When I reflect on the state of drug development in 2017, the opening lines of Charles Dickens’ A Tale of Two Cities comes to mind.
It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us.
If you’ve been watching the pharmaceutical industry, you’ll probably appreciate how these literary paradoxes capture both the incredible progress that has been made as well as the daunting challenges that remain. Here are seven of the biggest news stories from 2017 that exemplify the trend in both industry and regulatory towards a safer, more effective, and personalized approach to drug development.
1. First digital pill approved.
Last month, the US FDA approved the first digital pill—a medication that is embedded with a sensor that can detect whether and when a patient takes their medicine. The digital pill combines a 510(k) approved ingestible/wearable sensor with an FDA approved anti-psychotic drug to provide objective adherence information to the patient’s care team. Providing this information to doctors and/or designated family members is thought to facilitate medication adherence. Non-adherence to prescribed medications is a key issue facing our industry, costing the US economy between $100-300 billion annually, and representing between 3-10% of total healthcare costs. Medication adherence is particularly difficult for schizophrenia patients, which is probably why Otsuka chose to invest in this technology for its antipsychotic drug, Abilify. It remains to be seen whether this technology will actually improve medication adherence. There are also privacy concerns regarding who will have access to this information and the possibility that it may be misused. (Full story >)
2. FDA takes important steps to stem the tide of opioid misuse and abuse.
The opioid epidemic in the United States has become a serious public health problem with drug overdose deaths now comprising the leading cause of injury-related deaths. In September, the FDA Commissioner, Dr. Scott Gottlieb blogged about the steps that the agency is taking to stem the tide of opioid misuse and abuse. In particular, he noted steps to expedite the approval of generic versions of abuse-deterrent formulations (ADFs) of opioid drugs. These drugs are generally extended release formulations of opioids that are resistant to being crushed or dissolved. (Full story >)
In 2016, our Simcyp division received a grant from the FDA’s Office of Generic Drugs to develop a mechanistic modeling and simulation framework to perform virtual bioequivalence studies. This technology can support the development of generic ADFs of opioid drugs by helping avoid unnecessary clinical studies when the outcomes can be predicted accurately using the models.
3. FDA approves first gene-altering leukemia treatment, costing $475,000.
2017 is the year that the promise of immuno-oncology finally bore fruit. Immuno-oncology harnesses the patient’s own immune system to fight cancer. In August, the FDA approved Novartis’s Kymriah—a treatment that genetically alters a patient’s T cells (CAR-T cell therapy)—for children and young adults with B-cell acute lymphoblastic leukemia that has resisted standard treatment or relapsed. This “living drug” represents a paradigm shift in the treatment of cancer and other life-threatening diseases. (Full story >)
4. In a first, scientists edit genes inside a man’s body to try to cure a disease.
In another exciting gene therapy advance, this autumn saw the first procedure to try to treat a disease by editing a gene inside the body. While Kymriah involves removing a patient’s white blood cells, performing genetic engineering on them, and then transfusing them back into the patient, this was the first attempt to permanently change a patient’s DNA to cure a disease. The patient—Brian Madeux, 44—has the metabolic disease “Hunter Syndrome,” which is caused by mutations in a gene that produces an enzyme that metabolizes glycosaminoglycan carbohydrates. The buildup of glycosaminoglycans damages the lungs, heart, and nervous system. The treatment—under development by Sangamo Therapeutics—uses zinc finger nucleases to insert a gene that directs liver cells to make the missing enzyme. It is estimated that only 1% of liver cells would need to be corrected to treat the disease. Madeux’s doctors will follow up in the coming weeks to determine whether enough enzyme is being produced to have a therapeutic benefit. (Full story >)
5. Senate passes FDA funding and “right to try” drug bills.
The FDA Reauthorization Act of 2017 (FDARA) was passed by the US Congress and was signed into law by President Trump in late August. The FDARA reauthorizes the Prescription Drug User Act Fee Amendments (PDUFA) for the fifth time, the Medical Device User Act Fee Amendments (MDUFA) for the third time, and both the Generic Drug User Fee Amendments (GDUFA) and the Biosimilars User Act Fee Amendments (BsUFA). The FDARA is closely aligned with the recently approved 21st Century Cures Act. (Full story>)
We recently covered this topic in our blog, which underscores the importance of regulatory science and modeling & simulation as highlighted by FDA Commissioner Scott Gottlieb in his July 7 statement.1 PDUFA VI identifies how regulatory decision support tools can be leveraged to support the drug development and review process. The new section on Regulatory Decision Tools focuses on the use of quantitative methods for drug development to facilitate the development and application of exposure-based, biological, and statistical models derived from pre-clinical and clinical data sources, herein referred to as “model-informed drug development” (MIDD) approaches, specifically: physiologically-based pharmacokinetic modeling (PBPK); design analysis and inferences from dose-exposure-response studies; disease progression model development, including natural history and trial simulation; and immunogenicity and correlates of protection for evaluating biological products. The value and benefits of MIDD for regulatory decision-making can no longer be questioned. MIDD has become essential to modern drug development, impacting all phases of the process, used to increase our understanding of benefit/risk, determine go/no go decisions, assess safety and efficacy of new therapies, guide dose selection, address the needs of special populations, identify issues that need further characterization, answer myriad drug development questions, evaluate alternative formulations and drug indications, and inform drug labeling decisions.
6. Cancer drug proves to be effective against multiple tumors.
Historically, cancer has been categorized by the anatomical origin of the tumor—eg, “breast cancer,” “lung cancer,” “leukemia,” etc. And the anatomical origin of cancer dictated the approach to treatment. But, this framework appears to be changing. In July, Science published a paper reporting that a wide range of different cancer types with loss-of-function mutations in the mismatch repair pathway have favorable responses to PD-1 blockade immunotherapy.2 The FDA has approved the anti-PD-1 immuno-oncology drug, pembrolizumab (Keytruda), for patients whose cancers have this genetic abnormality.
Cancer cells overexpress PD-1 ligands (PD-L1/PD-L2), which bind PD-1 and thereby suppress the immune system. Immuno-oncology drugs can target the PD-1 signaling pathway in one of two ways. PD-1 inhibitors target PD-1 on T cells whereas PD-L1/PD-L2 inhibitors target the PD-L1/PD-L2 ligand expressed on tumor cells. Both types of inhibitors release the “brakes” that the tumor places on the immune system so that T-cells can identify and kill cancer cells.
Clinical development in immuno-oncology programs follows a condensed time line wherein clinical pharmacology is characterized as part of safety/efficacy studies rather than through healthy volunteer studies. In this compressed time line, modeling and simulation can be continuously applied to address questions regarding optimizing dosing, determining which intrinsic and extrinsic factors might cause variability in exposure, and predicting PK in unstudied populations. (Full story >)
7. When the immune system thwarts lifesaving drugs.
In May, the New York Times reported on the widespread problem of immunogenicity. While the immune system generally acts to protect us from harmful pathogens, it can also produce deleterious responses against medications. The propensity of a therapeutic protein product (a “biologic”) to generate immune responses to itself and to related proteins or to induce immunologically-related adverse clinical events is called “immunogenicity.”
According to the NYT article, it is difficult to predict which patients are at the highest risk of developing immune responses to their medications or which drugs are likely to be immunogenic. In a recent US FDA review of 121 approved biological products, 89% of them had immunogenicity reported and in 49% of cases it impacted efficacy. Immunogenicity is especially concerning for vulnerable populations with compromised immune systems, oftentimes the exact cohort receiving the biologic treatment. (Full story >)
Earlier this year, we launched the first global quantitative systems pharmacology (QSP) consortium to predict the immunogenicity of biologics and its impact on pharmacokinetics, efficacy, and safety in diverse patient populations. The QSP Immunogenicity Consortium brings together leading biopharmaceutical companies in a pre-competitive environment to cooperatively develop an Immunogenicity Simulator. This new tool will help inform the clinical development for biologicals by allowing sponsors to explore optimal dosing routes and regimens and answer “what-if” questions in virtual patient populations.
 Gottlieb S. (2017, July 7). How FDA Plans to Help Consumers Capitalize on Advances in Science [Blog post]. FDA Voice. Retrieved from https://blogs.fda.gov/fdavoice/index.php/2017/07/how-fda-plans-to-help-consumers-capitalize-on-advances-in-science/
 Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, … Diaz Jr LA. (2017, July 28). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349), 409-413. Retrieved from http://science.sciencemag.org/content/357/6349/409
At Certara, we are passionate about using science and technology to optimize drug development and improve health outcomes. It’s exciting to see the progress made in 2017, and we look forward to tackling some of the biggest problems in drug development in 2018. To learn more about how modeling and simulation can support focused and efficient immune-oncology development, please watch this archived webinar. From all of us at Certara, we wish you a Happy New Year!