The pharmaceutical industry (with a global turnover of $800 billion) which can be proud of its achievement for the progress in human Health, is now suffering from an unprecedented innovation crisis. Over the last fifteen years, the number of new drugs has fallen by a factor of three, despite an equivalent-fold rise in annual R&D expenditure! Despite good toxicity and efficacy results in animal models, 92% of all drug candidates fail in clinical trials due to poor safety or weak efficacy. Moreover, it takes an average of 16 years to get a drug to market. This innovation crisis has serious socio-economic consequences: the majority of the population is affected by non-treatable or poorly-treated diseases and this proportion is constantly rising in the elderly. Furthermore, worldwide awareness of medical and social priorities is growing. Faced with these changes, healthcare budgets across the globe are under pressure. It has become essential to find solutions - and rapidly.

Even though drug registration procedures have certainly become more stringent in recent years, many  scientists from academia and from industry consider that drug development failures are mainly due to biological complexity and that the current "one drug, one disease" paradigm (in which a single chemical entity is used to treat a generally multifactorial disease) has reached its limits.

The new paradigm developed by Pharnext targets all of today's major unmet medical needs (i.e. diseases that lack satisfactory treatments) by moving from conventional monotherapy to PleotherapyTM based on biological network extensive and proprietary new knowledge. PleotherapyTM combines in a single, patented PleodrugTM, mini-doses of several drugs already approved by healthcare authorities for other diseases - diseases that are unrelated from a clinical viewpoint but linked in terms of the underlying biological networks. PleotherapyTM is based on network pharmacology and targets several molecular nodes in a disease-perturbed network and thus helps to increase the treatment's efficacy and safety; thanks to the synergy between the drugs in the "cocktail", doses 10- to 100-fold lower than usual can be administered.

Each biological function is executed by a complex set of molecules, proteins and metabolites ( sugars, lipids, vitamins, metals and so on) orchestrated in a single network. The activities of all the molecules in the same network are interconnected; if the activity of one molecule varies, activity of the others will vary in such manner that the functional state of the network will be maintained. This is why life can be said to rely on regulated molecular networks. Since this regulation is robust, changing the state of a network by modifying the activity of a single molecule is rarely achieved. In most cases, changing the state of a function requires multiple actions on several molecules of its underlying network. This is also true of the triggering process for diseases, most of which are multifactorial. Moreover, different parts of the same network will be affected in different patients, resulting in disease heterogeneity - the same disease, the same network but different disease mechanisms.

Network robustness is the basis of the scientific rationale whereby diseases might be better treated by simultaneously targeting different proteins in the same network. It is well established that many diseases (such as cancer, arterial hypertension, bacterial infections, immunosuppression, AIDS, etc.) are better treated by using simultaneously several drugs (multi-target drug combination), each of which modulates the activity of a given protein of the same network …). This is the principle behind the increasingly popular "network pharmacology" approach, which simply aims at treating diseases by combining actions against different targets in the same network. This can be achieved by combining various drugs, the best-known advantage of which is the possibility of lowering the dose of each individual drug because of the synergistic or additive effect of such combinations. This results in safer treatments which can be designed into the upstream phases of pharmaceutical R&D, instead of being postponed as part of an empirical, post-marketing strategy.

All elements of PleotherapyTM based on netwotk biology have been demonstrated separately in man.

i) Combining drugs for the same indication results in higher efficacy and safety.

ii) Repurposing a single drug for a new indication is becoming common but mostly found by chance or by tedious and low yield high throughput screening  . A fair number of successes have been recently obtained in man with single "other disease" drugs deduced from embryonic reconstructed network built with human genetic data.

To date, systematic network pharmacology capacity has been mostly limited because overall biological networks involved in disease are still poorly known, especially in man. This is clearly the missing link. Pharnext has developed a sophisticated approach, called Nexus, for reconstructing extensive networks from complex human genetic data and functional genomics data. The efficacy of the process has been confirmed by the success rate observed when testing the deduced "other disease" drug candidate in relevant disease models. Indeed, the success rate is as high as 30% to 50 %, versus just a few percent as expected by chance.

Thanks to the Nexus process, Pharnext has the ability to systematically apply network pharmacology to most diseases.

Monotherapy is not really ending but it might have reached its limits as such. In fact, monotherapy is the starting point for PleotherapyTM, which combines several single-target drugs. Applied today to approved drugs, PleotherapyTM will probably evolve by including drugs designed for new targets but which have failed for efficacy or safety reasons; these compounds could be used at much lower doses by combining them with other drugs. PleotherapyTM might constitute an efficient drug rescue engine. Better network knowledge might also stimulate interest in the remaining orphan targets i.e. proteins that still lack drugs.

The Human Genome Program impact on the pharmaceutical industry has apparently been rather disappointing. Many new pharmaceutical targets have been identified but most new drugs have failed - probably because they were designed for monotherapy, which does not take biological complexity into account.

The real impact will become more visible now, since knowledge of the human genome sequence is enabling the exhaustive genetic analysis of most disease; it is now possible to analyze every human gene in thousands of individuals in a single experiment. This allows the reconstruction of overall disease networks which represent the starting points of network pharmacology - now considered as the new paradigm. Moreover, PleotherapyTM will probably take advantage of newly designed drugs which turned out to disappointing in monotherapy..

Network pharmacology is the science of designing multitarget treatments based on network knowledge, whereas PleotherapyTM is one of the potential outputs of this science: i.e. for a given disease, combining already approved drugs at low doses. As an alternative output of network pharmacology, one can imagine the creation of single new molecules capable of simultaneous targeting several proteins. This has the drawback of again relying on new molecules, which might still generate safety and regulatory problems. Moreover, it will be difficult, for the moment, to control the relative activity against each target and it will be a challenge to create complex molecules acting on more than 2 or 3 targets. In contrast, there is virtually no limit with drug mixture. Pharnext has already obtained good results with combinations of up to 6 drugs.

Yes, because new uses of existing drugs can be patented as an invention. Likewise, inventions involving a new dose or a new synergistic combination can also be protected. Moreover, a new formulation can improve the combination's pharmaceutical properties.

It has been suggested that personalized medicine can solve problems related to the individual variability in safety and efficacy which characterizes classic, single-target drugs but thid might become less an issue or even obsolete with PleotherapyTM. Firstly, PleodrugsTM would be much safer. Second, it is very likely that variability of response with conventional drugs often results from disease heterogeneity, i.e. different types of perturbation in the same network in different individuals. Therefore, using a single drug would generate a therapeutic response in some individuals only. Using a mixture of drugs that all hit the same network would generate a therapeutic response in more individuals, whereas the synergy of the cocktail means that each individual would respond better. So, PleotherapyTM would not only generate higher individual response rates (allowing lower doses) but also better population response rates (i.e. more responders). The increasingly challenged blockbuster model would therefore persist, thanks to PleotherapyTM.

Infectious diseases are primarily due to infectious agents and it is already common to use drug combinations to neutralize the latter (e.g. the AIDS virus and various bacterial infections, including tuberculosis). However, the tolerability to infectious agents varies from individual to individual, depending mostly on genetic factors. Many major infectious diseases (tuberculosis, viral hepatitis and even AIDS, for example) are known to have healthy carriers. Malaria kills 2 million children every year but many more children than that are infected. One can struggle against this particular fragility to infectious agents by analyzing the genetic factors that influence this fragility and then reconstructing the corresponding network. Hence, one could design PleodrugsTM which would protect fragile subjects.

To the best of our knowledge, Pharnext is the first company to implement such a systematic process based on advanced network biology and still benefits from several years' head start. However, we anticipate that this approach will become widely used in the coming decades.

Nexus is the process allowing Pharnext to reconstruct pathological molecular networks, the missing link in network pharmacology. Nexus is a labor intensive process lasting 10 months and based on a highly iterative usage of in house algorithms. Networks are deduced from complex human genetics data, functional genomics data and all kind of published biological and pharmacological data.

Part of the process has been applied for patent but most of it has been kept as trade secret.  The process, which cannot be automated, requires highly qualified scientists specifically trained for the purpose during 4 years. It reflects many years of scientific thinking and experience. In the next 2 years Nexus will have been applied to at least 15 diseases. Corresponding therapeutic and diagnostic patents will have been filed and will block competition.

The process can be applied to any chronic disease, provided enough genomics information is available (which is now the case for most diseases). Once a disease has been selected, the corresponding network is reconstructed in silico using the NexusTM process. Generally, around 50 off-patent, "other disease" drugs are deduced. These drugs are tested one by one in cell-based disease models and then animal disease models. Positive compounds are then tested in combinations. The most efficient, synergistic combination is selected as the lead, which enters into pharmaceutical development, including simplified regulatory preclinical studies,  then Phase I-IIa or even directly to Phase II . At this stage, the product will be licensed to a partner who will proceed with further development and marketing. The overall R&D process is shortened by several years, compared to the standard process - mostly during the preclinical phase because known, approved drugs are used. The first-in-man trial would occur generally 2-3 years after the R&D program initiation, instead the usual 6-8 years.

This process has been applied to Charcot-Marie-Tooth disease, where the corresponding network was reconstructed from the 30 human genes known to be involved in the disease. Different cocktails of existing "other disease", off-patent drugs were deduced and generated impressive results in relevant cell-based and animal models. When assembled into a single pill, these cocktails are expected to be safe in humans because (i) they are made up of approved drugs and (ii) each drug is administered at very low dose - up to 100 times less than for the standard indication. This dose lowering is possible because of two reasons i) the synergy/additivity between the combined drugs, which all focus on a single network and ii) when repurposing, the dose for the new indication may  be lower than for the first one (aspirin anticoagulant effect  when compared to its antalgic effect is observed at 8 times lower dose)    The CMT program entered into Phase II development  with PXT03003 , a  combination of 3 approved drugs at low dose,   in December 2010, only 3 years after initiation instead of the usual 8 years.

Besides Charcot-Marie-Tooth disease, Pharnext has developed a patented pipeline of PleodrugsTM on several severe neurological diseases (including Alzheimer's disease with anticipated entering in Man end 2011 or early 2012) and is extending it to the major unmet needs in human pathologies worldwide such as type II Diabetes. This might well be the first case in biotech history of a technology with such broad medical applications.

It is already known that combining drugs that act on several proteins in the same network is more efficient than using a single drug. Networks are robustly regulated and they can compensate when one single element is modified. Acting on several points circumvents this natural resistance. So, compared with single drugs, drug combination  are more likely to induce a clear therapeutic effect.

A good safety profile is expected firstly because PleotherapyTM uses approved drugs which, by definition, are safe for use in humans. Secondly, our preclinical data suggest that these approved drugs can be used at much lower doses than for their current indication - up to 10 to 100 times less! It is already known than combining synergistic drugs enables dose reductions and that with repurposed drugs, the doses  used for  different  indications might largely differ.

Most proteins belong to several different biological networks and are involved in several different biological functions. This is termed pleotropy. Therefore, one can expect that a drug targeting a given protein could be used for several different diseases. Pleotropy is a universal property of the components from any complex system. If, for example, we draw a parallel between humans and proteins, each human has also several, unrelated function, for example: being a parent, paying tax, consuming oxygen, etc.

Drug repurposing (also known as drug repositioning) is mostly achieved by serendipity while cautiously analyzing drug side effects. As an example, aspirin is well known to have at least 3 very different therapeutic effects as an antipyretic (lowering fever), an analgesic (decreasing pain) and an anticoagulant. However, a fair number of successes have been recently obtained in man with single "other disease" drugs for which the new indication was deduced from an embryonic disease network reconstructed from human genetic data.

At Pharnext, this latter process has been systematically implemented thanks to Nexus, its protected technology. Extensive diseased networks are reconstructed in man mostly from complex genetic and functional genomics data . These networks involve several hundreds or thousands of proteins, of which some are already targeted by approved drugs (but for other diseases - precisely because of pleotropy). In Pharnext's experience, by starting from about 1000 existing drugs, an average of 100 to 50 "other disease" drug candidates can be identified from a reconstructed network for any given pathology. The efficacy of these drugs alone and then in combination is tested in relevant disease models and then in man via a rather standard clinical development process, altough simplified because drugs have been already approved by regulatory authorities.

Mainly because pleotropy is now better understood since the human genome has been sequenced - especially following the realization that the number of human genes was rather small, relative to the large number of functions required for life. This suggests that each human gene and protein must be involved in several functions. Moreover, refined analysis of several protein functions has confirmed that pleotropy is quite common .

Starting from 2000 existing drugs, Nexus deduces about 50 "other disease" drugs in silico for a given disease; this is the first filter. These 50 drugs are then tested alone in relevant disease models. Drugs found to be individually effective are then assembled into preferred, low-dose combinations (according to Nexus in silico predictions) and are then tested in pertinent models.

We cannot rule out this possibility which is observed sometime with normal dosages; however, this is less likely to happen at the low doses used in PleotherapyTM. Moreover PleodrugTM safety will be assessed, when necessary against the usual, strict, regulatory standards. The Pharnext process also enables parallel, upstream design of independent back-up drug combination if problems occur during development.

Combining drugs is becoming a common process in pharmaceutical science. As usual, PleodrugsTM must satisfy normal regulatory standards including plausibility, safety and efficacy. Synergy or additivity between drugs must be scientifically proven when possible. PleotherapyTM will be especially useful when it (i) uses drugs that have been approved for other diseases at very low doses, (ii) has a high benefit/risk ratio and (iii) provides solutions for unmet medical needs.

This is a Pharnext trade secret for the moment

This would be achieved by giving an adult no more than the dose which would be given to a newborn in monotherapy - 25 to 100 times less, when even 10 times less would be satisfactory.

1. High Rate of single drug repurposing at low dose in models , reaching 20% to 50% of Nexus predicted drugs, in 5/5 unmet medical need diseases, validates robustness of Pharnext's technology and the pertinence of its new extensive disease networks generated from Human data.
2. Until now Pharnext was able to find PleodrugTM candidates in 3/3 unmet medical need within less than 3 years. As mentioned above, clinical development success rate of such candidates will be more than 3 times higher than classical drugs as expected with such low toxicity risk profiles:

i.e. Failure rate due to toxicity at each stage of development in human is well established. Since, as a result of low drug dosing of already approved drugs, the risk of toxicity of Pharnext PleodrugsTM become negligible, their development success rate can be calculated and is expected to reach up to 24 % instead of the classical 8 %. Moreover, as a better therapeutic efficacy is very likely when using combination, this success rate would be even higher.

3. CMT program entered in Phase II after only 3 years of Research instead of the usual 8 years with a 3 compounds PleodrugTM administered at 10 to 100 times lower doses.