by these institutions are jockeying for position in the market syndrome in infected paediatric patients might be licensed for commercialization with two other groups of products: vaccines remains a serious problem. A number of in the future, our results have likely under- and anti-infective drugs. The presence of drugs are effective against Staphylococcus, counted the total possible mAb candidates competitive products could be one explana- but some strains are now resistant to many by an unknown amount. tion for the dearth of anti-infective mAbs in of these drugs. We found that the preclinical group development. We examined marketed and A number of anti-infective drugs are comprised only eleven products under inves- pipeline vaccines and anti-infective drugs to in early stage clinical studies as treatments tigation by eight companies. Interestingly, assess whether these products might provide for hepatitis C and HIV. Two are currently the selection of targets seemed to be strongly competition to mAbs in development. We in Phase II studies: viramidine (Valeant influenced by the Category A, B and C prior- focused on products targeting hepatitis C and Pharmaceuticals) for hepatitis C and ity pathogens list used by US Centers for HIV viral infections, and B. anthracis, patho- maraviroc (Pfizer) for HIV. Very few Disease Control and Prevention and National genic Escherichia coli, and Staphylococcus products are in studies as treatments for Institutes of Health (NIH)9. Category A bacterial infections because most (76%) of the three bacterial pathogens; none are in agents are the highest priority and include anti-infective mAbs in the clinic (TABLE 2) are late-stage development. Pathogenic E. coli pathogens that are easily disseminated or treatments for these five pathogens. infections pose an especially difficult

Table 2 | Targets for anti-infective monoclonal antibodies at three stages* Opportunities for successful anti-infective mAb development do exist in these Target Priority Preclinical In clinical Discontinued pathogen study during clinical niche applications, however, and returns are category study not necessarily small. For example, the FDA- approved mAb treatment for respiratory Antiviral (unspecified 10 0 target) syncytial virus in high-risk infants, palivizumab, had global sales of nearly a billion Aspergillus fumigatus 10 0 dollars in 2004. In addition, the landscape Bacillus anthracis A3 3 0 of anti-infectives development in the US has Candida albicans 01 0 changed due to recent legislation, increased Clostridium difficile 01 0 emphasis by the National Institutes of Health on priority pathogens, and changes to FDA Cytomegalovirus 0 0 3 regulations. Specifically, numerous oppor- Escherichia coli B1 3 0 tunities are currently available for develop- (diarrheagenic) ment of anti-infective mAbs as bioterrorism Hepatitis B virus 0 1 1 countermeasures. Hepatitis C virus 0 2 0 The need for safe and effective anti-infective agents has taken on an added urgency Human 08 6 immunodeficiency virus since September 2001. Recent US legislation has made a substantial amount of money Human rhinovirus 0 0 1 available. Approved 21 July 2004, the Project Pseudomonas 01 1 BioShield Act amended the Public Health Rabies virus C 1 0 0 Service Act specifically “to provide protec- Respiratory syncytial 01 2 tions and countermeasures against chemical, virus radiological, or nuclear agents that may be used in a terrorist attack against the United SARS-associated C1 0 0 coronavirus States by giving the National Institutes of Health (NIH) contracting flexibility, infra- Sepsis 0 0 6 structure improvements, and expediting the Staphylococcus 13 0 scientific peer review process, and stream- Streptococcus mutans 01 0 lining the Food and Drug Administration 12 West Nile virus B 2 0 0 approval process of countermeasures” . Authorization for appropriation of up to Sum 11 25 20 US$5.6 billion for fiscal years 2004 through *Status as of June 2005. SARS, severe acute respiratory syndrome. 2013 was given to achieve the desired goals. Project BioShield provides financial incentives (for example, government challenge for anti-infective drug develop- clearly caused companies to proceed with purchase contracts) to companies that ment. The non-pathogenic strains are caution in this area. Treatment with mAbs invest in the development of bioterrorism beneficial intestinal flora and anti-infective is passive immunization, but unlike vac- countermeasures. However, it must be drugs are usually not selective enough to cination, anti-infective mAbs can provide noted that so far few companies have been differentiate one from the other variety. only short-term prophylaxis. The parenteral enticed by the opportunities, due in part routes of administration for mAbs are to the lack of a clearly defined market for Cautious optimism: 2006 and beyond decidedly less convenient than the oral the resulting products13. The deficiencies As technology advances in the 2000s, administration of many anti-infective of Project BioShield have been recognized companies are increasingly exploiting drugs. Production of mAbs is complicated and various new provisions and additional the benefits of mAbs (for example, high and costly compared with that of many vac- inducements are being considered for a specificity and effective recruitment of the cines and drugs. So far, the most optimistic revised version of the legislation14. The immune system), while reducing obstacles to overall approval success rate we calculated proposed Project BioShield II Act was their development (for example, anti-mAb for anti-infective mAbs (11%) is lower under discussion by the US Senate immune reactions and complex production). than that for anti-infective drugs (16%) Committee on Health, Education, Labor, In general, the unique functionalities and produced by major pharmaceutical firms11, and Pensions as of July 2005. higher probabilities of approval success though it must be noted that some of the Another source of funding for the of mAbs compared with small molecules approved anti-infective drugs are derivative development of anti-infective agents is make them attractive for diversification of versions of previously successful products, available through NIH ‘challenge grants’. company pipelines. However, only a small whereas the approved anti-infective mAb The programme specifically supports number of anti-infective mAbs are currently is novel. As a consequence of these factors, development of product candidates such as under clinical study and few seem ready to competition from vaccines and anti- therapeutics and vaccines against Category enter the clinic. infective drugs has focused mAb develop- A, B and C priority pathogens. Various Challenges specific to the development ment in niche applications in which phases of development can be funded of mAbs as anti-infective agents have medical need exists for new treatments. through challenge grants, including early

validation, production and preclinical and to ensure safe use, and patient labelling 5. Hector, R. F., Collins, M. S. & Pennington, J. E. Treatment of experimental Pseudomonas aeruginosa early clinical studies, though not all phases must explain that the approval was based on pneumonia with a human IgM monoclonal antibody. are covered in every request for applications efficacy studies conducted in animals alone. J. Infect. Dis. 160, 483–489 (1989). 6. Khazaeli, M. B., Conry, R. M. & LoBuglio, A. F. issued by NIH. Anti-infective mAb development is a Human immune response to monoclonal antibodies. Development of anti-infective agents difficult endeavour, but the prevailing condi- J. Immunother. 15, 42–52 (1994). 7. Angus, D. C. et al. E5 murine monoclonal can also be facilitated through use of FDA tions have opened up new opportunities. antiendotoxin antibody in Gram-negative sepsis: a regulations colloquially referred to as the Traditional approaches such as use of randomized controlled trial. JAMA 283, 1723–1730 (2000). ‘animal rule’. This rule was proposed in vaccines and anti-infective drugs have 8. Inglis, T. J. J. et al. Monoclonal antiendotoxin agent 1999 and published in final form in 200215. failed to control the spread of any number HA-1A (Centoxin). Lancet 341, 303 (1993). 9. National Institutes of Health web site [online], The animal rule states that FDA approval of infectious agents, so the need for novel may be based on evidence of effectiveness therapeutics still exists. A greater appreciation (2005). 10. Garber, D. A., Silvestri, G. & Feinberg, M. B. Prospects from adequate and well-controlled studies for the ease of both intentional and uninten- for an AIDS vaccine: three big questions, no easy in animals. However, safety in humans tional spread of infectious agents has caused answers. Lancet Infect. Dis. 4, 397–413 (2004). 11. Kola, I. & Landis, J. Can the pharmaceutical industry must also be established and results of the government to make additional funding reduce attrition rates? Nature Rev. Drug Discov. 3, animal studies must establish that the available for the development of anti-infective 711–715 (2004). 12. Project BioShield Act of 2004. US Public Law product is reasonably likely to produce products and to modify regulations for their 108–276 (2004 July 21); 42 USC 247d-6a; 1 clinical benefit in humans. Approvals under approval. Companies now need to capitalize 18 Stat. 835. 13. Usdin, S. Bioshield hammered. BioCentury 13(32), the rule therefore absolutely require the on these opportunities to meet the need for A14 (2005). existence of appropriate animal models for new anti-infective mAbs, though some cau- 14. Project BioShield II Act of 2005. S.975 (2005 April 29). the infectious diseases. tion is advisable in cases in which the markets 15. Federal Register. New drug and biological drug The animal rule regulations specify the for these products are not well defined. products; evidence needed to demonstrate effectiveness of new drugs when human evidence that is needed to demonstrate the Janice M. Reichert is at Tufts University, efficacy studies are not ethical or feasible. 67, effectiveness of new drugs and biological Tufts Center for the Study of Drug Development, 37988–37998 (2002). 192 South Street, Suite 550, Boston, drug products when human efficacy studies Acknowledgements are not ethical or feasible. These condi- Massachusetts 02111, USA. The authors gratefully acknowledge the assistance of the companies that provided survey data. We also thank G. Laroia tions exist for a number of anti-infective Matthew C. Dewitz is at New York University School for reviewing the manuscript and for providing helpful bioterrorism countermeasures because it of Law, 40 Washington Square, New York, comments and suggestions. is usually unethical to induce or encourage New York 10013, USA. Correspondence to J.M.R. e-mail: [email protected] Competing interests statement infection in human subjects as a means to The authors declare no competing financial interests. doi:10.1038/nrd1987 study product effectiveness, and rigorous DATABASES efficacy studies are not feasible in cases 1. Reichert, J. M. Monoclonal antibodies in the clinic. The following terms in this article are linked online to: of uncommon natural infections, such as Nature Biotechnol. 19, 819–822 (2001). OMIM: http://www.ncbi.nlm.nih.gov/entrez/query. 2. Reichert, J. M. Therapeutic monoclonal antibodies: fcgi?db=OMIM anthrax infection. A number of strings trends in development and approval in the US. Rheumatoid arthritis come attached to an approval under the Curr. Opin. Mol. Ther. 4, 110–118 (2002). 3. Reichert, J. & Pavlou, A. Monoclonal antibodies FURTHER INFORMATION rule — post-marketing studies must be market. Nature Rev. Drug Discov. 3, 383–384 (2004). Tufts Center for the Study of Drug Development: http:// done when such studies are ethical and 4. Reichert, J. M., Rosensweig, C. J., Faden, L. B. & csdd.tufts.edu/ Dewitz, M. C. Monoclonal antibody successes in the Access to this interactive links box is free online. feasible, the FDA may restrict distribution clinic. Nature Biotechnol. 23, 1073–1078 (2005).