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Bioterm Pharmaceutical Ltd.

UPDATED on 12/20/2017

https://www.verywell.com/pregnancy-4014665.

UPDATED on 4/20/2015

BioTerm already possess:

• The formulas for both situations: Preserving Pregnancy and Expatiating pregnancy. Both Formulas were already tested in the Lab and were reviewed by serious scientific advisory and were found sound.
• The basic design for the injection mechanism.
• BT has patented the use of Inducterm and preventrum, its human enzyme Collagenase product, which is a natural substance that is critically involved in the labor process. Inducterm & Preventrum used in local injections or cervical suppositories, degrades or maintains membranes and cervical tissues. Prevents or accelerates labor. To date, no side effects have been observed.
• Furthermore, the molecule is synthesized by genetic engineering, making its production safe and consistent. Ideal blood and tissue levels for labor induction are already known, making dosage trials shorter and the possibility of success higher. Potentially, it may be used for induction or prevention of labor in various medical situations, i.e., not only for post-term deliveries, but also in other gynecological procedures.
• Since the drug has been used previously for other indications (dermal wound cleaning) and is currently undergoing clinical trials for other bone and joint indications, extensive pre-clinical and phase II clinical trials for OB/Gyn indications by BT will not be necessary, thus saving substantial amounts of time and capital.

General scientific background

The initiation of labor involves two interdependent processes dilatation of the cervix (with or without membrane rupture) and the triggering of rhythmic contractions of increasing amplitude and frequency. The principal mechanism whereby the fetus maintains its immunological privileges in the uterus is the tight regulation of cytokine levels at the maternal–fetal interface. Progesterone has an important role in the maintenance of pregnancy by modulating antibody production and reducing the production of proinflammatory cytokines by direct and indirect action on immune cells. It is now believed that, at term, spontaneous uterine activity occurs secondary to modulation of the progesterone receptors in the decidua, amnion and cervix, creating a ‘functional’ progesterone withdrawal which allows the release of proinflammatory cytokines. This process of cervical ‘ripening’ precedes the myometrial contractions of labor by weeks. The most likely pathway for the initiation of preterm labor involves premature decidual activation occurring in the context of an occult upper genital tract infection, with release of cascades of proinflammatory cytokines in the cervix and the choriodecidual interface. Cytokines such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNFα) and IL-6 increase the production of matrix metalloproteinases (MMP-1, MMP-8 and MMP-9), which digest collagen type 1 in the extracellular matrix to induce cervical softening and effacement. This process is also thought to weaken the cervical mucus plug, further reducing the ability of the cervix to resist infection, with possible weakening and rupture of the membranes. Increasing myometrial contractility in the presence of subclinical infection probably involves the macrophage system and its cytokines, such as TNFα and IL-1, which stimulate prostaglandin production in the amnion and decidua. These proinflammatory cytokines have also been immunolocalized to leukocytes in the myometrium, resulting in an increase in the production of prostaglandins and oxytocin. This process of cervical effacement commences weeks before preterm labor occurs and can be recognized by shortening of the cervix on transvaginal ultrasound examination. Confirmatory evidence of this process is the finding that a cervical length < 15 mm is associated with a 22% incidence of significant elevation in amniotic fluid MMP-8 levels.

BioTerm product is based on the finding that during labor and until the end of the delivery, the amount of collagen in the cervix is usually significantly reduced. The collagen in the cervix and lower segment of the cervix is degraded as a result of an increase in the amount of collagenase (molecular weight of approximately 70,000 Dalton). The ratio of undissolved hydroxyproline in collagen to the total amount of protein in collagen generally is about 0,75 in women not in pregnancy. Such ratio is generally about 0.3 in women in active labor. This is an indication of the degree of degradation of collagen caused by collagenase in the lower segment of the cervix and the uterus in women in or nearing labor. Reduction in the amount of collagen results in a softening or ripening of the cervix, which allows dilation thereof and thereby facilitates birth.

Collagen is a naturally occurring fibrous protein found in humans and animals. Collagen is one of the most abundant proteins in mammals and comprised various naturally occurring amino acids, e.g. glycine, alanine, proline and hydroxyproline. The uterine cervix contains collagen which is degraded by the collagenase enzyme, particularly collagen type I and collagen type III. EP-A-543 476 discloses the use of interleukin-8 for inducing cervical ripening.

Induction of Labor

Various methods can be employed to determine whether or not the cervix is in a “favorable condition”. One such method is by means of measuring the Bishop score of the cervix of a woman in labor, e.g. to determine whether or not the cervix of a woman has reached a favorable condition of softness of ripeness prior to delivery. However, on occasion induction of labor is required when the cervix is in an “unfavorable condition”, and maintains the cervix in a firmer unripened condition which does not readily allow dilation thereof. Furthermore, access into and from the uterus is not necessarily limited to natural childbirth. For example, in various clinical situations, access into the uterus is required for purposes of curettage, while termination of pregnancy requires passage through the cervix of an embryo of foetus. It will be appreciated that in such cases, the cervix is unlikely to be in a favorable condition. It will be appreciated that the extent to which dilation of the cervix is required for childbirth is greater than what generally is required for early termination of pregnancy or curettage.

By reducing the collagen content (since it has been found that in case of the “unfavorable condition”, the collagen content has not been reduced by natural biological processes) process in the female body. Thus administrating the effective amount of a composition comprising collagenase to a female will create the needed effect.

In other words, collagenase is used in a method comprising including an effective amount of collagenase in the preparation of a composition suitable for softening or ripening the uterine cervix of female mammals, for inducing labour in female mammals and also for terminating pregnancy in female mammals.

By stimulating, enhancing of increasing the collagenase activity or amount of collagenase in the cervix of pregnant females, the cervix can be softened or ripened when desired, e.g. prior to termination of pregnancy or induction of labour. The collagenase administered may augment any naturally produced collagenase present in the cervix and/or stimulate the production of naturally occurring collagenase in the cervix.

Naturally, routine experimentation can be used to optimize the effective amount of collagenase required to be used in a substance or composition in accordance with the invention. The substance or composition comprising the collagenase could be administered in various forms and by various routes.

Prevention of Premature Labor

Preterm delivery, with its collateral effects on neonatal mortality, short- and long-term infant morbidity and astronomical healthcare costs, is the foremost problem in modern obstetrics. In spite of advances in obstetric care, the rate of prematurity has not decreased over the past 40 years and in developed countries there has been an increase, possibly as a result of assisted reproductive technology (ART) programs. The current frequency of PTBs is 12.5% in the USA and 5–9% in European and other developed countries4. Spontaneous PTB, with or without prior rupture of the membranes (PPROM), accounts for two-thirds of PTBs, with the remainder occurring as a result of obstetrically indicated preterm delivery due to conditions such as pre-eclampsia and intrauterine growth restriction (IUGR)4.

Prematurity remains a leading cause of neonatal morbidity and mortality in developed countries, accounting for 60–80% of deaths of infants without congenital anomalies. Greater attention is now being focused on very PTBs < 32 weeks’ gestation, because, although this group represents only 1–2% of all deliveries, it accounts for about 60% of perinatal mortality and nearly 50% of all long-term neurological morbidity5. Short-term morbidities associated with early preterm delivery include respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, patent ductus arteriosus and retinopathy of prematurity. Long-term morbidities include cerebral palsy, cognitive defects and social and behavioral problems. This recital of the well-known complications of early PTB does not convey the devastating effects on the parents of a severely damaged child, the daily disruption to normal life, the anxieties and stress, the constant visits to hospital, or the sense of isolation and social exclusion from other parents with normal children6. Nor does it convey the long-term pain and suffering and frustrated lives of the children who are affected, usually with multiple disorders7.

In purely financial terms, the short- and long-term costs of caring for PTBs are staggering. Short-term hospital costs in the USA, over the first year of life of short gestation/low birth-weight infants, were estimated to be $ 5.6 billion and estimates for the annual societal economic burden in the USA was at a minimum of $ 26.2 billion in 200510. A UK study using a decision-analytic model estimated the costs to the public purse of children born prematurely up to 18 years of age to be £2.95 billion ($ 4.6 billion). The model calculated that a hypothetical intervention that delayed PTB by 1 week across all gestational-age categories would reduce these costs to £1.95 billion. Judgment on the success or otherwise of any preventative treatment should focus on deliveries occurring before 33 completed weeks of gestation, when the morbidity and mortality rates are high and the incremental cost of care to 18 years of age, compared to a term survivor, is almost $ 100 00011.

BioTerm has invented an innovative injection mechanism into a lip of the cervix as a liquid, (preferably by injection into both lips) as the current preferred method of administration. The concentration range will be of 10-15 I.U. per gram of cervical tissue.

Current development – In order to move forward with this important breakthrough a few additional steps are needed among them:

• Finalizing the Injection mechanism.
• Testing for various efficacy amounts.
• Testing in Sheep. For efficacy and safety

• Assuming positive results these steps will provide the BioTerm with the ability to team up with big Pharma almost of its choosing. Thus setting the conditions in which production could be set in Israel.

 

Induction of Labour

There is a general confusion and disagreement about the safety and appropriate use of labor induction. As a result, use of induction varies widely from one caregiver or hospital to the next. Even the results of research studies on labor induction provide conflicting answers. Some common practices today are:

C-section – Reality is that the only practical option is an elective C-section. This probably occurs for many reasons going from lack of time of the doctor to follow-up a procedure requiring time and dedication, to the lack of understanding on the part of the pregnant women and family if the induction fails and sometime later a C-section becomes necessary. Even if cervix conditions are favorable, and there is a good prior history of vaginal deliveries only few obstetricians are committed to try a vaginal delivery.

Medications:

• Oxytocin:The body naturally produces the hormone oxytocin to stimulate contractions. Pitocin and Syntocinon are brand name medications that are forms of oxytocin that can be given through an IV at low doses to stimulate contractions. An intravenous infusion of oxytocin is used to induce labor and to support labor in case of difficult parturition. This drug is registered in many countries to suppress premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this purpose (ritodrine, salbutamol, and terbutaline). Researchers found that induction and augmentation of labor with oxytocin was an independent risk factor for unexpected admission to the NICU lasting more than 24 hours for full-term infants. Augmentation also correlated with Apgar scores of fewer than seven at five minutes. Oxytocin use may not be as safe as once thought.
• Pitocin – is a synthetic formof the naturally occurring hormone. Oxytocin is a liquid medication that stimulates contraction pattern. Pitocin is diluted with a standard saline solution an introduced into the body by IV drip. The medication is regulated on a medication pump. Pitocin is an attempt to minimize complications and to help mimic normal labor as much as possible. The Pitocin drip will normally be turned up every hour until you have reached the contraction pattern that they are looking for you to have. This may be different for each woman. Some practitioners turn the Pitocin up really quickly and others go more slowly. Some of this will depend on how you respond to the Pitocin and how well your baby responds to Pitocin. The problems with Pitocinis that the desired effect is also very dangerous – the induced force of the contraction may decrease uterine blood flow (This is also done during a natural contraction, but not for as long of a period and not as close together.). Therefore, reducing the oxygen to the baby. Using pitocin also requires continuous electronic fetal monitoring. This is because fetal distress is more common with pitocin use and needs to be detected if it occurs. Pitocin can be the beginning domino in the domino effect. The IV, the infusion pump, and the continuous monitoring will confine most mothers to bed, decreasing her ability to deal with the contractions naturally. With the more painful contractions a mother is more likely to need pain medication, such as an epidural anesthesia. (http://www.acog.org/About-ACOG/News-Room/News-Releases/2013/Study-Finds-Adverse-Effects-of-Pitocin-inNewborns)
• Prostaglandin: is a hormone-like substance that causes cervix to ripen, and which may stimulate contractions. The slow-release pessary, Propess, looks a bit like a small tampon. Vaginal prostaglandin is the most commonly recommended way to induce labour. However there is a very small risk that using vaginal prostaglandins may cause uterus to become overstimulated or hyper stimulated. This may reduce the oxygen supply to the baby. If this is the case, medication will be given to stop or slow down contractions. The advantages of taking oxytocin that it can initiate labor which might not have started on its own and it can speed up the pace of labor. The concerns: Labor can progress too quickly, causing contractions to become difficult to manage without pain medication. Oxytocin may need to be discontinued if contractions become too powerful and close together.

Mechanical methods –which were the first methods developed to ripen the cervix or induce labor can be found. Among them there are different types of catheters (including the Folley catheter) and laminaria introduced in the cervical canal or extra-amniotic space. Mechanical methods were never totally abandoned but extensively replaced by pharmacological methods in the last decades. There is a recent trend of reintroducing it for clinical use because of some advantages and availability of sterile devices, controlling one of the principal contraindications, infection. Potential advantages of mechanical methods in comparison with pharmacological ones include easy conservation, low cost and less side effects. Nevertheless, there is contraindication of its use in pregnant women with low inserted placentas, with premature rupture of membranes and as it was already stated there could be higher incidence of puerperal infection and discomfort among users of these methods. When compared with oxytocin as a standalone agent, mechanical methods also reduce the risk of performing a C-section. Among the methods employed are

• Uminaria – One of the mechanical methods is Uminaria (Laminaria digitata or Laminaria japonica), a seaweed that after dehydration acquires a hygroscopic ability. Prepared in the shape of a baton it can be used as a cervical dilator. Laminaria use has been described since the Eighteenth Century but its use was abandoned due to the risk of infection. In the 70’s with the new sterilization techniques its use was resumed with satisfactory results. Mechanism of action depends on the mechanical effect obtained through radial expansion which because it occurs slowly does no lesion the muscle fibers of the cervical canal. It also has a biochemical effect for it causes a foreign body reaction and local release of prostaglandins. Utilization time of laminaria may vary from 12 to 24 hours, nevertheless, because its maximum capacity of diameter increase occurs within approximately 12 hours it would be required to reassess the cervix during this period and replace the laminaria for another larger one when necessary. More recently clinical use for this purpose has been replaced by other more effective methods.
• Catheter – The use of a catheter in the extra-amniotic space occurred the first time in 1853 by Krause at that time a rigid catheter was used. After that the Foley catheter, a flexible catheter was used to induce labor in women with unripe cervices with 94% of success.At times this method is still described like the modified Krause method and because it is more acceptable and less risky it has been more utilized that the classically described method. The mechanism of the Foley catheter is based on the presence of a mechanical factor acting continuously on the cervix and in addition because it separates the chorion from the decidua releasing local prostaglandins.
• Artificial of the membranes (AROM) -When the bag of water (amniotic sac) breaks or ruptures, production of the hormone prostaglandin increases, speeding up contractions. Some health care providers might suggest rupturing the amniotic membrane artificially. A sterile, plastic, thin hook is brushed against the membranes just inside the cervix causing the baby’s head to move down against the cervix, which usually causes the contractions to become stronger. This procedure releases a gush of warm amniotic fluid from the vagina. Advantages include: Labor may be shortened by an hour; The procedure allows the amniotic fluid to be examined for the presence of meconium, which may be a sign of fetal distress; The heart rate can be monitored with direct access to the baby’s scalp.
• Extra-amniotic infusion is associated to the Foley catheter for labor induction has traditionally been used. Compared with the infusion of saline solution and PgE2there was a shorter permanence time with the balloon, less induction time and oxytocin need in the group using prostaglandin, however with no difference related to the type of delivery. As for the method described above, there are still many controversies. A study comparing misoprostol, Foley catheter and the association of the Foley catheter with prostaglandin E2 indicated no difference between these three methods of cervical ripening/labor induction. There was only a greater incidence of tachysistole with lower oxytocin need in the group using misoprostol but with no difference related to the type of delivery. Therefore, there is no need to use extra-amniotic solution injections (in this case prosta-glandin E2) for results are similar whether or not it is used. Some of advantages of the Foley catheter compared to other methods of cervix ripening and labor induction are: low cost, easy to use and principally the possibility of using it in women with prior C-sections. In Brazil its use is still rather restricted and there are no results of effectiveness studies already published.
• A Membrane weep – A membrane sweepis when a midwife or doctor sweeps their finger around the opening of the cervix. This action can stimulate labor. This procedure may be offered if the pregnancy is full-term and waiting for labor to start. During a sweep, the Dr carefully separates the membranes that surround the baby from the cervix to stimulate the production of prostaglandin. If the cervix is not dilated enough to do a sweep, they may stretch or massage the cervix instead. It can be uncomfortable if the cervix is difficult to reach, and may need to have several membrane sweeps before labor starts.

Labor prevention

Contrary to Labor induction there are very few intervention methods that support early Labour prevention. While modern medicine has made great strides in treating premature babies, there have been few advances when it comes to preventing or stopping preterm labor. In fact, the American College of Obstetricians and Gynecologists (ACOG) recently stated that the effectiveness of common treatments for preterm labor—such as bed rest, pelvic rest (abstaining from sex), and increased fluids—is not known.

“We don’t understand the mechanism of preterm birth enough to come up with safe, effective ways to prevent it,” says Ronald Gibbs, M.D., chair of the department of obstetrics and gynecology at the University of Colorado Health Sciences Center, in Denver. “Strategies so far have focused on trying to stop preterm labor, but that’s like closing the barn door after the horse is out.”

There is one very controversial drug:

Makena (hydroxyprogesterone) is a form of progestin, a man made form of a female hormone called progesterone. Makena is used to lower the risk of premature birth in a woman who has already had one premature baby. This medication will not stop premature labor that has already begun. Makena is not for use in women who have had more than one pregnancy. Makena may also be used for purposes not listed in this medication guide.

Softening of the cervix is associated with biological changes in the chemistry\biology manifested in changes such as: the glycosaminoglycan (GAG) concentration occurring before parturition (Uldbjerg et al., 1983; Cabrol et al., 1987).Since the early 80ies it was it was widely accepted that the cervix plays an active role in the process of labor and is not just under the control of uterine contractions. Whereas the onset of uterine contractions seems to be a sudden event, the process of cervical ripening is slow under normal conditions and appears to start early in the course of pregnancy (Uldbjerg et al., 1983). Preterm premature cervical ripening may be responsible for preterm birth and its prevention would require precise knowledge about the intimate mechanisms of cervical maturation. As this understanding matured and the research into it continued It was demonstrated that:

• One of the most relevant findings were that during labour several substances who have great importance change. Some of them are: increase in total GAGs; a relative decrease in sulphated GAGs (especially dermatan sulphate); an increase in hyaluronic acid (Danforth et al., 1974; von Maillot et al., 1979; Cabrol et al., 1985; Osmers et al., 1993) and tissue water content (Uldbjerg et al., 1983; Cabrol et al., 1985).
• These changes precede the more dramatic events associated with collagenase activity observed during labour (Uldbjerg et al., 1983).
• It was also observed that among Progesterone is necessary to maintain pregnancy and to prevent preterm birth in many mammalian species. Contrary to these animal species (i.e. sheep or rat), parturition in humans is not preceded by a drop in maternal plasma progesterone concentration (Anderson et al., 1985; Challis and Olson, 1988).

The theory of progesterone withdrawal was progressing it was further found that myometrial changes in hormone and/or receptor concentration (Ferré et al., 1978; How et al., 1995) and antiprogesterone compounds have demonstrated their ability to induce cervical ripening (Carbonne et al., 1995) and to favor labor induction (Cabrol et al., 1990a, 1991; Frydman et al., 1992).

• A supplementary material was found during the 90ies. Elastin was found to be critical to the structural integrity of a variety of connective tissues.
• Only a select group of enzymes has thus far been identified capable of cleaving insoluble elastin. (J Biol Chem.1991 Apr 25;266(12):7870-5.) This research found that that one or more of the metalloproteinases released by alveolar macrophages has elastase activity.

Dr. Shamir Leibovitz and his team continued this line of research. The result is BioTerm (BT). The company has patented the use of Inducterm and Preventrum, its human enzyme Collagenase product as well as Cytokine il1beta that stimulates locally the production of collagenase. These substances are natural substance and they are critically involved in the labor process.

The end product – will use Inducterm and Preventrum as a local injection by BT new device.

The general novelty of BioTerm – By stimulating, enhancing or increasing the collagenase activity or the amount of collagenase in the cervix of pregnant females, the uterine cervix can be softened or ripened when desired.

The Functional Novelty – The Inducterm\preventrum and the Cytokine will be injected locally to the Cervical resulting in membrane and cervical tissues natural degradation that will accelerates labor. The injection mecanisem is a new practical novelty by BioTerm. This combined solution provides a vastly superior efficacy compared to currently available products and is part of the trend of natural biological drugs\supplements. To date, no side effects have been observed.

Entry barriers by competitors are the patents and the future patents that company plans on future developments and updates of its future products

SOURCE

בקשה לתמיכה בתכנית מו”פ01/06/2015 – 31/05/2016

 

 

Revolution in treatment for pre-term labor and induction of labor that affect millions of women and newborn each year!

Bioterm Pharmaceuticals Ltd. is the developer of novel therapeutics for the treatment and prevention of pre-term labor and for the induction of labor that cause severe morbidity of millions of newborn worldwide.

The Company has patented the use of two molecules, its Preventerm molecule for the prevention of pre-term labor (PCT, pending) and its Inducterm molecule (approved patent) for labor induction, which are both multi-hundred million dollar markets.

Both molecules have been approved for therapy for unrelated indications, allowing BT a substantial acceleration of regulatory approvals. BT is currently seeking an equity investment of $ 7-9 million to complete Phase II clinical trials for Preventerm and pre-clinical trials for Inducterm, to broaden management, and to enhance marketing and business development activities in the U.S. and Europe.

 

The Mission:

To revolutionize pre – term labor and labor induction treatments which affect millions of women and newborn each year – globally

BT is developing novel and advanced products for two major medical indications in multi-hundred million-dollar markets. The Company’s mission is to become a leader in the development of obstetric pharmaceuticals, to improve healthcare delivery for patients, doctors and hospitals, and to provide an attractive return on investment for its shareholders and benefits for its strategic partners. Longer term, the

Company intends to apply its technology to additional lucrative markets such as veterinary obstetrics and to develop products for more OB/Gyn indications.

The Company was founded in 2002 by Dr. Israel Shamir Leibovitz MD, FCOG, a highly acclaimed gynecologist and prolific inventor, who functions as Chief Medical Officer and interim CEO; Prof. Eliezer Shalev, Director of clinical trials, chairman of the Department of Obstetrics and Gynecology of Haemek Hospital in Afula, Israel; and Prof. Daniel S. Seidman, MD, M.Sc, Associate Director of clinical trials and NIH grant application. Prof. Seidman is currently a Senior Physician and Associate Clinical Professor at the Sackler School of Medicine at Tel-Aviv University and one of the most fruitful Israeli medical researchers, with more than 400 publications.

BT is further augmented by highly esteemed scientific leaders in obstetrics in Europe and the U.S.: Prof. Robert L. Goldenberg, Co-Director of the Center for Research in Women’s Health at the University of Alabama (UAB) and formerly the Chairman of the Department of Obstetrics and Gynecology; Prof. Phillip Robert Bennett, MD, PhD, FRCOG, a Professor in Obstetrics and Gynaecology at the Imperial College School of Medicine, Institute of Obstetrics; Prof. Emile Papiernik, Chairman of the Department of Obstetrics and Gynecology at the Hôpital Cochin, Paris; and Dr. Joseph Blankstein, the Chairman of the department of obstetrics and Gynecology at Mount Sinai Hospital Medical Center in Chicago, Illinois. [CV’s available upon request.]

BT is currently seeking an equity investment of $6-$8 million to complete Phase II clinical trials for Preventerm and pre-clinical trials for Inducterm, to broaden management, and to enhance marketing and business development activities in the U.S. and Europe.

SOURCE

http://www.bio-term.com/