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The Future of Peptide Development in The Pharmaceutical Industry
The Future of Peptide Development in The Pharmaceutical Industry
Rodney Lax, Ph.D., Senior Director of Business Development North America, PolyPeptide Group
A couple of weeks ago I was asked how long I thought the current interest in peptides as drug candidates would last
before another class of molecule replaces them. My answer, based on the potential for new leads from genomics and the
length of clinical evaluation, was “about another 20 years”. I realized almost immediately that I have been saying that
for at least the last 10 years. Perhaps it is time to re‐think this one. Obviously, the interest in developing new peptide
therapeutics is going to be around a lot longer.
The growing significance of peptide therapeutics The potential of peptides should be no surprise.
So what has happened in the last decade that indicates Evolution has been honing the specificity of polypeptides
that peptides drugs have a long and secure future? for millions of years. Amino acid sequences –
whether they are in peptides or in proteins – control
Well, first there is increasing amount of statistical and direct all aspects of cellular function and coordinate
evidence to support this1. Forty years ago, back in the most intercellular communication. No other class of
seventies, the average frequency of peptides entering biological molecules offers the range of chemical
clinical trials was just over one per year. Ten and diversity that peptides and proteins possess. They are
twenty years on, it was 5 and 10 per year respectively, nature’s tool kit and the more we can use native
and as we approach the end of this decade, it looks peptides or closely related analogs, the safer and
like the annual number will be close to 20. There are more specific the drugs at the physician’s disposal.
now about 60 approved peptide drugs that will An advantage over small molecules is the fact that the
generate annual sales of approximately US$ 13 billion structural relationships between peptide drug
by the end of 2010. Although this only represents candidates and the physiologically active parent
about 1.5% of all drug product sales the numbers are molecules that they were derived from substantially
increasing dramatically with a current continuous reduces the risk of unforeseen side‐reactions. This is
annual growth rate (CAGR) between 7.5% and 10%. reflected in an over 20% probability of regulatory
There are about 140 peptide candidates in the clinic approval 2 , a rate which is double that of small
and (our best guess) about another 500 – 600 in molecules. In so far as they are composed of naturally
pre‐clinical development. occurring or metabolically tolerable amino acids, they
are generally non‐toxic and, as a result, toxicology
However it is more than just the numbers. Peptide studies often consume vastly more peptide drug
therapeutics are starting to show a maturity that substance than the subsequent clinical trials. Where
reflects their potential for addressing a growing range side‐effects occur, these are often related to dosage or
of medical challenges. While about half of the local reactions at the injection site. In general,
peptides in clinical trials target indications in peptides do not cause serious immune responses,
oncology, metabolic, cardiovascular and infectious although this must always be taken into consideration,
diseases, the total range of therapeutic areas particularly for longer sequences.
addressed encompasses a wide assortment of medical
disorders from endocrinological lesions through to The impact of new technologies
pain and hematology. A noticeable increase in the Peptides have not always been the most popular
number of peptides targeting metabolic disorders has candidates for drugs and it is worth asking why and
heralded a move towards longer and more complex what might have occurred to change the bias against
molecules. There is also a willingness of both the peptides as pharmaceutical agents. For many years,
pharmaceutical industry and its contract manufacturers peptide‐based therapies were regarded as being
to consider production scales of multi‐100 kg and limited to the treatment of hormonal lesions and later
even tons using both solid‐ and solution‐phase hormone‐dependent cancer. Other indications were
synthetic strategies. not obvious at the time. In addition, peptides – due
to their chemical structure – were expensive and
Not that shorter peptides (<10 residues) are going complicated pharmaceuticals to manufacture. They
away and the growing interest in peptide‐based also often had exceptionally short half‐lives making
therapeutic vaccines is currently opening up a whole chronic administration problematic and costly.
new market for such sequences. The manufacture of However, the main downside was the lack of oral
short sequences is significantly more economical than availability. With a few notable exceptions, peptides
for longer peptides (>30 residues). Such sequences, if are degraded to their component amino acids in the
required in large quantities, are also often amenable upper gut. Given the lack of patient compliance with
to solution‐phase approaches that offer scalability drugs that require chronic self‐injection – the
advantages over solid‐phase chemistry. exception being drugs for life‐threatening diseases
In passing, one should mention that there are still An unfortunate spin‐off of the lack of clear guidance
some peptides on the market that are isolated from for setting impurity profile specifications is that many
animal sources, but their numbers are dwindling. drug product manufacturers adopt the most
There is also some re‐emerging interest in using conservative and stringent limits for peptides
enzymatic procedures (reversed proteolysis) to (effectively using small molecule API guidelines for
synthesize specific sequences. The use of free amino complex peptides) in order to ensure that “no
acids as opposed to Fmoc‐derivatives as starting regulatory issues” arise. If one considers that most
materials has great economic appeal. peptide drugs have exceptionally low toxicity and are
administered at doses between 50 μg and 50 mg,
Current challenges requiring limits for individual, unidentified
One of the challenges facing the manufacturers of impurities of less than 0.1% constitutes an element of
both peptide drug substances and peptide drug “overkill”. While such caution may be warranted for
products today is the inability of regulatory authorities some products, for many it simply results in an
on different continents to come up with a harmonized unnecessary additional cost of goods.
set of guidelines that define what level of peptide
impurities can be present in peptide therapeutics. It While few companies can – at the start of product
is a challenge for two reasons. First, no‐one in the development – specify the final dose or will be
business is totally sure what is expected of them, and prepared to commit decisively to the commercial
– secondly – designing manufacturing processes to quantities that will eventually be required , a “best
produce a higher quality product than is required guess” of the commercial scale of manufacture, the
adds significantly to the cost of goods, possibly to the time‐line to achieve this and the anticipated cost of
point where an effective drug loses its economic goods helps CMOs design appropriate manufacturing
viability. processes. As a project moves from the multi‐100
gram to the multi‐10 kg scale and beyond, the process
The underlying issue is that the term “peptide” or will almost certainly have to evolve or change. The
even “complex peptide” is too vague to have failure to recognize this early in a project may result
meaningful regulatory usage. Peptides range from in progressing past a point of no return where
sequences containing only 2 amino acids, which are changes are not acceptable from a regulatory or
obviously “small molecules”, to sequences of up to economic standpoint. The choice of counterion is an
100 residues, where historically biochemists arbitrarily example. The solubility and stability of peptides can
decided that anything larger should be called a be influenced by their salt form and the initial choice
protein. That delineation is even fuzzier today where of counterion may be disadvantageous for large scale
– in deference to insulin as the long‐standing border manufacture. However, from a regulatory standpoint
line between recombinant and chemical synthesis – different salt forms of a peptide are considered to be
sequences longer than 50 amino acids are often different drug substances and changing from one to
referred to as “small proteins”. another may, therefore, be challenging.