L2: Drug + Vax Failures

When do drug candidates fail

Step 1-2: Discovery and Development

What % of drugs are rejected at this stage

Around 70-75% of initial candidates are rejected

• much cheaper to reject drugs at this stage

When do drug candidates fail

Step 3-4: Preclinical research

What percentage of drugs reach this stage?

~5-10% get through to this stage

When do drug candidates fail

Step 5-6: Clinical research trials

Very dew drugs get through into final stage 3 trials

When do drug candidates fail

Step 7: Stage 3 trials and FDA Drug Review

Rejection at this stage is very costly

The stages of drug development

•Step 1-2: Discovery and Development (~70% rejected)

•Step 3-4: Preclinical Research (~5-10% reach this stage)

•Step 5-6: Clinical Research trials (very few reach final stage 3 trials)

•Step 7: Stage 3 trials and FDA Drug Review

•Step 8: FDA Post-Market Drug Safety Monitoring

Why do drugs fail in clinical trials

1) Unavoidable failures:

• Efficacy and safety – primary reason for failure

2) Avoidable failures – poor planning

• Strategy – poor trial design

• Operational – no money

• Commercial – no market, competition

Primary reason for failure in drug trial

Efficacy and safety reasons

First major well documented drug failure in modern times + year

The Elixir Sulphonamide drug in 1937

How did the Elixir Sulphonamide drug failure occur + in what year

1937 Chief chemist dissolved the drug in diethylene glycol and added raspberry flavour.

– Over 100 died as a direct result of poisoning with diethylene glycol

– Chemist committed suicide while awaiting trial

What happened in response to the Elixir Sulphonamide drug failure

Congress passed the 1938 Food, drug and cosmetic act – required companies to perform animal safety tests on all new drugs

• Led to the empowerment of the FDA

Thalidomide scandal key dates and people

– Licensed in 1958 as a sedative and medication for morning sickness without being tested on pregnant women

– Birth defects first detected in 1961 by a midwife Pat Sparrow in a Sydney hospital (though Dr William McBride took the credit)

– German pediatrician Widukind Lenz proved the link to Thalidomide in 1961

Thalidomide scandal impact on foetus

More than 10,000 people effected by thalidomide ~40% died at birth

• Those that survived had limb, eye, urinary tract and heart defects, disfigurement, palsy, sensory impairment, skeletal defects

• The drug effected the fetus if taken between day 20-40 days after conception - severity and location of deformity was time dependent

Thalidomide scandal -changes to clinical practice

Changes to regulations for drug testing and clinical trials in many countries

– The Directive 65/65EEC1 in Europe

– Medicines Act in 1968 in the UK

– Kefauver-Harris Amendment (drug efficacy Amendment) 1962 in the US

• All of these made manufacturers provide stringent data and proof of drug safety before approval

• Made drug advertising disclose side effects (US)

The TGN1412 story

What is the drug for

TGN1412 (Theralizumab) - Promising CD28 super agonist

• Created by Thomas Hunig at University of Wurzburg and developed by TeGenero Immuno Therapeutics

– Designed to help immune system to treat rheumatoid arthritis and B cell chronic lymphocytic leukaemia

– The drug enhanced regulatory T cell activity

The TGN1412 story

First human trial for the drug

2006: eight volunteers (6 receiving the drug and 2 the placebo)

Patients started to suffer from severe headaches, muscle pain, nausea, vomiting, diarrhoea, severe fever, rash and rigors.

• After 4 hours patients suffered hypotension, tachycardia and onset of respiratory failure

The volunteers all suffered a severe ’cytokine storm’

The TGN1412 story

Why did humans have different response to drug than rats and macaques

• Rats did produce large numbers of T cells but not the cytokines

• The macaque CD28 differs by 4 AAs, including critically in the super antagonistic antiCD28 binding domain.

• Humans also have co-stimulatory molecules in endothelia cells that synergized with CD28 costimulation – massive cytokine response

• Human cells have minimal CD33 which downregulate these pathways while monkeys have high levels

The TGN1412 story

Impact on future clinical trials

22 recommended changes to Clinical trials subsequently:

• Changes to calculations in starting point for dosing

• More scrutiny to novel agents and access to independent opinion

• New guidelines for trials of drugs that have never been tested in humans.

• Make sure animal model is relevant

• Sequential clinical testing – don’t give to all participants at same time- monitor for ill effects after each one.

• Give drugs via slow infusion

• Accreditation scheme for companies running Phase 1 trials

• Improved transparency with clinical trial reports made publicly available.

Salk polio vaccine

Killed vaccine

• In 1953 Jonas Salk produced first successful polio vaccine from formaldehyde killed virus

• 1954 tested on 1.6 million children in Canada, Finland and USA

• Licensed in 1957

• Cases of polio declined from 58,000 to just 161 in the US by 1961

Sabin polio vaccine

1954 developed oral attenuated vax from mutant strains of polio

Tested on prisoners first - proved safety

Unable to do trial in USA - went to USSR in 1959

1960 approved to do trials in US and vax approved

The cutter incident

1954 production began

Cases of paralytic polio started to be reported after vaccination - all from the Cutter Laboratories

Cutter Laboratories were recalled.

• 380,000 doses had already been given. 260 cases of polio were reported from this vaccine, 192 with paralyses and 10 deaths.

• Issue was with poor filtration allowing clumps of virus that protected virions against killing and poor inactivation

The Cutter incident - Aftermath

– The attenuated Sabin vaccine was chosen over the killed Salk vax

– Although the Cutter Incident damaged the reputation of Salk’s vaccine, the Sabin vaccine had major advantages

– Led to improvements in government oversight of testing

Sabin vaccine major advantages over Salk vax

1) It was given orally, easy to administer and designed to mimic the natural route of infection via the intestine

2) It did not require cold chain storage so ideal for developing nations

3) The efficacy was similar but it provided life long immunity without the need for booster shots.

Rare adverse side effect of oral attenuated polio vax

Vaccine- associated paralytic polio (VAPP)

• Occurs in around 1:1 million vaccinations

• 1 case in the US, several in India

• It can lead to cVDPV and outbreaks of polio in regions where the vaccine uptake is low

• Is of higher risk of happening in people with immunodeficiencies

Vaccine- associated paralytic polio (VAPP) occurs from which vax and in what frequency

rare adverse effect of the oral attenuated polio vaccine (Sabin)

• Occurs in around 1:1 million vaccinations

The Dengvaxia controversy against Dengue infection

April 2016 the Phillipines launched the first vaccination program using Dengavaxia

– In November 2017 the company released statement saying that the vaccine should NOT be used in people

who had not had a prior Dengue infection.

– The Philippine Government then suspended vaccination

– Could lead to antibody enhancement and much more dangerous dengue hemorrhagic fever

– 3 children died of dengue after the vax

CSL COVID-19 vaccine

How it worked

Used a novel Molecular clamp mechanism

University of Queensland developed method to use a modified gp41 protein from HIV to ‘clamp’ the virus Spike

protein into the pre bound form making it easier to target with a vaccine

CSL COVID-19 vaccine

What went wrong

Vax was shown to be safe and stimulated strong neutralizing antibodies to SARS-cov-2

• However, in the first human all of the phase 1 participants also generated a weak antibody response to the GP41 HIV fragments

• While there was never any chance of an HIV infection the association with HIV was enough to terminate the project

Example of a vaccine will likely never be available due to lack of commercial interest

The Ross River virus vaccine against the commonest arbovirus infection in Australia

Who produced the first polio vaccine to be used commercially in the US?

A. John Enders

B. Jonas Salk

C. John Kolmer

D. Albert Sabin

B. Jonas Salk

TGN1412 was a?

A. Sulfonimide drug

B. An analgesic

C. A teratogenic degrader of transcription factors

D. A CD28 Super agonist

D. A CD28 Super agonist

The Elixir sulfanimide drug caused fatalities because?

A. It led to increased clotting in some patients

B. The active ingredient dose was too concentrated

C. It was dissolved in diethylene glycol to improve commercial sales

D. It was contaminated with a drug resistant enterococcus

C. It was dissolved in diethylene glycol to improve commercial sales