Insanity of Drug Development

peeping-tom-316125_1280Pharmaceutical drug development is generally complicated and expensive. I have no reason to believe this will ever change. In recent years, however, FDA makes an extra effort to help the industry to bring new promising treatments faster to the market. Despite that willingness to accelerate drug development, that is possible only in some cases, pharma and biotech still operate in a highly complex regulated environment, dealing with many issues that can surface out from the poorly predicted development and commercialization risks. Thus not all the drug candidates can and will reach the market.

To mitigate those uncertainties, every major pharma company sets their own drug discovery and development governance frameworks, proper decision gates and criteria to reduce the risks of drug development failure. However, even with rigorously followed company’s rules and policies, there is still a lot of room for unpredictability. In many ways, a success of the drug candidate is a combination of hard work of skilled and experienced cross-functional teams and good luck. However, looking across the industry, pharma seems to deal repeatedly with similar drug development problems that could be potentially minimized or entirely avoided. This is what the post is about. Let’s go through different types of drug development insanity and their consequences with a few practical examples.

Insanity type 1: “Jumping to conclusions too early.”

Case#1: tremelimumab, anti-CTLA-4 (Pfizer/AstraZeneca).

Issue: drug candidate discarded from the pipeline/out-licensed pre-maturely.

Consequences: AstraZeneca wins a potential blockbuster in I-O space: tremelimumab becomes one of AstraZeneca’s top drug prospects and is a leading example of the kind of cancer programs the pharma giant hopes to use to generate billions of dollars in new sales. Consequently, Pfizer pursues another anti CTLA-4 molecule in late 2016 to compensate the loss.

Timeline:

Apr 2008: Pfizer announced the discontinuation of a Phase III clinical trial of single-agent tremelimumab (CP-675,206) in patients with advanced melanoma, after the review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy.

Fall 2011: Tremelimumab is out-licensed to AstraZeneca (Medimmune).

Feb 2016: AstraZeneca and MedImmune, its global biologics research and development arm, announced publication in The Lancet Oncology of a Phase Ib study (study 006), showing antitumour activity of combination treatment with durvalumab and tremelimumab, in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), irrespective of PD-L1 status.

Sep 2016: Five years after tremelimumab was out-licensed, Pfizer decided to jump back into developing this cancer class after signing a deal worth $250 million with OncoImmune for an option on its preclinical CTLA-4 candidate ONC-392.

Insanity type #2: “Doing the same thing over and over and expecting a different result”(seems to be most common, similar to type #3 but with the negative outcome).

Case#2: tecemotide, therapeutic cancer vaccine (Merck KGaA).

Issue: development of ineffective drug candidate is pursued despite unclear or weak signs of activity.

Consequences: sunk development costs and wasted resources.

Timeline:

Mar 2006: study EMR 63325-005, Ph2, NSCLC, only subgroup analysis favorable.

Aug 2012: study START, EMR 63325-001, Ph3, NSCLC, Primary endpoint not met. Only subgroup analysis was favorable.

May 2014: EMR 63325-009 (Japan study), Ph1/2, NSCLC Primary endpoint and secondary endpoints not met. Subgroup analysis not favorable.

Sep 2014: Merck KGAA finally announced the discontinuation of the clinical development program of its investigational MUC1 antigen-specific cancer immunotherapy tecemotide (also known as L-BLP25) as a monotherapy in Stage III non-small cell lung cancer (NSCLC).

Case #3: solanezumab, monoclonal antibody & neuroprotector for patients with Alzheimer’s disease (Eli Lilly).

Issue: similar to above Case #2.

Consequences: significant sunk costs and wasted resources.

Timeline:

Aug 2012: the announcement of failed Phase 3s (Expedition 1 and 2).

Background: even though previously conducted Phase 2 showed no significant changes in cognition and memory, the company started two Phase 3 trials: EXPEDITION 1 and 2 (NCT00905372 and NCT00904683). Both studies were not able to show a difference in cognition and memory between the treated and the placebo group…

Jul 2013:…however, since the first two EXPEDITION trials show a positive effect in patients with mild Alzheimer’s disease, another phase 3 trial, EXPEDITION 3 (NCT01900665) was started.

Nov 2016: Lilly announces that another phase 3 trial, EXPEDITION 3 (NCT01900665) failed to show positive results.

Insanity type #3: “Prolonged drug development leading to a drug candidate which is a potential breakthrough (similar to type #2 but with the potentially positive outcome).

Case #4: inotuzumab ozogamicin, an antibody-drug conjugate for the treatment of cancers (Pfizer/Wyeth/UCB).

Issue: overall long development time, after 13+ years in a clinic and undergoing numerous clinical trials (19 listed as of Nov  2016 on clinicaltrials.gov) molecule not yet approved in any indication but surprisingly receives FDA BTD (Breakthrough Designation) for ALL in Sep 2015. One year later, Phase III trial gives mixed results [INO-VATE ALL study (NCT01564784].

Consequences: significant sunk development costs, the unknown faith of FDA approval, despite BTD granted in Oct 2015 (after 12 years in the clinic).

Timeline:

2003: Clinical program starts to advance later to a total of 19 studies as of Nov 2016.

Oct 2015: Inotuzumab Ozogamicin Receives FDA Breakthrough Therapy Designation for Acute Lymphoblastic Leukemia (ALL).

Sep 2016: Inotuzumab ozogamicin faces an uncertain path to FDA approval in acute lymphoblastic leukemia (ALL) following mixed Phase III trial results [INO-VATE ALL study (NCT01564784].

Results from the 326-patient study were published in August (Kantarjian, et al. N Engl J Med 2016;375:740-53), demonstrated the study met the primary endpoint of complete remission (CR) rate over six months, but not OS over 24 months. The post-hoc analysis, using RMST, nevertheless showed an OS benefit.

Insanity type #4: “Rushing drug development and taking too many risks.”

Case #5: TGN1412, monoclonal antibody (TeGenero, manufactured by Boehringer Ingelheim).

Issue: Cytokine storm in a Ph 1 trial of the anti-CD28 monoclonal antibody TGN1412 resulting in multiorgan failure of the human volunteers.

Timeline & ConsequencesAfter a drug is confirmed as safe and efficacious in preclinical studies, it is tested in healthy human volunteers for first in man trials. In 2006, a phase I clinical study was conducted for a CD28 superagonist antibody TGN1412 in six human volunteers. After very first infusion of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit. After this particular incident, a lot was changed over how first in man trials are approved by regulatory authorities and the way clinical trials are conducted.

Though there is always a risk involved with clinical trials, these risks can be potentially reduced. Drugs showing safety and efficacy in preclinical animal models may show very different pharmacological properties when administered to humans. Development of proper preclinical models which can efficiently predict drug behavior in humans is very essential, before testing a drug in a human subject. “First-in-man,” human trials of potent biological molecules should include initial testing on very less number of human volunteers before administration of a drug to a greater number of human volunteers.

Case #6: Chimeric Antigen Receptor Technology (CARs), Juno.

The issue, Timeline & Consequences

Jul 2016: Juno announced that three patients had died in one of its clinical trials, blaming a drug it was administering with a cancer-killing cell treatment code-named JCAR015. The Food and Drug Administration allowed the study to continue.

Nov 2016: Juno has announced that two more patients have died. All the deaths have the same cause: swelling and bleeding in the brain. Juno had voluntarily put the mid-stage study on hold and informed the U.S. Food and Drug Administration accordingly. The company is still evaluating the cause of the deaths and has not yet decided whether it will continue developing the drug (as of Nov 23rd).

It seems that Juno and the FDA moved too fast in trying to restart the studies. To be fair, intentions were good to speed development up as patients’ lives were at stake. Unfortunately, the good intentions here led to a tragedy.

Summary: All drugs candidates are different. It is hard to predict early their success or failure based on imperfect animal models or selection of the accurate indications leading to positive proof of concept in a clinic, without multiple trials and errors. This is particularly challenging when dealing with completely novel molecules and new mechanisms of actions. There is still a number of bets every company must take while moving the drug candidate to the next stage of development which in addition to teams’ cognitive bias result in either failed or successful drug candidates at the end. None of the pharma companies want intentionally to discard the valuable assets or burn cash for something that does not add any value to the patient and to the pipeline. However, those things happen and are inevitably part of the drug development madness.

References:

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