`STUDIES
`WHERE PHASE
`2 AND PHASE 3
`TRIALS HAD
`DIVERGENT
`RESULTS
`
`January 2017
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`Regeneron Pharmaceuticals, Inc. Exhibit 2046 Page 1
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`22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results
`
`
`Table of Contents
`I.
`Overview ............................................................................................................................................................... 2
`II.
`Clinical Trials: Understanding Medical Product Testing ...................................................................................... 2
`III.
`Flexibility in Clinical Trial Design ........................................................................................................................ 3
`IV.
`Case Studies ........................................................................................................................................................... 5
`A. Phase 3 Trials Demonstrating Lack of Efficacy in a Promising Experimental Therapy....................................... 5
`1.
`Bitopertin ...................................................................................................................................................... 5
`2.
`Brivanib ......................................................................................................................................................... 6
`3.
`Capsaicin Topical Patch (Qutenza) ............................................................................................................... 8
`4.
`Darapladib ..................................................................................................................................................... 9
`5.
`Dexmecamylamine ...................................................................................................................................... 10
`6.
`Exhale Drug-Eluting Stent .......................................................................................................................... 11
`7.
`Experimental HSV-2 Vaccine ..................................................................................................................... 12
`8.
`Glutamic Acid Decarboxylase Vaccine ...................................................................................................... 13
`9.
`Imiquimod (Aldara 5% Cream) .................................................................................................................. 14
`10.
`Iniparib ........................................................................................................................................................ 15
`11.
`Lithium ........................................................................................................................................................ 16
`12. MAGE-A3 vaccine ..................................................................................................................................... 17
`13.
`NicVAX Vaccine ........................................................................................................................................ 18
`14.
`Velimogene Aliplasmid (Allovectin-7) ....................................................................................................... 19
`B. Phase 3 Trials Demonstrating Lack of Safety in a Promising Experimental Therapy ........................................ 20
`15.
`Olanzapine Pamoate (Zyprexa Relprevv) ................................................................................................... 20
`C. Phase 3 Trials Demonstrating Lack of Efficacy and Lack of Safety in a Promising Experimental Therapy ..... 21
`16.
`Aliskiren (Rasilez, Tekturna) ...................................................................................................................... 21
`17.
`CoStar Drug-Eluting Stent .......................................................................................................................... 22
`18.
`Figitumumab ............................................................................................................................................... 23
`19.
`Recombinant Factor VIIa (NovoSeven) ...................................................................................................... 24
`Semagacestat ............................................................................................................................................... 25
`20.
`21.
`Torcetrapib .................................................................................................................................................. 26
`22.
`V710 vaccine............................................................................................................................................... 27
`Discussion ............................................................................................................................................................ 28
`V.
`Conclusions ......................................................................................................................................................... 29
`VI.
`Appendix A: RCTs and Clinical Trial Design Considerations ....................................................................................... 31
`Appendix B: Methods ..................................................................................................................................................... 32
`Appendix C: Summary Table ......................................................................................................................................... 34
`References ....................................................................................................................................................................... 36
`
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`22 Case Studies Where
`Phase 2 and Phase 3 Trials Had Divergent Results
`
`Overview
`
`
`I.
`
`Pre-market clinical testing usually progresses in phases, with increasingly rigorous methods at each
`phase. Product candidates that appear insufficiently safe or effective at one phase may not proceed to the
`next phase. Roughly 9 in 10 drugs/biologics that are tested in humans are never submitted to FDA for
`approval.[1] Typically, a candidate drug is submitted to the FDA for marketing approval after phase 3
`testing. In recent years, there has been growing interest in exploring alternatives to requiring phase 3
`testing before product approval, such as relying on different types of data and unvalidated surrogate
`endpoints.
`
`To better understand the nature of the evidence obtained from many phase 2 trials and the contributions of
`phase 3 trials, we identified, based on publicly available information, 22 case studies of drugs, vaccines
`and medical devices since 1999 in which promising phase 2 clinical trial results were not confirmed in
`phase 3 clinical testing.* Phase 3 studies did not confirm phase 2 findings of effectiveness in 14 cases,
`safety in 1 case, and both safety and effectiveness in 7 cases. These unexpected results could occur even
`when the phase 2 study was relatively large and even when the phase 2 trials assessed clinical outcomes.
`In two cases, the phase 3 studies showed that the experimental product increased the frequency of the
`problem it was intended to prevent.
`
`This paper is not intended to assess why each of these unexpected results occurred or why further product
`development was not pursued. Rather, these cases, chosen from a large pool of similar examples,
`illustrate the ways in which controlled trials of appropriate size and duration contribute to the scientific
`understanding of medical products.
`
`II. Clinical Trials: Understanding Medical Product Testing
`
`In the classical drug development paradigm, pre-market clinical trials for drugs are conducted in three
`phases. The trials at each phase have a different purpose and help scientists answer different questions.
`
`
`
`
`• Phase 1 Trials. In phase 1, researchers test the potential product in humans for the first time, to
`identify rudimentary product characteristics, such as how the body metabolizes a drug and how
`long it stays in the body, and to provide evidence that the product is not too toxic for further
`human testing. The treatment group is small (typically 20 – 80 healthy volunteers), but allows
`researchers to begin to evaluate the treatment’s safety, adjust dosing schemes, and start to identify
`side effects. This information guides the design of phase 2 studies.
`
`• Phase 2 Trials. Phase 2 studies are intended to explore the effectiveness of the product for a
`particular indication over a range of doses, and to assess short-term side effects. These studies
`typically involve a few hundred patients who have the target condition, but do not generally have
`other diseases that might obscure the effect of the drug on the target condition. Phase 2 trials may
`be randomized and/or controlled, but often measure laboratory values or other biomarkers rather
`than clinical outcomes (i.e., effects on how a patient feels, functions, or survives). When a phase
`
`
`* For the purposes of this analysis, the terms “trial” and “study” are used interchangeably.
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`2 study does assess clinical outcomes, it is usually for relatively short periods of time and in a
`relatively small number of people. Sponsors assess phase 2 results to determine if the preliminary
`results are sufficiently promising to justify a phase 3 study.
`
`• Phase 3 Trials. Compared to phase 2 trials, the goal of phase 3 trials is to test the experimental
`product in larger groups of people (typically 300 – 3000), in people who are more similar to those
`likely to use the product once marketed, and for longer periods of time. Phase 3 studies generally
`assess clinical outcomes, and are designed to determine whether the demonstrated benefits of the
`product outweigh its risks.
`
`As discussed in Section III, below, the appropriate size and duration of clinical trials varies significantly
`from condition to condition, and product to product.†
`
`For most approved drug products, clinical evaluation may be continued even after a product is on the
`market. These studies are termed phase 4 trials, and can be helpful to uncover information on new uses
`that can be shared with health care providers to refine prescribing advice or can indicate that new
`warnings should be added to the product’s label.
`
`III. Flexibility in Clinical Trial Design
`
`In practice, clinical testing progression and design has become increasingly flexible as the science of
`clinical trials has evolved. Phase 1 might be combined with phase 2 if the drug is expected to have
`toxicity unacceptable for healthy volunteers. If the product’s mechanism of action and safety profile are
`well characterized, phase 2 testing may be shortened or skipped altogether. When there is sufficient
`evidence that a change in a biomarker reliably predicts a clinical benefit, the biomarker can serve as a
`surrogate measure for that clinical benefit in a trial, and the effect of the product on the surrogate measure
`can be a basis for product approval. Surrogate measures are often biomarkers that help diagnose or
`monitor a disease, such as blood pressure to predict stroke risk or the amount of human
`immunodeficiency virus in the blood to predict the development of acquired immunodeficiency
`syndrome.
`
`The nature of definitive trials also varies. Larger and longer trials may be needed if, for example, the
`condition to be treated is chronic or if the event the drug is intended to prevent occurs infrequently.
`Smaller or shorter trials may be needed where, for example, the drug produces a dramatic improvement in
`patients, or is intended for short-term conditions like many infections. Other factors, such as whether the
`condition is widespread or rare, whether it is life-threatening, and whether there are other effective
`treatments for the condition are also important in determining what kind of clinical testing is appropriate.
`
`Where a drug or biologic is intended to treat a serious condition for which there are limited available
`alternative therapies, FDA has implemented four separate expedited development and review
`programs.[2] For example, when there is evidence that a biomarker is “reasonably likely to predict”
`
`† Medical device testing often does not follow this “phase 1 - 3” paradigm or use the same “phase 1 – 3”
`vocabulary. In some cases, practical limitations related to the device or disease condition may limit the
`feasibility of a large randomized, controlled trial design. But the need, in certain circumstances, for one
`or more large well controlled studies to determine whether a device actually improves clinical outcomes
`can be equally applicable. Such trials serve a purpose similar to phase 3 drug and biologic trials. For
`editorial convenience, we use the phrase “phase 3” throughout the document to refer to both phase 3 drug
`and biologics trials, as well as “pivotal” and similar trials for devices.
`
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`clinical benefit, that biomarker can be a basis for approval under FDA’s accelerated approval authority.
`In these situations, sponsors have been required to conduct post-market confirmatory studies to further
`define the clinical benefit of the drug.
`
`While clinical testing progression and design has become increasingly flexible, and advances in
`biomedical science and statistics have enabled introduction of non-traditional study designs and data
`sources into phase 3 testing, a randomized, controlled, clinical trial (RCT) of a size and duration that
`reflect the product and target condition remains the gold standard for determining whether there is an
`acceptable benefit/risk profile for drugs and biologics. For more discussion on clinical trial design,
`including the unique features of RCTs that make such trials more likely to be definitive, see Appendix A.
`
`
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`IV. Case Studies
`
`The methods underlying case selection, as well as a discussion of the limitations of this study, are
`described in Appendix B.
`
`A. Phase 3 Trials Demonstrating Lack of Efficacy in a Promising Experimental
`Therapy
`1. Bitopertin
`
`Product
`Sponsor
`Purpose
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent results in phase 3 trial
`
`Bitopertin
`Roche
`Add-on treatment of schizophrenia
`No
`
`Lack of efficacy
`Despite statistically significant results in reducing the
`symptoms of schizophrenia in phase 2, in phase 3 trials
`Bitopertin failed to improve the negative symptoms of
`schizophrenia.
`
`
`Schizophrenia is a chronic brain disorder in which people abnormally interpret reality and features three
`symptom categories: positive, negative and cognitive. Positive symptoms include hallucinations and
`delusions, while negative symptoms may include social withdrawal, lack of motivation, and reduced
`emotional reactivity. Cognitive symptoms include problems with memory and concentration.
`
`Schizophrenia typically requires lifelong treatment with antipsychotic medications, which come in two
`types: typical and atypical. Both types block the brain’s dopamine pathway, but atypical antipsychotics
`are less likely to cause certain undesired side effects (e.g., movement problems), making them useful for
`long-term management of patients with schizophrenia. However, atypical antipsychotics are still
`associated with undesirable side effects such as weight gain, increased cholesterol, and movement
`disruption.
`
`Like dopamine, glycine is a neurotransmitter that has been implicated in the schizophrenia disease
`process. Over the past years, researchers have noted that people with schizophrenia have a decreased
`level of glycine in their blood and cerebrospinal fluid.[3] Bitopertin increases the availability of glycine
`in the synapse (the connection between nerve cells), suggesting a novel approach in the treatment of
`schizophrenia. A placebo-controlled, double-blind, eight week study randomized over 320 patients across
`66 sites worldwide. The study found a statistically significant 25% reduction in negative symptoms
`among those patients who received the drug compared to those who received placebo.[4]
`
`Three subsequent double-blind, placebo-controlled phase 3 studies evaluated the efficacy and safety of
`bitopertin when added to conventional drugs in patients with negative symptoms of schizophrenia. These
`studies together followed over 1800 patients for one year or more, and measured improvement in a
`patient’s negative symptoms compared to symptoms before treatment began. However, results from two
`of these phase 3 studies found no evidence of a statistically significant improvement in negative
`symptoms over baseline in patients who received bitopertin add-on therapy compared to those who
`
`received placebo.[5, 6]
`
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`2. Brivanib
`
`
`Product
`Sponsor
`Purpose
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent results in phase 3 trial
`
`Brivanib
`Bristol-Myers Squibb
`Treatment of hepatocellular cancer
`No
`
`Lack of efficacy
`Despite promising anti-tumor activity in phase 2 trials, in phase
`3 trials Brivanib failed to improve overall survival of patients
`compared to approved treatment, and demonstrated identified
`unexpected toxicities.
`
`
`Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, occurring in four out
`of five cancers that start in the liver.[7] Treatment options for liver cancer, depending on the stage and
`severity of cirrhosis, include surgery to remove the tumor, embolization to block blood supply to the
`tumor, radiation, and transplantation.[8, 9]
`
`The only FDA-approved drug is sorafenib, which delays tumor growth and improves survival by
`inhibiting certain signals used in cell growth or function.[10, 11] Generally, sorafenib is administered to
`patients who are not candidates for local-directed therapies. To treat those patients who do not respond to
`sorafenib or who have severe side effects related to the drug, brivanib was developed. Brivanib inhibits a
`novel growth factor, in addition to those growth factors targeted by sorafenib.
`
` A
`
` phase 2 trial was conducted in which 55 patients with advanced HCC received a daily dose of brivanib
`in the first-line setting.[12] According to the published report, using computed tomography
`(CT)/magnetic resonance imaging (MRI) measurements of tumor volume, one patient had a complete
`response, three had a partial response, and 24 had stable disease following exposure to brivanib. A
`second cohort of 46 patients received brivanib after failing sorafenib therapy or discontinuing sorafenib
`due to intolerable side effects.[13] Using the same CT/MRI tumor measurement criteria, according to the
`published report, two patients had a partial response and 19 had stable disease following treatment.
`Together the studies showed that brivanib showed antitumor activity, with almost half of participants
`being classified as having stable disease following treatment. The investigators also reported a
`manageable safety profile for patients with advanced HCC.
`
`Several phase 3 RCTs designed to isolate the effects of brivanib, confirmed statistically significant
`antitumor activity, but found no evidence that treatment with brivanib improves the overall survival of
`patients with HCC. One phase 3 study, designed to compare brivanib to sorafenib, randomized over
`1,100 patients with advanced HCC who had no prior drug treatment to receive either brivanib or
`sorafenib.[14] The median overall survival was 9.5 months in the brivanib group and 9.9 months in the
`sorafenib group, and the primary objective (i.e., non-inferiority of survival) of the study was not met. The
`authors concluded that brivanib was “less well-tolerated” than sorafenib, as patients receiving brivanib
`had significantly higher rates of decreased appetite, fatigue, hypertension, nausea, and low blood sodium
`levels. The authors also stated that patients who received brivanib had a more pronounced decline in
`physical function and in role function.
`
`Another phase 3 study randomized 395 patients with advanced HCC in patients who previously received
`sorafenib to receive either brivanib or placebo.[15] This study did not demonstrate a statistically
`significant improvement in overall survival in patients who received brivanib as compared to placebo.
`
`
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`A third phase 3 study investigated whether brivanib could increase survival compared to placebo in Asian
`patients with advanced hepatocellular carcinoma who failed prior treatment with sorafenib; however, this
`study was discontinued by its sponsors and no results are available.[16]
`
` A
`
` fourth phase 3 study compared brivanib as an additional treatment to chemoembolization with those
`receiving only chemoembolization in patients with HCC.[17] However, this trial was terminated early
`after the two other phase 3 studies mentioned above failed to show improvement in overall survival of
`patients with HCC. At termination, this study showed that brivanib had not improved overall survival
`(26.4 vs. 26.1 months).
`
`
`
`
`
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`3. Capsaicin Topical Patch (Qutenza) ‡
`
`
`Product
`Sponsor
`Purpose
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent results in phase 3 trial
`
`Capsaicin topical patch (Qutenza)
`NeurogesX
`Treatment of HIV-associated nerve pain
`Yes, treatment of shingles-associated nerve pain.
`
`Lack of efficacy
`Despite demonstrated efficacy in a related condition and
`positive clinical results in a proof of concept study, in an RCT
`pain control was similar in the Qutenza and control groups.
`
`
`Many HIV patients experience a burning-type of pain, often in the feet or hands, as a result of nerve
`damage. Called HIV-associated distal symmetric polyneuropathy (HIV-DSP), it is the most common
`nerve complication of HIV infection, affecting over 50% of patients.[18-20]
`
`Qutenza is made from capsaicin, the pungent component that makes chili peppers hot. Capsaicin acts on
`certain pain receptors in the skin by desensitizing nerve endings, resulting in analgesia and pain relief. In
`2009, FDA approved Qutenza (8% patch) as a medicated skin patch for pain relief in patients with post-
`herpetic neuralgia, a painful complication following shingles.[21]
`
`Researchers also studied the efficacy of capsaicin in a related intended use, painful HIV-DSP. An open-
`label pilot study assessed the efficacy and safety of NGX-4010 (capsaicin 8% patch) in twelve patients
`with HSV-DSP.[22] Following a single 60-minute NGX-4010 application, these patients were followed
`up for 12 weeks. The majority of these patients reported a significant reduction in pain, prompting the
`researchers to proceed to a large, controlled clinical trial.
`
`In two similarly designed RCTs, 800 patients with HIV-DSP were randomized to receive NGX-4010 or a
`0.04% concentration control patch. This low concentration control patch was considered too weak to
`actually treat HIV-DSP, but strong enough to cause the localized skin reactions that are common with
`capsaicin so that patients would not know to which group they had been assigned. While the initial study
`found significant pain relief with NGX-4010 over 12 weeks of treatment compared to controls, these
`findings were not replicated in the second study.[22, 23]
`
`In 2012, a FDA Advisory Committee analyzed the two controlled trials and agreed that there was no
`substantial evidence of effectiveness for Qutenza in treating HIV-DSP.[24] The Advisory Committee did
`not recommend the approval of Qutenza, and FDA did not approve the drug.[25]
`
`
`
`
`
`
`‡ Product names in parentheses are brand names.
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`4. Darapladib
`
`
`
`Product
`Sponsor
`Purpose
`
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent results in phase 3 trial
`
`Darapladib
`GlaxoSmithKline
`Add-on to a statin for prevention of cardiovascular disease
`complications in patients with prior heart attack
`No
`
`Lack of efficacy
`Despite exciting biomarker evidence in phase 2, in phase 3
`trials darapladib failed to reduce the risk of heart attack or
`cardiac death compared with placebo in patients with chronic
`cardio vascular disease.
`
`
`Cholesterol builds up in blood vessels of patients with cardiovascular disease, hardening the arteries in an
`inflammatory process called atherosclerosis.[26] Atherosclerosis restricts blood flow to the heart muscle,
`causing heart attacks.
`
`Atherosclerosis is thought to be driven by inflammation. Lp-PLA2 is a protein produced by
`inflammatory cells, and blood levels of Lp-PLA2 are thought to predict heart attack risk.[27] A phase 2
`study found both impressively reduced blood levels of Lp-PLA2 and stabilized atherosclerotic plaques in
`patients administered darapladib in addition to a statin (a cholesterol-reducing medication), compared to
`placebo plus a statin.[28] Another phase 2 study indicated that darapladib significantly reduced
`interleukin-6, another cardiovascular inflammatory marker.[29] Mechanistically, then, darapladib seemed
`promising. Human Genome Science CEO Tom Watkins predicted that darapladib was a “blockbuster in
`the making.”[30]
`
`The phase 3 STABILITY trial randomized over 15,000 patients with chronic, stable heart disease to take
`darapladib and a statin or a placebo and a statin, and monitored their cardiovascular outcomes over a
`median of 3.7 years.[31] The STABILITY trial’s primary outcome measures were cardiovascular death,
`heart attack, and hospitalization for acute cardiac events. An additional phase 3 trial, the SOLID-TIMI 52
`trial, randomized over 13,000 patients to receive either darapladib or a placebo within 30 days of a heart
`attack and followed their cardiovascular outcomes over a median of 2.5 years.[32] The study’s primary
`outcome measures were cardiovascular death, nonfatal heart attack, and nonfatal stroke.
`
`Neither study demonstrated benefit. Primary outcome event rates were 10.4% on placebo and 9.7% on
`darapladib in STABILITY, a difference that was not statistically significant. Primary outcome event rates
`in SOLID-TIMI 52 were 15.6% on placebo and 16.3% on darapladib, a lean in the opposite direction that
`was also not statistically significant.[33]
`
`
`
`
`
`
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`5. Dexmecamylamine
`
`Product
`Sponsor
`Purpose
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent results in phase 3 trial
`
`Dexmecamylamine
`Targacept/AstraZeneca
`Add-on treatment of depression
`No
`
`Lack of efficacy
`Despite statistically significant results on measures of
`depression in phase 2, in the phase 3 trial dexmecamylamine
`proved no more effective than a placebo as add-on treatment for
`depression.
`
`First-line therapies for depression include selective serotonin reuptake inhibitors (SSRIs) and serotonin-
`norepinephrine reuptake inhibitors (SNRIs). These drugs increase the amount of serotonin and
`norepinephrine in the brain − neurotransmitters known to have a role in mood.[34]
`
`Researchers have also hypothesized that drugs that activate certain other receptors called nicotinic neural
`receptors, such as the drug dexmecamylamine, could normalize the activity in these receptors and
`potentially be a treatment for depression.[35] In 2009, a phase 2 trial randomized 270 participants on
`SSRIs to receive either dexmecamylamine or placebo over a course of eight weeks. The study found that
`those who took dexmecamylamine improved more on a standard depression scale compared to
`placebo.[36]
`
`With these promising phase 2 results, dexmecamylamine underwent four phase 3 studies in which a total
`of 614 study participants whose depression did not improve with standard SSRI or SNRI therapies were
`randomized to receive dexmecamylamine or placebo while continuing their SSRI or SNRI therapy. After
`eight weeks of add-on treatment, these studies found no difference between the treatment effects of
`dexmecamylamine and placebo in treating depression on standard depression scales in any of the phase 3
`studies.[37-39]
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`6. Exhale Drug-Eluting Stent
`
`Product
`Sponsor
`Purpose
`
`FDA-approved for any indication at
`time of initiation of phase 3 trial
`Problem identified in phase 3 trial
`Divergent result in phase 3 trial
`
`Exhale Drug-Eluting Stent
`Broncus Technologies
`Reduction of shortness of breath in patients with
`emphysema
`No
`
`Lack of efficacy
`Despite statistically significant results on measures of lung
`function and symptoms in phase 2, in the phase 3 trial the
`Exhale Stent failed to improve lung function or symptoms
`in patients with emphysema.
`
`
`Emphysema is a disease in which air sacs in the lungs called alveoli are gradually destroyed. Alveoli
`inflate and deflate with breathing, allowing inhaled oxygen to enter the blood and carbon dioxide to be
`exhaled. In emphysema, the alveoli hyperinflate and eventually rupture, trapping air in the lungs. As a
`result, fresh, oxygen-rich air cannot enter the lungs properly, causing progressive shortness of breath. It is
`frequently caused by many years of smoking and has no cure. Treatment for emphysema is intended to
`relieve symptoms, prevent complications, and slow disease progression. Therapies may involve smoking
`cessation, oxygen supplementation, medications such as bronchodilators (drugs that widen airway
`passages), surgery to reduce lung volume, and lung transplantation.[40]
`
` A
`
` new bronchoscopic procedure was designed to reduce hyperinflation and improve airflow in
`emphysema. Called airway bypass, the procedure involves insertion of a flexible tube called a
`bronchoscope through the mouth so that the airways can be visualized. Once a diseased site is identified,
`a needle pierces the airway wall to create a new passage so that trapped air can escape.[41] A device
`smaller than a pencil eraser called the Exhale Drug-Eluting Stent is then placed in the newly created
`passageway to keep it open. A drug is included in the stent to prevent tissue growth in the new passage.
`A phase 2 study assessed the effects of the Exhale stents in 35 patients with severe emphysema by
`measuring how well their lungs took in and released air and whether their symptoms improved.[42] At
`the 6-month follow-up, there were statistically significant improvements in symptoms and various indices
`of lung function, as compared to baseline, leading researchers to conclude that the stents reduce
`hyperinflation and provide clinical improvement.
`
` A
`
` phase 3 study further investigated whether these Exhale airway stents could improve lung function and
`reduce breathlessness in severely affected emphysema patients.[43] More than 300 patients were
`ra