New Drug Update 2019 December 2019

11/25/2019

Presented by:

C. Wayne Weart Pharm D, BCPS, FASHP, FAPhA Professor of Clinical Pharmacy and Outcome Sciences Professor of Family Medicine MUSC, Charleston, SC [email protected]

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation. I do not speak for or consult with any pharmaceutical manufacturer.

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Pharmacist Objectives

› New Drug Update › At the completion of this activity, the pharmacist will be able to: › Discuss the new guidelines for patients with asthma, lipids, and resistant hypertension and the evidence on which they are based, and how to apply them in selected patients › Describe the current information concerning newly FDA approved medications (pharmacology, pharmacokinetics, efficacy and safety data, drug interactions, dosing, monitoring, and cost) in the selection of evidence-based pharmacotherapy

Technician Objectives

› At the completion of this activity, the pharmacy technician will be able to: › Discuss the new guidelines for patients with asthma, lipids, and resistant hypertension and the evidence on which they are based, › Describe the current information concerning newly FDA approved medications (pharmacology, pharmacokinetics, efficacy and safety data, drug interactions, dosing, monitoring, and cost)

HPV9 Vaccine (Gardasil-9) by Merck • December 10, 2014 The FDA approved nine-valent HPV vaccine (V503, Gardasil-9) that includes coverage for 6, 11, 16, and 18—just like HPV4—but also for five additional high cancer- risk strains: 31, 33, 45, 52, and 58. – What might it offer vs. the current vaccines? • Additional 25% CIN 2 or cervical lesions • Additional 18% vaginal cancer cases • Additional 15% cervical cancer cases • Additional 4% of oropharyngeal cancer cases • The FDA has stated that “Gardasil 9 has the potential to prevent approximately 90 percent of cervical, vulvar, vaginal and anal cancers.”

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ACIP Meeting 10-19-2016

• The ACIP recommended that 11- to 12-year-olds receive 2 doses of human papillomavirus (HPV) vaccine at least 6 months apart rather than the previously recommended 3 doses to protect against cancers caused by HPV infections. Teens and young adults who start the series later, at ages 15 through 26 years, will continue to need 3 doses of HPV vaccine to protect against cancer-causing HPV infection. • October 7, 2016, the FDA approved adding a 2-dose schedule for 9-valent HPV vaccine (Gardasil 9) for adolescents aged 9 through 14 years

HPV-9 Vaccine • What is the recommendation for persons with immunocompromising conditions? • CDC recommends 3 doses of HPV vaccine (0, 1–2, 6 months) for immunocompromised people age 9 through 26 years. • People whose immune responses might be lower, for example due to HIV infection, cancer, autoimmune disease, or taking immunosuppressant medications, should receive 3 doses to make sure they get the most benefit. • However, children with asthma, diabetes, and other conditions that would not suppress immune response to HPV vaccination can receive a 2-dose schedule.

HPV-9 Vaccine

• October 5, 2018 the FDA approved Human Papillomavirus (HPV) 9-valent Vaccine, Recombinant (Gardasil-9) expanding the approved use of the vaccine to include women and men aged 27 through 45 years of age. • In approximately 3,200 women 27 through 45 years of age, followed for an average of 3.5 years, HPV-9 vaccine (Gardisil-9) was 88 percent effective in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine. • Data in men is based upon immunogenicity data from a clinical trial in which 150 men, 27 through 45 years of age, received a 3-dose regimen of HPV-9 vaccine (Gardasil-9) over 6 months. • The ACIP reviewed the data on October 25, 2018 and voted during meeting on June 26, 2019.

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ACIP Meeting 6-26-2019 • In a 10-4 vote, the committee also recommended adults ages 27 through 45 who had not been adequately vaccinated make shared decisions with their doctors about getting vaccinated with the HPV-9 vaccine. Adults older than 45 who had not been vaccinated are not advised to do so, since HPV vaccines are not licensed for use in that age group. • Consider patients with new or multiple sexual partners or other high-risk patients who have not been vaccinated previously? – MMWR August 16, 2019 / 68(32);698–702

PCV-13 Vaccine for patients 65 and older? • 6-26-2019 the ACIP vote was close, with eight members voting to remove the recommendation of PCV-13 vaccine for all patients age 65 and older and six voting to continue it. In a 13-1 vote that followed, the committee recommended what’s known as a “shared clinical decision making” — in effect leaving it up to doctors and their patients aged 65 and older to decide whether they should get a single dose of Prevnar 13. • In 2014 the committee agreed that it might need to revisit the advice because of the effect the vaccine was having in children, who also receive it. In short, older adults were benefiting from the use of the vaccine in small children. With fewer kids sick with pneumococcus, fewer cases in older adults were being seen as well.

Who might benefit the most from PCV-13? • In a review of medical data from a community in Finland the following conditions were significantly more common among pneumonia patients than among control subjects: heart disease (38.4% versus 23.0%), lung disease (13.0% versus 3.8%), bronchial asthma (11.9% versus 3.1%), immunosuppressive therapy (2.7% versus 0.8%), alcoholism (2.2% versus 0.3%), and institutionalization (8.6% versus 3.9%). (The American Journal of Medicine 1994; 96:313-320)

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Tdap (Adacel Vaccine) by Sanofi Pasteur

• January 15, 2019 - The Food and Drug Administration (FDA) has expanded the use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis [Tdap] vaccine adsorbed (Adacel, Sanofi Pasteur) to allow for repeat vaccination in patients 10–64 years old ≥8 years after the first Tdap vaccination. Adacel is approved for active booster immunization against tetanus, diphtheria, and pertussis. • The approval was based on data from the Td537 study which included individuals 18–64 years old who had received a dose of Adacel 8–12 years prior (N=1330). Participants were randomized to receive either a second dose of Adacel (N=1002) or Td vaccine (tetanus and diphtheria toxoids adsorbed; N=328). Blood samples for immunogenicity analyses were obtained from participants pre-vaccination and approximately 28 days post-vaccination, the rates of seroprotection against tetanus and diphtheria were >99% in both groups.

Tdap

• Oct. 25, 2019 The CDC’s Advisory Committee on Immunization Practices recently voted unanimously to recommend that either Td or Tdap may be used for the decennial Td booster, as tetanus prophylaxis for wound management in nonpregnant patients who previously received Tdap, and as additional doses of the catch-up immunization series for tetanus, diphtheria and pertussis in patients 7 years of age or older, including those who are pregnant.

Hepatitis A Update 2018 • ACIP Meeting Oct 2018: Hepatitis A vaccination: Homelessness – ACIP Working Group Recommendations: • Pros: Protection of a vulnerable population • Providers are more likely to administer vaccine to homeless persons if homelessness is an ACIP recommended indication for vaccination • Vaccination of homeless persons would reduce an at risk population and therefore reduce the risk of large-scale outbreak, and increase the herd immunity among the homeless population over time • Vaccinating homeless in an outbreak setting and controlling an outbreak among homeless is challenging compared to integrating services into a familiar setting • Routine vaccination is likely less costly than vaccination as part of an outbreak response • Cons: Vaccine administration record-keeping • Limited published data exist on hepatitis A or vaccination that specifically focuses on persons who are homeless • Routine vaccination of homeless who do not utilize health services might not be feasible

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Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation • In the study, over 1800 patients aged 18 and older who'd undergone autologous hematopoietic stem cell transplantation in the prior 50–70 days were randomized to receive the vaccine or placebo (two doses 1–2 months apart). During a median 21 months' follow-up, herpes zoster was confirmed significantly less often in the vaccinated group (30 vs. 94 cases per 1000 person-years). • Infectious diseases specialist Dr. Paul Sax weighs in: "Although recombinant zoster vaccine is not yet formally endorsed in its label for immunocompromised hosts, this study supports what many clinicians have already done — expanded its indications to populations at greater risk of developing herpes zoster. We should expect the guidelines about this vaccine to expand regarding its broader use.“ – JAMA 2019;322(2):123-133 16

FDA Head Warns Feds May Intervene if States Don't Strengthen Vaccine Laws • 2-20-2019 FDA commissioner Scott Gottlieb said that the federal government may have to take action if states don't strengthen their laws on vaccine exemptions, CNN reports. • Seventeen states allow families to choose not to vaccinate their children based on personal beliefs. Forty-seven states allow religious exemptions. • Measles outbreaks in the U.S. have infected 127 people so far in 2019; most were unvaccinated. (4/3/2019 465 cases including 150+ from Rockland County, NY)

'Unethical Physicians' Aid Surge in Vax Exemptions • At two public charter schools in the Sonoma wine country town of Sebastopol, more than half of the kindergartners received medical exemptions from state-required vaccines last school year. The cities of Berkeley, Santa Cruz, Nevada City, Arcata, and Sausalito all had schools in which more than 30% of the kindergartners had been granted such medical exemptions. (CDC estimates medical exemptions should be a fraction of 1% and include children who are allergic to vaccine components, who have had a previous reaction to a vaccine, or whose immune systems are compromised, including kids being treated for cancer). • Nearly three years ago, with infectious disease rates ticking up, California enacted a fiercely contested law barring parents from citing personal or religious beliefs to avoid vaccinating their children. Children could be exempted only on medical grounds, if the shots were harmful to health. (Miss, WV and now Maine have passed similar legislation while Washington has just eliminated the personal exemption) • Some physicians are wielding that power liberally and sometimes for cash: signing dozens -- even hundreds -- of exemptions for children in far-off communities. (MedPage Today 4-10-2019) 18

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US Measles Cases and Outbreaks

Number of Measles Cases Reported by Year 2010-2019 (as of August 8, 2019) In 31 States

1250 cases as of 10-3-19 largest # since 1992 with 2237 cases and 4 deaths

From January 1 – October 3, 2019, 119 of the people who got measles this year were hospitalized, and 61 reported having complications, including pneumonia and encephalitis. https://www.cdc.gov/measles/cases-outbreaks.html

MMWR Weekly / October 11, 2019 / 68(40);893–896

Measles • In 2000, endemic measles was declared “eliminated” from the U.S. (absence of continuous disease transmission for greater than 12 months) • Importation of measles will continue to occur as measles is endemic in many other parts of the world. • Measles cases are still reported in the U.S., including among adults - Most cases related to travelers who bring measles back from overseas (2/3 from unvaccinated U.S. residents, 1/3 from unvaccinated foreign visitors) • 2 doses of MMR (measles-mumps-rubella) vaccine are 97% effective at preventing measles; 1 dose is 93% effective. Protection lasts for life. – There are no recommendations to receive a third dose of MMR vaccine during measles outbreaks. • The majority of people who get measles are unvaccinated. – http://www.immunize.org/cdc/cdc-measles-us-3-28-2019.pdf 21

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Measles • Acute viral illness with prodrome of fever, malaise, cough, coryza (runny nose), and conjunctivitis, followed by maculopapular rash • Potential complications: pneumonia, encephalitis, and death • Measles is highly infectious Average incubation period (between exposure and rash onset): 14 days (range, 7-21 days) • Before the U.S. measles vaccination program started in 1963, each year in the U.S. – 3–4 million people got measles – 400–500 of them died – 48,000 were hospitalized – 4,000 developed encephalitis because of measles 22

Measles and the Immune System?

• Nov. 2019 A study, led by investigators at Harvard Medical School (HMS), Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, evaluated the effect the measles virus can have on the body’s immune memory by studying 77 unvaccinated children before they contracted the natural measles virus infection and again two months after contracting the disease. (Science 01 Nov 2019: 366, 599-606) • Researchers found that the virus had wiped out anywhere from 11 to 73% of the different antibodies a person had previously had to fight disease— whether it was antibodies protecting against the influenza, herpes virus, or pneumonia. • The study supports the idea of “immune amnesia” or the idea that the measles virus can partially obliterate immune memory the body has stored due to previously encountered pathogens, researchers said. 23

Mumps Outbreak Mumps Outbreak at Temple University in Philadelphia March 2019 (99 cases) and College of Charleston Sept – Nov 21, 2019 (51 cases) so far. • From January 1 to Oct. 11, 2019, 48 states and the District of Columbia in the U.S. reported mumps infections in 2618 people to CDC. • Recognition, Testing, and Management: – When evaluating patients with parotitis without an apparent cause, area providers should recognize the increased likelihood of mumps infection among patients who are associated with Temple University and consider mumps infection in other patients with parotitis.

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Mumps Cases as of Oct. 11, 2019

Mumps Outbreak • When mumps is suspected, providers should: – Place patients with suspected mumps on droplet precautions, which includes the use of surgical masks for healthcare workers with close patient contact. – Collect a buccal swab, urine, and serum for mumps testing. – Advise patients who have suspected or confirmed mumps infections to self-isolate, avoid travel, and limit close contact with others for 5 days following onset of parotitis. – In October 2017, ACIP recommended a third dose of a mumps-containing vaccine for persons previously vaccinated with 2 doses of a mumps-containing vaccine who are identified by public health as at increased risk for mumps because of an outbreak to improve protection against mumps and its complications. • The mumps vaccine component of the MMR vaccine has a lower effectiveness compared to the measles and rubella components. Mumps vaccine effectiveness has been estimated at a median of 78% (range: 49%−91%) for 1 dose and a median of 88% (range: 66%−95%) for 2 doses.

Mumps Outbreak Mumps Outbreak at Temple University in Philadelphia March 2019 (99 cases) and College of Charleston fall 2019 (11 cases) • From January 1 to July 19, 2019, 45 states and the District of Columbia in the U.S. reported mumps infections in 1,799 people to CDC. • Recognition, Testing, and Management: – When evaluating patients with parotitis without an apparent cause, area providers should recognize the increased likelihood of mumps infection among patients who are associated with Temple University and consider mumps infection in other patients with parotitis.

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Baloxavir marboxil (Xofluza) by Shionogi/Roche • Oct 24, 2018 the FDA approved baloxavir marboxil (Xofluza) for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. The drug is the first new medication for influenza with a novel mechanism in the last 20 years and it was granted Priority Review by the FDA. • A single-dose oral medicine with a novel proposed mechanism of action that inhibits polymerase acidic endonuclease, an enzyme essential for viral replication with demonstrated efficacy against a wide range of influenza viruses, including oseltamivir-resistant strains and avian strains (H7N9, H5N1) in non-clinical studies. • In clinical trials of baloxavir marboxil, resistant viruses were detected in 23.4 percent of participating patients younger than 12 years old in Japan.

Baloxavir marboxil (Xofluza) • CAPSTONE-1 was a phase III multicenter, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of Xofluza in 1,436 people age 12 and older in the US and Japan during the 2016-2017 season. • The primary endpoint of the study was time to alleviation of symptoms. • Doses: weight-based single doses of baloxavir (40-79 Kg = 40 mg and > 80 Kg = 80 mg) and oseltamivir 75 mg twice daily for 5 days. (Available as 2 or 4 x 20 mg tabs and 1 or 2 x 40 mg tabs per blister card) ~$165.00/single dose GoodRx.com 11-26-18 • Oseltamivir (Tamiflu) 75 mg x 10 caps Brand ~$165.00 and generic ~$50.00 GoodRx.com 11-26-18 – N Engl J Med 2018; 379:913-923

Baloxavir marboxil - Xofluza • The median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir (median time 54 hours versus 54 hours). Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. (N Engl J Med 2018; 379:913-923) • Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. 30

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Baloxavir marboxil (Xofluza) • Roche recently announced that the global phase III CAPSTONE-2 study assessing the safety and efficacy of baloxavir marboxil in people at high risk of complications from the flu, as defined by the CDC, met the study’s primary objective and showed superior efficacy in the primary endpoint of time to improvement of influenza symptoms versus placebo. – Result: Among 2184 randomized pts, 1163(53%) comprised the ITTI population (47.9% A/H3N2, 6.9% A/H1N1, 41.6% B). The most common risk factors were asthma or chronic lung disease(39.2%) and age ≥65 years (27.4%). Time to improvement in flu symptoms (TTIIS) was significantly shorter in BXM than PLC (median 73.2hr vs 102.3hr, p<0.0001) and numerically shorter than Os (81.0 hr, p=0.8347). TTIIS in BXM pts with A/H3N2 virus (median: 75.4 hr) was significantly shorter than in PLC (100.4 hr; P =0.0141) and was significantly shorter in pts with influenza B (74.6 hr) than in either PLC (100.6 hr; P =0.0138) or Os (101.6 hr; P =0.0251). (ID Week 2018 Late Breaker-Saturday, October 6, 2018: 10:50 AM) 31

Baloxavir marboxil (Xofluza)

• T1/2 ~ 79 hours • Weight based dose taken with or without food • Co-administration of baloxavir with dairy products, calcium- fortified beverages, polyvalent cation-containing laxatives, antacids or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc) reduce plasma concentrations and should be avoided. • LAIV should not be considered effective if treated with baloxavir if administered concurrently or within about 2 weeks after LAIV

CWW2 Baloxavir marboxil (Xofluza) • Baloxavir will also be further studied in a phase III development program including pediatric populations, post- exposure prophylaxis and severely ill hospitalized people with influenza, as well as to assess the potential to reduce transmission in otherwise healthy people. • Oseltamivir: Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and 1 year of age who have been symptomatic for no more than 48 hours. (3 mg/Kg BID x 10 days of 6 mg/ml oral susp) • Treatment/Prophylaxis of influenza A and B in patients 1 year and older is weight based. 15 kg or less 30 mg BID/30 mg QD; 15.1-23 kg 45 mg BID/45 mg QD; 23.1-40 kg 60 mg BID/60 mg QD; >40 kg adult dose

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CWW2 C. Wayne Weart, 5/7/2019 11/25/2019

Baloxavir marboxil (Xofluza)

• October 17, 2019 the FDA has expanded the indication for baloxavir marboxil tablets (Xofluza, Genentech) to include people at high risk of developing influenza-related complications (i.e. patients with conditions such as asthma, chronic lung disease, diabetes, heart disease, or morbid obesity and for adults aged 65 years or older). • Single weight based dose (40 or 80 mg)

Baloxavir marboxil (Xofluza) • Researchers in Japan find evidence that some strains (6 to date) of the virus are resistant to the new baloxavir. – 1/27/2019 According to the Japanese National Institute of Infectious Disease (NIID), baloxavir-resistant viruses were found in two of four primary school students in Yokohama in generic screenings in December conducted after they developed flu symptoms earlier the same month. – The mutated viruses were 76 to 120 times more resistant to the new anti-flu drug than unmutated ones detected in the other two children. – In clinical trials of baloxavir marboxil, resistant viruses were detected in 23.4 percent of participating patients younger than 12 years old.

High- Moderate- and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel) 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Therapy Therapy Therapy Daily dose lowers LDL–C on Daily dose lowers LDL–C on Daily dose lowers LDL–C average, by approximately average, by approximately on average, by <30%

≥50% )* 30% to <50%

Atorvastatin (40†)–80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10–20 mg Simvastatin 20–40 mg‡ Lovastatin 20 mg Pravastatin 40 (80) mg Fluvastatin 20–40 mg Lovastatin 40 mg Fluvastatin Pitavastatin 1 mg XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg Specific statins and doses are noted in bold that were evaluated in RCTs. 36

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Top 10 Top 10 Take Home Messages 3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. • Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. • In very high-risk ASCVD patients, it is reasonable to add ezetimibe to maximally tolerated statin therapy when the LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L). (NNT at 7 years 50 IMPROVE-IT Trial) • In patients at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable, (NNT 30 at 2.8 years LDL >/=100 mg/dl Odyssey Outcomes Trial, NNT 50 at 3 years Fourier Trial) although the long-term safety (>3 years) is uncertain

Top 10 Top 10 Take Home Messages 4. In patients with severe primary hypercholesterolemia (LDL- C level ≥ 190 mg/dL[≥4.9 mmol/L]) without calculating 10- year ASCVD risk, begin high-intensity statin therapy without calculating 10-year ASCVD risk. •If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable • If the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) & the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncertain and economic value is low at mid-2018 list prices.

IMPROVE-IT: Results • The results of IMPROVE-IT (AHA 11/17/2014 Scientific Sessions). The study included more than 18 000 patients from 39 countries who were stable following ACS (<10 days). Patients were randomized to one of two treatment strategies: simvastatin 40 mg alone or simvastatin 40 mg plus ezetimibe 10 mg. They were followed for a minimum of 2.5 years or until the study investigators accrued 5250 clinical events. • At baseline, the mean LDL-cholesterol level among the ACS patients was 95 mg/dL in both treatment arms. With simvastatin 40 mg, LDL-cholesterol levels were reduced to 69.9 mg/dL at 1 year. The addition of ezetimibe 10 mg to simvastatin further lowered LDL-cholesterol levels, to 53.2 mg/dL at 1 year. Over 7 years, there remained a significant difference between the two treatments in the achieved LDL- cholesterol levels. – N Engl J Med 2015;372:2387-97

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IMPROVE-IT Primary End Point and Individual Components (7-Year Event Rates) Clinical Outcomes Simvastatin, n=9077 Ezetimibe/Simvastatin, n=9067 (%) P (%)

Primary end point 34.7 32.7 0.016 (Cardiovascular death, MI, unstable angina, coronary revascularization, or stroke)

All-cause death 15.3 15.4 0.782

MI 14.8 13.1 0.002

Stroke 4.8 4.2 0.052

Ischemic stroke 4.1 3.4 0.008

Unstable angina 1.9 2.1 0.618

Coronary 23.4 21.8 0.107 revascularization

Primary combined endpoint at 7 years: RRR 6.4%; ARR 2.0%; NNT 50 MI at 7 years: ARR 1.7%; NNT 59 Ischemic stroke at 7 years: 0.7%; NNT 142 'Modest' Benefit When Adding Ezetimibe to Statins in Post-ACS Patients. Medscape.Nov 17, 2014.

Alirocumab-Praluent •Supplied in single-dose pre-filled pens and single-dose prefilled glass syringes. Each pre-filled pen or pre-filled syringe is designed to deliver 1 mL of 75 mg/mL or 150 mg/mL solution. (available in cartons containing 1 or 2, pre-filled pens and 1 or 2, pre-filled syringes). •Dose 75-150 mg SC every 2 weeks or 300 mg every 4 weeks •Cost: $14,600.00/year •Now $5,850.00/year 41 41

ODYSSEY OUTCOMES Trial Patient Disposition

Randomized 18,924 patients After Acute Coronary Syndrome

99% on a statin and ~47% Alirocumab Placebo on high intensity statin and (N=9462) (N=9462) 14-15% 0n ezetimibe in both arms Follow-up*: median 2.8 (Q1–Q3 2.3–3.4) years 8242 (44%) patients with potential follow-up ≥3 years MACE: CHD death, non- 1955 patients experienced a primary endpoint fatal MI, ischemic stroke, 726 patientsdied or unstable angina • Premature treatment requiring hospitalization discontinuation 1343 (14.2%) 1496(15.8%) • Blinded switch to placebo (2 consecutive LDL-C values <15 730 (7.7%) Not applicable mg/dL) Patients lost to follow-up (vital status) 14 9 *Ascertainment was complete for 99.1% and 99.8% of potential patient-years of follow-up for the primary endpoint 42 and all-cause death, respectively 42

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LDL-C: ITT and On-Treatment Analyses

103.1 Placebo 105 96.4 93.3 ITT On-treatment* 90 101.4 75 66.4 Alirocumab 60 ITT† 45 48.0 On-treatment* 39.8 30 53.3 15 42.3 37.6 0 enLDL-C (mg/dL) Mean

0 48 12 16 20 24 28 32 36 40 44 48 Months Since Randomization

*Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo 43 †All LDL-C values, including those after premature treatment discontinuation, blinded down titration, or blinded switch to placebo 43

Primary Efficacy and Components

Alirocumab Placebo Log-rank Endpoint, n (%) (N=9462) (N=9462) HR (95% CI) P-value

MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003 NNT 59 CHD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38

Non-fatalMI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006 NNT 100 Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01 NNT 250 Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02

Primary Efficacy in Main Prespecified Subgroups

Incidence (%) Subgroup Patients Alirocumab HR (95% CI) p-value* Placebo

*P-values for interaction

20 20 20 <80 mg/dL 80 to <100 mg/dL 100 mg/dL 16 16 16

12 12 12

Placebo 8 8 8 AE(%) MACE Alirocumab (%) MACE (%) MACE 4 4 4

0 0 0 0 123 4 0 123 4 0 123 4 Years Since Randomization Years Since Randomization Years Since Randomization Number at Risk Number at Risk Number at Risk Placebo 3583 3347 3122 1290 256 Placebo 3062 2889 2708 1195 195 Placebo 2815 2568 2371 986 178 45 Alirocumab 3581 3365 3183 1327 233 Alirocumab 3066 2880 2732 1194 213 Alirocumab 2814 2602 2431 1053 207

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Efficacy: Subgroup with Baseline LDL-C 100 mg/dL (Median Baseline LDL-C 118 mg/dL)

Alirocumab Placebo Absolute Endpoint, n (%) (N=2814) (N=2815) risk reduction HR (95% CI) (%)/NNT MACE 324 (11.5) 420 (14.9) 3.4/30 0.76 (0.65, 0.87)

CHD death 69 (2.5) 96 (3.4) 1.0/100 0.72 (0.53, 0.98)

CV death 81 (2.9) 117 (4.2) 1.3/77 0.69 (0.52, 0.92)

All-cause death 114 (4.1) 161 (5.7) 1.7/59 0.71 (0.56, 0.90)

J. Wouter Jukema et al. J Am Coll Cardiol 2019;74:1167-1176

2019 The Authors 47

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Alirocumab-Praluent INDICATIONS AND USAGE (FDA label 4-26-2019) • Prevention of Cardiovascular Events - PRALUENT is indicated to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease. • Primary Hyperlipidemia (including heterozygous familial hypercholesterolemia) - PRALUENT® is indicated as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL- C). 49

Evolocumab – Repatha by Amgen • FDA approved 8-27-2015 a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated as an adjunct to diet and: for the treatment of patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol(LDL- C). • Patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C when other LDL-C lowering therapies are not adequate (e.g., statins, ezetimibe, LDL apheresis). 50 50

Evolocumab – Repatha

• Available as: • Injection: 140 mg/mL in a single –use prefilled syringe • Injection: 140 mg /mL in a single –use prefilled SureClick ® autoinjector • Cartridge 420 mg/3.5 ml for Pushtronex System • Cost: $542.31/140 mg dose WAC or about $14,100.00/year for the every other week dosage. Now $5850.00/year Storage: Keep in the refrigerator. Prior to use, allow to warm to room temperature for at least 30 minutes. Alternatively, for patients and caregivers, the drug can be kept at room temperature (up to 25°C (77°F)) in the original carton. However, under these conditions , the medication must be used within 30 days. 51 51

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Fourier Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe) 69% on high intensity statin and LDL-C ≥70 mg/dL or Mean LDL 92 5% ezetimibe non-HDL-C ≥100 mg/dL

RANDOMIZED Evolocumab SC DOUBLE BLIND Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM

N Engl J Med 2017; 376:1713-1722 Sabatine MS et al. Am Heart J Follow-up Q 12 weeks 52 2016;173:94-101 52

53 N Engl J Med 2017; 376:1713-1722 53

Types of CV Outcomes

Evolocumab Placebo (N=13,784) (N=13,780) Endpoint HR (95% CI)

3-yr Kaplan-Meier rate

CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92) NNT 50

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) NNT 50

CardiovascularHosp for unstable death angina 2.52.2 2.42.3 1.050.99 (0.88-1.25)(0.82-1.18)

MICoronary revasc 4.47.0 6.39.2 0.730.78 (0.65-0.82)(0.71-0.86) NNT 5346

Urgent 3.7 5.4 0.73 (0.64-0.83) Stroke 2.2 2.6 0.79 (0.66-0.95) NNT 250 Elective 3.9 4.6 0.83 (0.73-0.95) Death from any cause 4.8 4.3 1.04 (0.91-1.19) 54 N Engl J Med 2017; 376:1713-1722 54

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Summary for Evolocumab •  LDL-C by 59% • Consistent throughout duration of trial • Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl) •  CV outcomes in patients already on statin therapy • 15%  broad primary endpoint; 20%  CV death, MI, or stroke • Consistent benefit, incl. in those on high-intensity statin, low LDL-C • 25% reduction in CV death, MI, or stroke after 1st year • Long-term benefits consistent w/ statins per mmol/L  LDL-C • Safe and well-tolerated • Similar rates of AEs, including DM & neurocog events w/ Evolocumab & placebo • Rates of Evolocumab discontinuation low and no greater than placebo • No neutralizing antibodies developed

55 N Engl J Med 2017; 376:1713-1722 55

Evolocumab - Praluent Indications: (FDA label 2-2017) • to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. • as an adjunct to diet, alone or in combination with other lipid- lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C). • as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL- C

PCSK9 Inhibitor Price Update • Reuters (2/11/2019) reports Regeneron and Sanofi announced that they would reduce the list price of cholesterol drug alirocumab (Praluent) by 60% to $5,850.00/year. The price reduction follow a similar move by rival Amgen Inc which cut evolocumab (Repatha) by 60% to $5,850.00 per year in Oct 2018 in hopes of increasing use of the drug.

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REDUCE-IT Trial with Icosapent ethyl (EPA, Vascepa) • September 2018 Amarin/Kowa announced the topline results of the Reduce-It Trial a cardiovascular (CV) outcomes study of icosapent ethyl (VASCEPA) capsules met its pre-specified primary composite endpoint (4 point MACE of CV death, nonfatal myocardial infarction (MI, including silent MI), nonfatal stroke, coronary revascularization, and unstable angina requiring hospitalization) in the intent – to - treat population: • Randomized 8,179 patients (~70% with ASCVD) on a 1:1 basis to statin plus VASCEPA 4g/day or statin plus placebo and compared the incidence of MACE between treatment arms over a median period of 4.9 years. • Baseline LDL-C controlled to between 41-100 mg/dL (median baseline 75 mg/dL) by statin therapy and with various cardiovascular risk factors including persistent elevated TGs between 150-499 mg/dL (median baseline 216 mg/dL) and either established cardiovascular disease (secondary prevention) or diabetes mellitus and at least one other CV risk factor (primary prevention) • Showed reduction in a composite of major adverse cardiovascular events (MACE) of approximately 25% ‒ P value <0.001 (highly statistically significant) • N Engl J Med 2019; 380:11-22 58

FDA - Approved Indication and Limitations of Use for VASCEPA

• Icosapent ethyl (VASCEPA) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia. • In patients with severe hypertriglyceridemia, the effect of icosapent ethyl on cardiovascular mortality or morbidity or on the risk of pancreatitis has not been determined. • The daily dose of icosapent ethyl is 4 grams per day taken as four 0.5- gram capsules or two 1-gram capsules twice daily with food. • Cost 1 Gm caps x 120 ~ $242.00, 500 mg caps x 240 ~$282.00 GoodRx.com 9/26/18

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ADA 2019 Standards of Medical Care in Diabetes Update 3/28/2019 • Section 10, on cardiovascular disease and risk management, was revised to include a recommendation based on the outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial (REDUCE-IT) advising that icosapent ethyl be considered to reduce cardiovascular risk in patients with diabetes and atherosclerotic cardiovascular disease, or other cardiac risk factors, who are taking a statin and have controlled low-density lipoprotein cholesterol (LDL-C) but elevated triglycerides. • The FDA granted priority review to Amarin’s Vascepa with an Advisory Comm. hearing scheduled for late this year.

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Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association Circulation. 2019;140:00–00. DOI: 10.1161/CIR.0000000000000709 • “We conclude that prescription n-3 FAs, whether EPA+DHA or EPA- only, at a dose of 4 g/d, are clinically useful for reducing triglycerides, after any underlying causes are addressed and diet and lifestyle strategies are implemented, either as monotherapy or as an adjunct to other triglyceride-lowering therapies.” • “The use of n-3 FAs (4 g/d) for improving ASCVD risk in patients with HTG is supported by a 25% reduction in major adverse cardiovascular end points in REDUCEIT, a randomized placebo-controlled trial of EPA- only in high-risk patients on statin therapy. Results from the STRENGTH trial, a randomized placebo-controlled cardiovascular outcomes trial of 4 g/d prescription EPA+DHA in patients with HTG and low HDL-C on statins, are anticipated in 2020.”

Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage?

• The Kailuan study is a community-based multicenter prospective cohort study in Tangshan, an industrial city in China, designed to investigate risk factors of chronic disease. • There were 753 incident ICH cases during 9 years of follow-up. The ICH risk was similar among participants with LDL concentrations of 70 to 99 mg/dL and those with LDL-C concentrations≥100 mg/dL. In contrast, participants with LDL-C concentrations <70 mg/dL had a significantly higher risk of developing ICH than those with LDL- C concentrations of 70to 99 mg/dL; adjusted hazard ratios were 1.65 (95% confidence interval [CI] 1.32–2.05) for LDL-C concentrations of 50 to 69 mg/dL and 2.69 (95% CI 2.03–3.57) for LDL-C concentrations <50 mg/dL. • Neurology®2019;93:e445-e457

20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia • A 20-year follow-up study of statin therapy in children with FH followed 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. • Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima–media thickness. • The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. • N Engl J Med 2019;381:1547-56

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20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia • The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter — a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter) were achieved in 37 patients (20%). • Mean progression of carotid intima–media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings. • The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (CV events 1% vs. 26% and death 0% vs. 7%). • N Engl J Med 2019;381:1547-56

20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia N Engl J Med 2019;381:1547-56

Which diuretic would you recommend for BP lowering?

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Aged over 55 years or black person of African or Aged under Caribbean family origin of Summary of 55 years any age antihypertensive drug treatment A C1 Step 1 Key A + C1 A – ACE inhibitor or low-cost Step 2 angiotensin II receptor blocker (ARB) A + C + D C – Calcium-channel blocker Step 3 (CCB) D – Thiazide-like diuretic Resistant hypertension A (chlorthalidone 12.5-25 mg or + C + D + consider further diuretic Step 4 indapamide 2.5 mg) (low dose spironolactone 25 mg) or alpha- or (1) - A CCB is preferred but consider a thiazide-like beta-blocker diuretic if a CCB is not tolerated or the person has edema, evidence of heart failure or a high risk of Consider seeking expert advice heart failure. 37

Thiazide Diuretics Differ in Their Antihypertensive Effects

Week 2 Week 4 Week 6 Week 8 Office –4.5 ± 2.1 –7.6 ± 2.8 –9.3 ± 3.2 –10.8 ± 3.5 Blood –15.7 ± 2.2 –17.4 ± 2.9 –19.6 ± 3.4 –17.1 ± 3.7 p = 0.001 p = 0.069 p = 0.109 p = 0.842 6 Pressure* 2 -2 -6 -10 -14

(mm (mm Hg) -18 Hydrochlorothiazide 50 mg daily -22 Week 8–Week 0 Chlorthalidone 25 mg daily -26 Change in Ambulatory Systolic Blood Pressure -30 Hours 6am 8am 10am 12pm 2pm 4pm 6pm 8pm 10pm 12am 2am 4am *All values are expressed as means ± the standard deviation. The p values reported are Bonferroni adjusted p values (unadjusted p value  4 tests). Reprinted from Ernst ME, et al. Hypertension. 2006;47:352-358, Slide Source with permission from Lippincott Williams & Wilkins. Hypertension Online www.hypertensiononline. org 71

Indapamide vs. HCTZ in Patients with Impaired Renal Function and Hypertension • 28 patients with impaired renal function and moderate hypertension. The patients had elevated blood pressure for 2-27 years and impaired renal function for 1-15 years before entering the study. Their ages ranged between ,32-70 years and their initial creatinine clearance was between 32 and 80 ml/min/1.73 m2 body surface area. There were 16 female and 12 male patients. They were randomly assigned for treatment with 2.5 mg of indapamide/day (14 patients) or with 50 mg of hydrochlorothiazide/day (14 patients) all patients were seen every 3 months and followed for 24 months. • BP reductions were similar and maintained for the 24 months of follow- up

– (Am J Cardiol l996;77:23B-25B) 62

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Indapamide vs. HCTZ in Patients with Impaired Renal Function and Hypertension

• Creatinine clearance increased progressively in 13 of the 14 patients treated with indapamide; it rose from 58 +/- 4.4 to 72 +/- 4.4 ml/min/1.73 m2 body- surface area (p < 0.01) by the end of the treatment. In contrast, creatinine clearance fell progressively in 13 of the 14 patients who were managed with hydrochlorothiazide; it fell from 65 +/- 3.0 to 53 +/- 3.0 ml/min/1.73 m2 body surface area (p < 0.01) by the end of the study. • Creatinine clearance increased by 28.5 +/- 4.4% with indapamide treatment and decreased by 17.4 +/- 3.0% with thiazide therapy, a statistically significant difference (p < 0.01). – (Am J Cardiol l996;77:23B-25B) 63

Spironolactone for Hypertension. Cochrane Database of Systematic Reviews 2010 • Meta-analysis of the 5 cross-over studies found a reduction in SBP of 20.09 mmHg (95%CI:16.58-23.06,p<0.00001) and a 6.75 mmHg (95%CI:4.8- 8.69,p<0.00001) reduction in DBP. These results were statistically significant and there was no evidence of heterogeneity between the studies. There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. • In other words, it appears that doses >50mg/day do not produce further reductions in either SBP or DBP. • One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP: -9.9 (95%CI:-21.15,1.35); DBP -2.34 (95%CI:-7.92,3.06). 65

Diuretics

Cost and T1/2: • Chlorthalidone 25 and 50 mg tabs generic $17-38.00/30 tabs – T1/2: 40-60 hrs • Indapamide 1.25 and 2.5 mg tabs generic $4-20.00/30 tabs – T1/2: 14-26 hrs • Hydrochlorothiazide 12.5, 25 and 50 mg tabs generic $4-11.00/30 tabs – T1/2: 6-15 hrs • Spironolactone 25 and 50 mg tabs generic $4-15.00/30 tabs – T1/2: 1.4 – 16.5 hrs active metabolite • Eplerenone 25 and 50 mg tabs generic $38-150.00/30 tabs – T1/2: 3-6 hrs 66

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AHA Scientific Statement: Resistant Hypertension

• Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. • Management of RH includes maximization of lifestyle interventions, use of or substitution of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised. • (Hypertension. 2018;72:e53-e90).

Efficacy and safety of once vs. twice daily dosing of lisinopril for hypertension

• Patients previously receiving lisinopril 20 mg were placed into the once- daily cohort if changed to 40 mg once daily or into the twice- daily cohort if changed to 20 mg twice daily. Efficacy outcome measures were change in systolic blood pressure and diastolic blood pressure and achievement of blood pressure control (<140/90 mm Hg). (Lisinopril the second most prescribed antihypertensive has a T1/2 of 12 hours) • Of 90 patients included (45 per cohort), the mean age was 61.8 years and 17.8% were black. Once- and twice- daily administrations were associated with blood pressure reductions of 6.2/1.5 mm Hg and 16.5/5.9 mm Hg, with a 10.2/4.3 mm Hg greater reduction with twice- daily administration (systolic blood pressure, P=.016; diastolic blood pressure, P=.068). • Twice- daily lisinopril dosing was associated with greater systolic blood pressure reductions compared with the same total daily dose administered once daily. • J Clin Hypertens. 2017;19:868–873 (Univ of Colorado and Univ Florida)

New 2019 GINA Asthma Guidelines April 12. 2019 Global Initiative for Asthma begun 1993 a joint effort between NHLBI/NIH/WHO

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The 12-year history behind changes in GINA 2019

 In the meantime, GINA challenged conventional criteria for initiation of ICS . During preparation for 2014 GINA revision, we identified no evidence for the recommendation to withhold ICS until symptoms were more than twice weekly . This was investigated in data from the START study (Pauwels, Lancet 2003). A post hoc analysis found that ICS halved the risk of serious exacerbations even in patients with symptoms 0-1 days a week at entry (Reddel, Lancet 2017)  GINA found no evidence to support a Step 1 SABA-only recommendation . The lack of evidence for SABA-only treatment contrasted with the strong evidence for safety, efficacy and effectiveness of treatments recommended in Steps 2-5 . In 2014, as an interim safety measure, GINA restricted SABA-only treatment to patients with symptoms less than twice a month and no risk factors for exacerbations  2018: Review of evidence for mild asthma, including SYGMA studies . A careful review of GINA conflict of interest processes was undertaken first

GINA 2018 – main treatment figure

Step 1 treatment is for patients with symptoms

Previously, no controller was recommended for Step 1, i.e. SABA-only treatment was ‘preferred’

GINA 2018, Box 3-5 (2/8) (upper part) © Global Initiative for Asthma, www.ginasthma.org 80

Background to changes in 2019 - the risks of SABA-only treatment

 Regular or frequent use of SABA is associated with adverse effects . b-receptor downregulation, decreased bronchoprotection, rebound hyperresponsiveness, decreased bronchodilator response (Hancox, Respir Med 2000) . Increased allergic response, and increased eosinophilic airway inflammation (Aldridge, AJRCCM 2000)  Higher use of SABA is associated with adverse clinical outcomes . Dispensing of ≥3 canisters per year (average 1.7 puffs/day) is associated with higher risk of emergency department presentations (Stanford, AAAI 2012) . Dispensing of ≥12 canisters per year is associated with higher risk of death (Suissa, AJRCCM 1994) © Global Initiative for Asthma, www.ginasthma.org 81

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Short-acting beta-agonist use and its ability to predict future asthma-related outcomes

Medicaid Commercial

Each additional SABA canister resulted in an 8% to 14% and 14% to 18% increase in risk of an asthma-related exacerbation in Annals of Allergy, Asthma & Immunology 2012; 109:403-7 children and adults, respectively.

GINA 2019 – landmark changes in asthma management

 For safety, GINA no longer recommends SABA-only treatment for Step 1 . This decision was based on evidence that SABA-only treatment increases the risk of severe exacerbations, and that adding any ICS significantly reduces the risk  GINA now recommends that all adults and adolescents with asthma should receive symptom-driven or regular low dose ICS-containing controller treatment, to reduce the risk of serious exacerbations . This is a population-level risk reduction strategy, e.g. statins, anti- hypertensives

Box 3-5A Confirmation of diagnosis if Adults & adolescents 12+ years necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Personalized asthma management: Inhaler technique & Assess, Adjust, Review response adherence Patient goals Symptoms Exacerbations Side-effects Lung function Patient satisfaction Treatment of modifiable risk factors & comorbidities STEP 5 Non-pharmacological strategies Education & skills training High dose Asthma medication options: ICS-LABA Asthma medications STEP 4 Adjust treatment up and down for Refer for individual patient needs phenotypic STEP 3 Medium dose assessment STEP 2 ICS-LABA Low dose ± add-on PREFERRED STEP 1 therapy, ICS-LABA CONTROLLER Daily low dose inhaled corticosteroid (ICS), e.g.tiotropium, to prevent exacerbations As- or as-needed low dose ICS-formoterol * anti-IgE, and control symptoms needed anti-IL5/5R, low dose anti-IL4R Other ICS-formoterol Leukotriene receptor antagonist (LTRA), or Medium dose High dose Add low dose controller options Low* dose ICS low dose ICS taken whenever SABA taken † ICS, or low dose ICS, add-on OCS, but taken whenever ICS+LTRA # tiotropium, or consider SABA is taken † add-on LTRA # side-effects PREFERRED As-needed low dose ICS-formoterol * As-needed low dose ICS-formoterol ‡ RELIEVER Other As-needed short-acting β -agonist (SABA) reliever option 2 * Off-label; data only with budesonide-formoterol (bud-form) ‡ Low-dose ICS-form is the reliever for patients prescribed bud- † Off-label; separate or combination ICS and SABA inhalers form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic © Global Initiative for Asthma, www.ginasthma.org rhinitis and FEV >70%1 predicted 84

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Step 2 – there are two ‘preferred’ controller options

Regular low dose ICS with as-needed SABA  Evidence . A large body of evidence from RCTs and observational studies that low dose ICS substantially reduces risks of severe exacerbations, hospitalizations and death e.g. Suissa, NEJMed 2000; Suissa, Thorax 2002; Pauwels, Lancet 2003; O’Byrne, AJRCCM 2001 . Serious exacerbations halved even in patients with symptoms 0-1 days per week (Reddel, Lancet 2017) . Improved symptom control and reduced exercise-induced bronchoconstriction  Values and preferences . High importance was given to preventing asthma deaths and severe exacerbations . However, we were aware that poor adherence is common in mild asthma in the community, and that this would expose patients to the risks of SABA-only treatment

Step 2 – two ‘preferred’ controller options

As-needed low dose ICS-formoterol (off-label; all evidence with budesonide- formoterol)  Evidence . Direct evidence from two large studies of non-inferiority for severe exacerbations vs daily low dose ICS + as-needed SABA (O’Byrne, NEJMed 2018, Bateman, NEJMed 2018) . Direct evidence from one large study of 64% reduction in severe exacerbations vs SABA-only treatment (O’Byrne, NEJMed 2018) . Symptoms reduced; one study showed reduced exercise-induced bronchoconstriction  Values and preferences . High importance was given to preventing severe exacerbations, avoiding need for daily ICS in patients with mild or infrequent symptoms, and safety of as-needed ICS- formoterol in maintenance and reliever therapy, with no new safety signals . Lower importance given to small non-cumulative differences in symptom control (ACQ- 5 difference 0.15 vs MCID 0.5) and lung function compared with daily ICS . Makes use of normal patient behavior (seeking symptom relief) to deliver controller

Box 3-5B Confirmation of diagnosis if Children 6-11 years necessary Symptom control & modifiable risk factors (including lung function) Personalized asthma management: Comorbidities Assess, Adjust, Review response Inhaler technique & Symptoms adherence Child and parent Exacerbations goals Side-effects Lung function Child and Treatment of modifiable risk parent factors & comorbidities STEP 5 satisfaction Non-pharmacological strategies Education & skills Refer for Asthma medication options: training phenotypic Asthma STEP 4 Adjust treatment up and down for medications assessme individual child’s needs nt STEP 3 Medium dose ± add- ICS-LABA STEP on Low dose Refer for PREFERRED 2 therapy, STEP ICS-LABA, or expert advice CONTROLLE Daily low dose inhaled corticosteroid (ICS) 1 (see table of ICS dose ranges for children) medium dose e.g. anti- R ICS IgE to prevent exacerbations and control symptoms Othe Low dose ICS Leukotriene receptor antagonist (LTRA), Low dose High dose Add-on anti- r controller taken whenever or low dose ICS taken whenever SABA ICS+LTRA ICS- LABA, or IL5, or add-on options SABA taken*; or taken* add- on low dose daily low dose tiotropium, or OCS, ICS add-on LTRA but consider RELIEVE As-needed short-acting β2 -agonist (SABA) R side- * Off-label; separate ICS and SABA inhalers; only one study in children effects

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Children 6-11 years

 Step 4 . Medium dose ICS-LABA, but refer for expert advice  Step 3 . Low dose ICS-LABA and medium dose ICS are ‘preferred’ controller treatments . No safety signal with ICS-LABA in children 4-11 years (Stempel, NEJMed 2017)  Step 2 . Preferred controller is daily low dose ICS . Other controller options include as-needed low dose ICS taken whenever SABA is taken, but only one study in children (Martinez, Lancet 2011) . Studies of as-needed ICS-formoterol are needed; maintenance and reliever therapy with low dose budesonide-formoterol in children 4-11 years reduced exacerbations by 70-79% compared with ICS and ICS-LABA (Bisgaard, Chest 2006)  Step 1 . Low dose ICS whenever SABA taken (indirect evidence), or daily low dose ICS © Global Initiative for Asthma, www.ginasthma.org 88

Type 2 Asthma • Allergic asthma, which is associated with allergic rhinitis, atopy, and elevated IgE levels, is characteristic of approximately half of all patients with asthma. About half of individuals with severe asthma exhibit the type 2 phenotype with increases in T helper 2 cells. These cells secrete IL-4, IL- 5, and IL-13, which increase the proliferation, survival and recruitment of eosinophils and increase IgE levels. • There are five FDA approved monoclonal antibodies that affect the pathways involved in either the allergic or type 2 inflammatory phenotypes of asthma.

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Biologic Therapies for Treatment of Asthma Associated with Type 2 Inflammation

Mepolizumab (Nucala) is also approved for kids age 6-11 at 40 mg SC Q 4 weeks ICER Final Evidence Report December 20, 2018

Effects of Biologic Therapies for Type 2 Asthma • “Review of the 5 drugs currently approved for uncontrolled moderate to severe asthma suggest that they are safe and effective. All five drugs reviewed reduced the number of asthma exacerbations compared with placebo, modestly improved day-to-day quality of life, and available data suggest few harms. None of the drugs prevented most exacerbations requiring systemic corticosteroids or improved average daily quality of life to a degree considered clinically significant. Thus, the net health benefit for all five drugs is at best incremental.” – ©Institute for Clinical and Economic Review, 2018 Page ES7 Final Evidence Report – Biologic Therapies for Treatment of Asthma 92

Biologic Therapies for Treatment of Asthma Associated with Type 2 Inflammation

ICER Final Evidence Report December 20, 2018

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ICS/LABA Combinations for Asthma • Advair Diskus: fluticasone propionate & salmeterol BID (asthma age 4 and older) 2015 US sales $4.7 billion (# 7 in US sales) • Advair HFA BID (asthma age 12 and older) • Symbicort: budesonide & formotorol BID (asthma age 6 and older) • Dulara: mometasone furoate and formoterol BID (asthma age 5 and older) • Breo Ellipta: fluticasone furoate & vilanterol QD (asthma age 18 and older) • AirDuo Respiclick: fluticasone propionate & salmeterol BID (asthma age 12 and older) • Several AB Rated Advair Diskus generics either have been approved (Mylan and GSK/Prasco) or awaiting FDA approval including Sandoz 94

Fluticasone propionate and salmeterol inhalation - Wixela Inhub by Mylan • January 30, 2019: Wixela Inhu is the first FDA-approved therapeutically equivalent generic of Advair Diskus (twice daily fluticasone propionate and salmeterol inhalation powder) for certain patients 4 years and older with asthma or adults with chronic obstructive pulmonary disease (COPD). Expected availability by mid to late February 2019. • In the 28-day, randomized, double-blind, placebo-controlled, parallel group study of 1,128 adult asthma patients conducted to evaluate the local (lung) bioequivalence of Wixela Inhub 100 mcg/50 mcg and Advair Diskus 100 mcg/50 mcg, the two treatments produced equivalent efficacy. Both treatments were safe and well-tolerated with lower numbers of withdrawals due to asthma compared to the placebo group. • The treatment, the first generic of Advair, is approved in three doses and will be priced between $93.71 and $153.14 (about 70% less) the company said. 95

Fluticasone propionate and Salmeterol inhalation powder – Wixela Inhub Inhaler Mylan’s product (Wixela Inhub) is available in 3 strengths 100 mcg/50 mcg, 250 mcg/50 mcg and 500 mcg/50 mcg at wholesale acquisition costs (WACs) that are 70% less than Advair Diskus and 67% less than GSK’s/Prasco’s authorized generic. As of March 2019 Mylan has already achieved about a 25% market share.

$93.71 vs. Advair 100/50 - $345.00; $116.44 vs Advair 250/50 - $420.00; $153.14 vs. Advair 500/50 - $550.00 96

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Fluticasone propionate and Salmeterol inhalation powder – Wixela Inhub Inhaler • As of April 19, 2019 Wixela Inhub Inhaler had already achieved a 28% market share which is still climbing. • May 18, 2019 Mylan announced four scientific abstracts from the Wixela™ Inhub™ (fluticasone propionate and salmeterol inhalation powder, USP) development program that will be presented at the 2019 American Thoracic Society International Conference, May 17 – May 22. The data, available for the first time publicly, further supports the FDA’s approval in January 2019 of Mylan's Abbreviated New Drug Application for Wixela Inhub, which is indicated for certain patients with asthma or chronic obstructive pulmonary disease (COPD). 97

Fluticasone propionate and Salmeterol powder Diskus by Prasco Laboratories

Generic

Advair Diskus

Fluticasone propionate /Salmeterol inhalation powder AirDuo RespiClick

• Fluticasone • Instruct patients to not open their inhaler unless they are taking a dose. Repeated propionate/salmeterol xinafoate opening and closing the cover without MDPI 118/13.2 mcg had similar taking medication will waste medication clinical efficacy with lower and may damage the inhaler. systemic exposure when • Advise patients to keep their inhaler dry and clean at all times. Never wash or put any compared to the 50 mcg of part of the inhaler in water. salmeterol in fluticasone propionate/salmeterol 100/50 mcg dry powder inhaler • AirDuo RespiClick has a yellow cap - approved age 12 and above

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Fluticasone propionate/Salmeterol Dry Powder RespiClick Inhalers by Teva

Air Duo Brand ~ $250.00 Generic Fluticasone/Salmeterol ~ $90.00

NOT generic or AB rated for Advair Diskus

100

Migraine Headache • Migraine has a global prevalence of 15 to 18% and is a leading cause of disability worldwide. • Chronic migraine (CM), occurring in approximately 2% of the population, has been defined as the occurrence of at least 15 days with headache per month for at least 3 months. • Episodic migraine (EM), has been defined as 0 to 14 days with headache per month. • The relationship between EM and CM is complex. EM progresses to CM at the rate of 2.5% per year, and CM often remits to EM (2-year transition rate of 26%).

101

Erenumab-aooe (Aimovig) by Amgen and Novartis • May 17, 2018 The U.S. Food and Drug Administration approved erenumab-aooe (Aimovig) for the preventive treatment of migraine in adults. The treatment is given by once-monthly self- injections. Erenumab-aooe is the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks. • Erenumab is a human immunoglobulin G2 (IgG2) monoclonal antibody. Erenumab is specific and selective to CGRP receptors, exerting action by full competitive inhibition of the receptor.

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FDA Updates Guidance on Nonproprietary Naming of Biological Products • The FDA released updated guidance for the “Nonproprietary Naming of Biological Products,” originally released in January 2017. The updated guidance explains that: • The FDA intends to designate a proper name that is a combination of the core name and the distinguishing suffix that is devoid of meaning and composed of four lowercase letters – Example - Erenumab-aooe (Aimovig)

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Erenumab-aooe (Aimovig) • Pharmacokinetics: Median time to peak concentration after subcutaneous administration of erenumab 1 mg to 210 mg ranged from 4 to 11 days (mean ~ 6 days). • The estimated elimination half-life of erenumab in a typical 70 kg person receiving erenumab 70 mg subcutaneously is approximately 21 days. • Erenumab-aooe is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

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Erenumab-aooe (Aimovig) • 955 patients with a history of episodic migraines (with or without aura) for at least 12 months • Primary End Point: Mean reducon in MMD from baseline was −3.2 days with erenumab 70 mg (P<0.001 vs placebo), −3.7 days with erenumab 140 mg (P<0.001 vs placebo), and −1.8 days with placebo during weeks 13 to 24. ~ 1 to 2 days reducon per month. • Secondary End Point(s): Reduction in MMD of 50% or more was achieved by 43%, 50%, and 27% of patients in the erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively (P<0.001 for both erenumab groups vs placebo). The number needed to treat was 6.3 for erenumab 70 mg versus placebo and was 4.4 for erenumab 140 mg versus placebo. • Exploratory patient-reported outcome values showed improvements from baseline in quality of life, disability, and migraine-related impact on life. • Erenumab adverse reactions and tolerability were similar to placebo. – N Engl J Med 2017; 377:2123-2132 105

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Erenumab-aooe (Aimovig)

Chronic Migraine

The Lancet Neurology Volume 16, Issue 6, June 2017, Pages 425-434

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Erenumab-aooe (Aimovig) The autoinjector should be stored refrigerated at 2° C to 8° C (36° F to 46° F) in the original carton to protect from light until time of use (do not freeze or shake). Cost $600.00 for 2 Sure Click Leave the autoinjector at room temperature for at least 30 minutes before injecting. If removed from the refrigerator, the autoinjector can be kept at room temperature in the original carton up (up to 25°C [77°F]) for up to 7 days. The needle shield within the white cap of the AIMOVIG prefilled autoinjector and gray needle cap of the prefilled syringe contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.

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Erenumab-aooe (Aimovig)

• Cost $600.00 for 2 SureClick autoinjector

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Erenumab-aooe (Aimovig) • In a 1-year open-label extension study in 451 patients with chronic migraine, patients taking 140 mg and 70 mg of erenumab experienced reductions of average monthly migraine days of 10.5 days and 8.5 days, respectively, compared to a baseline of 18.1 days. Patients treated with Aimovig experienced reductions in monthly migraine days of: • 50 percent or more: 67 percent on 140 mg and 53 percent on 70 mg • 75 percent or more: 42 percent on 140 mg and 27 percent on 70 mg • 100 percent reduction: 13 percent on 140 mg and 6 percent on 70 mg – Amgen press release 6/28/2018

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Fremanezumab-vfrm (Ajovy) by Teva • 9/14/18 FDA approved Fremanezumab-vfrm for the prevention of migraines in adults. • A fully humanized IgG2Δa/kappa monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand that binds to the CGRP ligand and blocks its binding to the receptor. Fremanezumab-vfrm is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. • Recommended Dosage: Two subcutaneous dosing options of fremanezumab-vfrm are available to administer the recommended dosage: – 225 mg monthly, (available in 225 mg/1.5 mL single-dose prefilled syringe) or – 675 mg every 3 months (quarterly), which is administered as three consecutive subcutaneous injections of 225 mg each. Cost ~$400.00/prefilled syringe

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Fremanezumab-vfrm (Ajovy) • Remove fremanezumab-vfrm/AJOVY from the refrigerator. Prior to use, allow the medication to sit at room temperature for 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. Do not use if it has been at room temperature for 24 hours or longer.

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Fremanezumab-vfrm (Ajovy)

• After single subcutaneous (SC) administrations of 225 mg, 675 mg, and 900 mg fremanezumabvfrm, median time to maximum concentrations (tmax) was 5 to 7 days. Dose-proportionality, based on population PK, was observed between 225 mg to 900 mg. Steady state was achieved by approximately 168 days (about 6 months) following 225 mg SC monthly and 675 mg SC quarterly dosing regimens. • Fremanezumab-vfrm was estimated to have a half-life of approximately 31 days. • Fremanezumab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

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Fremanezumab-vfrm (Ajovy)

Episodic Migraine

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Fremanezumab-vfrm (Ajovy) • Study 2 (NCT 02621931) included adults with a history of chronic migraine (patients with ≥15 headache days per month). All patients were randomized (1:1:1) to receive subcutaneous injections of either fremanezumab 675 mg starting dose followed by 225 mg monthly, 675 mg every 3 months (quarterly), or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant, preventive medication. • 1130 patients (991 females, 139 males), ranging in age from 18 to 70 years, were randomized. A total of 1034 patients completed the 3- month double-blind phase.

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Fremanezumab-vfrm (Ajovy)

Chronic Migraine

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Fremanezumab-vfrm (Ajovy)

• In 3-month placebo-controlled studies, treatment-emergent ADA responses were observed in 6 out of 1701 (0.4%) fremanezumab- treated patients. One of the 6 patients developed anti-fremanezumab neutralizing antibodies at Day 84. In the ongoing long-term open-label study, ADA were detected in 1.6% of patients (30 out of 1888). Out of 30 ADA-positive patients, 17 had a neutralizing activity in their post- dose samples. Although these data do not demonstrate an impact of anti-fremanezumab-vfrm antibody development on the efficacy or safety of fremanezumab in these patients, the available data are too limited to make definitive conclusions.

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Fremanezumab-vfrm (Ajovy) • The most common adverse reactions were at the injection site (eg, injection-site pain, injection-site erythema), and occurred in 47% of the group receiving fremanezumab quarterly, 47% of those receiving fremanezumab monthly, and 40% of the placebo group. The most common adverse event was injection-site pain, which occurred in 30% of the fremanezumab quarterly group, 26% of the fremanezumab monthly group, and 28% of the placebo group • Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria, were reported with fremanezumab in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required corticosteroid treatment. Most reactions were reported from within hours to one month after administration.

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Galcanezumab-gnlm (Emgality) by Lilly • 9/27/18 FDA approved galcenezumab-gnlm for the prevention of migraines in adults. A humanized IgG4 monoclonal antibody specific for calcitonin-gene related peptide (CGRP) ligand and blocks its binding to the receptor. (Note-only the 120 mg dose after a loading dose of 240 mg is FDA approved)

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Galcanezumab-gnlm (Emgality) Pharmacokinetics: • The time to maximum concentration is 5 days, and the elimination half-life is 27 days. • Galcanezumab-gnlm is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. • The pharmacokinetics of galcanezumab-gnlm were not affected by age, sex, race, or subtypes of migraine spectrum (episodic or chronic migraine), based on a population pharmacokinetics analysis. Body weight has no clinically relevant effect on the pharmacokinetics of galcanezumab-gnlm. • Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab-gnlm. • Galcanezumab-gnlm is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

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Galcanezumab-gnlm (Emgality)

Episodic Migraine

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Galcanezumab-gnlm (Emgality)

• Chronic Migraine: REGAIN Study 3 (NCT02614261) included adults with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once- monthly subcutaneous injections of Galcanezumab 120 mg, Galcanezumab 240 mg, or placebo over a 3-month treatment period. All patients in the 120 mg group received an initial 240 mg loading dose. (Note-only the 120 mg dose after a loading dose of 240 mg is FDA approved)

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Galcanezumab-gnlm (Emgality)

Chronic Migraine

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Galcanezumab-gnlm (Emgality)

• Adverse Effects: Injection site reactions (18% galcanezumab vs. 13% placebo) include multiple related adverse event terms, such as injection site pain, injection site reaction, injection site erythema, and injection site pruritus. Hypersensitivity reactions (e.g., rash, urticaria, and dyspnea) have been reported • Immunogenicity: With 12 months of treatment in an open-label study, up to 12.5% (16/128) of galcanezumab-treated patients developed anti- galcanezumab-gnlm antibodies, most of whom tested positive for neutralizing antibodies. • Although anti-galcanezumab-gnlm antibody development was not found to affect the pharmacokinetics, safety, or efficacy of galcanezumab in these patients, the available data are too limited to make definitive conclusions. 123

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Galcanezumab-gnlm – Emgality

• March 2019 the Food and Drug Administration “granted Priority Review for the supplemental Biologics License Application (sBLA) for galcanezumab (Emgality) for the prevention/treatment of episodic cluster headache in adults • Cluster headache is a form of headache that produces extreme pain and tends to occur in clusters, often at the same time(s) of the day, for several weeks to months. The headaches are accompanied by symptoms that may include: bloodshot eyes, excessive tearing of the eyes, drooping of the eyelids, runny nose and/or nasal congestion and facial sweating. Some people experience restlessness and agitation. Cluster headache attacks may strike several times a day, generally lasting between 15 minutes and three hours.

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Galcanezumab-gnlm – Emgality • June 4, 2019 The FDA approved Emgality for the treatment of cluster headaches. The FDA said “Emgality provides patients with the first FDA-approved drug that reduces the frequency of attacks of episodic cluster headache, an extremely painful and often debilitating condition,” • Episodic cluster headache recommended dosage: 300 mg (administered as three consecutive injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.

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Galcanezumab-gnlm – Emgality • The pivotal clinical trial enrolled a total of 106 patients (88 males, 18 females) ranging in age from 19 to 65 years were randomized to galcanezumab 300 mg vs. placebo and treated monthly for 8 weeks. A total of 90 patients completed the 8-week double-blind phase. In the prospective baseline phase, the mean number of weekly cluster headache attacks was 17.5, and was similar across treatment groups.

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Galcanezumab-gnlm – Emgality

127

Galcanezumab-gnlm – Emgality

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Galcanezumab-gnlm – Emgality

Storage and Handling: • Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect Emgality from light until use. • Do not freeze. • Do not shake. • Emgality may be stored out of refrigeration in the original carton at temperatures up to 30°C (86°F) for up to 7 days. Once stored out of refrigeration, do not place back in the refrigerator. Dosage: 300 mg (three consecutive subcutaneous injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period. Cost: reported to be the same cost per mg as existing products?

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Investigational Oral CGRP Antagonists “gepants”

• The oral calcitonin gene-related peptide antagonist ubrogepant has been submitted to the FDA and the PDUFA data is scheduled for the fourth quarter of 2019, according to an Allergan press release. • Data from 3,358 patients with migraine (with and without aura) randomized in an approximate 1:1:1:1 ratio to receive either a 25-mg dose, 50-mg dose or 100-mg dose of ubrogepant (Allergan) or placebo. Patients were labeled as triptan-effective, triptan-ineffective or triptan- naive based on previous treatment attempts. Results found across all subgroups, those who received ubrogepant had higher response rates for 2-hour pain freedom and most bothersome pain symptom. • Atogepant and Rimegepant – for both treatment and prevention – American Headache Society Annual Scientific Meeting; July 11-14, 2019; Philadelphia.

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Lasmiditan – Reyvow C-?by Lilly • Oct 11, 2019 the FDA approved Lasmiditan - Reyvow tablets for the acute (active but short-term) treatment of migraine with or without aura (a sensory phenomenon or visual disturbance) in adults. Lasmiditan is not indicated for the preventive treatment of migraine. • Lasmiditan binds with high affinity to the 5-HT1F receptor. Lasmiditan presumably exerts its therapeutic effects in the treatment of migraine through agonist effects at the 5-HT1F receptor. • Lasmiditan is awaiting DEA scheduling.

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Lasmiditan – Reyvow C-? • In a human abuse potential (HAP) study in recreational poly-drug users (n=58), single oral therapeutic doses (100 and 200 mg) and a supratherapeutic dose (400 mg) of lasmiditan were compared to alprazolam (2 mg) (C-IV) and placebo. • With all doses of lasmiditan, subjects reported statistically significantly higher “drug liking” scores than placebo, indicating lasmiditan has abuse potential. In comparison to alprazolam, subjects who received lasmiditan reported statistically significantly lower “drug liking” scores. In the HAP study, euphoric mood occurred to a similar extent with lasmiditan 200 mg, 400 mg, and alprazolam 2 mg (43-49%). A feeling of relaxation was noted in more subjects on alprazolam (22.6%) than with any dose of lasmiditan(7-11%). • Phase 2 and 3 studies indicate that, at therapeutic doses, lasmiditan produced adverse events of euphoria and hallucinations to a greater extent than placebo. However these events occur at a low frequency (about 1% of patients).

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Lasmiditan – Reyvow C-? DOSAGE AND ADMINISTRATION • The recommended dose of Lasmiditan is 50 mg, 100 mg, or 200 mg taken orally, with or without food as needed. No more than one dose should be taken in 24 hours, and lasmiditan should not be taken unless the patient can wait at least 8 hours between dosing and driving or operating machinery. • A second dose of lasmiditan has not been shown to be effective for the same migraine attack. • Available as 50 mg 100 mg tabs • The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.

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Lasmiditan – Reyvow C-? • There is a risk of driving impairment while taking lasmiditan. Patients are advised not to drive or operate machinery for at least eight hours after taking lasmiditan, even if they feel well enough to do so. Patients who cannot follow this advice are advised not to take lasmiditan. The drug causes central nervous system (CNS) depression, including dizziness and sedation. It should be used with caution if taken in combination with alcohol or other CNS depressants. • The most common side effects that patients in the clinical trials reported were dizziness, fatigue, a burning or prickling sensation in the skin (paresthesia), and sedation. 134

Lasmiditan – Reyvow C-?

Lasmiditan is associated with mean decreases in heart rate of 5 to 10 beats per minute (bpm) and it may increase BP by 2-7 mm Hg over the first hour after dosing but it is typically gone by 2 hours post dose.

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Lasmiditan – Reyvow C-? • The effectiveness of lasmiditan for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials. A total of 3,177 adult patients with a history of migraine with and without aura treated a migraine attack with lasmiditan in these studies. Although patients were allowed to take a rescue medication two hours after taking lasmiditan, opioids, barbiturates, triptans and ergots were not allowed within 24 hours of the study drug’s administration. Twenty-two percent of patients were taking a preventive medication for migraine.

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Lasmiditan – Reyvow C-?

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Combo Sumatriptan and Naproxen sodium

Trexamet 85/500mg tabs x 9 Brand ~$1,000.00 generic 9 tabs ~$225.00-400.00 Sumatriptan generic 50 and 100 mg tabs x 9 ~ $6.00-60.00 Naproxen sodium 275 mg tabs x 20 ~ $15.00-23.00 (GoodRx.com 10=24-19) 138

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The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice • Measuring the response to anti-CGRP mAbs will be patient- and healthcare professional dependent and will be guided by the same outcome metrics described previously for preventive treatments, with emphasis on migraine/headache days, migraine-related disability, impact, and functional impairment. • Measuring outcomes for patients on mAbs and making a decision regarding continuation requires 3 months of outcome data for patients receiving monthly injections or 6 months of follow-up for a treatment designed for quarterly injection or infusion. – a significant proportion of patients who do not achieve at least a 50% reduction in MHDs in the 4 weeks after the first SC dose may achieve a response in the 4 weeks after a second dose. Similarly, a smaller yet significant proportion of patients will respond in 4 to 8 weeks after a third consecutive SC dose. Headache 2019;59:1-18 139

The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice

Headache 2019;59:1-18 140

Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (NEJM on-line 3-12-2018) • 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). CARES Trial • In the modified intention-to-treat analysis, a primary end-point (the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina) event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). • All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death 1.34 [95% CI, 1.03 to 1.73]), febuxostat 134 cases (4.3%) vs. allopurinol 100 cases (3.2%) RRI 34%, ARI 1.1%, NNH 91.

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New Black Box Warning for Febuxostat (Uloric)

• . [2-21-2019] The U.S. Food and Drug Administration (FDA) has concluded there is an increased risk of death with febuxostat (Uloric) compared to another gout medicine, allopurinol. This conclusion is based on our in- depth review of results from a safety clinical trial that found an increased risk of heart-related death and death from all causes with febuxostat. • FDA is requiring a Black Box Warning and limiting the approved use of febuxostat to certain patients who are not treated effectively or experience severe side effects with allopurinol. • Counsel patients to seek medical attention immediately if they experience chest pain, shortness of breath, rapid or irregular heartbeat, numbness or weakness on one side of the body, dizziness, trouble talking, or a sudden severe headache while taking febuxostat

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New Black Box Warning for Hypnotics

• [04-30-2019] The Food and Drug Administration (FDA) is advising that rare but serious injuries have happened with certain common prescription insomnia medicines because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake. These complex sleep behaviors have also resulted in deaths. These behaviors appear to be more common with eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist) than other prescription medicines used for sleep.

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New Black Box Warning for Hypnotics

• Between December 16, 1992, and March 13, 2018. Of the 66 cases, 20 cases were reported as resulting in fatal outcomes. Forty-six cases reported serious non-fatal injuries; these patients usually did not remember experiencing these complex sleep behaviors. • The adverse events included falls (n=22) with serious injuries such as intracranial hemorrhages, vertebral fractures, and hip fractures. Other events included self-injuries (n=7), fatal falls (n=6), accidental overdoses (n=5), hypothermia (n=5), suicide attempts (n=5), apparent completed suicides (n=4), fatal motor vehicle collisions (n=4), gunshot wounds (n=3), carbon monoxide poisoning (2), drowning or near drowning (n=2), burns (n=2), and homicide (n=1).

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Glucose-lowering medication in type 2 diabetes: overall approach.

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EMPA-REG OUTCOME Trial

• The primary outcome (CV mortality, non-fatal MI and non-fatal stroke) occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). – Median follow-up 3.1 years – ARR = 1.6%, NNT 63 – No significant differences in rates of MI or CVA – No significant difference with 10 vs. 25 mg doses. – Death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction; ARR = 2.2%, NNT 46 • N Engl J Med 2015;373:2117-28

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EMPA-REG OUTCOME Trial

• Hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction) NNT 72 • Death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction) NNT 39 • Among patients receiving empagliflozin, there was an increased rate of genital infection (1 in 20 or 5%) but no increase in other adverse events. NNH 20 – N Engl J Med 2015;373:2117-28

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Empagliflozin - Jardiance • FDA approved to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. Based on Empa-Reg Outcomes Trial

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Credence Trial • A double-blind, randomized trial in 4401 patients with type 2 diabetes and albuminuric chronic kidney disease were randomized to receive canagliflozin 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (eGFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. Trial stopped early. – NEJM 4-14-2019 (published on line)

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Credence Trial

Primary outcome (primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. RRR 30% NNT 22 at 2.6 years

NEJM 4-14-2019 (published on-line) 152

Credence Trial

The geometric mean of the urinary albumin-to-creatinine ratio was lower by 31% (95% CI, 26 to 35) on average during follow- up in the canagliflozin group

The least-squares mean (±SE) change in the estimated GFR slope was less in the canagliflozin group than in the placebo group (–3.19±0.15 vs. –4.71±0.15 ml per minute per 1.73 m2 per year), for a between-group difference of 1.52 ml per minute per 1.73 m2 per year (95% CI, 1.11 to 1.93). During the first 3 weeks, there was a greater reduction in the estimated GFR in the canagliflozin group than in the placebo group (– 3.72±0.25 vs. –0.55±0.25 ml per minute per 1.73 m2),

NEJM 4-14-2019 (published on-line) 153

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Credence Trial

• Amputation - Canagliflozin 70/2200 vs. Placebo 63/2197 (3.2% vs. 2.87%) HR 1.11 (0.79–1.56) NS • Fracture - Canalizflozin 67/2200 vs. Placebo 68/2197 (3.05% vs. 3.1%) HR 0.98 (0.70–1.37) NS • Ketoacidosis - Canagliflozin 11/2200 vs. Placebo 1/2197 (0.5% vs. 0.05%) HR 10.80 (1.39–83.65) NNH 222 – NEJM 4-14-2019 (published on-line)

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Credence Trial

For glycated hemoglobin, the least-squares mean level at 13 weeks was lower in the canagliflozin group than in the placebo group by 0.31 percentage points (95% CI, 0.26 to 0.37), and the between-group difference narrowed thereafter NEJM 4-14-2019 (published on-line) Supplemental Appendix 155

Label Change 9, 2019 Canagliflozin - Invokana

• FDA approval to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria. Based upon CREDENCE Trial data • Contraindications: Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 who are being treated for glycemic control • Patients on dialysis • There are insufficient data to support dosing recommendations for initiation of therapy in patients with an eGFR < 30 mL/min/1.73 m2 with albuminuria greater than 300 mg/day or in patients with an eGFR < 45 mL/min/1.73 m2 with albuminuria less than or equal to 300 mg/day.

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Credence Trial • 4-14-2019 The National Kidney Foundation stated “If this supplemental indication is approved by the Food and Drug Administration (FDA), it would be the first new treatment for diabetic kidney disease (DKD) in decades." • We look forward to data in patients without diabetes but with CKD as well as those with eGFR less than 30 ml/min. • Current SGLT-2 class data suggest reduced efficacy in lowering A1c with decreasing eGFR. • Will , results of Credence change our guidelines?

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DECLARE-TIMI-58 Trial • Dapagliflozin Effect on Cardiovascular Events A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients With Type 2 Diabetes • A Phase III cardiovascular (CV) outcomes trial (CVOT) for dapagliflozin (Farxiga), the broadest SGLT2 inhibitor CVOT conducted to date. The trial evaluated the CV outcomes of dapagloflozin vs. placebo over a period of up to five years (median 4 years), across 33 countries and in more than 17,000 adults with type-2 diabetes (T2D) who have multiple CV risk factors (59.4% had at least one RF of dyslipidemia, HBP or smoking) or established CV disease (40.6% had ASCVD upon entry). • Mean A1c 8.3% +/- 1.2%, mean age 63.8 yrs +/- 6.8 yrs; duration of diabetes 11.8 +/- 7.8 yrs, 62.6% male and body mass index 32.1 ± 6.0 kg/m2 • Diabetes Obes Metab. 2018 May;20(5):1102-1110

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Median 17,000 patients with Type 2 DM F/U 4 yrs and CV risk or ASCVD followed for NNT mean 4 years 40

NEJM November 10, 2018 DOI: 10.1056/NEJMoa1812389 Outcomes driven by hospitalization for heart failure and renal effects 159

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Label Change 10,2019 Dapagliflozin - Farxiga

• FDA approval to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. Based upon the DECLARE Trial. • To reduce the risk of hospitalization for heart failure, the recommended dose is 10 mg once daily. • Dapagliflozin is not recommended when the eGFR is less than 45 mL/min/1.73 m2

160

Concerns with SGLT-2 Inhibitors? • I would not routinely recommend an SGLT-2 inhibitor in the following patients: – Patients with impaired renal function (eGFR of < 30 ml/min). – Patients with diabetic neuropathy, previous foot ulcers, previous amputations and/or peripheral vascular disease. – Patients at risk for falls or with orthostatic hypotension. – Patients with a history of osteoporosis, osteopenia, decreased BMD or history of fractures. – Patients with frequent UTI’s or fungal infections. – Patients with poor hygiene, bladder leakage, urinary incontinence, prostatectomy.

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LEADER CV Safety Trial with Liraglutide

• 9340 patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. – The median follow-up was 3.8 years. • The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (HR 0.87; 95% CI , 0.78 to 0.97; P<0.001 for noninferiority; P = 0.01 for superiority) ARR 1.9%, NNT=53 – N Engl J Med 2016; 375:311-322July 28, 2016

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LEADER CV Safety Trial with Liraglutide

• Death from cardio-vascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P = 0.007). ARR 1.3%, NNT 77 • The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (HR 0.85; 95% CI, 0.74 to 0.97; P = 0.02). ARR 1.4%, NNT=72 – N Engl J Med 2016; 375:311-322July 28, 2016

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LEADER CV Safety Trial with Liraglutide

• The rates of nonfatal myocardial infarction (HR 0.88), nonfatal stroke (HR 0.89), and hospitalization for heart failure (HR 0.87) were all nonsignificantly lower in the liraglutide group than in the placebo group. – N Engl J Med 2016; 375:311-322July 28, 2016 • FDA approved 10/2017 to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.

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Semaglutide CV Data – SUSTAIN 6 Trial

• Sustain 6 randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly (GLP-1 agonist) semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. • The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. – At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. – Mean duration of diabetes was 13.9 years and mean HbA1c was 8.7%. 93.5% were taking antihypertensive medication, 76.5% were receiving lipid-lowering drugs, and 76.3% were receiving antithrombotic medications. – NEJM on-line 9-16-2016

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Semaglutide CV Data – SUSTAIN 6 Trial • The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). NNT 45 • Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). • Rates of death from cardiovascular causes were similar in the two groups. – NEJM on-line 9-16-2016

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Rewind Trial with Dulaglutide • The REWIND trial of 9901 people had a long median follow-up period of 5·4 years, recruited a low proportion of people (31·5%) with previous cardiovascular disease, a high proportion of women (46·3%), and followed people with a mean HbA1c of 7·3%. Patients were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. • The primary outcome was the first occurrence of the composite endpoint (3Point MACE) of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. • The primary composite CV outcome occurred in 594 (12·0%) participants in the dulaglutide group and in 663 (13·4%) participants in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067).

 www.thelancet.com Published online June 10, 2019 http://dx.doi.org/10.1016/S0140-6736(19)31149-3 1

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www.thelancet.com Published online June 10, 2019 http://dx.doi.org/10.1016/S0140-6736(19)31149-3 1 168

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Oral Semaglutide – Rybelsus by Novo Nordisk • 9/20/2019 The FDA approved the first oral GLP-1 agonist oral semaglutide – Rybelsus by Novo-Nordisk. • Rybelsus (semaglutide) tablets 7 mg or 14 mg once a day is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. • Tablets 3 mg, 7 mg and 14 mg • Cost: list price of $26 per day, or $772 per 30 tablets across all doses—a price that’s “in-line with injectables” from that same class.

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BOX WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration- dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined • RYBELSUS® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of RYBELSUS® and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS®

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Oral Semaglutide – Rybelsus Limitations of Use: • Not recommended as first-line therapy for patients inadequately controlled on diet and exercise. • Has not been studied in patients with a history of pancreatitis. – After initiation of oral semaglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, oral semaglutide should be discontinued. • Not indicated for use in patients with type 1 diabetes mellitus or treatment of diabetic ketoacidosis.

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Oral Semaglutide – Rybelsus • Once-daily tablet formulated with SNAC • SNAC (Sodium-N-[8-(2-hydroxybenzoyl) amino] caprylate) – Carrier molecule that enhances absorption – Forms weak noncovalent bonds with oral semaglutide – Local buffering effect: Prevents breakdown by gastric enzymes and stomach acid – Locally absorbed in the stomach near the site of tablet erosion – Once absorbed, the weak bonds break and SNAC is rapidly eliminated by the kidneys with an average T1/2 of 1.3 hrs for SNAC. • Once in the blood stream oral semaglutide binds to albumin in the bloodstream resulting in a long half-life (168 hours) • Considered safe in patients with eGFR: 30-59 ml/min per CKD-EPI

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Oral Semaglutide – Rybelsus Important Administration Instructions: • Instruct patients to take oral semaglutide at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water only. Waiting less than 30 minutes, or taking oral semaglutide with food, beverages (other than plain water) or other oral medications will lessen the effect of oral semaglutide by decreasing its absorption. Waiting more than 30 minutes to eat may increase the absorption of oral semaglutide. – The estimated absolute bioavailability of semaglutide is approximately 0.4%-1%, following oral administration as recommended. • Swallow tablets whole. Do not split, crush, or chew tablets. • Recommended Dosage: Start oral semaglutide with 3 mg once daily for 30 days. The 3 mg dose is intended for treatment initiation and is not effective for glycemic control. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily. Dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose. 173

Phase 3 Clinical Trials PIONEER 1 c • Monotherapy

PIONEER 2 c • Oral semaglutide vs. empagliflozin

PIONEER 3 c • Oral semaglutide vs. sitagliptin (long-term)

PIONEER 4 c • Oral semaglutide vs. liraglutide

PIONEER 5 c • Patients with moderate renal impairment PIONEER 6 c • Cardiovascular outcomes

PIONEER 7 c • Flexible dose escalation PIONEER 8 c • Oral semaglutide as an insulin add-on

PIONEER 9 c • JAPAN monotherapy

PIONEER 10 c • JAPAN OAD combination Novo Nordisk. Capital Market Days, 2017. 174

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• 2-22-2018 PIONEER 1 was a 26-week, randomized, double-blinded, placebo- controlled, four-armed, parallel-group, multicenter, multinational trial comparing the efficacy and safety of three dose levels of once-daily oral semaglutide vs placebo in people with type 2 diabetes treated with diet and exercise only. 703 people were enrolled in PIONEER 1 and randomized 1:1:1:1 to receive either a dose of oral semaglutide (3, 7 or 14 mg) or placebo once daily. The primary endpoint was change in HbA1c from baseline at week 26. • Patients treated with 3, 7 and 14 mg oral semaglutide achieved reductions in HbA1c of 0.8%, 1.3% and 1.5%, respectively, compared to a reduction of 0.1% in people treated with placebo from a mean baseline of 8.0%. • Patients treated with 3, 7 and 14 mg oral semaglutide experienced a weight loss of 1.7 kg, 2.5 kg and 4.1 kg, respectively, compared to a weight loss of 1.5 kg in people treated with placebo. (mean baseline body weight of 88 kg and a BMI of 31.8 kg/m2) – The most common adverse event for all three oral semaglutide doses was mild to moderate nausea(5-16% vs. 6% placebo), which diminished over time. 175

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• Oral Semaglutidevs. Empagliflozin Added On to Metformin Monotherapy in Uncontrolled Type 2 Diabetes: PIONEER 2 • oral semaglutide (sema) 14 mg once daily (N=411) was compared with the SGLT2i empagliflozin (empa) 25 mg QD (N=410) in patients (pts) with T2D uncontrolled on metformin in a 52-week randomized, open-label trial • Proportions of adverse events (AEs) were similar between oral sema (70.5%) and empa (69.2%). The most frequent AEs with oral sema were mild/moderate gastrointestinal events. Premature trial product discontinuations due to AEs were 11% (oral sema) vs. 4% (empa).

Diabetes 2019 Jun; 68(Supplement 1): -. https://doi.org/10.2337/db19-54-OR 176

• 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. – (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). – JAMA. 2019;321(15):1466-1480

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Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea The PIONEER 3 Randomized Clinical Trial

JAMA. 2019;321(15):1466-1480

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Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea - The PIONEER 3 Randomized Clinical Trial • Symptomatic hypoglycemia were experienced by 4.9% (23/466), 5.2% (24/464), and 7.7% (36/465) of patients in the 3-, 7-, and 14-mg/d semaglutide groups, respectively, and by 8.4% (39/466) in the sitagliptin group. (These episodes mainly occurred in patients prescribed background metformin with sulfonylurea). • Adverse events led to premature discontinuation for 5.6% (26/466), 5.8% (27/464), and 11.6% (54/465) in the 3-, 7-, and 14-mg/d semaglutide groups, respectively, and 5.2% (24/466) for sitagliptin, with gastrointestinal adverse events being the primary cause in all treatment groups. (For a substantial proportion of patients in the 7- and 14-mg/d semaglutide groups who discontinued because of an adverse event, the onset of the causative event occurred during the dosage-escalation period). JAMA. 2019;321(15):1466-1480 179

Oral Semaglutide – Rybelsus

• Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial • 711 patients were randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) were female and the mean age was 56 years • weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (–1·5 kg, 95% CI –2·2 to –0·9; p<0·0001) and placebo (ETD –4·0 kg, –4·8 to –3·2; p<0·0001). • Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]).

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Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5) • Patients were aged 18 years or older, with type 2 diabetes (diagnosed ≥90 days before screening), had a HbA1c of 7·0–9·5% and moderate renal impairment (Chronic Kidney Disease-Epidemiology Collaboration [CKD- EPI] stage 3), defined as an eGFR of 30–59 mL/min per 1·73 m2, 324 patients were randomly assigned (1:1) to receive either once-daily oral semaglutide (escalated to 14 mg) or placebo, in addition to their background medication (metformin, sulfonylureas, both or basal insulin with or without metformin) and followed for 26 weeks. • Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. – Lancet Diabetes Endocrinol 2019; 7: 515–27 181

Oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5)

Lancet Diabetes Endocrinol 2019; 7: 515–27 182

Oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5)

4 8 14 20 26 wks Lancet Diabetes Endocrinol 2019; 7: 515–27

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Oral Semaglutide – Rybelsus • PIONEER 6 Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (NEJM 2019; 381:841-851) – 3,183 patients (median age 66 years, 68% male) with type 2 diabetes at high cardiovascular risk having standard-of-care treatment were randomized to oral semaglutide (target dose 14 mg) once daily vs. placebo • patients ≥ 50 years old had established cardiovascular disease or chronic kidney disease; patients ≥ 60 years old had cardiovascular risk factors only • patients were taking metformin (77%), insulin (61%), sulfonylureas (32%), sodium- glucose cotransporter 2 inhibitors (9.6%), antihypertensive medication (94%), lipid- lowering medication (85%) and antiplatelet or antithrombotic medication (79%) – major adverse cardiovascular event (3 point MACE) defined as cardiovascular death (including death from undetermined causes), nonfatal myocardial infarction, or nonfatal stroke N Engl J Med 2019;381:841-851

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Oral Semaglutide – Rybelsus • Results comparing oral semaglutide vs. placebo in intention-to-treat analysis (median follow-up 15.9 months) • 3 Point MACE in 3.8% vs. 4.8% (hazard ratio 0.79, 95% CI 0.57-1.11, noninferiority met, p=0.17 for superiority N.S.) – Cardiovascular death in 0.9% vs. 1.9% (p < 0.05, NNT 100) – Nonfatal myocardial infarction in 2.3% vs. 1.9% (not significant) – Nonfatal stroke in 0.8% vs. 1% (not significant) – All-cause death in 1.4% vs. 2.8% (p < 0.05, NNT 72) – Unstable angina resulting in hospitalization in 0.7% vs. 0.4% (not significant) – Heart failure resulting in hospitalization in 1% vs. 1.5% (not significant) • N Engl J Med 2019;381:841-851 185

Oral Semaglutide – Rybelsus

Glycated hemoglobin levels decreased more in the oral semaglutide group than in the placebo group (mean change from baseline to end of trial, – N Engl J Med 2019;381:841-851 1.0 vs. –0.3 percentage points), as did body weight (mean change from baseline to end of trial, –4.2 kg vs. –0.8 kg)

N Engl J Med 2019;381:841-851 186

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Oral Semaglutide – Rybelsus Adverse Events: • Discontinuation due to adverse event in 11.6% vs. 6.5% • Any serious adverse event in 18.9% vs. 22.5% • Acute kidney injury in 2% vs. 2.3% • Acute pancreatitis in 0.1% vs. 0.2% • Retinopathy or related complication in 7.1% vs. 6.3% • Severe hypoglycemia in 1.4% vs. 0.8% • Malignant neoplasm in 2.6% vs. 3% – N Engl J Med 2019;381:841-851

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Oral Semaglutide – Rybelsus Drug Interactions: • Semaglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other oral medications. • Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with oral semaglutide in a drug interaction study.

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Immunogenicity: • Across the placebo- and active-controlled glycemic control trials with antibody measurements, 14 (0.5%) oral semaglutide-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in semaglutide. • Of the 14 semaglutide-treated patients that developed semaglutide ADAs, 7 patients (0.2% of the overall population) developed antibodies cross-reacting with native GLP-1. The neutralizing activity of the antibodies is uncertain at this time.

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Romosozumab - Evenity by Amgen/UCB • April 9, 2019 the FDA approved Evenity (romosozumab-aqqg) to treat osteoporosis in postmenopausal women at high risk of breaking a bone (fracture). These are women with a history of osteoporotic fracture or multiple risk factors for fracture, or those who have failed or are intolerant to other osteoporosis therapies. • Romosozumab-aqqg increased the risk of cardiovascular death, heart attack and stroke in the alendronate trial, but not in the placebo trial. Therefore, Evenity contains a boxed warning on its labeling stating that it may increase the risk of heart attack, stroke and cardiovascular death and should not be used in patients who have had a heart attack or stroke within the previous year. Health care professionals should also consider whether the benefits of romosozumab-aqqg outweigh its risks in those with other risk factors for heart disease and should discontinue the drug in any patient who experiences a heart attack or stroke during treatment.

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Romosozumab - Evenity • Romosozumab, a monoclonal humanized neutralizing antibody, works by binding and inhibiting activity of the glycoprotein sclerostin, which is produced by osteocytes and is involved in the regulation of bone formation and resorption. It increases bone formation and, to a lesser extent, decreases bone resorption resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength. • Subcutaneous administration of romosozumab to women and men with low bone mineral density (BMD) for 3 months resulted in an improvement in trabecular and cortical bone mass, structure, and bone stiffness that persisted for at least 3 months after the last dose.

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Romosozumab - Evenity • The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks. • Development of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. Among 5914 postmenopausal women treated with romosozumab-aqqg 210 mg monthly, 18.1% of subjects developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing which led to decreased mean romosozumab-aqqg concentrations up to 63%. Antibodies to romosozumab-aqqg were generally not associated with changes in the efficacy or safety of romosozumab-aqqg.

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Romosozumab - Evenity • Study 1 (NCT01575834) was a randomized, double-blind, placebo-controlled study of postmenopausal women (<3% from North America) aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than or equal to −2.5 at the total hip or femoral neck. Women were randomized to receive subcutaneous injections of either romosozumab-aqqg 210 mg SQ every month (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% of women had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to open-label anti-resorptive therapy (denosumab 60 mg SQ every 6 months) for 12 months while remaining blinded to their initial treatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24. • BMD increases from baseline were greater with romosozumab at 12 months: 13.3% at the lumbar spine (95% CI, 11.9% to 14.7%), 6.9% at the total hip (95% CI, 5.6% to 8.1%), and 5.9% at the femoral neck (95% CI, 4.3% to 7.4%) (P<0.001 for all comparisons to placebo). BMD continued to increase in the romosozumab group during the second year with denosumab therapy.

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After romosozumab-aqqg discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on antiresorptive therapy 195

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• A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. All of these biopsies were adequate for qualitative histology and 138 (90%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from women treated with romosozumab- aqqg showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralization defects, or marrow fibrosis.

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• Major Adverse Cardiac Events (MACE) in Study 1 • During the 12-month double-blind treatment period of the placebo- controlled trial (Study 1), myocardial infarction occurred in 9 women (0.3%) in the romosozumab group and 8 (0.2%) women in the placebo group; stroke occurred in 8 women (0.2%) in the romosozumab group and 10 (0.3%) women in the placebo group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.5%) in the romosozumab group and 15 (0.4%) women in the placebo group. The number of women with positively adjudicated MACE was 30 (0.8%) in the romosozumab group and 29 (0.8%) in the placebo group, yielding a hazard ratio of 1.03 (95% confidence interval [0.62, 1.72]) for romosozumab compared to placebo.

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• Study 2 (NCT01631214) was a randomized, double-blind, alendronate- controlled study of postmenopausal women aged 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to −2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. Women were randomized (1:1) to receive either monthly subcutaneous injections of romosozumab-aqqg (N = 2046) or oral alendronate 70 mg weekly (N = 2047) for 12 months, with 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment. • Romosozumab-aqqg significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. The treatment differences in BMD were 8.7% at the lumbar spine, 3.3% at the total hip, and 3.2% at the femoral neck.

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33 months median F/U duration

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• Major Adverse Cardiac Events (MACE) in Study 2 • During the 12-month double-blind treatment period of the active- controlled trial (Study 2), myocardial infarction occurred in 16 women (0.8%) in the romosozumab group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 women (0.6%) in the romosozumab group and 7 (0.3%) women in the alendronate group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.8%) in the romosozumab group and 12 (0.6%) women in the alendronate group. The number of women with positively adjudicated MACE was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for romosozumab compared to alendronate. Reason for Box Warning!!

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• Romosozumab vs Teriparatide: Phase 3 randomized, open- label, multicenter study enrolled 436 women (60 to 90 years of age) with postmenopausal osteoporosis who had received oral bisphosphonate therapy for at least 3 years immediately prior to screening. They also had to have a BMD T-score of -2.5 or less at lumbar spine, total hip, or femoral neck and a history of nonvertebral fracture after age 50 or vertebral fracture. • Mean patient age was 72 years, and baseline T-score was -2.2 for total hip, -2.9 for lumbar spine, and -2.5 for femoral neck. • Intervention: Patients were randomized to treatment with romosozumab 210 mg once monthly (n=218) or teriparatide 20 mcg (n=218) once daily for 12 months.

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Primary End Point(s): • Mean percent change from baseline in total hip BMD, according to dual-energy x-ray absorptiometry scan, was 2.6% (95% CI, 2.2% to 3%) with romosozumab and –0.6% (95% CI, – 1% to –0.2%) with teriparatide (P<0.0001) Secondary End Point(s): • Total hip BMD change at months 6 and 12 was larger with romosozumab than with teriparatide (P< 0.0001): 2.3% (95% CI, 1.9% to 2.7%) with romosozumab versus –0.8% (95% CI, – 1.2% to –0.4%) with teriparatide at month 6; and 2.9% (95% CI, 2.5% to 3.4%) with romosozumab versus –0.5% (95% CI, –0.9% to 0%) with teriparatide at month 12.

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Romosozumab - Evenity Warnings and Precautions: • Hypersensitivity: Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria. Discontinue romosozumab if a clinically significant allergic reaction occurs. • Hypocalcemia: Adequately supplement calcium and vitamin D during treatment with romosozumab. • Osteonecrosis of the Jaw: Monitor for symptoms. Consider discontinuation of therapy based on benefit-risk assessment. • Atypical Femoral Fracture: Evaluate new or unusual thigh, hip, or groin pain to rule out an incomplete femur fracture.

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Romosozumab - Evenity Dosage/Administration: • Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other subcutaneously in the abdomen, thigh or upper arm once every month. • Each dose should be administered by a healthcare provider. • The treatment duration for romosozumab is 12 monthly doses. • Patients should be adequately supplemented with calcium and vitamin D during treatment • Limitations of Use: Limit duration of use to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered. • Carton of two 105 mg/1.17 mL single-use prefilled syringes. • Refrigerate at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Can be kept at room temp (<77degrees F) for up to 30 days. • Allow to sit at room temperature for at least 30 minutes before injecting. 205

Inhaled Levodopa – Inbrija by Acorda Therapeutics

• Inbrija (in-BRIH-jah) is the first INHALED levodopa for adults with Parkinson’s disease. • Think of Inbrija as a fast-acting dose of levodopa. It joins Apokyn (apomorphine) injection...the only other “rescue” option. • Inbrija works in about 10 minutes...and lasts about an hour. • It will be used to treat “off-time”...when scheduled meds wear off early or kick-in late and symptoms (rigidity, tremor, etc) worsen. Up to 90% of Parkinson’s patients have these symptoms after 10 years of therapy. • But Inbrija won’t REPLACE daily meds. Patients will still need scheduled carbidopa/levodopa...and may also use add-ons such as dopamine agonists (pramipexole, etc), MAO-B inhibitors (rasagiline, etc) or COMT inhibitors (entacapone, etc). • And it’s a specialty med costing about $32/dose...less than Apokyn at about $200/dose. 206

Inhaled Levodopa – Inbrija

• Plus each dose of Inbrija’s requires loading the inhaler with a capsule...inhaling...removing the cap...and repeating. This could be difficult for some patients with Parkinson’s disease. • Optimize carbidopa/levodopa schedules and add-on meds to minimize off- time...BEFORE considering Inbrija. • For example, use lower doses of carbidopa/levodopa more often...or a longer- acting option (Rytary, etc). • Save Inbrija for patients with unpredictable off-time episodes...or when other med adjustments don’t do the trick. • Tell patients Inbrija may lead to cough...but early evidence doesn’t suggest changes in lung function. • But don’t use Inbrija in patients with COPD, asthma, or other respiratory diseases...due to the risk of bronchospasm.

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Inhaled Levodopa – Inbrija

Dosing One dose (84 mg) = two 42-mg capsules No more than 1 dose per OFF period May be taken as needed up to a maximum of 5x per day when symptoms start to return Average number of doses in clinical trials: ~2 per day Important Administration Instructions For oral inhalation only; INBRIJA capsules must not be swallowed as intended effect would not be obtained INBRIJA capsules are only for use with the INBRIJA inhaler Effective only in combination with CD/LD Capsules should be stored in their blister package and only removed immediately before use

Demonstrated Usability 99.8% (628/629) of randomized patients in the 2 clinical trials demonstrated the ability to self-administer INBRIJA while in an OFF period after 208

Inhaled Levodopa – Inbrija

• If you have recurring or sporadic "off" times, you may want to consider Inbrija. But because this is an add-on medication, it may be helpful to first ensure your current treatment is working as well as it can. Adjustments to how and when you take your medications could lessen "off" time. • For some people, separating levodopa from high-protein meals (meat, fish, nuts or beans, for example) by 30 to 60 minutes may ease symptoms. Levodopa and dietary protein are absorbed in the same part of the gut. When you take medication and protein at the same time, less medication may be absorbed, potentially leading to "off" time. • .

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Inhaled Levodopa – Inbrija • Changing your medication's dose or timing also may help. If your symptoms start to return gradually about an hour before every levodopa dose, for example, your doctor may recommend you take it more often or increase the dose, or add a longer-acting PD drug to prevent "wearing off." • If you still have "off" time despite dietary and medication adjustments, Inbrija may be an option. Even for those whose symptoms are fairly well controlled, it may be good to have a rescue therapy on hand just in case "off" time comes on at an unpredictable or inconvenient moment.

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Istradefylline – Nourianz by Kyowa Kirin, Inc. • August 27, 2019 after more than 10 years the FDA approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing "off" episodes. • Istradefylline belongs to a class of medications called “adenosine A2A antagonists,” which work differently from all currently available Parkinson’s drugs. By blocking the brain chemical adenosine, it boosts the signaling of dopamine, the brain chemical that decreases in Parkinson’s. • The drug has been sold in Japan since 2013 but was previously rejected by the FDA in 2008. At that time, the agency raised concerns about its efficacy and asked for more data.

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Istradefylline – Nourianz • The adenosine A2A receptor antagonist idea had its fair share of failures, too. In 2010, Vernalis and partner Biogen halted development of their candidate vipadenant after toxicity concerns were noticed in preclinical studies. Then, in 2013, Merck & Co. threw in the towel with preladenant after a preliminary review of data from late-stage trials found it didn’t work well enough. Most recently, in 2017, Acorda Therapeutics ditched tozadenant—which it acquired via its $363 million Biotie takeover—after patient deaths in phase 3.

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Istradefylline – Nourianz • Adenosine A2A receptors are highly localized to the striatum and GPe, which is part of the basal ganglia-thalamo-cortical. This circuit has two outputs, a direct and an indirect pathway, which are controlled by dopamine D1 and D2 receptors, respectively. In PD, decreased excitatory activity of the direct pathway and increased inhibitory activity of the indirect pathway causes an imbalance that results in motor dysfunction. It has previously been demonstrated that adenosine A2A receptor activation selectively induces activation of the indirect pathway via dual modulation of receptors in both the striatum and GPe. Blockade of the adenosine A2A receptors in the striatum and GPe antagonizes the hyperexcitability of GABAergic striatopallidal neurons caused by loss of D2 receptor activation in PD, resulting in improvement of motor function via normalization of balance in the basal ganglia 213

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Istradefylline – Nourianz • Istradefylline exhibits dose-proportional pharmacokinetics after multiple oral doses from 20 mg to 80 mg (2 times the maximum recommended dosage). Steady-state was reached within 2 weeks of once-daily dosing. • The AUC increased 1.25-fold when istradefylline was coadministered with a standard high-fat meal, compared with administration in a fasted state, not significant. • The mean terminal half-life (t1/2) for istradefylline at steady-state is approximately 83 hours. • Istradefylline is primarily metabolized via CYP1A1 and CYP3A4, with minor contribution from CYP1A2, 2B6, 2C8, CYP2C9, CYP2C18, and 2D6. Six metabolites have been identified in human plasma.

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Istradefylline – Nourianz • DRUG INTERACTIONS: Strong CYP 3A4 inhibitors: (e.g., itraconazole, ketoconazole, clarithromycin) Recommended maximum dosage with concomitant use is 20 mg once daily. • Strong CYP 3A4 inducers: Avoid use (rifampin) decreased istradefylline Cmax and AUCinf by 45% and 81%, respectively. • Tobacco smoking decreased istradefylline steady-state systemic exposures by 38% to 54% , which may decrease efficacy. Therefore, the recommended istraadefylline dosage in patients who smoke 20 or more cigarettes per day (or the equivalent amount of another tobacco product) is 40 mg once daily.

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Istradefylline – Nourianz • The safety of istradefylline was evaluated in 734 patients with Parkinson’s disease (PD) taking a stable dose of levodopa and a DOPA decarboxylase inhibitor, with or without other PD medications, in four randomized, multicenter, double-blind, placebo-controlled trials 12 weeks in duration. • The most common adverse reactions in which the frequency for istradefylline was at least 5%, and greater than the incidence on placebo, were dose related and included: dyskinesia (15-17% vs. 8% placebo), dizziness (3-6% vs. placebo 4%), constipation (5- 6% vs. placebo 3%), nausea (4-6% vs. placebo 5%), hallucination (2-6% vs. placebo 3%), and insomnia (1-6% vs. placebo 4%). 216

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Istradefylline – Nourianz • The efficacy of istradefylline for the adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes was shown in four randomized, multicenter, double-blind, 12- week, placebo-controlled studies. The trial enrolled 1143 patients with a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years) that were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least one year, with stable dosage for at least 4 weeks before screening. – Patients continued levodopa treatment with or without concomitant PD medications, including dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%), provided the medications were stable for at least 4 weeks before screening and throughout the study period. The studies excluded patients who had received a neurosurgical treatment for PD. 217

Istradefylline – Nourianz • The primary efficacy endpoint was the change from baseline in the daily awake percentage of “off” time, or the change from baseline in total daily “off” time, based on 24-hour diaries completed by patients. A change from baseline in “on” time without troublesome dyskinesia (i.e., “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia) was a secondary efficacy endpoint. • Compared with patients on placebo, patients treated with istradefylline 40 mg/day experienced an additional increase from baseline in “on” time without troublesome dyskinesia of 0.96 hours (nominal p=0.026) in Study 1, and of 0.55 hours (nominal p=0.135) in Study 2.

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Istradefylline – Nourianz • Study 3 and Study 4 were conducted in Japan. In these studies, patients were randomized equally to once daily treatment with istradefylline 20 mg, 40 mg, or placebo. • In Study 3, compared with placebo, an additional increase from baseline in “on” time without troublesome dyskinesia of 0.57 hours (nominal p=0.085) and of 0.65 hours (nominal p=0.048), respectively, were observed in patients treated with istradefylline 20 mg or 40 mg respectively. • In Study 4, the corresponding increases in “on” time without troublesome dyskinesia were 0.83 hours (nominal p=0.008) for istradefylline 20 mg and 0.81 hours (nominal p=0.008) for 40 mg. 219

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Istradefylline – Nourianz • The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily. – May be taken with or without food. – Patients with hepatic impairment: Maximum recommended dosage with moderate hepatic impairment is 20 mg once daily; use of in patients with severe hepatic impairment should be avoided. – Patients who smoke 20 or more cigarettes per day (or the equivalent of another tobacco product): Recommended dosage is 40 mg once daily. • Cost: available as 20 and 40 mg tablets

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