eTute 5 - Follow-On Drugs from Rival FirmseTute 5 - Follow-On Drugs from Rival Firms

Answer 1

While a drug might have been designed to bind strongly to one particular drug target, so-called primary drug target, the reality is that when administered to patients, it often interacts with other secondary drug target(s), thereby causing unanticipated physiological responses known as side effects. Pharmacologists call this tendency to bind to multiple drug targets non-specificity.

Answer 2

Once a drug is in widespread use, the extent of its side effects usually become increasingly obvious. Such awareness of a drug’s shortcomings can fuel efforts by researchers in rival drug companies to produce safer ‘second-gen’ drugs.

Question 3

First-gen drugs

Answer 3

Let’s imagine that an innovative first generation drug has entered the market due to its ability to bind to a particular primary drug target, shown in blue below. This ability accounts for its desirable effects within the lungs, for example, so let’s say the drug is used to treat patients with asthma. As the first drug of its kind, no other medicines are available that interact with the same primary drug target, so the drug receives strong sales.

Question 3

First-gen drugs

Answer 3

With ongoing use, however, it becomes obvious that many patients experience unpleasant side effects such as headaches or nausea while taking the drug. These occur due to interactions with secondary drug target in the gut and nervous system, shown in red below.

Question 4

First-gen drugs

Answer 4

While exploring this problem, researchers in a rival company discover that the primary drug target contains a tiny unused pocket on the zone of the protein where the drug normally binds. As the diagram shows, this pocket is vacant when the first gen drug binds to the drug target. The researchers get excited upon finding that the secondary drug target that causes side-effects doesn’t contain such a pocket.

Question 4

First-gen drugs

Answer 4

Question 5

Second-gen (follow-on) drugs

Answer 5

Question 6

Second-gen (follow-on) drugs

Answer 6

The medicinal chemists at the rival company begin designing new molecules that possess similar chemical structures to the first gen drug, but they contain extra atoms or different functional groups that allow them to interact with the previously unused pocket in the drug binding site in the primary drug target.

Question 6

Second-gen (follow-on) drugs

Answer 6

Medicinal chemists use all sorts of different functional groups when making a library of drug analogues. These are either atoms or small groups of atoms that can be added to particular sites on the drug molecule, altering its structure in subtle ways.

Question 7

Second-gen (follow-on) drugs

Answer 7

In the simplified example below, the second gen drug is shown in green. Compared to the first gen drug it contains a single extra carbon in the form of a methyl group (-CH3). This methyl group helps the drug bind to the spare pocket in the primary drug target, yet the molecule has little affinity for the secondary drug target which lacks the pocket. This seems to reduce the prospect of side effects in humans.

Question 8

Second-gen (follow-on) drugs

Answer 8

When tested in humans, the second-gen drug is as effective at relieving asthma symptoms as the first-gen drug, but it causes less headaches and nausea. Enhancing its drug target selectivity has dramatically improved the pharmacological profile of the drug.

Question 9

Second-gen (follow-on) drugs

Answer 9

After the second-gen drug is released onto the market, doctors note that it is less unpleasant for patients, so they start switching asthma sufferers to the newer drug. It quickly gains market share while sales of the older first-gen drug slowly decline.

Answer 10

Question 10

3. Case study: Part I - hypertension has consequences

Answer 10

One of our main lessons in PHAR1101 is that we really need a vibrant pharmaceutical innovation sector because disease patterns are continually changing. Success in the battle against one disease can often mean that people instead begin dying of something else. Pharmacological research needs to be very agile and have plenty of room to respond quickly to newly emerging diseases.

Answer 11

This was especially true during the twentieth century when the development of penicillin and other antibiotics meant that the medical wards of large hospitals were no longer full of patients suffering from untreatable infectious disease.

Answer 12

But very soon, these wards filled up again with patients dying of unrepeatable diseases of old age such as neurodegeneration, cancer, and cardiovascular disease. One emergent killer during this period was hypertension, an elevation in blood pressure.

Question 12

The Yalta Conference & FDR’s health

Answer 12

US President Franklin D Roosevelt (‘FDR’) had been diagnosed with hypertension in 1937, but by November of 1944, when he was re-elected to a record fourth presidential term, his blood pressure reached a whopping 250/150 mmHg (a healthy value is <120/<80 mmHg).

Question 13

The Yalta Conference & FDR’s health

Answer 13

An electrocardiogram showed that FDR’s heart was dangerously enlarged. Due to the political pressures of wartime, knowledge of FDR’s ill-health was withheld from the American people.

Question 14

The Yalta Conference & FDR’s health

Answer 14

A few months later, FDR was involved in the momentous Yalta Conference that involved leaders of the Allied Powers in negotiations over the territorial carve-up of Europe and Asia after the impending collapse of the Nazi empire.

Question 15

The Yalta Conference & FDR’s health

Answer 15

According to observers, FDR’s performance during the week-long conference was undermined by declining health, with proceedings punctuated by his frequent need for periods of bed rest. Noting FDR’s condition, Winston Churchill’s attending doctor uttered a gloomy prognosis; “I give him only a few months to live.”

Question 15

The Yalta Conference & FDR’s health

Answer 15

True enough, FDR died barely two months later during a visit to Warm Springs, Georgia. Complaining of a “terrific headache”, FDR collapsed to the floor, with his doctor recording an extraordinary blood pressure of 300/190 mmHg. He was pronounced dead a few hours later.

Question 16

4. Case study: Part II - what happened next

Answer 16

FDR’s rapid declining health during his final years was a likely consequence of the end organ damage that occurs in patients with untreated high blood pressure.

Answer 17

As shown below, at least five tissues or organs incur damage in hypertensive patients; brain, kidneys, heart, eyes, and blood vessels. The cumulative toll upon the health of hypertensive individuals and the wider healthcare sector is enormous.

Answer 18

The kidneys are usually the most vulnerable, with damage to this organ often appearing in a hypertensive patient before pathological changes become obvious in other tissues.

Question 19

Needed: More Knowledge & Drugs

Answer 19

The American populace was shocked by the death of a popular president who was believed to be in good health. FDR’s death inevitably raised the public profile of hypertension and highlighted the need for a better understanding of the causes of cardiovascular disease.

Question 20

Needed: More Knowledge & Drugs

Answer 20

The US government allocated funds to set up the Framingham Heart Study which used epidemiological tools to study heart disease in successive generations of residents in Framingham, a blue-collar town not far from Boston in Massachusetts. This famous study has provided much valuable knowledge concerning the negative impact of high blood pressure, uncontrolled cholesterol and other factors in human health and well being.

Question 21

5. Case study: Part III - Renin and the ACE inhibitors

Answer 21

The following decades saw many effective drugs introduced, but the development of captopril and the so-called ACE Inhibitors was especially significant. But where did this journey begin?

Answer 21

We have to go back to Europe in the late nineteenth century. The pioneering Finnish physiologist Robert Tigerstedt carried out research at the Karolinksa Institute in Stockholm, where Tigerstedt and his doctoral student, Per Bergman, used rabbits to test their hypothesis that “a blood pressure raising substance is formed in the kidneys and passed into the blood”.

Answer 22

Tigerstedt and Bergam believed there might be an endogenous hypertensive substance that is released from the kidney. Using crude kidney extracts, they isolated a substance they called renin. But another forty years would pass before the full significance of their discovery was appreciated.

Answer 23

In the 1930s, renin was found to be a protease, a class of enzymes that digests proteins. But unlike the proteases in the gut that break down proteins indiscriminately, renin had a very selective effect. Its protease properties allowed it to convert a blood protein known as angiotensinogen into a short, 10-amino acid peptide known as angiotensin I.

Answer 24

Further research revealed that angiotensin I is inactive until it gets chopped down further by an all-important enzyme known as angiotensin-converting enzyme, or ACE, to form a shorter peptide called angiotensin II.

Answer 25

The most powerful blood pressure-increasing substance present in the human body, Angiotensin II targets receptors on blood vessels, known as AT1 receptors, to cause a strong constriction of the blood vessels. This causes a strong increase in blood pressure.

Answer 26

Think of it like a horror movie series. In Angiotensin, the first movie, villain Renin converts innocent angiotensinogen to a shorter peptide. Thankfully angiotensinogen, under their new name angiotensin I, is relatively harmless.

Answer 26

A summary of the renin-angiotensin system (RAS) is shown below. Discovering that human kidneys respond to chronic stressful situations by releasing more renin into the blood helped clarify the role of the renin-angiotensin system in the development of high blood pressure.

Answer 27

But in the sequel - Angiotensin II: Revenge of the Receptors - arch-villain ACE attacks and causes angiotensin I to manifest as a much more dark force: angiotensin II, which then wreaks a reign of terror on the defenceless townspeople of Bloodvessel.

Answer 28

Question 28

6. Case study: Part IV - bring on the snake venom!

Answer 28

The venom of some snake species produces a dramatic fall in blood pressure, causing the shock symptoms seen in such snakebite victims. The mechanisms underlying this effect remained obscure until a Brazilian postdoctoral researcher in John Vane’s lab, Sergio Ferreira, began studying the pharmacological properties of venom from a Brazilian arrowhead viper.

Answer 29

But this also meant that drugs that could block angiotensin II formation - perhaps by inhibiting the ACE enzyme directly - might be useful in lowering blood pressure.

Answer 30

Ondetti’s lab went on to make some of the greatest breakthroughs in the history of cardiovascular medicine - the discovery of the ACE inhibitors.

Answer 30

Vane got very interested when Ferreira found that the venom strongly blocked the enzyme ACE, thereby preventing the conversion of angiotensin I into the blood pressure raising peptide angiotensin II. Vane realised that this ability to block ACE could be the basis for a blood pressure-lowering drug.

Answer 31

His clinical colleagues in England thought the idea was bonkers. However, after visiting the Squibb Institute for Medical Research in New Jersey, Vane successfully convinced US researchers that his idea was worth following up. An Argentinian scientist at Squibb named Miguel Ondetti became fascinated with identifying ACE inhibitors in the viper venom.

Question 32

Teprotide: First-gen ACE inhibitor

Answer 32

Ondetti’s lab began by fractionating the viper venom, trying to identify the constituents that blocked ACE. They isolated several peptides that attracted their interest, including one venom peptide, teprotide, that was a strong ACE inhibitor. Teprotide was a short peptide containing just nine amino acids.

Question 33

Teprotide: First-gen ACE inhibitor

Answer 33

Ondetti began making large quantities of teprotide to allow testing of its pharmacological properties in animals and humans. The results were encouraging since teprotide produced a clear reduction in blood pressure in hypertensive patients.

Question 34

Teprotide: First-gen ACE inhibitor

Answer 34

Although it seemed to be an effective first-gen ACE inhibitor, teprotide suffered from a major drawback: the drug couldn’t be taken by mouth and had to be given via intravenous injection. (As a peptide, teprotide was broken down by the proteases in the digestive tract that efficiently degrade dietary proteins).

Answer 34

Remember that when converting angiotensin I (10 amino acids) to the blood pressure-increasing bad-guy peptide angiotensin II (8 amino acids), ACE chops off the last 2 amino acids? It does so by breaking the peptide bond between the last 2 amino acids and the third amino acid. Then researchers realised that the full peptide wasn’t involved: only the final 2 amino acids really mattered.

Question 35

7. Case study: Part V - time for second- and third-gen

Second- and third-gen oral ACE inhibitors

Answer 35

Ondetti’s lab made over 2,000 different peptides while trying to find an orally active ACE inhibitory peptide, but they all failed to work when given by mouth. Finally, progress was made when researchers began to understand the interactions of peptide substrates and inhibitors with the ACE enzyme - basically, three types of chemical bonds form between angiotensin I and ACE.

Answer 36

Ondetti’s lab made about 60 small noncleavable molecules that mimicked the final 2 amino acids in the teprotide inhibitor, testing them in a simple bioassay for ACE activity.

Answer 37

This knowledge led Squibb scientists to design a small molecule ACE inhibitor that mimicked the binding of the last 2 amino acids to the active site of ACE, and yet was chemically modified so that it didn’t contain a cleavable peptide bond. Such a molecule might still take advantage of the 3 binding interactions within the active site (shown as red squiggles below).

Answer 38

Answer 38

The sulfur atom greatly strengthened the bonding interactions between captopril and ACE, ensuring the drug is a very strong enzyme inhibitor. Because the drug would bind strongly to the enzyme, it would prevent access to the active site by angiotensin I. This inability to form angiotensin II caused a drop in blood pressure when hypertensive lab animals were treated with captopril.

Answer 39

Best of all, captopril was active in humans with high blood pressure when given via the oral route. The drug was approved for use in Britain in 1981. Although initially greeted with caution by many doctors due to its historical origins as a stripped-down snake venom constituent, before long the clinical effectiveness of ACE inhibitors became undeniable.

Question 39

Captopril - second-gen ACE inhibitor

Answer 39

This effort led the Squibb scientists to identify captopril as an effective inhibitor of ACE activity. As shown in the simplified image below, captopril contains a sulfur atom (S) in the form of a sulfhydryl (-SH) group (also known as a thiol group).

Answer 40

Question 41

Enalapril - third-gen ACE inhibitor

Answer 41

Although the development of captopril was a major achievement, the drug had some significant limitations. Firstly, side effects are often a problem for drugs containing sulfhydryl groups, and this proved to be the case with captopril. Patients taking the drug complained of intense itching sensations, a loss of taste, and a persistent dry cough.

Answer 41

The rapid metabolism of captopril was another problem, so patients had to take the drug 3 times daily.

Answer 41

These problems inspired the development of enalapril, an orally active ACE inhibitor that doesn’t contain sulfur atoms. This excellent follow-on drug was introduced in 1985 and due to its improved safety profile began displacing captopril from the market.

Answer 42

Over the next 20 or so years, over a dozen ACE inhibitors were introduced in various markets around the world. This family of drugs have had a major clinical impact, and remain widely used during the treatment of hypertension and many other cardiovascular diseases.

Answer 42

The development of the ACE inhibitors confirms the power of imitative drug discovery to produce improved medicines that are easier for patients to take as well as more effective and safer.

Answer 43

The improvements between different generations within a therapeutic class can sometimes seem modest. This growing availability of multiple medications is stressful for doctors who may feel they can’t keep abreast with the rising availability of new drugs.

Question 43

8. Three issues with follow-on drugs

Answer 43

1) Crowded marketplace
2) Stifled innovation
3) Cost escalation

Question 44

1) Crowded marketplace

Answer 44

Although ongoing improvement in the effectiveness and safety of drugs is a desirable outcome of imitative drug discovery, one downside is that the market can become crowded with lots of drugs that seem quite similar to each other.

Answer 45

This situation can also be confusing to patients, especially if switches are made from one member of a therapeutic class to another. In elderly and other patients who are often receiving multiple drugs simultaneously for different conditions (known as polypharmacy), keeping track of the reasons for taking individual medicines can be hard. Having lots of similar drugs available on the marketplace only exacerbates these challenges.

Answer 46

Some claim that this tendency is making the pharmaceutical industry less innovative in overall terms, since it breeds an environment where companies are less willing to gamble on high-risk scientific theories. Since most if not all of the great discoveries made by the giants of pharmaceutical history have been seen as dubious to some of their contemporaries, some fear that this risk-averse mentality could lead to a stifling of fresh scientific thinking.

Question 46

2) Stifled innovation

Answer 46

One criticism of follow-on drug discovery is that after an innovative first-in-class medicine is released, other drug companies feel obligated to jump into the same therapeutic class by producing their own versions of the medicine. Very often, funds and resources will be diverted from other projects to support the new project. In this situation, company executives may feel that developing a better copy of some other proven drug is a safer commercial option than continuing their own projects that seem more risky.

Question 47

3) Cost escalation

Answer 47

In recent decades, the costs associated with bringing a new drug to market have risen significantly, in part due to the costly human testing protocols that must be completed to satisfy national regulatory agencies. Yet while these regulatory requirements have helped make new drugs safer, they have also made them costlier.

Answer 48

Thus doctors can be faced with balancing the higher costs of late generation drugs against cheaper first or second gen members of the same therapeutic class. While newer, more expensive medicines are often a better choice on safety and efficacy grounds, this is not invariably the case. Very often in many patients, older drugs work just fine.