`
`New Directions in Drug
`Development: Mixtures,
`Analogues, and Modeling
`
`Joxun A. GALLOWAY, MD
`
`Success in modern medical research is acheived when basic and clinical information
`about a given disorder converges, either intentionally or fortuitously, with the
`availability of technology or other means to design and apply interventions for the
`disorder in question. A prime exampleis the discovery ofinsulin andits replacement
`in patients with IDDM in 1923. Seven decades later, the focus of diabetes manage-
`mentis on improvement in metabolic controlto forestall the chronic complications
`of the disease and improvethe quality oflife of patients with the disease. Metabolic
`control is being addressed through the development of insulin analogues using
`sophisticated techniques to understand ‘the chemistry of insulin and to modify it
`using rDNA technology. The objective of these efforts is to simulate normalinsulin
`secretion with subcutaneously injected agonists. Quality-of-life needs are being
`addressed with delivery devices, insulin mixtures, and insulin analogues. Although
`none of these improvements parallel the discovery of insulin, they do provide an
`optimistic outlook for patients with diabetes mellitus.
`
`hen the progress made in the
`treatment of diabetes mellitus
`during the past two decades is
`considered, the needs and challenges for
`the final decade of this century become
`evident.For instance, the introduction of
`patient self-monitoring of blood glucose
`and laboratory measurementof glycosy-
`lated hemoglobincalled attention to the
`failure of commonly used regimens to
`normalize blood glucose. The shortcom-
`ings of these regimens led to and facili-
`
`tated the use of conventional intensive
`insulin treatment programs and CSII or
`pumps. Acceptance of CSII has been
`based largely on the belief, against which
`no effective counter can be found, that
`optimizing blood glucose controlis most
`efficiently achieved by simulating normal
`insulin secretion.
`The use ofintensified regimens
`has been limited by three significant fac-
`tors. First, until very recently there has
`been a paucity of incontrovertible evi-
`
`SPOSHSHOHOSSHSSHSSHSHHHSHSHHSHHHHSHHHOHHSHHSHSHSHOHSHHHHHHHHHHHHHHHHHEOOED
`
`From theLilly Research Laboratories, Eli Lilly, Indianapolis; and the Departmentof Medicine,
`Indiana University School of Medicine, Indianapolis, Indiana.
`Address correspondence and reprint requests to John A. Galloway, MD, Lilly Research
`Laboratories, Mail drop, 2128, Lilly Corporate Center, Indianapolis, IN 46285.
`IDDM, insulin-dependent diabetes mellitus; NIDDM,non-insulin- dependentdiabetes mel-
`litus; CSII, continuous subcutaneousinsulin infusion; DCCT, Diabetes Control and Compli-
`cations Trial; HPI, human proinsulin; IGF-I, insulin-like growth factor-I; BHCP, biosynthetic
`human C-peptide; HGP, hepatic glucose production; CV, coefficient of variation.
`
`long-term
`dence, based on controlled,
`clinical
`trials,
`that lowering blood glu-
`cose will forestall development of the
`chronic complications of diabetes. For-
`tunately,
`the results of the DCCT (1)
`point unmistakably to the importance of
`glycemic control in preventing the pro-
`gression of retinopathy, nephropathy,
`and neuropathy in patients with IDDM.
`Although the DCCT results are also rel-
`evant to NIDDM, thefindingsof the U.K.
`Prospective Diabetes Study (2), which
`will be available in 1994, should be par-
`ticularly instructive regarding the bene-
`fits and risks of glycemic control
`in
`NIDDM patients. It should be pointed
`out, however, that based on random, un-
`controlled trials and anecdotal experi-
`ence, the impressions are extantthat gly-
`cemic controlis very important in IDDM
`and useful in NIDDM. Thesenotions will
`be supported bytheresults of the afore-
`mentioned controlledclinical trials. Sec-
`ond, glycemic control, particularly in in-
`dividuals with IDDM, imposes enormous
`burdens on the patient's life-style and
`quality oflife. Thus, those who choose to
`self-monitor their blood glucose are in a
`constantstate of vigilance with respect to
`their well-being in general, and the pos-
`sibility of hypoglycemia in particular.
`For this reason, interventions or treat-
`ment
`improvements that
`the person
`without diabetes may perceive as trivial
`or marginal maybe highly useful to the
`patient with diabetes. Third, factors re-
`lated to compliance and theinability or
`unwillingness of patients to make the
`necessary quality-of-life sacrifices un-
`doubtedly constitute the major impedi-
`ment to normalization of blood glucose
`in most patients (3). Nonetheless,
`ic is
`clear that certain properties of commer-
`cially available insulin preparations pre-
`clude the simulation of normal insulin
`secretion and its metabolic benefits. For
`this reason, the principal manufacturers
`of insulin are engaged in vigorous com-
`petition to produce insulin agonists that
`can more closely replicate endogenous
`insulin secretion orits effects.
`
`16
`
`DiABETES CARE, VOLUME 16, SUPPLEMENT 3, DECEMBER 1993
`
`MSNExhibit 1029 - Page 1 of 8
`MSNv. Bausch - IPR2023-00016
`
`

`

`
`Galloway
`
`
`
`
`Figure 1—Seruminsulin and blood glucosere-
`sponses of normal subjects to a standard diabetic
`diet (30 kcal/kg) given as 2/7 with each main
`meal and 1/7 at bedtime. From Galloway and
`Chance (4). © by Elsevier.
`
`IRIpUimi insulin
`Plasma“‘Free”
`
`IRIpUimi 024 681012
`
`“Free”
`
`t
`Insulin
`Injected
`
`injected
`
`Time (hours)
`
`20
`16
`Time (hours)
`
`24
`
`28
`
`32
`
`36
`
`tion of basal insulin secretion, which is
`usually in the range of 5-10 U/ml
`(30-60 pM)(Fig. 1), is to restrain HGP
`in the postabsorptive state. Because fast-
`ing blood glucose has an extremely high
`correlation with HGP and is the base on
`which prandial glycemia is added during
`the next 24h, simulation of this phase of
`insulin secretion is highly desirable, par-
`ticularly in individuals with NIDDM. In
`Lilly clinicaltrials of patients with IDDM
`as well as NIDDM, thesingle blood glu-
`cose value that correlated best with gly-
`cohemoglobin was the value taken after
`an overnight fast and collected at
`the
`studysite (4). The function of the other
`componentof endogenousinsulin secre-
`tion,
`the meal-stimulated phase,
`is to
`promote disposal of ingested nutrients,
`principally glucose, into the periphery.
`As indicated in Fig. 1, this phase, which
`is characterized by a rise in serum hor-
`moneto concentrations of 80-120 U/ml
`Figure 2—Mean serum free insulin responses
`(480 to 720 pM), is exquisitely sensitive
`of 6 IDDMpatients to ultralente pork insulin
`to, and therefore synchronized with, the
`(0.8 Ufkg subcutaneously). Patients were main-
`rise in blood glucose in response to
`tained euglycemic with a glucose clamp tech-
`meals. In addition, once the meal glyce-
`This paper reviews the rationale
`nique. A: Responsesto dosing at 0, 24, and 48 h.
`for and methods used to develop specific
`mia has subsided,there is a promptre-
`B: The response over 36hto a single dose at time
`turn to the basal or postabsorptivelevel.
`insulin analogues, and describes how
`0. Courtesy ofJ.E. Gerich.
`The physiological importance of proper
`certain insulin mixtures and analogues
`mayhave a positive effect on the quality
`timing of the premeal insulin dose has
`been clearly demonstrated in both
`oflife of patients with NIDDMas well as
`those with IDDM.
`sulin, 0.2 U/kg subcutaneously, do not
`NIDDM(5) and IDDM (6).
`As suggested above, presently occur until 3 to 4hafter injection and
`
`NORMALINSULIN SECRETION
`available insulins or insulin regimens are
`are present as long as 8 h. The adminis-
`AND ITS SIMULATION BY
`generally incapable of simulating the
`tration of regular insulin by CSII would
`seem to be an ideal method for mimick-
`INJECTED ““INSULINS”’ — As sug-
`basal or meal-stimulated components of
`normal insulin secretion. For instance, as
`gested above, the mostefficient method
`ing normal insulin secretion. However,
`indicated in Fig. 2, even ultralente pork
`for achieving metabolic control in IDDM
`Fig. 4 shows that patients with IDDM on
`insulin, which presumably would behave
`CSII treated with basal-bolus programs
`patients is to simulate normal endoge-
`have higher than normal serum insulin
`nous insulin secretion.It is therefore ap-
`like ultralente human insulin, is not truly
`propriate to identify the essential com-
`a basal insulin, as it has peaks that occur
`concentrations throughout the day and
`ponents of endogenousinsulin secretion
`night, probably as a result of the long-
`15-20hafter injection. With respect to
`the meal-stimulated component, al-
`acting nature of the premeal bolus infu-
`in the nondiabetic individual, review the
`deficiencies of presently available insulin
`though the serum hormoneprofile and
`sions of neutral regular insulin.
`The discussion above has focused
`preparations, and indicate what might or
`glucodynamic effects of neutral regular
`should be doneto simulateit orits effects
`on the acute benefits of simulating nor-
`human insulin, which is the fastest-
`with insulin agonists manufactured by
`acting commercially available insulin,
`mal insulin secretion on glucose metab-
`would be expected to simulate that of
`olism. However, because conventional
`rDNAtechnology.
`insulin treatmentusually results in aver-
`As indicated in Fig. 1, normal
`normal insulin secretion, Fig. 3 shows
`insulin secretion consists of basal and
`that it does not. Hereit is clear that the
`age serum insulin concentrations 2.-4
`times normal (7), and hyperinsulinemia
`meal-stimulated components. The func-
`peak effects of neutral regular humanin-
`
`Diabetes CARE, VOLUME 16, SUPPLEMENT 3, DECEMBER 1993
`
`MSN Exhibit 1029 - Page 2 of 8
`MSNv.Bausch - IPR2023-00016
`
`

`

`New directions in drug development
`
`
`
`Humyiin Riv
`
`wee asc
`
`(mg/min)
`GlucoseConsumption
`
`
`Figure 3—Pharmacodynamic responses of 6
`normalvolunteer subjects to neutral regular hu-
`man insulin rDNA (Humulin R) 0.2 U/kg by
`bolus intravenous infusion and by subcutaneous
`injection. Subjects were kept euglycemic with a
`Biostator. Note that the peak effect of subcuta-
`neous Humulin occurs after 3 h and that glucose
`is still being infused at 8 h after the subcutaneous
`injection. From Galloway (8). © by the American
`Diabetes Association.
`
`may bea significant risk factor for coro-
`nary heart disease (8,9), an important
`long-term advantage to simulating nor-
`mal insulin secretion may be reduction
`in chronic hyperinsulinemia.
`
`METHODS TO DEVELOP INSULIN
`ANALOGUES — With the deficien-
`cies of conventional insulins described,
`the discussion now tums to methods
`used in the development of improved
`
`
`
`Serum“FreeInsulin”
`
`—— csi
`~~~ Conventional insulin treatment
`
`(uU/m)&’888
`DSSs 7
`
`9 11
`
`13 15 17:19 2123 1
`Clock Time (hours)
`
`35 7
`
`Figure 4—Mean serum free insulin concen-
`trations in 5 patients with IDDM whoreceived
`pork insulin either by CSII or with conventional
`twice-daily regimens of NPHandneutralinsulin
`at 0730 and 0430. With CSII, meal boluses were
`given at 0700 and 1100 and at 1630 and 2130.
`Basalinsulin was 50-60% ofthe total daily dose.
`From Galloway and Chance (4). © by Elsevier.
`
`(It
`“insulins,” or insulin analogues.
`should be noted that thefirst analogue of
`human insulin was beef insulin, which
`has been in use for 70 years.) Basically,
`two approaches can beused in develop-
`ing insulin analogues. Thefirstis to iden-
`tify an “insulin” that has been found to
`have attractive pharmacological proper-
`ties and adapt it for human use. An ex-
`ampleofthis processis the selection and
`development of HPI (10). Studies in an-
`imals and humans demonstrated that
`pork proinsulin was a soluble, interme-
`diate-acting insulin agonist
`that ap-
`peared to berelatively hepatospecific.
`Thus, in proinsulin there seemed to be
`the possibility of developing an interme-
`diate-acting insulin agonist that was free
`of protamine or excess zinc, and with
`effects on the liver that might be
`uniquely efficacious in NIDDM,a disor-
`der characterized by excessive HGP
`amongotherdefects (8,11). Accordingly,
`HPI was produced by rDNA technology
`and clinical studies were undertaken.
`Pharmacology studies in dogs,
`normal volunteer subjects, and patients
`with NIDDM demonstrated that, com-
`pared with insulin for equivalent sup-
`pression of HGP,
`the effect of HPI on
`peripheral glucose disposal was less than
`that of insulin;
`that is, consistent with
`the finding with pork proinsulin, HPI
`was relatively hepatospecific (10). Al-
`though the differences between HPI and
`insulin were clear and distinct
`in all
`studies,
`they were quantitatively un-
`impressive. However, an unexpected
`pharmacological finding was that the in-
`trapatient CV in serum hormoneconcen-
`trations and glycemic response was
`~50% of that observedwith insulin. De-
`spite these apparent pharmacological
`benefits, controlled clinicaltrials failed to
`demonstrate better glycemic control in
`the HPI-treated group (10).
`Of noteis that as the multicenter
`clinical trials were nearing completion, a
`report occurred indicating that HPI was
`more active when injected into the ab-
`domen than into the arm or thigh, sug-
`gesting the possibility of partial uptake
`
`by the portal vein with direct access to
`the liver. The potential
`importance of
`this finding is evidenced by another pre-
`liminary report that showed that HPI was
`equipotentwith humaninsulin when ad-
`ministered intraperitoneally (12). Al-
`though injection sites were random in
`the multicenter trials, at one center
`where the investigator used just the ab-
`dominalsite, HPI was found to be supe-
`rior to insulin (13). However, before an
`appropriate studyto evaluate the impor-
`tance of injection site on the bioactivity
`of HPI could be undertaken, a potentially
`significant
`toxicity issue arose. Specifi-
`cally, in one study of insulin-naive pa-
`tients, in which ~70 were randomized to
`insulin and 70 to HPI, there were 6 myo-
`cardial infarctions, including 2 deaths,in
`the HPl-treated group after
`1 year of
`treatment, but none in the insulin-
`treated group (10). This finding, com-
`bined with the failure to demonstrate
`improved metabolic control with HPI
`versus insulin across the multicenter
`clinical trials, led to the suspension of
`development of HPI. Although a causal
`relationship between the use of HPI and
`the cardiovascular events was not estab-
`lished, it should be noted that because
`the hypoglycemic potency of HPL was
`only 4.0 to 5.7 U/mg, serum hormone
`concentrations in HPl-treated patients
`were exceedingly high—up to 1000
`times normal. Nonetheless, experience
`with HPI combined with an expanding
`literature linking the possible mitogenic
`effects of hyperinsulinemia to atheroscle-
`rosis (9,10,14) has clearly added theis-
`sues of mitogenicity,
`including both
`atherogenicity and, by implication, car-
`cinogenicity, to the developmental agenda
`for insulin analogues. Indeed,
`in vitro
`studies have suggested that certain insulin
`analogues have greater effects (binding to
`vascular smooth muscle and/orcell prolif-
`eration) than human insulin or HPI (15).
`Becauseofthe attractiveness of an
`intermediate-insulin agonist that would
`be soluble and contain no excess zinc,
`researchers proceeded with the develop-
`mentof a normal metabolite of HPI, des
`
`18
`
`DuaseTes CARE, VOLUME 16, SUPPLEMENT 3, DECEMBER 1993
`
`MSN Exhibit 1029 - Page 3 of 8
`MSNv. Bausch - IPR2023-00016
`
`

`

`
`Galloway
`
`
`
`Figure 5—Metabolites or intermediates formed by the conversion of HPI to insulin. The des 64,65 HPI (dPRO) form (shown upper left) is the result
`of a split between 65 and 66 (or Al and C65), followed by removal of the Arg and Lys residues at positions 64 and 65. From Galloway etal. (10).
`®by the American Diabetes Association.
`
`64,65 HPI (des 64,65 HPI, or “dPRO”)
`(Fig. 5). Data generated in humans with
`this analogue are very preliminary,
`whereas studies in dogs (16) suggest that
`des 64,65 HPIis intermediate acting and
`has a hypoglycemic potency comparable
`to that of insulin. Therefore, serum hor-
`mone concentrations after administra-
`tion of des 64,65 HPI should besignifi-
`cantly lower than those seen after HPI.
`The fact that animal studies comparing
`des 64,65 HPI with insulin and HPI (17)
`have disclosed that the hepatic extraction
`coefficient and hepatic half-life of the des
`64,65 analogueis closerto that of insulin
`than HPI reduces the likelihood that the
`des 64,65 analogue will be hepatospe-
`cific. On the other hand, the consistent
`absorption kinetics seen with HPI would
`be expected with des 64,65 HPI.
`The second method for develop-
`ing improved insulins is that of com-
`puter modeling, which is usually per-
`
`formed by a computational chemist. This
`is a multicomponenttechnique that uses
`a computer programmed with physico-
`chemical and biological information de-
`veloped on insulin over several decades.
`Computer modeling allows the chemist
`to generate virtually infinite iterations of
`the possibilities of intramolecular rela-
`tionships to explain or extrapolate the
`behaviorof insulin or its analogues un-
`der various conditions without actually
`undertaking arduous and expensive pre-
`clinical or clinical
`tests (18-20). This
`use of a computer can generate vital
`information conceming stability, self-
`association, and pharmacological activ-
`ity, including receptor binding, mitoge-
`nicity, and immunogenicity.
`Modeling (computational chem-
`istry) is usually used in conjunction with
`experimental chemistry. An example is
`the developmentof the Lys,Pro analogue
`of humaninsulin, a fast-acting insulin
`
`analogue that has been synthesizedin the
`Lilly Research Laboratories (5,21). For
`instance, the long-acting nature of neu-
`tral regular insulin (described above) has
`been understood to beattributedto its
`tendency to self-associate into dimers,
`tetramers, hexamers, and polymers, with
`absorption of subcutaneously injected
`insulin occurring onlyafter it has disso-
`ciated into a less aggregated form (6). It
`was notedthat IGF-I has manystructural
`similarities to insulin in the COOH-
`terminus of the B-chain but does not
`self-associate. Therefore, attention was
`focused on an importantdifference be-
`tween the two polypeptides B28 and B29
`on the B-chain, where the sequence is
`Pro,Lys for insulin and Lys,Pro for IGF-I
`(22). Using molecular modeling, with
`help from a Cray 2 supetcomputer,
`it
`was possible to visualize and compre-
`hend the dynamics of the intramolecular
`behaviorthat results in self-association.
`
`Diaberes CARE, VOLUME 16, SupPLEMENT 3, DECEMBER 1993
`
`MSNExhibit 1029 - Page 4 of 8
`MSNv. Bausch - IPR2023-00016
`
`19
`
`

`

`New directions in drug development
`
`Lys (B28), Pro (B29) — HumanInsulin
`
`A-CHAIN "
`
`2
`
`RRL Muse
`4018 46
`47
`18
`
`19 2
`
`Figure 6—Lys(B28), Pro(B29)-Human insulin. This analogue is identical to human insulin except
`at positions B28 and B29 where the sequenceof the two residues has been reversed and arein the same
`order as in IGF-I, a polypeptide which doesnotself-associate. Courtesy of R.E. Chance.
`
`It was ascertainedthat the reversal of the
`Pro,Lys sequence in the B28—29 region
`of insulin (Fig. 6)
`increased the free-
`energy barrier to self-association. Mod-
`eling also predicted that the Lys,Lys an-
`alogue wouldbeclose to native insulin in
`self-association and showed that the po-
`sition of the Pro in the sequence was
`critical to controlling self-association. As
`indicated first
`in studies in dogs (23)
`(Fig. 7), in normal humans (24) the ab-
`sorption and glucodynamiceffects of the
`Lys,Pro analogue of humaninsulin,
`Lys,Pro human insulin, are significantly
`more rapid in onset that those of human
`insulin rDNA (Fig. 6). Of interest is the
`fact that the slight change in the struc-
`ture of human insulin had an insignifi-
`canteffect on affinity for IGF-I receptors
`or insulin receptors on placental mem-
`branes (21,25). Thus,
`it would appear
`that the Lys-Pro analogue and otherfast-
`acting analogues (6,26) will have the
`pharmacological properties necessary for
`producinga rapid, timely, and adequate
`increase in serum hormone concentra-
`tion to promote disposal of ingested nu-
`trients efficiently. Table 1 shows the pro-
`
`file of an ideal fast-acting insulin
`analogue.
`An issue not addressed aboveis
`that of immunogenicity. The importance
`of lack of immunogenicity is based on
`studies in patients with and without an-
`tibodies to animal insulins, which have
`demonstrated that antibodies may delay
`the effect of injected insulin (27). This
`being the case,if a fast-acting analogueis
`immunogenic, antibodies could be
`formed that would delay and therefore
`
`Table 1—Features of an ideal fast-acting
`insulin analogue
`
`Primary metabolic function
`Promotion of peripheral glucose disposal
`Specifications
`Time-action profile:
`Onset <1 h after subcutaneous
`
`injection
`Duration of <4h
`Metabolic >>> mitogenic effects
`Nonimmunogenic
`Chemically stable
`Mixable with long-acting insulin and
`insulin analogues
`
`110
`= 100
`90
`3 60
`
`2=
`
`i 708 6a)
`g 40
`10
`
`0~
`
`@ LYS28PRO2Insulin, NOB
`4 Noutrol regular Hi rDNA
`150 180 210 240 270
`
`60 -30 0
`
`30
`
`90
`60
`Minutes
`
`120
`
`Figure 7—Serum insulin and blood glucose re-
`sponses of normal fasted anesthetized male bea-
`gle dogs after subcutaneous administration of 0.1
`U/kg of neutral regular humaninsulin rDNA or
`the Lys,Pro analogue of human insulin. From
`Galloway et al. (23). © by Elsevier.
`
`20
`
`DiaBetes CARE, VOLUME 16, SupPLEMENT 3, DECEMBER 1993
`MSNExhibit 1029 - Page 5 of 8
`MSNv. Bausch - IPR2023-00016
`
`neutralize the pharmacodynamic effectit
`was designed to deliver. One can only
`speculate on the potential importance of
`the proimmunogeniceffects of episodic
`exposure, a sine qua non offast-acting
`analogue use, and the anti-immunogenic
`effects of reducing thesize of the peptide
`that might stimulate antibody formation.
`As indicated above, based on the
`pharmacokinetic shortcomings of ul-
`tralente insulin and the suspension of
`trials with HPI,a significantclinical need
`exists for a basal insulin agonist. Table 2
`lists the features identified as being de-
`sirable in the ideal long-acting insulin
`analogue. Novo-Nordisk has reported an
`analogue (NovoSol basal) (28) with ab-
`sorption and duration of action appar-
`ently substantially slower and more con-
`sistent than that ofultralente beef insulin
`and without peaks. However,
`the ab-
`sence of additional information on this
`analogue precludes further discussion.
`Becauseof the extraordinary challenge of
`
`~co
`868888
`
`
`
`SerumInsulin(zU/m))
`
`@ LYS28PROZInaulin, NoB
`& Noutral rogulor Hi 1DNA
`
`
`
`30
`
`90
`60
`Minutes
`
`120
`
`150 180 210
`
`240 270
`
`5 0
`
`-60-30 0
`
`

`

`Table 2—Features of an ideal long-acting
`insulin analogue
`
`Primary metabolic function
`Suppression of HGP
`Specifications
`Time-action profile:
`Onset >4 h after subcutaneous
`injection
`Duration of >24h
`Once-daily injection
`Low intrasubject CV of response
`Metabolic >>> mitogenic effects
`Hypoglycemic potency = or > human
`insulin
`Nonimmunogenic
`Chemically stable
`Mixable with short-acting insulin and
`insulin analogues
`
`developing an analogue to meetthe spec-
`ificationslisted in Table 2, it seems un-
`likely that such a compound will be
`available in the immediate future. In ad-
`dition,
`the possibility of developing a
`long-acting analogue that could simulate
`the pulsatility of normal- basalinsulin se-
`cretion (29) seems exceedingly remote.
`
`trol with this device has not been shown
`to be superior to that achieved with in-
`tensive conventional
`treatment. None-
`theless, the convenience afforded to pa-
`tients by pen injectors is undeniable.
`The availability of insulin mix-
`tures, especially 70% NPH and 30% reg-
`ular insulin, has providedpatients with a
`convenient methodfor taking two insu-
`lins and has obviatederrors inherent in
`the multiple-step procedure ofself-
`mixing. The useof premixturesofinsulin
`may or may not improve metabolic con-
`trol. Bell et al. (40) demonstrated better
`control in patients with NIDDM using
`prefilled insulin mixtures. However,in a
`study of patients with IDDM, Corcoran
`and Yudkin (41) failed to demonstrate an
`advantage in metabolic control. The in-
`creasing acceptance in the marketplace
`of premixed insulins suggests that
`the
`convenience they offer is clearly satisfy-
`QUALITY-OF-LIFE ISSUES —
`ing a patient need and supports the in-
`The above discussion has focused on
`troduction of mixtures with other pro-
`portions of NPH and regular insulin
`how improvements in the pharmacoki-
`netics and/or pharmacodynamics of in-
`(e.g., 50/50, 80/20).
`sulin preparations might result in im-
`Finally,
`insulin analogues have
`the potential to improve the quality of
`proved metabolic control, which,
`in
`life of patients with diabetes (6). For in-
`turn, may reduce the complications of
`HUMAN C-PEPTIDE — A substance
`stance,
`it has been proposed that
`the
`diabetes. No less importantto the patient
`with diabetes are interventions and tech-
`fast-acting insulin analogues will have
`prepared by rDNA (30) that has attrac-
`niquesthat will improve his or her qual-
`tive physiological properties, as opposed
`two important benefits. First, because of
`their rapid absorption, analogues can be
`ity oflife. Undoubtedly, the most impor-
`to HPI, which has desirable features but
`given substantially closer to meals than
`tant tool in recent years for improving
`only in pharmacological doses, is BHCP.
`Although C-peptide is cosecreted from
`conventional neutral regular insulin,
`the quality oflife of patients with diabe-
`whichtypically must be administered 30
`tes mellitus has been self-monitoring of
`normal B in quantities that are equimolar
`to 45 minute before a meal to match the
`with insulin and is present in the circu-
`blood glucose. Two other developments,
`pharmacodynamic effect with the pran-
`however, also deserve mention: pen in-
`lation, until recently, no physiological
`dial glucose rise. Second, the rapid de-
`jectors and premixtures of NPH andreg-
`function had been assigned to this pep-
`cline in serum hormoneconcentrations
`ular insulin. The availability of these
`tide. For this reason, the C-peptide de-
`and effect of the fast-acting insulin ana-
`penlike devices, which accurately deliver
`ficiency that accompanies insulin defi-
`insulin (regular alone or in combination
`logues may decrease the frequency of
`ciency in IDDM has been regarded as
`
`having no consequence. Recently, inves- with NPH) fromaprefilled cartridge,
`between-meal hypoglycemia.
`Indeed,
`give patients a simple, convenient
`this mayalso result in a major reduction
`tigators in Stockholm reported that acute
`infusions of BHCP to mimic normal
`method for delivering insulin without
`of the nearly threefold increase in the
`frequency of serious hypoglycemia, as
`plasma concentration of C-peptide in
`havingto carry insulin vials (36). These
`C-peptide-negative patients with IDDM
`devices undoubtedly have improved
`compared with patients with only mod-
`reduced glomerular hyperfiltration with-
`quality of life for patients by facilitating
`erately to poorly controlled diabetes
`out affecting renal plasma flow (1). Ina
`multiple-dose insulin therapy (37,38).
`(42).
`Although occasional reports indicate that
`preliminary report, this group indicated
`that the addition of BHCP, administered
`use of pen injectors improves metabolic
`for 30 days by CSII in amounts equimo-
`control (39), in general, metabolic con-
`
`Galloway
`
`lar with insulin in patients with IDDM,
`reduced glomerular hyperfiltration and
`capillary leakage (measured by vitreous
`fluorophotometry) and possibly im-
`proved metabolic control (32). In vitro
`studies have shown that BHCP promoted
`the transport of 3-O-methylglucose in a
`dose-dependent mannerin muscle spec-
`imens taken from healthy volunteer sub-
`jects (33) but not
`in muscle from
`NIDDM patients (34). These findings, if
`confirmed, could have important impli-
`cations for treatment of patients with
`IDDM. However, because C-peptide
`concentrations usually are normal orel-
`evated in patients with NIDDM (35),
`C-peptide replacement
`therapy is un-
`likely to be of benefit. Nonetheless,if the
`findings in IDDM are confirmed,serious
`consideration will be given to adding
`BHCPtoinsulin for patients with IDDM.
`
`CONCLUSIONS — The perpetual in-
`teraction of new basic andclinical infor-
`
`Diasetes CARE, VOLUME 16, SUPPLEMENT 3, December 1993
`
`MSNExhibit 1029 - Page 6 of 8
`MSNv. Bausch - IPR2023-00016
`
`

`

`New directions in drug development
`
`mation on diabetes, modern technology,
`and patients’ quality- of-life needs is pro-
`ducing a slowly rising spiral of improve-
`mentin the treatment ofand outlook for
`patients with diabetes mellitus. It is cer-
`tain that these positive trends will con-
`tinue. Their absolute impact at a given
`future date, however, remains uncertain.
`
`thank James E.
`Acknowledgments— 1
`Shields, PhD, and Richard D. DiMarchi, PhD,
`for their careful review of the manuscript;
`Janet S. Hanshew andJanet H. Potvin, PhD,
`for helpful suggestions andediting ofthe ar-
`ticle; and Karen L. Dosch for typing the final
`drafts of the manuscript.
`
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