You probably know that drugs can get very expensive. What do you think – what percentage of new drugs actually provide significant therapeutic benefit compared to existing treatments? And do you think that drugs with a low clinical benefit are indeed priced any cheaper than highly beneficial ones?
Beyond drug prices, we will also talk about cancer “approvals gone wrong”. These were shown only after their regulatory approval to lead to equal or even worse outcomes for patients. One of these debated drugs ultimately led to bankruptcy of the company who developed it. However, the molecule has some nice chemistry behind it. You know the channel – we will take any opportunity to study organic synthesis that we get.
Healthcare Spending and Drug Prices
Let’s face the facts – healthcare spending has grown much faster than gross domestic product – in the US and everywhere else. Drug costs are one driver behind this. The most extreme example is perhaps cancer, where we can observe almost exponential growth of drug costs over the last 50 years.
The US spent $4.2 trillion on healthcare in 2021. Who paid the bill, and on what? As you can see, government spending on Medicare and Medicaid is about 40%, whereas patients paid out-of-pocket for 10% of costs. On the other hand, hospital care received the bulk of spend with 31%, with prescription drugs coming in at 9%. Increasing drug costs are problematic, but as we see, they are not the only reason behind high healthcare spend.
Initially expensive branded drugs are becoming much cheaper after entry of generic drugs. Fortunately, this leads to more accessible, vital treatment options for patients. This is where we have the crux: While standards of care improved across all diseases, new medicines need to continuously drive improvement in therapeutic benefit.
Let’s imagine we have a new drug in a disease that affects the liver, demonstrating it slows loss of liver function by 25%. Sounds good in theory, but let’s assume this was only tested against placebo and already approved treatments have shown similar results in their trials. If we ignore any benefits on things like safety or durability of response, this means the relative therapeutic benefit of this therapy would be rather low. On the other hand, a new drug showing superior efficacy to other already approved treatments would be much better. Instead of “me-too” drugs, we would want any new drugs to significantly improve on existing drugs. The problem is that this has not been the case in past years.
The Therapeutic value of new drugs
The authors of the first piece of research looked at the last decade’s new drug approvals and their ratings of therapeutic value from health technology assessment bodies in France and Germany. These agencies assess the added benefits of a drug’s approved indication compared with existing therapies. This tells us whether there is major, considerable, minor, or no benefit of a new drug. The underlying criteria are slightly different across countries but capture the drug’s effect on reduction of disease duration or side effects, for example. If any of the two agencies rated a drug as providing considerable or major benefit, the authors consider it a high value drug in their analysis.
The sad result is that only 40 to 50% of drugs approved by the US FDA or European EMA regulator are high value drugs. But check out the second set of bars. These refer to approved uses in additional diseases or indications after a drug’s first approval. In these settings, are even less likely to be quote-unquote better drugs.
Drugs with multiple indications
But why can drugs have more than one indication? As most of you know, a single mechanism of action can apply to different diseases. For instance, immuno-oncology drugs like PD1 inhibitors can be applied across solid tumors. Keytruda, the soon-to-be world’s best-selling medicine, is approved in more than a dozen different tumor types. Beyond oncology, we have complement inhibitors like Soliris which you might remember if you watched the previous video on the world’s most expensive drugs. Because the complement immune pathway is involved in many diseases, it is possible that the same drug which saves kidneys might save eyes as well.
On one hand, patients benefit because they get one more option which might help them go into disease remission (not always). It also makes sense for pharmaceutical companies to get rewarded by bringing innovation to more patients. Because clinical development costs billions, they maximize product revenues during their limited window of exclusivity.
But the reality shatters this pleasant theory: Only 40% of drugs in supplementary indications bring significant new benefit. If we look at the relative rate, drugs are less and less likely to bring new therapeutic benefit in every follow-on indication.
Some caveats remain, like questions behind the precise logic of defining something as high therapeutic benefit. There are specific local factors, like France using their own therapeutic strategy as a criterion. But more important is that while a drug might not be high value on average, sub-segments of patients with specific mutations or other characteristics might respond very well. We know who might respond best for some drugs but for most, this is less clear.
Value of Accelerated approvals & Friends
This research confirms what others have found before. An interesting second analysis differentiated the therapeutic value of normal drugs and those with expedited approval. The exception is awarded for drugs which major promise in diseases with high unmet (e.g., certain cancers, rare diseases). The logic is obvious: imagine there is a drug which shows drastic tumor shrinkage in an early phase 2 clinical trial. Instead of waiting 3-4 years for larger and longer-term data, an accelerated approval might be lifesaving for many patients. Accelerated approvals require drug developers to run confirmatory trials in parallel. The hope is that the drug will show full efficacy and safety retrospectively. In a minute, we will talk about two cases where this unfortunately was not the case.
The publication at hand also included other expedited regulatory mechanisms in their analysis such as fast track and priority review, as well as breakthrough therapy designations.
So, what do you think is value-add of these expedited programs? As you might expect and can see in the much higher purple band, drugs under expedited mechanisms are more likely to have high therapeutic value.
Most program types are in a similar range, with breakthrough designations coming in highest – 60% are indeed high value. While normal approvals are at a crappy 13%, drugs with 3 or more designations are at 65%. These designations are awarded during development, so before the clinical product profile become clear. Thus, it’s obvious that we will never get to let’s say 90% for breakthroughs, simply because drugs which appear very promising in phases 1 or 2 might prove out to be only mediocre after a larger scale phase 3 trial. Still, regulatory agencies should give additional explanations or disclaimers to set more realistic expectations for patients and doctors.
Are Drugs getting More expensive?
Finally, let’s see what a 2020 study has to say, covering 65 cancer drugs across countries. The sad insight: low-benefit drugs are just as expensive as high-benefit medicines. You can see that the blue and red distributions are awfully close to each other, with no statistically significant differences between them. From this chart, you can also immediately see why the US is the major pharmaceutical market globally, with drug costs roughly 1.3-times higher than in the European countries.
In summary, new drugs do not always mean innovation, breakthroughs are not always proven to be true breakthroughs, and a high price does not mean high value. Did any of these statistics surprise you? On an optimistic side, we should remember that this is just theory and does not reflect the real-world use of these drugs. Patients will not switch to a new drug which works just as well as what they are already on, and payers would restrict coverage for high-price drugs with dubious efficacy.
Approvals gone wrong – Avastin in metastatic Breast Cancer
However, as we alluded to at the start, there are unfortunately cases where drugsare proven to be quote unquote useless. Let’s check out two examples, and then dive into some chemistry.
The first one is Avastin, which is a VEGF-targeting antibody which suppresses the growth of new blood vessels. This hinders supply nutrients to the cancer, slows its growth, and therefore slows cancer progression.
The FDA approved Avastin in a broad set of tumors. So, we can see the theme of supplemental indications mentioned in the first part. The problem really was around its accelerated approval in metastatic breast cancer (2008). At the time, the FDA’s Oncology Advisory committee, so an outside advisory panel, had actually recommended 5 to 4 against the approving Avastin in metastatic breast cancer. This mixed opinion was because Avastin at the time did not extend life.
We look at the details of the clinical study comparing Avastin as an add-on to chemotherapy. Overall survival – the time from trial entry to patient death – is the gold standard primary endpoint in cancer trials but takes more time and patients to collect. Avastin missed the mark on this important metric. Avastin’s OS is numerically higher, 26.7 months vs. 25.2 months, but this is not statistically significant as indicated by a p value of higher than 0.05.
However, progression free survival improved significantly. PFS is the time between treatment start and first evidence of disease progression, or also death. PFS data is available earlier than OS, so it serves as a surrogate endpoint. So essentially, Avastin reduced the speed of progression by more than 5 months, but patients were ultimately not living longer. Also, their subjective quality of life did not increase either. You might think: If the drug slows down progression, should we approve it nevertheless?
What was The Problem?
An additional problem was the overall 20% increase in adverse events with Avastin. Toxic effects like hypertension or infections increased significantly. This resulted in 6 deaths due to Avastin. So, considering all this evidence, the accelerated approval was quite optimistic but understandable given the lack of other treatments that showed similar PFS benefit.
As we learned, accelerated approvals require parallel studies which intend to confirm the drug’s benefit. However, the opposite happened.
Looking at the AVADO trial comparing two doses of Avastin, the extended PFS was still there. However, with just under 1 month difference between trial arms, this was significantly lower than expected. More importantly, patients on Avastin had numerically shorter OS. Because of the high p value, we can’t really say if this means Avastin is indeed worse or just equal to chemo. This led the FDA to withdraw the metastatic breast cancer indication for Avastin.
Interestingly, the European regulator EMA did not follow suit. In their view, benefits outweigh risks given positive albeit small PFS benefit and lack of statistically significant detrimental effect on OS.
Approvals gone wrong – rucaparib in 3rd line ovarian cancer
The second case study is Rucaparib, which was indicated, among other uses, for third-line treatment in ovarian cancer. It belongs to the class of PARP inhibitors which interfere with DNA repair mechanisms.
Like the results for avastin, rucaparib extended the median progression-free survival by 5 months. Patients with DNA repair deficient tumors responded even better as they are more prone to PARP inhibition. This seemed like a solid benefit at the time – but can you guess the problem?
Four years after its approval, now in 2022, more mature data on overall survival came in. The harsh reality – across different data cuts, patients on treatment again did not live longer. Again, we need to check the p value to see that even in the BRCA mutated sub-group, the potential strong responders, the seemingly beneficial effect is not statistically significant. This led to a voluntary withdrawal in the third-line indication by the company. Unfortunately, a somewhat desperate filing of rucaparib as a first-line therapy by the company did not work out either.
If you watched my previous video, you would remember that pharmaceutical companies burn a lot of money on development and operations. Clovis tried to cut costs through lay-offs and raise additional money, but ultimately had to throw in the towel and file for bankruptcy.
In summary, PFS benefit does not necessarily translate into true survival benefit – which is ultimately most important. Also, we saw that the FDA and EMA can reach different scientific conclusions looking at the same data.
organic synthesis of rucaparib
Finally, it’s chemistry time. Here we have two things to check out. First, we will look at just one part of Rucaparib’s original large scale process route, and second, go through a more efficient synthesis in full.
The process route, albeit long, has an interesting reaction early on. It starts with a nitration of this benzoic acid – which selectively nitrates meta to the acid. So far, nothing special – most of you should know the selectivity. Doing a nitration with 23L concentrated nitric acid is nothing so sneeze at, but we are more eager to see what happens after this step, and a simple esterification. It’s a Leimgruber-Batcho indole synthesis which leverages the moderate acidity at the benzylic position of these nitroarenes. In the first step, the benzyl anion is formed and attacks the reagent, dimethylformamide dimethylacetal. This adds one carbon to the system and after spontaneous elimination of methanol, a conjugated link is formed.
The second step of the indole synthesis is the reduction of the nitro-group. The liberated nucleophilic aniline can intramolecularly cyclize with the iminium, and again eliminate dimethylamine to create the aromatic indole. Although you might expect that immediate intramolecular attack in a 5-endo-trig fashion would give an anion that is very much stabilized through the ester group, I think that’s kinetically disfavoured work due to Baldwin’s rules.
Second synthesis of rucaparib
The remaining steps are not revolutionary so we will instead look at the very direct synthesis published in 2022. The starting material is already highly functionalized, but you can buy this commercially so it’s fair game. The first step is a Heck-reaction with the highly reactive aryl iodide. Next, the aryl amine was condensed with an aldehyde bearing the other half of rucaparib. At this point, we essentially already have all atoms that we need already, it’s just about linking them and getting to the right oxidation states.
To create the indole, the chemists used a cyanide-catalyzed imino-Strecker reaction – you might remember this one as a prime example of Umpolung chemistry. The mechanism starts with nucleophilic addition of cyanide to the aldimine. The negative charge first sits on nitrogen, but rapidly tautomerizes alpha to the nitrile. Now, we have the typical Stetter 1,4-conjugate addition onto the vinyl nitrile. Finally, just like we’ve seen in the previous Leimgruber-Batcho synthesis, elimination delivers the indole. This regenerates the catalytic cyanide which is why the reaction works with just 20 mol% of sodium cyanide.
Well, what do we do next with the nitrile? You’ve guessed it – we need to reduce it to the amine, and link it to the ester. Because typical hydrogenation did not result in any reaction, the authors looked for other reducing agents. Interestingly, the generation of nickel boride from nickel chloride and sodium borohydride worked smoothly and chemoselectively, leaving the ester group in peace. The lactamization occurred spontaneously in situ, so that was quite convenient as well. The ultimate step was a simple deprotection of the amine sitting at the other side of the molecule, completing the total 5-step synthesis.
That’s it for this time. As always, I will catch you in the next one.
Key References:
- Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study: BMJ 2023, 382, e074166
- Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study: BMJ 2020, 371, m3434$
- rices and clinical benefit of cancer drugs in the USA and Europe: a cost-benefit analysis: Lancet Oncology 2020, 21, 664
- The US FDAs withdrawal of the breast cancer indication for Avastin (bevacizumab): Saudi Pharm J 2012, 20, 381
- Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: Results from AVADO: Eur J Cancer 2011, 47, 2387
- Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer: N Engl J Med 2007, 357, 2666
- Multikilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor: OPRD 2012, 16, 1897
- Total Synthesis of Rucaparib: JOC 2022, 87, 4813
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