Orkambi (engl. Version)

Orkambi® - a critical review

For the first time, Orkambi® makes a causal therapy of Cystic Fibrosis possible for homogenous F508del patients. In Germany the health care bears the expenses, but little has been discussed publically about the uses and risks of Orkambi®. The hopes and excitement surrounding Orkambi® should not outweigh consideration of how it is used and the risks involved. This especially concerns the prophylactic treatment of young patients with good lung functions. We, a small group of parents and patients, would like to encourage the discussion of critical questions:

1. To what extent does Orkambi® improve lung function?

Orkambi® has two constituents: Lumacaftor at a dosage of 400mg and Ivacaftor at 250mg per 12 hours. Two licencing trials involved a total of 740 patients. The change in lung function was the “primary endpoint”, making it the most important tested value. To what extent did the lung function improve during the trials? This was measured through the “ppFEV1” (percent predicted forced expiratory volume in 1 second), this means the maximum amount of exhaled air as a percentage of the predicted average value in healthy people. The absolute change of FEV1% compared with the placebo amounted to +2.5 %1) (in words: two point five percent) at the end of 24 weeks in both licencing trials.

2. Is a 2.5 % increase of the FEV1 relevant?

Is it even possible to feel a lung function increase of 2 to 3 %? The joint federal committee (G-BA) criticised in their report2), that the relevance of the primary endpoint FEV1% for patients is unclear as it is only a stand-in parameter for the patient’s health and life expectancy. It also pointed out that not even every third patient taking Orkambi® achieved a FEV1% increase of 5 % or more. The pharmaceutical company (manufacturer) countered this criticism in the hearing3): The patients felt a “great effect” and unlike symptomatic treatments, Orkambi® led to patients “actually having less Cystic Fibrosis”.

3. How comparable is a 2.5 % increase?

Tobramycin (TOBI®) improves the FEV1 value by about 6 %, Dornase alfa (Pulmozyme®) by about 4 to 5 %, thus both drugs can be seen as being “more price-worthy”. Even without medicine, CF-patients can improve their FEV1 by more than 2.5 %: doing sports 3 times a week for 30 minutes in a time frame of six months significantly improved the lung functions in a small study by about 10 % in comparison to the group that did not do any sports. The level of fitness also increased significantly. In this study there were no unwanted side effects. Other Cystic Fibrosis studies showed that sport significantly increases the quality of life.

4. Why doesn’t the quality of life increase?

According to the report of the G-BA2) the fluctuating study results during the trial period for the self-evaluation of quality of life showed no statistically significant differences (statisticians describe a test result as significant if the possibility that the test result is false in reality falls under a previously defined percentage, mostly 5 %) in nearly all partial analyses of the questionnaire (so called “domains”). The questionnaire for parents and carers also showed no significant results for the majority of these domains. Why the quality of life did not show any significant improvement at the end of the 24-week trial remains unclear.

5. Is the decrease of exacerbation significant?

During licensing trials, a plan of how the trial results will be analysed is published in advance to prevent the manner of analysing being subsequently adjusted to achieve better results. For this, there is also a hierarchy of analysis: only when more importantly-weighed parameters are significant, less important parameters are also analysed. Under this principle the decline of exacerbation of two parallel Orkambi®-licensing trials could not be analysed, because the hierarchically higher classified quality of life had not improved4). The published result is merely the summary of the data of both studies (“pool”): in the placebo group 43 % experienced deterioration (exacerbation) within 24 weeks in comparison to 29 % in the Orkambi® group. Moreover, other drugs such as hypertonic saline solution, Pulmozyme and Azithromycin can reduce deterioration (exacerbation) in a comparable manner. Pulmonary exacerbation is usually an increase of the symptoms which requires the intensification of treatment. During licensing trials, exacerbation was defined as a change in the antibiotic treatment (IV, inhalated or oral) due to at least four indications from a list of symptoms. Imagine this, the patient goes to the CF-clinic and says: “I am a bit more tired than usual, I am coughing more, I have a runny nose and I also have more mucus.” The doctor says: “Then inhalate with Cayston for 14 days instead of Colistin.” And hey presto, he writes down exacerbation! Could this special definition, in combination with a possibly patchy blinding (see below), already explain why patients in the placebo group had more exacerbation?

6. Are the studies relevant for German patients?

According to the report of the G-BA2) there are dependencies regarding the region in some evaluations. The pharmaceutical company’s reaction to the G-BA’s2) critical question during the hearing3), whether Orkambi® has shown more effect in America than in Europe was: “We assume that it is mostly a false-positive result in the sense that (…) there is no systematical difference which we can explain” (hearing3), pages 16 – 17). Shouldn’t this restraint also apply to the study results, which speak in favour of the drug? The G-BA has come to the conclusion (benefit assessment2), page 64): applicability of the study results to the German care context could not be shown!

7. What do we know about the side effects?

According to the licensing trials2), severe side-effects are rare and are even rarer in combination with the drug. Examples for unwelcome effects were elevated liver function readings, respiratory symptoms, reactive respiratory diseases, menstrual irregularities. According to the manufacturer, the drug was thus proved to be safe and unproblematic.

But what happens, in real life, when the drug is prescribed beyond the 24 weeks of the study? According to a Forbes article from March 2017, “up to every third patient”, who started taking Orkambi® outside of clinical studies, stopped taking it due to tightness and difficulties when breathing! And on social media and in personal messages patients describe further severe side-effects such as dizziness, acne, vision problems, loss of hair, sudden sweating and depression after longer treatment in addition to the known tightness when breathing. These symptoms had not (yet) occurred during the period of the study. Some individual patients reported that their hair fell out in clumps, so that bald patches were visible.

In Germany, doctors are legally obligated to report even the suspicion of side-effects, particularly when connected with new drugs, to the Federal Institute for Drugs and Medical Devices (Deutsches Bundesinstitut für Arzneimittel und Medizinprodukte - BfArM). By June 2017, only 19 suspected cases for Orkambi® had been reported in the Database on Adverse Drug Reaction of the BfArM6). But reporting the suspicion of side-effects is the legal duty of a doctor. If a patient stops Orkambi® e.g. due to constant tightness in the lungs, this should turn up in the database. In their own interest, patients themselves should insist on the reporting of side-effects or report the side-effects themselves. How else can the authorities gain all the necessary information needed to get a complete picture about the safety of the drug?

8. Is depression a concern with Orkambi®?

A CF-clinic in North Carolina (USA) reported in March 20177) that five female adolescents suffered from anxiety and depression after taking Orkambi®. In this clinic, this was a quarter of the female adolescents, who had taken Orkambi®. During this time two girls attempted suicide! Within three weeks, the condition of four of the five girls improved greatly after they stopped taking Orkambi®. Can this be explained solely through the interaction of Orkambi® with other drugs? The doctors in North Carolina suspect that Orkambi® has a direct effect on the chloride ion channel (CFTR) in the brain. The pharmaceutical company had not identified any relevant psychological side-effects in either licensing trials; only two of nine incidents were then connected to Orkambi®, because depression and anxiety occurs more often with CF patients. In any case, the doctors in North Carolina recommend close monitoring for signs of new or increased depression and anxiety when taking Orkambi® and to immediately stop taking Orkambi® if depression appears.

9. Is it possible that there were deficiencies during the blinding?

A drug’s real medical effect is supposed to be determined during double-blind trials. For this reason, a trial is conducted in placebo-controlled mode and only the difference between the two studies is evaluated. While doing this, it is important that neither patient nor doctor know if a placebo or the drug is being taken. This necessary lack of knowledge (blinding) can be destroyed when the active substance produces even slight side-effects. What is the consequence? A patient who suspects that he or she is “only” receiving the placebo, and another patient who suspects that he or she is receiving an active substance will evaluate their health differently (this effect can even be measured if one group receives a placebo and the other group receives a harmless substance that causes a slight tingling sensation). Insufficient blinding, even if it only affects a few patients during the trial, can artificially create the significance of trial results and produce the wrong conclusion that ineffective drugs are effective8).

Statements from trial participants indicate that the blinding did not always work during the Orkambi® studies, because “purge” was reported to be a typical early side-effect: a productive cough, during which one feels that all of the mucus in the lungs needs to be coughed up. If purge occurs, the patient suspects that he or she has received the active substance – if not, the patient suspects he is receiving the placebo. Thus, many study participants were sure that they knew whether they had received the placebo or not. Therefore, we are left with another important question: is the result of the trials still significant despite the possible failure of blinding amongst some of the patients?

10. Why is the price kept secret?

According to G-BA2), Orkambi® and its subsequent costs amount to 195,993 euros per year per patient. Taking into account the 2578 patients in Germany who would qualify to take this drug (homozygous dF508), the financial burden on the health care sector can be estimated at 500 million euros per year. To offer a comparison: Cystic Fibrosis care in CF-clinics, including staff and laboratory costs, amount to approximately 2,000 euros per patient per year, so only 1 % of the cost of this drug!

The World Health Organisation WHO demands pricing that takes the therapeutic added value into account. This is different in Germany. Here the pharmaceutical companies unilaterally set their list price and then negotiate it with the health insurance funds. However, instead of stating the negotiation results for Orkambi®, the umbrella organisation of the statutory health insurance funds states “yearly treatment costs: refund amount negotiated. The manufacturer has not agreed to making this public.”9). Why does a Cystic Fibrosis patient, who has statutory health insurance, not have the right to know how much the pharmaceutical companies are being reimbursed for their drug by the solidarity-based health care system? This secrecy contradicts our concept of the basic principal of access to official information in accordance with section 1 of the Freedom of Information Act.

11. Effects on life expectancy

Orkambi® extends life expectancy by 6.8 years – this is what specialists in the pharmaceutical company calculated10)! To calculate this number, they feed a mathematical model with survivor data gathered from trials and patient registers. The pharmaceutical company sees this as an important benefit and points out, that early treatment with Orkambi® could lead to a larger benefit regarding the survival of patients.

Through these calculations, we can only see that innumerable estimated(!) parameters were calculated until the calculations came up with the result of 6.8 years. But we also know that older patients were alive before Orkambi®. Patients, who extended their life expectancy prognosis by decades. Nobody knows how old they will be, because the CF-demographic pyramid is changing rapidly! It is unclear to us, how one can mathematically calculate 6.8 years of extended life expectancy from a 2.5 % FEV1 increase. How many cases of death were there during the trial period and how many in the “matched” control group? Can a statistically solid difference in life expectancy for CF patients really be deduced from this? Did the consequences of side effects play a role in the analysis? Johann Grolle, author at Der Spiegel, summarized his impression in this way: “Whether Orkambi® really extends life expectancy, is anybody’s guess.”11)

12. Important questions remain unanswered

How does the low effect of the drug compare to the high price and the observed side effects? Why is the billed price shrouded in secrecy? Why was a decrease of exacerbation described as significant in comparison to the original analysis plan? We should be talking about all of these questions says Prof. Martin Mayer at the East Carolina University: “Patients deserve a transparent and comprehensible discussion about Orkambi® before they consider this treatment option. (…) Hope and excitement for new causal therapies for CF should not be allowed to influence the interpretation of research results.”4)

The names of the authors are known to the editorial department.