UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC
`
`Petitioner,
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`
`Patent Owner
`
`Case: IPR2015-01836
`
`Patent No. 7,932,268
`
`DECLARATION OF DANIEL J. RADER, M.D.
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC
`
`Petitioner,
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`
`Patent Owner
`
`Case: IPR2015-01836
`
`Patent No. 7,932,268
`
`DECLARATION OF DANIEL J. RADER, M.D.
`
`
`
`Introduction and Qualifications
`
`1.
`
`1, Daniel J. Rader, submit the following sworn declaration in PTAB
`
`lPR2()15—01835 and lPR2015-01836 in support of the validity of U.S. Patent Nos.
`
`7,932,268 (“the ’268 patent”) and 8,618,135 (“the ’l35 patent”).
`
`I am the named
`
`inventor of the ’268 and ’135 patents.
`
`I have personal knowledge of the facts
`
`stated herein.
`
`2.
`
`I am the Seymour Gray Professor of Molecular Medicine and Chair of
`
`the Department of Genetics at the University of Pennsylvania Perelman School of
`
`Medicine.
`
`I am a medical doctor with over 25 years of experience treating
`
`patients, with a focus on treating patients suffering from lipid disorders.
`
`3.
`
`I received my BA. from Lehigh University (summa cum laude) in
`
`1981, and my M.D from Medical College Pennsylvania (summa cum laude) in
`
`1984.
`
`I completed my internship and residency in internal medicine at Yale—New
`
`Haven Hospital.
`
`1 also completed a fellowship at the NIH National Heart, Lung
`
`and Blood Institute.
`
`4.
`
`I joined the University of Pennsylvania (“Penn”) in 1994 as Director,
`
`Preventive Cardiovascular Medicine and Lipid Clinic, a position i continue to hold
`
`today. As part of my work at the Preventive Cardiovascular Medicine and Lipid
`
`
`
`Clinic, I see approximately 400 patients a year, primarily those with lipid
`
`disorders.
`
`I also lecture and train medical students in the field of lipid disorders.
`
`5.
`
`My research focuses on lipid disorders and related metabolic
`
`disorders.
`
`I have been involved in a number of clinical trial programs testing new
`
`compounds or treatment regimens, including more than 20 clinical trials focusing
`
`on the treatment of lipid disorders, primarily Phase I and II trials.
`
`I have over 400
`
`publications in peer-reviewed journals, treatises, and other scientific and medical
`
`publications.
`
`I have authored the chapter on Lipoprotein Disorders in the last
`
`several editions of Harrison’s Textbook of Medicine, the premier medical
`
`textbook.
`
`6.
`
`I have served as a reviewer of the draft report of the Expert Panel on
`
`Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
`
`Treatment Panel or ATP). ATP III constituted the National Cholesterol Education
`
`Program’s (NCEP’s) updated clinical guidelines for cholesterol testing and
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`management, and became the standard of care for management and treatment of
`
`cholesterol levels after it was released in 2001.
`
`7.
`
`I have received numerous grants, prizes, and awards over my career,
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`including election to the National Academy of Medicine (formerly the Institute of
`
`Medicine), and the American Heart Association’s Clinical Research Prize.
`
`
`
`8.
`
`I serve as Deputy Editor of the journal Arteriosclerosis Thrombosis
`
`and Vascular Biology, on the editorial boards of several other journals, and as a
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`reviewer on dozens of other peer—reviewed journals in the medical research field.
`
`Exhibit 2030 is a complete copy of my C.V.
`
`9.
`
`I have been and currently am a consultant to Aegerion
`
`Pharmaceuticals, Inc.
`
`Background on Lipid Diseases and Treatment
`
`10.
`
`Cholesterol is a type of lipid used by cells in the human body for a
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`Variety of purposes, including to produce cell membranes. Cholesterol is
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`transported in the blood by lipoproteins. Lipoproteins transport cholesterol
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`because it is not soluble in water.
`
`I I.
`
`There are a number of different types of lipoproteins. Low density
`
`lipoprotein (or LDL), Very low density lipoprotein (VLDL), high density
`
`lipoprotein (or HDL), are a few examples. As is apparent in their nomenclature,
`
`lipoproteins are classified by their relative densities. Each type of lipoprotein
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`carries cholesterol, but lipoproteins differ in their relationship to risk of heart
`
`disease. For example, a high level of LDL cholesterol (LDL-C) is associated with
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`an increased risk of arthrosclerosis, or the hardening of human arteries, and can
`
`lead to heart disease.
`
`In contrast, high HDL cholesterol (HDL—C) levels are
`
`
`
`associated with reduced risk of heart disease. Hypercholesterolemia is a condition
`
`characterized by the presence of elevated levels of cholesterol in the blood.
`
`Hypercholesterolemia can be inherited due to mutations in certain genes, and is
`
`associated with increased risk of heart disease.
`
`12.
`
`Treatment for hypercholesterolemia has changed dramatically over
`
`the last few decades. The discovery of compounds effective in treating lipid
`
`disorders has allowed cardiovascular physicians like me to effectively treat patients
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`with elevated levels of cholesterol. Among the most common treatment options
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`for hypercholesterolemia are therapeutic drug classes known as statins
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`(atorvastatin, simvastatin, etc), fibrates (fenofibrate, gemfibrozil, etc), or the
`
`cholesterol absorption inhibitor ezetimibe. In my practice, I regularly treat patients
`
`with hypercholesterolemia with these types of drugs, in addition to a suggested
`
`regimen of a low—fat diet and regular exercise.
`
`Background on HOFH and Its Treatment
`
`13.
`
`Some forms of hypercholesterolemia, however, are more complex to
`
`treat and have required more significant intervention on the part of the physician.
`
`One such disease is homozygous familial hypercholesterolemia (“HOFH”). HGFH
`
`is a serious, rare and life—threatening genetic disease usually caused by mutations
`
`in the low density lipoprotein (LDL) receptor. Total plasma cholesterol levels are
`
`
`
`significantly elevated and markedly premature atherosclerotic vascular disease is
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`the major consequence of the disease.
`
`14.
`
`I first learned to care for patients with HoFH while at the NIH, and
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`since that time I have had on average, in any given year, anywhere between 5 and
`
`8 patients in my clinical practice with HOFH.
`
`15.
`
`For a long time, treatment of HOFH was extremely challenging for
`
`lipid expert physicians like me. HoFH patients are usually treated with statin
`
`therapy, but statins are not all that effective in controlling the cholesterol levels in
`
`the blood or preventing the progression of heart disease. HoFH patients taking
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`statins only experience a 0—20% reduction in lipoprotein levels. Up until recently,
`
`HOFH patients were left with a small number of treatment options.
`
`16.
`
`One such treatment approach involves LDL apheresis, a procedure
`
`roughly analogous to kidney dialysis, which is a physical purging of the blood to
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`remove LDL cholesterol. Patients have the 3-4 hour procedure involving two
`
`intravenous lines every one to two weeks. This procedure is very taxing on
`
`patients and treats the symptoms of the disease as opposed to the disease
`
`mechanism itself, and it is also costly. While apparently beneficial, the apheresis
`
`treatment merely delays the progress of the disease.
`
`
`
`17. Another treatment approach that has been used for HoFH is liver
`
`transplantation. This is generally a treatment of last resort, as it requires lengthy
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`time on a transplant list and involves life—threatening complications and lifelong
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`immunosuppressive therapy.
`
`Discovery of MTP and the Development of MTP Inhibitor Lomitapide
`
`18.
`
`In the late 1980s and early 1990s, during my fellowship at NIH, I
`
`studied the genesis and manifestation of a number of different lipid disorders,
`
`including abetalipoproteinemia, an autosomal recessive disease that is
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`characterized by an absence of plasma proteins that contain apolipoprotein B,
`
`including absence of LDL.
`
`19.
`
`I worked with Dr. Richard Gregg and Dr. John Wetterau, both
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`scientists in the Department of Metabolic Disease at Bristol-Myers Squibb
`
`(“BMS”), on studying a protein called microsomal triglyceride transfer protein
`
`(“MTP”). In one study, we investigated the possibility that a defect in MTP may
`
`be the cause of abetalipoproteinemia. We discovered that MTP is genetically
`
`absent in patients with abetalipoproteinemia and published our findings in the
`
`journals SCIENCE (Absence Ofll/IlCi‘0S0i71al Triglyceride Transfer Protein in
`
`Individuals with Abetalipoproteinemia, SCIENCE No. 258, November 1992, EX.
`
`2056) and Nature (Cloning and gene defects in microsomal triglyceride transfer
`
`
`
`protein associated with abetalzpoproteinaemia, NATURE 365, 65-69, September
`
`1993, Ex. 2052)). This discovery proved that MTP plays a critical role in the
`
`generation of VLDL and LDL by the liver and chylomicrons by the intestine. We
`
`postulated that MTP mediated the transfer of lipoproteins from their site of
`
`synthesis in the endoplasmic reticulum membrane to nascent lipoprotein molecules
`
`within the endoplasmic reticulum. This work suggested that MTP could be a novel
`
`therapeutic target to reduce LDL.
`
`20.
`
`As a result of our work on MTP and its role in abetalipoproteinemia,
`
`Wetterau and Gregg launched a drug discovery program at BMS focused on
`
`developing a class of compounds that could inhibit MTP, otherwise known as MTP
`
`inhibitors. The theory behind the program was that drugs that inhibit MTP might
`
`be able to reduce the production of VLDL and LDL and, in doing so, lead to a
`
`decrease in LDL cholesterol levels.
`
`21. Doctors Wetterau and Gregg introduced me to a compound that was
`
`discovered at BMS and given the name BMS—20lO3 8, now known as lomitapide.
`
`At that time, BMS had already conducted preclinical testing and a Phase I study to
`
`evaluate the safety of varying doses of lomitapide in healthy volunteers.
`
`22.
`
`I learned that in the Phase I clinical trial, C\/145-002, lomitapide was
`
`given to patients at doses ranging from l0 mg/day to 100 mg/day. Patients were
`
`
`
`tested to evaluate adverse events. A nuclear magnetic resonance spectroscopy
`
`(NMRS) method was used to assess and determine the percentage of fat in the
`
`liver. The CV145-002 study concluded that all doses of lomitapide, 10 mg-100
`
`mg/day, resulted in an increase in hepatic fat content. See Exhibit 2078, BMS—
`
`201038 Investigator Brochure General Addendum, CV145—002, Multiple Dose PO,
`
`pp. 47-49, October 1, 1997. Exhibit 2078 is a true and accurate copy of the BMS—
`
`201038 Investigator Brochure General Addendum, which I reviewed during the
`
`Phase II clinical study involving 25 mg/day lomitapide discussed below.
`
`23.
`
`It was discovered in these CV145—002 clinical studies that lomitapide
`
`causes severe gastrointestinal side effects. These side effects included nausea and
`
`diarrhea. See id. In clinical trial CV145—002, a total of 36 volunteers were
`
`randomized 2:1 (active:placebo) in each dose group to receive either 10, 25, 50 or
`
`100 mg/day of Bl\/1S—201038 or placebo for 14 days. Although a time- and dose-
`
`related decrease in LDL—cholesterol was observed, all doses caused gastrointestinal
`
`side effects, with more frequent and severe gastrointestinal side effects at higher
`
`doses. Indeed, in subjects randomized to the 100 mg/day dose, all subjects stopped
`
`treatment by day 8 due to severe gastrointestinal adverse effects including nausea
`
`and diarrhea. Further, the mean hepatic fat content increased from 1.9% at
`
`
`
`baseline to 8.8% at the end of the study for the groups receiving 10 mg, 25 mg, and
`
`50 mg lornitapide for 14 days. See id.
`
`The Phase II Clinical Study Involving 25 mg/day Lomitapide
`
`24. Due to my prior relationship with Dr. Gregg and Dr. Wetterau, I
`
`became involved in clinical testing conducted by BMS on lomitapide. At some
`
`point, I learned that Dr. Gregg and Dr. Wetterau were working on a MTP inhibitor
`
`drug project, and I expressed an interest in working on clinical trials in that
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`program.
`
`I was one of the clinical trial investigators for CV145-009, a Phase II
`
`clinical trial. The primary purpose of the trial was to study the effects of chronic
`
`dosing of BMS-201038 on GI side effects, hepatic fat accumulation (as measured
`
`by NMRS), and LDL—C reduction. The study ran for approximately ten months,
`
`from February to December 1999. See Exhibit 2080, Abbreviated Clinical Study
`
`Report for CVl45—009, January 7, 2002. Exhibit 2080 is a true and accurate copy
`
`of the Abbreviated Clinical Study Report for C\/145-009 that I helped prepare for
`
`submission to the FDA.
`
`25.
`
`CVl45—009 was a double—blind, placebo-controlled study including 76
`
`patients (38 on placebo, and 38 on 25 mg/day lomitapide). We selected a 25
`
`mg/day dose of lomitapide in the study because it had been shown to have good
`
`LDL—lowering efficacy in the prior trial, although it was associated with significant
`
`10
`
`
`
`nausea, vomiting, and diarrhea side effects. All subjects entered into a 4-5 week
`
`single arm placebo period, and then the 38 patients randomized into the active
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`treatment drug arm received 25 mg of lomitapide daily for 4 weeks. See id.
`
`26.
`
`Preliminary analysis of the Phase II data revealed that lomitapide
`
`showed significant efficacy in reducing cholesterol in humans. In CVl45-009, it
`
`was shown that LDL cholesterol decreased by 65% in patients who received 25 mg
`
`BMS—20lO38 over four weeks. See id.
`
`27. However, lomitapide 25 mg/day also produced significant and
`
`limiting side effects. Nine patients, nearly 25%, discontinued the study due to
`
`adverse events while receiving lomitapide, several after only 3-4 days of being on
`
`lomitapide. No subjects discontinued due to any adverse events while taking
`
`placebo. See id. The majority of patients on the lomitapide active treatment arm
`
`reported frequent GI side effects. The reported adverse events included
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`gastrointestinal related events (nausea, diarrhea, abdominal pain, flatulence, weight
`
`loss, etc.). Id. There were a total of 105 adverse events in 35 of 38 patients who
`
`received lomitapide in the study. Id.
`
`28.
`
`In addition, there was a significant increase in hepatic fat content in
`
`patients treated with 25 mg/day of lomitapide as compared to placebo. Absolute
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`fat content increased by 20.6% in just 4 weeks of 25 mg/day lomitapide, reflecting
`
`l l
`
`
`
`a 300% (or 3-fold) increase in the amount of hepatic fat. In contrast, there was
`
`very little change in absolute fat content (O.3—0.9%) in the patients treated with
`
`placebo. See Ex. 2080.
`
`29.
`
`In View of the Phase II study results in CVl45—009, specifically the GI
`
`side effects and increased hepatic fat, BMS discontinued further clinical
`
`development of BMS20l038 due to safety concerns. See id.
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`Donation and Use of BMS-201038 at Penn for HOHF
`
`30. Despite the major GI side effects and increase in hepatic fat with
`
`lomitapide seen in study CV145—OO9, I believed that the dramatic clinical efficacy
`
`in LDL—C reduction of lomitapide made it a viable molecule for potential .J.rther
`
`development for use in patients with HoFH, where the unmet medical need was
`
`substantial. However, I knew that the gastrointestinal side effects would need to be
`
`better controlled and that the hepatic fat increase would be a safety issue.
`
`3 l.
`
`Soon after the termination of lomitapide development by BMS, I
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`approached BMS with the idea of donating the molecule to Penn so that we could
`
`test it in patients with HoFH, for which there were no efficacious cholesterol-
`
`lowering treatments.
`
`32. My proposal—-—-that a major drug company donate a compound to a
`
`research university for potential further development when the compound was
`
`12
`
`
`
`known to have major issues with tolerability and safety—was unconventional.
`
`Indeed, BMS did not want to be held liable if some devastating event were to
`
`happen as a result of the further clinical development of the compound. BMS
`
`considered the proposal for more than a year before agreeing to move forward. On
`
`Aug. 21, 2002, at my request, and following a number of discussions with
`
`scientists at BMS and administrators at Penn, BMS transferred lomitapide to Penn
`
`for use in the development of a potential treatment for severe hypercholesterolemia
`
`and HoFH. Exhibit 2001, Donation Transfer Agreement.
`
`I am not aware of any
`
`other examples of such drug company donations of drug candidate molecules to
`
`research universities that have taken place before or after. Exhibit 2001 is a true
`
`and accurate copy of the Donation Transfer Agreement that I received from
`
`Bristol—Myers Squibb. See id. at 30-44.
`
`Forced—Titrati0n Dosing of Lomitapide in Patients with HOFH
`
`33.
`
`I knew that lomitapide had shown efficacy in reducing levels of LDL—
`
`C in humans. I believed that the mechanism of action, through inhibition of MTP,
`
`might be particularly effective in HOFH patients because it bypassed the genetic
`
`defect that caused HOFH, namely the lack of the LDL receptor, and, as a result, it
`
`was a reasonable strategy to use to lower LDL—C levels in HoFH patients.
`
`l3
`
`
`
`34.
`
`I posited that one way that its gastrointestinal side effects and even
`
`liver fat accumulation might be reduced is by starting at a very low dose and
`
`slowly titrating the dose upward over time.
`
`I theorized that the particular
`
`mechanism by which lomitapide caused the gastrointestinal side effects and
`
`accumulation of hepatic fat may make a forced titration dosing regimen successful
`
`in overcoming these liabilities of the drug. Specifically, I reasoned that if we
`
`started at a very low dose of lomitapide that caused no gastrointestinal side effects,
`
`the cells in the intestine and the liver may be able to adapt to the MTP inhibition by
`
`increasing their ability to burn or dispose of fat before being overloaded with lipid
`
`(the cause of the GI side effects and hepatic fat accumulation). Once the intestine
`
`and the liver were adapted to this low dose, an increase in the dose would be better
`
`tolerated and induce yet further adaptation, allowing yet a further increase in dose.
`
`In this way, I hypothesized that the intestine and the liver would acclimate to and
`
`better tolerate the drug at higher doses needed for effective LDL—C reduction.
`
`I
`
`knew of no drug candidates, including other MTP inhibitors, at the time in which
`
`such side effects were known to be reduced through such an approach. However, I
`
`was quite familiar with lomitapide by this time and had given the approach a lot of
`
`thought; because there was such a significant unmet medical need for new
`
`therapies for patients with HoFH, it seemed worth testing my hypothesis.
`
`I4
`
`
`
`35.
`
`Thus, the invention provides a method of treating patients suffering
`
`from hypercholesterolemia while reducing the side—effects of the treatment, by
`
`administering to patients an amount of lomitapide effective to treat
`
`hypercholesterolemia using a dosing regimen that achieves effective reduction in
`
`LDL—C levels while reducing and/or eliminating the side—effects associated with
`
`the use of lomitapide.
`
`I developed a protocol for a small clinical trial that would be
`
`the first evaluation of the safety, tolerability and pharmacodynamics of lomitapide
`
`in patients with HOFH. In November 2002, I submitted documentation to the FDA
`
`requesting amendment of IND 50,820 to include the new indication of HOFH.
`
`36.
`
`By at least December 2, 2002, I had developed a clinical protocol for
`
`a Phase I/II open—label, dose—escalation study to determine the safety, tolerability
`
`and efficacy of the MTP inhibitor lomitapide in patients with HoHF, which was
`
`designed for acclimation and better tolerance of the drug response at higher doses.
`
`See Exhibit 2077, December 2002 Final Clinical Trial Protocol Submitted to IRB.
`
`The objective of the study was to determine the safety, dosing regimen, and
`
`efficacy of MTP inhibitor lomitapide in patients suffering from HoFH. The
`
`primary objective was to evaluate the safety and tolerability of a dosing regimen,
`
`given as an initial, sub-therapeutic dose and then force~titrated up for an additional
`
`three doses, each dose for 4 weeks, for a total for a period of sixteen weeks.
`
`IS
`
`
`
`Exhibit 2077 is a true and accurate copy of the final clinical trial protocol that I
`
`submitted to the Investigational Review Board (IRB) at Penn. My lomitapide trial
`
`was funded by the Doris Duke Charitable Foundation.
`
`37.
`
`The clinical trial protocol that I developed called for starting patients
`
`at a very low (sub—therapeutic) dose and force—titrating them to a therapeutic dose.
`
`“Forced titration” is a dosing regimen that includes a mandatory dose increase up
`
`to a final target dose. As mentioned above, the rationale for the forced—titration
`
`method was to gradually acclimate the intestine and the liver to the inhibition of
`
`MTP by starting with a very low dose of the compound that would have no GI side
`
`effects but also little or no efficacy in lowering LDL—C levels). Because I knew
`
`from prior studies that even 10 mg/day of Iomitapide caused side effects, I knew
`
`that we needed to start much lower than that if we wanted to evaluate whether this
`
`tolerance—building titration regimen would work.
`
`I accordingly selected a dose of
`
`0.03 mg/kg every day for the initial dose, which would mean the average patient
`
`received approximately 2 mg of the compound in the first dose. See Ex. 2077.
`
`38.
`
`I wanted to target the highest dose at somewhere between 50-100 mg
`
`per day, reasoning that such a dose would be required for suff1cientLDL~C
`
`reduction in patients with HOFH. Based on an average patient weight of
`
`approximately 70 kg, I decided to target 1.0 mg/kg as the highest dose at the end of
`
`16
`
`
`
`the forced dose titration. In the Phase I trials, the majority of subjects taking 50
`
`mg/day had major GI side effects, and in those taking 100 mg/day all subjects had
`
`withdrawn from treatment within 7 days due to intolerable Gl side effects.
`
`Furthermore, in the Phase II trial, even 25 mg/day was associated with a high rate
`
`of major GI side effects (and a major increase in hepatic fat after 4 weeks of
`
`treatment). Therefore, I knew full well that achieving a dose of 50-100 mg per day
`
`and having patients tolerate this dose would be extraordinarily challenging.
`
`39.
`
`The other doses were selected by increasing each dose by a half—log
`
`unit, approximately tripling the dose at each dose level, so that the dosing regimen
`
`had the following LOUT doses: 0.03 mg/kg/day, 0.1 mg/kg/day, 0.3 mg/kg/day, and
`
`1.0 mg/kg/day. A ‘/2—log dose escalation was selected because it allowed patients
`
`to receive a dosage regime ranging from known sub—therapeutic to known-
`
`therapeutic ranges in four dose levels. Each patient would start with the initial
`
`dose for four weeks and would then be force—titrated up through at least three more
`
`doses, each given for a four—week period. We selected a four—week period per dose
`
`to give the intestine and liver enough time to acclimate and adjust to each dose
`
`before the increase to the next dose. We used a mg/kg/day dosing strategy to
`
`account for the fact that people of substantially varying ages and weights would be
`
`included in this very small study of only 6 HoFH patients. However, 1
`
`l7
`
`
`
`contemplated that an approved drug might use a mg/day dosing strategy, as this is
`
`more conventional and would be easier to administer.
`
`40.
`
`Unlike other clinical trials, such as dose escalation or dose finding
`
`trials, we were not trying to identify a single, effective and well—tolerated dose for
`
`each patient. Instead, we were evaluating a force—titration regimen that required
`
`patients to receive an initial very low, sub—therapeutic dose followed by at least
`
`three substantially increased doses of lomitapide to confirm that this forced-
`
`titration regimen would reduce side effects. This objective was clearly stated in
`
`the IRB—approved protocol, “8.4 Dose Selection”:
`
`Because this study will include adolescents of varying body size and weight,
`the dose will be based on weight rather than a fixed dosing. BMS—20l 038
`[lomitapide] has been studied in phase I trials at doses as low as 5 mg in
`adults. Therefore, we chose a very low dose (0.03 mg/kg body weight) for
`this trial, fully expecting this dose to be safe but also unlikely to be
`efficacious with regard to cholesterol lowering. There are at least two major
`reasons for starting at a dose of 0.03 mg/kg body weight. First, because
`adolescents will be included, to ensure a high level of safety and tolerability
`at the initial starting dose in this study. Second we hypothesize that the
`steatorrhea and lipid liver accumulation may be reduced by the initiation of a
`very low dose of the drug with a gradual up titration. The remaining three
`doses were chosen by calculating ‘/2-log units of the previous dose. We
`picked an upper dose of 1 mg/kg based on data from the animal study by
`Wetterau, revealing greater than an 80% reduction in LDL—C using 10
`mg/kg, with an ED50 of 1.9 mg/kg.
`
`Exhibit 2077 (emphasis added).
`
`l8
`
`
`
`41. My hypothesis that a forced titration with lomitapide would improve
`
`patient tolerance of the drug was met by skepticism by certain of my colleagues at
`
`BMS. They felt a dose of 1 mg/kg could not be administered in a tolerable
`
`fashion.
`
`I was certainly pleasantly surprised when all six patients were able to
`
`titrate to and tolerate well a dose of 1 mg/kg. The scientists at BMS who were
`
`intimately familiar with and had developed this compound, lomitapide, told me
`
`that they had never thought about dosing it in this manner, with a forced—titration
`
`regimen starting at a low dose. Before my proof—of—concept trial, they believed it
`
`to be unlikely, based on all the phase I and II data, that we could get up to these
`
`high doses in view of the fact that even 10 mg/day caused side effects, and doses of
`
`25 mg caused a significant percent of patients in our prior study to discontinue due
`
`to G1 side effects.
`
`42.
`
`On or about March 30, 2003, I received a communication from the
`
`IRB noting that my protocol was reviewed and approved on March 18, 2003. Ex.
`
`2079. Attached as Exhibit 2079 is a true and accurate copy of the approval
`
`notification that I received from Joseph R. Sherwin, Ph.D., Executive Chairman of
`
`the IRB.
`
`43. We proceeded to enroll patients in the trial shortly after approval. The
`
`lomitapide forced dose titration trial was conducted at Penn under my direction and
`
`l9
`
`
`
`supervision. We enrolled a total of six HOFH patients in the clinical trial. The
`
`body weight of the patients enrolled in the study ranged from 56 to 85 kg, with the
`
`average patient weighing somewhere between 62.5 and 74.9 kg. Each of the six
`
`patients successfully completed the trial and received all four forced titrated doses
`
`of lomitapide per the clinical protocol. The first patient received the first dose
`
`during the week of June 30, 2003, and the study was complete on January 18,
`
`2004. See Exhibit 2082, February 9, 2004 Memorandum Summarizing Data from
`
`6 Enrolled Patients. Attached as Exhibit 2082 is a true and accurate copy of a
`
`memorandum that I prepared summarizing the data from the six enrolled patients.
`
`44. During the course of the trial, as the Principle Investigator, I received
`
`reports from patients regarding their condition and, in particular, their tolerance to
`
`each titrated dose of lomitapide.
`
`I also received and reviewed interim results as
`
`each patient completed the trial. By the end of October 2003, two of the six
`
`patients had completed the clinical trial. Those patients were not only able to
`
`complete the trial, taking up to 1 mg/kg/day of lomitapide (approximately 60-70
`
`mg/day of lomitapide), but they successfully stayed on each dose for the four—week
`
`duration set forth in the protocol. This was astounding to me, in view of the fact
`
`that prior clinical experience with lomitapide indicated that doses between 50—l00
`
`20
`
`
`
`mg/day could not be taken by patients for more than a few days in view of the
`
`tolerability issues, particularly the severe gastrointestinal side effects.
`
`45. Attached as Exhibit 2081 is a true and accurate copy of an interim
`
`clinical study summary that I prepared for and submitted to the Doris Duke
`
`Charitable Foundation on or about October 2003. In the report, I stated:
`
`We have initiated a phase I/II clinical trial of an MTP inhibitor in patients
`with homozygous FH. Six patients have been enrolled and two have
`completed the dose escalation treatment phase of the protocol. Tolerability
`has been surprisingly good, and there have been no major safety issues; a
`few patients have had increased liver function tests that were dealt with by
`reduction in dose as per protocol. Excitingly, we have seen major reductions
`in plasma cholesterol levels, though we await more data before reporting on
`the efficacy results.
`
`Ex. 2081 at l.
`
`46.
`
`By January 8, 2004, 3 patients had completed the study; a fourth was
`
`finishing the following week; the fifth and sixth patients were finishing soon
`
`thereafter. Attached is a true and accurate copy of an e—mail I sent on January 4,
`
`2004 to Dr. Peter Adamson, the Chief of Clinical Pharmacology and Therapeutics
`
`at the Children’s Hospital of Philadelphia, regarding one of the patients in the
`
`study. In that e—mail, I note that “3 patients have completed the study, and the
`
`fourth comes of the drug early next week, and the 5th and 6th [I come off late next
`
`week. Overall, we are very encouraged by the tolerability of the drug and anxious
`
`2l
`
`
`
`to fully evaluate the efficacy regarding cholesterol lowering.” Ex. 2005 at 9. The
`
`results were “encouraging” because of the tolerability of the drug. Specifically, at
`
`least three patients had finished the study now, and, as I noted above, had been
`
`able to tolerate the lmg/kg dose—a dose that was double or higher than the dose
`
`(25 mg/day) found intolerable in the prior Phase I BMS studies.
`
`47.
`
`By January 18, 2004, all the patients had completed the forced-
`
`titration dosing regimen trial for lomitapide. See Exhibit 2082. Based on the data
`
`we gathered and I had reviewed, we concluded that the forced dose titration
`
`regimen I developed resulted in a significant decrease in gastrointestinal side
`
`effects, allowing patients to achieve higher doses than they could have taken had
`
`they originally been placed on such a high dose. In addition, I was pleased to note
`
`that the increases in hepatic fat in this trial were quantitatively substantially less
`
`than in the previous Phase II trial of 25 mg/day for only 4 weeks. This
`
`demonstrated to me that my forced—dose titration regimen reduced hepatic fat
`
`accumulation, as I had hypothesized.
`
`48.
`
`These trial results further demonstrated to me that forced-titration
`
`dosing regimens in which the dose increased at rates less than the 3-fold dose
`
`increase of the clinical trial also could result in a significant decrease in
`
`gastrointestinal side effects and increased tolerance of the drug. Specifically, a
`
`22
`
`
`
`more gradual introduction of the patient to the drug, such as a 2-fold dose increase,
`
`provides the patient with a greater opportunity to acclimate to the drug. If
`
`tolerance for lomitapide is achieved using a forced—titration dosing regimen having
`
`3-fold dose increases, as was demonstrated in the clinical trial, tolerance is
`
`expected for a forced—titration dosing regimen having 2—fold dose increases.
`
`I also
`
`concluded that the dosing intervals of 4 weeks used in the clinical trial could be
`
`shortened or lengthened, to adjust to the individual patients’ abilities to acclimate
`
`to each dose.
`
`49.
`
`In addition, the reduction in percentage of non-HDL and total
`
`cholesterol was significant for each HOP}-I patient. On average, non-HDL
`
`cholesterol was reduced by between approximately 30% and 60% at the 1.0 mg/kg
`
`dose, and total cholesterol was reduced by between approximately 31% and 60% at
`
`that dose. In addition, apoB was also reduced by between approximately 15% and
`
`55% at the 1.0 mg/kg dose. See Exhibit 2082.
`
`50.
`
`Prior clinical trial experience with lomitapide demonstrated that such
`
`a reduction in non-HDL and total cholesterol would not have been achieved or
`
`expected because patients were unable to tolerate doses higher than 50 mg/day for
`
`more than seven days, and as a result of our titration regimen, they were able to
`
`23
`
`
`
`tolerate doses higher than 50 mg/day and even up to approximately 80 mg/day for
`
`at least four weeks.
`
`51.
`
`The results of the dose-—escalation study were published in the New
`
`England Journal of Medicine. Ex. 2004, Cuchel, et al., Inhibition ofMicrosomal
`
`Triglyceride Transfer Protein in Familial Hypercl/zolesterolemia, N ENG J MED
`
`356:l48-56 (2007).
`
`U.S. Patent Nos. 7,932,268 and 8,618,135
`
`52.
`
`The Penn Center for Innovation filed a provisional patent application
`
`disclosing and describing my invention and naming me as the inventor with the
`
`US. Patent Office on March 5, 2004 (the March 2004 Provisional Application No.
`
`60/550,915).
`
`I executed a Power of Attorney for the provisional application on or
`
`about May 24, 200
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