Small Molecule, Peptide, and Protein-based Drugs – The Differences and Similarities
Biotechnology has created a broad range of therapies, called biologics which include vaccines, cell or gene therapies, therapeutic protein hormones, cytokines and tissue growth factors, and monoclonal antibodies. In this discussion we will focus on the subset of biologics that are protein-based drugs which are presently managed by the FDA Center for Drugs Evaluation and Research (CDER): monoclonal antibodies, cytokines, tissue growth factors and therpeutic proteins. Some of the data that we will show includes all biologics. Modern protein-based drugs arise through the processes of genetic engineering.
It has been a little over thirty years since human insulin received U.S. approval (1982) as the first genetically engineered protein-based drug. Since then protein-based drugs have become a major force in the bio/pharmaceutical industry. As seen in Table 1, based on worldwide sales, eight out of the top 20 biopharmaceuticals in 2012 were Protein-based Drugs. (Ref 1, 2) In fact seven of the top 10 were protein-based drugs!
Table 1, Eight of the Top Twenty Biopharmaceuticals Worldwide in 2012 are Protein-based Drugs (Data from references 1, 2 US Ranking.3 Copaxone ranked 9th in US Sales (Ref 3), and was unranked in worldwide sales. (Ref 1&2)
This may come as a surprise to many in the U.S. where protein-based drugs have yet to achieve such a prominent stature. In 2012 Humira, Enbrel, Remicade, Neulasta and Rituxan were in the top 10 drugs based on U.S. sales, but the small molecules Nexium, Abilify, Crestor, Advair, and Cymbalta were the top five. (Ref 3) None of the biomolecular drugs were in the top 10 in the U.S. in 2010.4 (How the rankings of drugs in the U.S. could be so different from the rest of the world is a whole other discussion.) In any event, the rise of protein-based drugs into the top tier is a recent phenomenon.
This may come as a surprise to many in the U.S. where protein-based drugs have yet to achieve such a prominent stature. In 2012 Humira, Enbrel, Remicade, Neulasta and Rituxan were in the top 10 drugs based on U.S. sales, but the small molecules Nexium, Abilify, Crestor, Advair, and Cymbalta were the top five. (Ref 3) None of the protein-based drugs were in the top 10 in the U.S. in 2010.4 (How the rankings of drugs in the U.S. could be so different from the rest of the world is a whole other discussion.) In any event, the rise of protein-based drugs into the top tier is a recent phenomenon.
Peptides are a hybrid class of drugs. They tend to be equated with proteins because of size, amino acid content and because oral activity is rare. But peptides truly bridge the gap between small molecules and proteins, in terms of physical properties, range of therapy areas and means of production. They are managed by CDER along with small molecules. Actually insulin sits right on the cusp of the protein-based world. For a number of reasons it is both a peptide and a protein-based drug. Due to such confusion many studies on small molecule and protein-based drugs either disregard peptides or lump them with small molecules or proteins.
Let us compare and contrast these three types of drugs – small molecule, peptide and protein-based drugs, and see how the Industry deals with three seemingly very different types of drugs.
The bio/pharmaceutical industry embraces the discovery and development of small molecule drugs and peptides (both referred to as New Chemical Entities or NCEs) and protein-based drugs, also called biologics (also referred to as New Biological Entities or NBEs).5 Small Molecule, peptide and protein-based drugs can take on different names over the lifetime of drug discovery and development and marketing, as shown in Fig 1 and described in Ref 5.
Figure 1, Small Molecules, peptides and proteins can take on different names over the lifetime of drug discovery and development and marketing. Biosimilars are also referred to as Follow-on Biologics. Phase length is not implied by the size of stage marker. *NME relates to the first approvable drug as opposed to second indications or new formulations. (Ref 5) The application for a generic small molecule is an “Abbreviated New Drug Application” (ANDA) which doesn’t require clinical trials to prove equivalency. Processes for biosimilars or follow-on biologics are in the discussion stage.
A biotechnology company or a biopharmaceutical company tends to focus on the discovery and development of protein-based drugs. A bio/pharmaceutical company will have the resources to discover and develop both types of drugs, NCEs and NBEs.
Since the early ‘80s the number of INDs per year from NCEs has leveled off while the INDs from NBEs have increased and helped maintain an increasing number of INDs/year (up to 1993).6 Trusheim et al. and others have studied the number of new small molecule drug approvals (NMEs) compared to new biologic drug approvals (new BLAs) in the period between 1988-2008, Table 2.7
Table 2, Numbers of New Small Molecule Drug Approvals per Year (NMEs) Compared to New Biologic Drug Approvals (new BLAs) 1988-2008. (Ref. 7) Biologics here are not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins. Last line* shows therapeutic proteins and Mabs from Reichert 8 We extended the tally by Reichert beyond 2003 by adding our own count of Mab and therapeutic protein new BLAs from annual FDA reports through 2008. Mullard 9 and Kneller 10 recently published counts of NMEs and New BLAs which differ somewhat from Trusheim (Ref 7) or Reichert (Ref 8). We are not in a position to rectify the differences, except to offer a potential explanation – certain small peptide and protein drugs may be considered either biologics or small molecules (Kneller considered such drugs to be biologics).
The analysis by Trusheim et al. was not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins. They found that from 1988 to 2003 the industry averaged 34 NMEs and new BLAs per year, whereas from 2004-2008 the industry averaged only 21 NMEs and new BLAs per year. Within those two periods the percentage of new BLAs was quite similar (31% vs 32%). (Ref 7) To add some perspective we include the mabs and therapeutic proteins counted by Reichert. (Ref 4) By the numbers, all biologics are making a substantial contribution to the number of new drugs approved per year.
By 1997 worldwide sales of biologics were over $7 billion dollars. The global sales of biologics have continued to rise – monoclonal antibodies alone in 2006 totaled $4.7 billion dollars.11
A popular misconception is that in the early days most of the new biologics were discovered and developed within biotech companies. Certainly few of the classically NCE-oriented companies entered the NBE arena – The pharmaceutical companies J&J (Ortho Biotech), Lilly and Roche were early players, getting BLAs approved in the ‘80s, Table 3.12
Table 3, Early Biotech and Drug Company Protein-Based Drug Approvals (without Diagnostics) (Ref 8, 9)
But 50% of the BLAs in the 80’s came from drug companies. In the ‘90s, 52% of the BLAs came from drug companies (data from Table 3). Thus while a lot of investment may have gone into biotech startups, it was the previous experience of the drug companies with bringing drugs to market that made them at least equal partners in that aspect of protein-based R&D. Still only 17 drug companies and 16 biotech companies got BLAs in the ‘80s and ‘90s which is a small subset of the pharmaceutical industry. By 1998 the PhRMA determined that more than 140 US-based companies were engaged in protein-based drug development. (Ref 8) Most likely many more pharmaceutical companies were investing in biotech in that period. The investment in protein-based drugs was enormous and the payout uncertain. As with the discovery and development of any drug it took years before the new biotechs achieved their first BLA, over 14 years on average, Table 4.
Table 4 Early Biotech Approvals – Years Since Founding. (Based on data from Ref 9 )
While many of the discoveries of new protein-based drugs continue to originate in biotech companies, the clinical development of new protein-based drugs are increasingly supported by large pharma which had been NCE-oriented, Table 3.13
In recent years most of the large pharma have gained an expertise in biologics through entry into field, and also through acquisitions and are now bio/pharmaceutical companies, Table 5. (Ref 8). The acquisition of Genzyme by Sanofi-Aventis is a most recent example.14
Table 5, Notable Acquisitions and Partnerships involving Biologics (Ref. 8, Ref. 10, Ref. 11)
A recent collaborative study by Deloitte and Thomson Reuters showed that the twelve top bio/pharmaceutical companies all had biologics in their late stage portfolios, ranging from 21-66% of their portfolios (avg. 39%).15
Prior to the ‘80s there were sufficiently few protein-based drugs that the very term “pharmaceutical” or “drug” was taken to mean small molecule. With the exception of insulin, the few proteins approved for human use were administered by a trained health practitioner and were often considered “therapies”. Thus one may see the comparison of “small molecule drugs (or pharmaceuticals) versus large molecule therapies”. Here we will consider a large molecule therapy that is regulated by CDER to be a protein-based type of drug or pharmaceutical.
The term for first small molecule drug approval, or New Molecular Entity (NME) could in theory be applied to first biologic approval, but because NME has long been associated with small molecules and because the approval processes are different, NME is not associated with first biologic approval – which is simply called a new BLA. (Ref. 5)
On March 23, 2010 President Obama signed into law the Biologics Price Competition and Innovation Act (BPCIA) which provides for biosimilar biologic drug approvals, as part of the omnibus health care bill. As the FDA develops guidelines for biosimilar approvals and begins to review applications for biosimilars, biologics will begin to enter the large generics market in the U.S. Of course most of these biologics will be protein-based drugs.
The Processes that Give Rise to Protein-Based Drugs. Human insulin was the first recombinant biopharmaceutical approved in the U.S. in 1982. Prior to that protein products approved for use in humans were extracted from natural sources. It is beyond the scope of this website to delve into the details of the processes that give rise to small molecule, peptide or protein-based drugs. The following are good general references that cover the processes involved in the discovery and development of both small molecule drug, peptide and protein-based drugs.16,17
The Progression of Technologies that Fueled the Development of Small Molecule, Peptide and Protein-based Drugs. In this attempt to contrast small molecule drugs with peptide and protein-based drugs an important theme arises. There was a similar progression of technologies that fueled the development of small molecule, peptide and protein-based drugs. Small molecules went through this progression first, but peptides and proteins have followed the same path.
- Working with What Nature Provides
- Early Remedies. The first remedies came from the isolation and purification of pharmacologically important compounds from nature.
- Developing Methods for Reliable Synthesis. As the market grew for these early pharmaceuticals, the demand for the purified compounds increase. Once methods for reliable synthesis are achieved, a number of technological advances may follow.
- Going Beyond What Nature Provides
- Searching for Analogs with Enhanced Properties. Through methods of synthesis analogs of the native substance can be obtained. Structure-Activity relationships lead to the discovery of medicines with properties that exceed what nature provides.
- Target-Based Lead Identification. The study of molecular interactions of drug and biological target are now feasible. Substances with structures unrelated to the native remedy can be evaluated for their potential as therapeutic agents to the disease indication.
- Combinatorial Chemistry. In principle, rapid synthesis of thousands of analogs will speed the search for analogs with optimal properties. If a target-based screen can be included in ant iterative cycle the identification of novel agents can occur even faster.
The reader will likely understand the small molecule analogy to this progression. In our e-book, discussed below, we show how peptide and protein-based drugs have gone through the progression.
Understanding the Differences and Similarities Between Small Molecule, Peptide and Protein-Based Drugs. Now, more than ever, anyone interested in understanding the bio/pharmaceutical industry will need to understand the differences and similarities between small molecule, peptide and protein-based drugs and their discovery and development as drugs.
We provide several ways to learn more about this subject.
A. Dr. Samanen periodically gives presentations on the subject, as noted in our Meetings and Presentations page.
B. We have prepared a e-Book entitled “Small Molecule, Peptide and Protein-Based Drugs – The Differences and Similarities.” In this e-book, we endeavor to shed light on the differences and similarities in the discovery and development of small molecule, peptide and protein-based drugs. The paper is packed with references gleaned from our review of the literature. It covers the recent study by Trusheim et al. (Ref. 7) and includes highlights from the recent analysis of drug approvals sponsored by the Biotechnology Industry Organization.18
We have organized the discussion into the following topics.
1. How Do Small Molecule Drugs Differ from Peptide and Protein-Based Drugs?
One has only to consider the size of biologics to recognize that the technologies that give rise to protein-based drugs must be considerably different from the classical small molecule drugs and from peptide drugs. Genentech equates the difference between aspirin (21 atoms) and an antibody (~25,000 atoms) to the difference in weight between a bicycle (~20 lbs) and a business jet (~30,000 lbs).19 We will consider how they differ with respect to distribution, metabolism, serum half-life, typical dosing regimen, toxicity, species reactivity, antigenicity, clearance mechanisms, and drug-drug interactions (especially small molecule/biologic drug interactions). We also consider differences in Success Rates, Cycle Times, Cost, CMC and Pricing Strategies.
A project leader who has worked in one field and is now facing the prospect of leading a project in the other field should become familiar with these differences as they will give rise to issues that the project leader may not have faced before.
2. Historical Changes in FDA Biologics Oversite in Response to the Biotech Boom
Prior to the ‘80s biologics were extracted from natural sources and required different regulatory oversight than that of small molecule drugs. Since then, the production of biologics shifted to recombinant proteins, which involved more consistent production processes, and the number of approvals has risen dramatically. We will review how FDA oversight has changed to accommodate the boom in biotechnology.
3. The Progression of Technologies that Fueled the Development of Small Molecule, Peptide and Protein-based Drugs.
As mentioned above, we show how peptide and protein-based drugs have gone through the progression of technologies that first occurred for small molecule drugs.
4. Case Studies – Glycoprotein IIB/IIIA Antagonists, and Insulin
We take a close look at the development of GPIIB/IIIA antagonists which provided small molecule, peptide and protein-based drugs, provided a first example of rational design of Oral Nonpeptide Mimetics from Peptides, and were one of the first successful examples of inhibitors of protein-protein interaction.
Insulin! So many firsts! One could write a history of drug discovery on insulin and the field of agents to manage diabetes. We cover the highlights.
5. Biosimilar and Biobetter Macromolecules versus Generic Small Molecules
Those early biotechnology wonder drugs are now facing patent expiration. The industry has been engaged in an intense debate as to how a generic protein-based drug, aka biosimilar or follow-on biologic) can be approved and managed by the same regulations that govern generic small molecule drugs. The issues are complex, arising out of the considerable differences between small molecules and biologics. More recently big biopharma have taken an interest biobetters. A biobetter is a biologic which has a purposefully modified structure from the original that allows it to be afforded patent protection and pricing strategy akin to the original biologic because it is in some way “better” than the original.
6. Discovery and Preclinical Stages – Where the Technologies Differ the Most– Small Molecules vs Biologics
It is in the stages of Discovery and Preclinical Development where the technologies are most different. We outline the differences and similarities between small molecules and biologics in Lead Discovery, Lead Optimization and Preclinical Development.
7. Small Molecule and Biologics Approvals by Therapy Areas
With technological advances in the discovery and development of biologics most therapy areas (80%) are now amenable to either a small molecule or biologic strategy.
8. Managing Small Molecule, Peptide & Protein-Based Drug R&D in the Same Company
The bio/pharmaceutical company that has the resources to discover and develop all of these types of drugs will inevitably face the challenge of organizing these activities. The reader will learn that small molecules and peptides can be readily managed in the same manner. We argue that the fact that small molecule/peptides and biologics can be managed with the same milestones and stages argues for treating both strategies in the same portfolio. The savvy portfolio manager will understand the differences and ensure the differences are transparent from a portfolio perspective.
To find out how to obtain a copy of this e-book, please click on this LINK which takes you to the Downloads page at www.jamessamanenconsulting.com.
C. If you have an individual need that is not met by these options please contact us. We welcome the opportunity to serve you.
- J. D. Carroll, “The 15 best-selling drugs of 2012”, October 9, 2012, http://www.fiercepharma.com/special-reports/15-best-selling-drugs-2012. ↩
- “Top 20 Best-Selling Drugs of 2012”, http://www.genengnews.com/insight-and-intelligenceand153/top-20-best-selling-drugs-of-2012. ↩
- “Top 100 Drugs for 2012 by Sales”, http://www.drugs.com/stats/top100/2012/sales. ↩
- M. Herper, The Best-Selling Drugs In America”, Apr. 19, 2011 http://www.forbes.com/sites/matthewherper/2011/04/19/the-best-selling-drugs-in-america/. ↩
- Small molecule and peptide drugs that are approved by the FDA are referred to as New Chemical Entitites (NCEs) while the approved biologics are referred to as New Biological Entities (NBEs). The new drug application for an NCE is called a New Drug Application (NDA) whereas a new drug application for an NBE is called a Biologic License Application (BLA). Since NDAs can be granted for secondary indications and formulations of previously approved drugs the term New Molecular Entity (NME) is given to those NDAs that are first in kind. This can lead to some confusion, since the FDA can also grant BLAs to secondary indications and formulations. But even within the FDA NME continues to be used only for first small molecule drug approvals. First protein-based drug approvals are simply referred to as New BLAs. The term NME became important with the Hatch-Waxman Act to provide extra protection to new drug NDAs, which tend to suffer longer approval times than NDAs for new formulations or second indications as discussed in – www.fdli.org/pubs/journal/toc/vol54_2.html ↩
- J. A. Dimasi, “New Drug Development in the United States from 1963 to 1999”, Clin. Pharmacol. Ther. 69, 286-296, 2001. ↩
- M. R. Trusheim, M. L. Aitken, and E. R. Berndt, “Characterizing Markets for Biopharmaceutical Innovations: Do Biologics Differ from Small Molecules?” Forum for Health Economics & Policy, 2010 13, issue 1, article 4. ↩
- J. Reichert “Biopharmaceutical Approvals in the U.S. Increase”, Reg. Affairs Journals Pharma, July, 1-7 2004. ↩
- A. Mullard, “2010 FDA Approvals”, Nat. Rev. Drug Disc. 2011, 10, p82-85. ↩
- R. Kneller, “The importance of New Companies for Drug Discovery: Origins of a Decade of New Drugs”, Nat. Rev. Drug Disc. 2010, 9, p867-882. ↩
- K. Maggon, “Monoclonal Antibody Gold Rush” Curr Med Chem 2007 14 p1978-1987. See also A M Thayer , “Great Expectations” Chem Eng News 1998 No. 76. ↩
- J. M. Reichert, and c. Paquette, “Therapeutic recombinant proteins: Trends in US approvals 1982 to 2002”, Curr. Op. Mol. Ther. 2003 5 p139-147. ↩
- “Biotech – Lifting Big Pharma’s prospects with biologics”, The Money Tree Report, PricewaterhouseCoopers and the National Venture Capital Association based on data provided by Thomson Reuters, 2009. ↩
- Financial Times, February 16, 2011 “Conditional payment cure for pharma deals”. ↩
- Deloitte Thompson Reuters 2009 “Is R&D Earning its Investment?” www.deloitte.com/assets/Dcom-UnitedKingdom/…/UK_LS_RD_ROI.pdf. ↩
- “Biotechnology”, Chapter 12 in Bert Spilker, “Guide to Drug Development, A Comprehensive Review and Assessment”, Wolters Kluwer, Lippincott Williams & Wilkins, New York, 2009, p. 119-131. ↩
- “Drug Discovery: Large Molecule Drugs”, Chapter 4, Rick Ng, “Drugs, from Discovery to Approval”, 2nd Ed. 2009, pp. 93-135, and other sections relating to protein-based drugs, e.g. “Manufacture of Large Molecule APIs (Recombinant DNA Methods, Chapter 10.5, pp. 340-348. ↩
- BIO CEO & Investor Conference, February 15th, 2011BIO. ↩
- Please refer to: http://www.gene.com/gene/about/views/followon-biologics.html. ↩