Vaccines for non-infectious diseases?

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Who is developing antibody-inducing vaccines for unconventional indications like different chronic diseases, addictions, autoimmune and genetic diseases? Are there vaccines which cure or prevent cancer, Alzheimer´s disease,  Parkinson´s disease or Huntington´s disease? Can we decrease high cholesterol and prevent cardiovascular diseases by a vaccine? Can be a cocaine addiction treated by a vaccine? Or can somebody quit smoking by a simple vaccination?

Results from which clinical trials are expected to be available this year? Which indications are the most attractive for vaccine developers? What are the strategies companies adopt for vaccines development? How to define an ideal vaccine composition which enables to induce a strong, effective and long lasting antibody response? What target is the mostly employed when we talk about antibody-inducing vaccines for unconventional indications? What are highs and falls of vaccines development? Do you want to compare target product profiles for more than 100 active vaccine candidates? Which companies and academic institutions are the most active in vaccines development for unconventional indications? What are the technologies behind? Many answers can be found in the report “Active immunization for unconventional indications”.

Vaccines are one of the most important treatments ever developed. Since 1796 when the first vaccine was tested (against smallpox), vaccines have saved millions of lives and many infectious diseases have been eradicated. This is a continuous process.

A traditional vaccine is a prophylactic vaccine which usually induces long-life immunity against exogenous or foreign antigens expressed on microorganisms. Usually, but not in all cases, these exogenous antigens induce a robust immune response where innate and specific immunity is involved. Immunization with weakened or dead microorganisms or their parts which have been made synthetically, protects against diseases caused by them.

Lessons have been learnt from infectious diseases and years ago people started to study vaccines for chronic diseases too, where a new challenge was introduced- inducing immune reaction against the own molecules which were thought to be involved in pathological processes. These own molecules could either be modified or overexpressed in the body or they could simply attain a structure which changed their function from a protective or normal one to a pathological one. What is important is that the body itself is not able to produce an adequate immune reaction to eradicate such overexpressed or modified molecules. There are successful efforts to help the immune system in chronic diseases by passive vaccination- by infusion of monoclonal antibodies. Therefore the way for using vaccines in indications such as cancer, metabolic diseases, cardiovascular diseases and other chronic diseases is laid open.

Furthermore, there are aims to use vaccines to tackle the “over” reaction of the immune system as is seen in allergic reactions. Here, instead of whole allergen hyposensitization being used, which is a long-lasting, expensive and sometimes not a very effective way to prepare an allergic person to be exposed to their allergen(s), new allergy vaccines are developed in a sophisticated way by creating synthetic vaccines with defined allergen antigens inducing an immune response shifting from IgE to IgGs production or vaccines simply targeting IgE itself.

We should not forget efforts made to use vaccines in the fields of human addictions, biological weapons and recently also in genetic diseases.

All these attempts try to use the best from a vaccine approach- a specific and long-lasting effect and the feasibility to treat a large number of the population without exhausting health insurance systems.

It needs to be said that in contrast to infectious disease vaccines, vaccines inducing antibodies and used for unconventional indications within the scope of the report are, with the exception of two of them, intended to be therapeutic vaccines. There is still a long way to go until there will be working prophylactic vaccines which could be used to protect people from diseases such as various cancers, Alzheimer’s disease, seasonal allergy, smoking addition or obesity. Results from therapeutic vaccinations along with intensive biomarker research and an in depth understanding of the etiology of diseases are paving the way for prophylactic vaccines.

The majority of vaccines for unconventional indications are in development in biotech companies and at universities.

There are however also some big pharma companies involved at the moment in active development which indicates that this approach to bring vaccines to unconventional indications has attracted attention also from big pharma players, sometimes with their own experience with vaccines against infectious diseases.

The year 2016 will be quite unique in regards to development of active vaccinations for non-traditional indications within the scope of the report– there should be results available from about 20 Phase III to Phase I trials.

Cell vaccine Algenpantucel-L has failed in a Phase III

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The IMPRESS Phase III trial NCT01072981 has been to assess an overall survival after treatment with a regimen of adjuvant therapy (Gemcitabine alone or with 5-FU chemoradiation) with or without HyperAcute®-Pancreas (Algenpantucel-L) immunotherapy in  patients with surgically resected pancreatic cancer. The study started in 2010.

An opposite of what was expected has happened as announced in May 2016 by NewLink Genetics. The median survival was 30.4 months and 27.3 months for the control and study groups, respectively.

When the report “Active immunization for unconventional indications” was in preparation, it were included among antibody-inducing vaccines also cell vaccines from the company named NewLink Genetics. The cell vaccines have been developed via their HyperAcute® platform. They are included in the mentioned report under the “Selected special antibody-inducing vaccines”. These cell vaccines are inducing polyclonal antibodies and a T-cell response as well.

The way how cancer cell antigens are introduced within the HyperAcute® platform to an immune system looks very elegant. Algenpantucel-L consists of 2 pancreatic cancer cell lines (HAPa-1 and HAPa-2) that have been modified to express α-gal. After destroying of infused cells by hyperacute reaction the antigens present on these cells are processed by patient´s immune cells. Because cancer-specific antigens within Algenpantucel-L are shared by cancer cells in the patient, patient cancer cells are believed to be targeted by the immune system. The Phase II showed an improved survival in patients who raised antibodies against mesothelin, carcinoembryonic antigen and α-gal.

As mentioned in the report, it was expressed an opinion that by using allogeneic cancer cell lines one cannot introduce patient-specific antigens if such antigens exist and are of importance. However, Phase II clinical trial data had been very encouraging, particularly for patients who demonstrated humoral immunologic responses. So, it seemed that this approach had worked despite the cell lines possess “generic” and not patient-specific antigens and despite other cell line antigens, not so much defined and identified, have been also introduced to the immune system of a patient without knowing their exact effect.

Algenpantucel-L has had an ambition to become the first product with an FDA approval for the adjuvant treatment of patients with surgically resected pancreatic cancer.

Another Phase III trial, PILLAR (NCT01836432) starting in 2013 should assess an effect of Algenpantucel-L in combination with chemotherapy. The Phase II (NCT02405585) trial which started in 2015 and which should continue until 2020, combines a neoadjuvant chemotherapy followed by stereotactic body radiation therapy (SBRT) with Algenpantucel-L in borderline resectable pancreatic cancer patients.

In light of the negative IMPRESS Phase III results, the company will focus on other promising opportunities in their pipeline, which by other words can mean considerations of future of the HyperAcute® platform. It will be very interesting to see results and analysis from the study, especially an immune response and correlations with an overall survival, if the company is willing to share them. Knowledge from this failed trial can add a puzzle piece to a general understanding of immunotherapy and its applicability for patients.

NewLinks Genetics has had several other candidates among the most advanced vaccines in development in the scope of the “Acute immunization for unconventional indications” report. The company also develops check-point inhibitors (indoleamine 2,3-dioxygenase pathway inhibitors) for cancer indications  and vaccines for infectious diseases (influenza and Ebola). The company has adopted an interesting strategy to combine their proprietary check-point inhibitors with other “activators” of immune system (e.g. PD-1 inhibitors) and with chemotherapy.

After the OBI-822/821 vaccine in February 2016 did not meet the primary endpoint in the Phase II in breast cancer (however patients who demonstrated an immune response (IgG or IgM) showed highly significant improvement in progression-free survival; OBI Pharma is continuing towards a Phase III based on results of this subset population) and the Celldex´ Rintega vaccine in March 2016 failed to improve overall survival of glioblastoma patients in comparison to the control arm in the Phase III, Algenpantucel-L is another vaccine therapy this year which did not meet primary endpoints despite very promising results in previous clinical phases.

If you are interested to see target product profiles of other more than 100 antibody-inducing vaccines in active development for unconventional indications, if you want to get information about dozens of stopped vaccine projects and if you want to know which results can be awaited in 2016, have a look in the report “Active immunization for unconventional indications”. The report can also be obtained via the Research and Markets.

Photo: © National Cancer Institute/ John Keith (Photographer)

The fatal BIA 10-2474 trial and lessons learned (?)

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The Phase I trial with the BIA 10-2474 drug of the Portugese company Bial done in French Rennes was stopped in January 2016 after occurring serious complications in 6 volunteers from the same trial arm. One man died.

ANSM, the French regulatory authority, released on 19th April 2016 a final report which summarizes findings of the BIA 10-2474 trial by the special scientific committee (CSST) established in January 21st, 2016. Aim of this committee was to analyze mode of action and possible toxicity of the BIA 10-2474 (direct or indirect), to formulate hypothesis to explain toxicity and to adopt global recommendations for first-in-human (FIH) trials.

The BIA 10-2474 belongs to a class of fatty acid amid hydrolase (FAAH) inhibitors which act by degrading an enzyme anandamide, a mediator of endocannabinoid system. There have been more than 6 drug candidates in development, no one yet marketed due to low efficacy. These drugs have been developed for such indications like pain, vomiting, anxiety, mood disorders, Parkinson´s disease, Huntington´s disease and some cardiovascular indications by companies like Sanofi-Aventis, Astellas, BMS, Pfizer and Janssen. Janssen voluntarily suspended its Phase II trials with JNJ-42165279 until they will have more information. Bial has tested its drug for neuropathic pain. Bial has 6 candidates in its pipeline, with one product already marketed for one indication in EU and USA and one product registered, both in central nervous system indications.

The committee at ANSM had a closer look on preclinical findings on the BIA 10-2474 and the Investigational Brochure (IB) accompanied the FIH filing. The BIA 10-2474 showed in in vitro studies quite low activity, in other words IC50 lies in a micromolar range. For those involved in small molecule drug development it is obvious that this compound was quite weak since usually companies move to further development compounds with a nanomolar range found in vitro. Actually, when the molecule was compared to an existing reference molecule in animal pain killing tests, BIA 10-2474 was less effective. Interestingly, the reference molecule values were removed from one figure in the IB.

Further, the drug was not very specific and it also expressed a very narrow concentration range between an absence of inhibition and total inhibition. The latter fact means that even a small concentration change can lead to a significant effect.

When compared to other developmental molecules in the class, based on preclinically obtained characteristics on specificity and efficacy, the BIA 10-2474 was not very competitive to stronger candidates (e.g from Pfizer or Janssen).

What was quite unusual was toxicology testing of BIA 10-2474 in 4 different animal models- rat, mouse, dog and monkey and in addition, in rabbits for fertility and reproduction studies. Toxicology studies are prerequisites for clinical testing, they are done in a GLP (Good Laboratory Praxis) environment and are quite expensive. There was no noticeable toxicity found in particular organs except of gametes (observed also with other FAAH inhibitors). On the basis of NOAEL (no observed adverse effect level), 100 mg dose was chosen as the highest dose in humans. However, the study in dogs had to be redesigned since serious pulmonary events and signs of motor coordination problems occurred. In dogs, the NOAEL was set to 20 mg.

The CSST committee in its report concluded based on information provided that the BIA 10-2474 could not be a priori regarded as a risk product according to valid criteria and therefore was allowed to continue to a first-in-human trial.

The BIA 10-2474 trial started in 2015 (no information in usual clinical trials registers) and had several arms, consisting of single doses (ranging from 0,25 to 100 mg) and repeated doses (from 2.5 mg to 50 mg). Analysis during the trial showed 50% of FAAH inhibition in humans with a 0,25 mg dose and the dose 5 mg showed nearly 100% FAAH inhibition. This was however far less (10x) than the extrapolated dose from animal studies. The volunteers were involved in the injection schedule sequentially, based on results from previous treatments to increase safety of participants.

In January 10th, 2016, one man was hospitalized after the 5th injection of the 50 mg dose (cumulative dose 250 mg). Other 5 were at that time without apparent problems. They got their 6th injection next morning (cumulative dose 300 mg) without waiting for results of the hospitalized man. Then, 2 to 4 days after the last injections these 5 people were also hospitalized due to brain bleeding and other neurological symptoms and the first man died at the 3rd day after first symptoms occurred. No other volunteers except of this cohort #5 (repeated 50 mg dose) showed any marks of toxicity, especially not of neurological origin.

The committee has concluded that the toxic effect was clearly linked to the BIA 10-2474 molecule. It is likely caused by the molecule itself outside of the endocannabinoid system (not connected to the drug class effect). Toxicity of the BIA 10-2474 can be caused by its binding to other brain cell structures:

  1. Due to low drug specificity for the target enzyme
  2. Due to use of repeated dose well above the dose causing in human complete inhibition (5mg, found during the trial)
  3. Due to gradual accumulation in brain (effect on brain functions occurred after the 5th injection of 50 mg dose. A single 100 mg dose did not cause any effect).

The committee, despite concluding that there was a rationale behind allowance of the candidate for clinical testing, mentioned that there was a fair number of errors, inaccuracies, reversing numbers, erroneous translations of document sources in the IB provided by the company.

According to the report in Nature, many researchers believe that BIA 10-2474 is acting ‘off-target’. After publication of the Clinical Study Protocol, there were efforts to assess these “off-targets”, e.g. one company involved its proprietary software and predicted a mechanism by which the drug candidate could cause the death and serious adverse effects in the trial.

The most important are lessons we could learn and recommendations of the committee:

  1. Focus on preclinical efficacy
  2. Include neuropsychological evaluation and cognitive tests for drug candidates affecting central nervous system
  3. For the first-in-human studies do not expose all subjects of a cohort/arm to experimental treatment at the same time (as happened in the BIA 10-2474 trial)
  4. Dose escalating strategies for first-in-humans studies should involve considerations based on clinical and pharmacological common sense
  5. A debate is needed on European and international level about access to data of first in human administration and to toxicological data in order to protect persons involved in future trials.

Especially the last point is very important- should be a trade secrecy more than a human life? I am sure we agree it should not.

Update: “A French health ministry (on 23.5.2016) ruling faulted both Portugal-based Bial-Portela and the French laboratory Biotrial for a failed drug trial that left one patient dead and five others hospitalized earlier this year. Marisol Touraine, France’s health minister, said that although neither company violated health legislation in France, both share responsibility over the dosage of the medication given to patients as well as criticism over the time it took to seek medical assistance after the first patient became ill, Reuters reported Monday”. More  information here.

Update 2: 27.5.2016 “The European Medicines Agency (EMA) has started a review of the guidelines that describe first-in-human clinical trials and the data needed to enable their appropriate design and allow initiation. The review will identify which areas may need to be revised in the light of the tragic incident which took place during a Phase I first-in-human clinicial trial in Rennes, France, in January 2016.” This action is directly connected to the recommendation No. 5 of the CSST as mentioned above.

Cyclodextrin for cardiovascular diseases treatment?

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Cardiovascular diseases are the leading cause of deaths worldwide. Atherosclerosis is a state when plaques consisting also of free cholesterol are continuously clogging arteries and this leads to high heart pressure and at the end to brain strokes or heart infarcts.

As a prospective promising therapy for treating atherosclerosis, scientists found out that cyclodextrin can be used. Findings were published in Science Translational Medicine in April 6th.

Cyclodextrin mediates its effect in vivo on reprogramming macrophages and decreasing inflammatory response in cholesterol-containing arteries. Cyclodextrin also increases cholesterol solubility, so it dissolves cholesterol crystals. Interestingly, the effect was observed even after continuing a cholesterol-rich diet.

Cyclodextrins form a family of cyclic oligosaccharides and they are used e.g in food industry for preparation of cholesterol-free products. They are also important for pharmaceutical industry since they can increase solubility of water insoluble drugs and therefore increase their availability in a body. One of the cyclodextrins- α-cyclodextrin- has a verified health claim in EU for its ability to decrease sugar after a high-starch meal and is part of some weight loss supplements.

What is interesting on the above mentioned article is also a fact that it was initiated by a mother of two children who have a rare Niemann-Pick Type C disease.

The disease is accompanied by a cholesterol accumulation in a body. The twins were the first people with this fatal disease treated by cyclodextrin. Treatment had good results and the mother contacted scientists and suggested them to use the agent for treatment of atherosclerosis. After series of animal experiments scientists were able to show that cyclodextrin has indeed effect on cholesterol and atherosclerosis. A mother of twins is also a co-author of the scientific paper.

Sources:

  1. News source: Cyclodextrin dissolves away cholesterol crystals. Eurekalert

Prostate cancer and combined therapy

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“Prostate cancer patients and their doctors may want to think twice about the best timing for chemotherapy or radiation therapy in conjunction with a common nonsurgical treatment, based on international research findings led by UT Southwestern Medical Center investigators.”

Scientists found out that usual medical androgen deprivation therapies (ADTs) like chemotherapy or radiotherapy deprive also patient´s adaptive immune system and any subsequent immunotherapy will be then compromised. The surgical ADT- castration- works in combination with immunotherapy.

The ADTs are used for 50 years. Progress in immunotherapy led to some promising candidates and as a logical step, combination of ADTs and immunotherapy for prostate cancer started to be used. However, using medical ADT in this combination order leads to the relapses in prostate cancer commonly seen in clinical trials.

Reduction of T-cell response against the prostate cancer induced by some androgen receptor antagonists was found by researchers as a main mechanism of this effect.

As a take-home message from this scientific work is that physicians will have to carefully think about possible combination strategies in advance before starting radiotherapy or chemotherapy for prostate cancer. And if immunotherapy is an option, one should consider timing and method of the ADT to be used.

Sources:

  1. News source: Common prostate cancer treatments suppress immune response and may promote relapse, Eurekalert.
  2. Scientific paper: Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse. DOI: 10.1126/scitranslmed.aad5659
©https://ec.europa.eu/programmes/horizon2020/

Rare diseases and Horizon 2020

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What do you think have diseases like Huntington´s disease, Fabry disease, Amyotrophic lateral sclerosis, Fragile X syndrome and cystic fibrosis in common? They belong to rare diseases, diseases that affect no more than 5 people out of 10 000 in EU which means that about 250 000 people maximally are affected by a single disease. However, in most cases there is 1 person in 100 000 affected by a disease. It is therefore not so hard to imagine that this number of patients is not so attractive for drug developers since they reasonably expect that they cannot get returned their investment into a drug development by selling such medicine on this small market.

Just to imagine how many people together are affected by rare diseases- a few numbers from the European Medicine Agency (EMA) webpage: There exist 5000 to 8000 distinct rare diseases, affecting between 27 mil and 36 mil people in EU. Most of the rare diseases are caused by a genetic origin and rest is accounted to degenerative and proliferative causes.

Taken in account that there are a few medicines available and there is a lack of any scientific information about most of the rare diseases, we can see an urgent unmet medical need here and millions of people left without any hope.

Despite predominantly governments are in duty to take care of public health and act in public interest and to provide help also to people with rare diseases, we see numerous initiatives supporting development of orphan drugs funded above all by non-governmental bodies.

On the European level, the European commission via the EMA supports similarly to the Food and Drug administration (FDA), orphan drugs development. In case of the EMA regulatory body, an orphan drug must meet certain criteria:

  • it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
  • the prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
  • no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

This is quite straightforward definition. Such medicine can then benefit from certain incentives such as protection from competition once on the market (for 10 years) or protocol assistance. There are further incentives for SMEs like reduced fees and administrative and procedural assistance from EMA.

As we will discuss next, in frame of the Horizon 2020, an EU funding program for scientific projects, there have been calls running and in preparation to support development of orphan drugs.

In the past, there have been already some calls within the Horizon 2020 which fully or partly touched rare diseases like PHC-14-2015, FPA-01-2014, SC1-PM-12-2016 or INFRAIA-1-2014-2015. For the open calls, we can mention the NMBP-10-2016 call (Nanoformulation of biologicals) ending in May 2016 and ERN-01-2016 (ERN-2016 – European Reference Networks – Framework Partnership Agreement) with deadline in June 2016 which are partly focused also on rare diseases.

Two forthcoming calls are the most relevant and specifically focused on rare diseases.

The SC1-PM-03-2017 call (Diagnostic characterisation of rare diseases) will be open in July, 29th, 2016 and closed in April, 11th, 2017. Aim of this call is to apply genomics and other –omics or high–throughput approaches for molecular characterization of rare diseases. This is thought to be a large-scale proposal with an expected EU contribution at around 15 mil EUR. The selected proposal shall contribute to the objectives of, and follow the guidelines and policies of the International Rare Diseases Research Consortium IRDiRC (www.irdirc.org).

The second call SC1-PM-08-2017 (New therapies for rare diseases ) is fully dedicated to clinical development of orphan drugs, it is planned to be open in July 2016 and a deadline for the 1st stage is planned to be in October 2016 and for the 2nd stage in April 2017.

There are certain prerequisites to be fulfilled to apply for this call:

1) Orphan designation has been given by the European Commission (via EMA),

2) The proposed clinical trial design takes into account recommendations from protocol assistance given by EMA (The protocol assistance from EMA which is a kind of scientific advice attracts fees. For more details see the EMA web page), and

3) A clear patient recruitment strategy is presented.

Again here, the proposals should follow the guidelines and policies of IRDiRC.

According to the SC1-PM-08-2017 topic description, “the intervention must have been granted the EU orphan designation at the latest on the date of the full proposal call closure”. The whole procedure for orphan drug designation at EMA takes in full about 11,5 months from date of filing (it is also recommended to have free pre-submission meetings with the EMA Orphan Medicines Office and EMA Scientific Advice Office). So, if a drug developer does not have yet an orphan drug designation for a drug to be a part of the SC-1-PM-08-2017 call, it has to be applied at latest in next few days to keep Horizon 2020 timelines. Otherwise this call will be applicable only to drug developers having already the orphan drug designation or being already in process of getting it.

Though drug developers have not had in the past so much interest in orphan drug development, situation is changing due to more factors. An increasing support from EU, governments and non-governmental organizations is one reason. A second factor is that companies can use the orphan drug  as a “lift” for other drugs, e.g targeting the same molecule. Orphan drugs will take advantages of its designation to get incentives and to be on market quicker than a usual drug and to get longer protection and the second-use drug can profit from that. At last, involvement in development of a drug for people left without any hope and even knowing that the direct return of investment will be low or none, can improve public image of pharmaceutical industry and companies involved. None of these reasons is bad and if at the end they improve understanding of rare diseases and can help millions of people, this is something which counts and matters.

Picture used at this post ©https://ec.europa.eu/programmes/horizon2020/

Another CETP inhibitor failure

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Highly awaited results from the Phase III study with evacetrapib which was stopped in October 2015 on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events were presented recently at the American College of Cardiology’s 65th Annual Scientific Session. The original article you can find here.

Results clearly showed that despite significant decrease of “bad” cholesterol- LDL (i.e LDL- low density lipoprotein) and increase of “good” cholesterol- HDL (high density lipoprotein), the rate of cardiovascular events was not reduced.

It means that cardiovascular deaths, heart attacks, strokes and others occurred at the same rate in people who has lowered “bad” cholesterol as compared to placebo treated people with no cholesterol lowering

High cholesterol is thought to be a risk factor for heart and vascular failures and changing a lipoprotein profile is thought to modify this risk. Diet recommendations as well as drug treatments by statins, PCSK9 inhibitors, selective cholesterol absorption inhibitors, bile acids-binding drugs and other lipid lowering therapies are ways how to lower LDL currently in clinic. In case of statins, large population studies showed an effect on cardiovascular diseases rate. A new group of cholesterol-lowering drugs targeting the PCSK9 molecule (among them two approved and marketed monoclonal antibodies) is awaiting outcome studies on modification of cardiovascular events soon, showing clearly significant cholesterol lowering in indications where statins were not effective or tolerated.

Evacetrapib belongs to a class of CETP inhibitors. CETP is a “cholesterylester transfer protein” which transfers cholesterol from HDL to VLDL (very low density lipoprotein) and LDL. Evacetrapib as a CETP inhibitor thus increases HDL and lowers LDL. The investigational name for this drug is LY2484595 and it has been in development at Eli Lilly and Company. The drug was tested in more than 12 000 people and most probably only such high participants number tested through sufficient time period could show a meaningful outcome.

This class of drugs has faced already a 3rd failure, all small molecules. The first failure, Torcetrapib, was in development at Pfizer and was stopped in 2006 after excessive deaths in the Phase III. Roche´s Dalcetrapib development discontinued in 2012 due to a lack of efficacy.

There are two candidates in active development at Merck and Amgen. Merck´s Anacetrapib is currently in 3 Phase II studies- NCT00685776 (a long-term study since 2008, running until 2017), NCT01252953 (REVEAL, running until 2017) and NCT01524289 for heterozygous familial hypercholesterolemia patients in combination with statins (results will be available in 2018). The drug previously also showed significant effect on cholesterol levels.

Another CETP inhibitor, originally developed by Dezima and Xention as TA-8995 and which is now in portfolio of Amgen as AMG 899 showed promising results on LDL decreasing and HDL increasing in the TULIP Phase II as announced in 2015 and it was claimed that it is the most potent CETP inhibitor in means of cholesterol lowering. There is no active clinical trial with AMG 899 or TA-8995 running according to www.clinicaltrials.gov.

Of course, now, everybody is watching whether it will be possible to see an effect on cardiovascular diseases rate with these two active CETP drugs.

Let´s have a look on other cholesterol-lowering drugs, PCSK9 inhibitors. Two monoclonal antibodies were approved and marketed in 2015, other drugs are in development at Pfizer, Lilly, AFFiRiS, Alnylam and others. These drugs are of other class than CETP inhibitors, lowering LDL and increasing HDL by other mechanisms. Several “outcome” trials are running with Pfizer´s bococizumab and Amgen´s and Sanofi´s/Regeneron´s marketed mAbs to bring an evidence that these drugs in parallel to modifying a lipoprotein profile can also reduce cardiovascular diseases rate. Pfizer recently announced positive results on one Phase III study with bococizumab which met its primary endpoints and led to a significant LDL decrease. The study is expected to be a part of potential regulatory filing.

It automatically comes to one´s mind: Why significant decrease of bad cholesterol and increase of good cholesterol induced so far by CETP inhibitors was not accompanied by any effect on prevention of cardiovascular mortality and morbidity? Can this happen also with other cholesterol-lowering drugs of the same class and of other classes? What mechanisms prevented a positive impact of cholesterol lowering on cardiovascular diseases incidence? Coming years will bring answers.

Scientists now speculate that new ways of cholesterol lowering are needed. In light of CETP inhibitors failures there could be however a lower appetite of drug developers to bring another drug to development without a strong evidence of its potential to affect the cardiovascular disease rate in parallel to cholesterol lowering. It will be also interesting to watch how PCSK9 inhibitors will perform in outcome studies and whether they will translate significant cholesterol lowering  into prevention of cardiovascular deaths and diseases. There is a hope for that.