Cannabinoid Therapies- Therapeutics turning a corner

Published on 22 May 2019

Author: Maxim Jacobs

Maxim joined the healthcare team in 2014 from Guidepoint Global, where he was a director of survey and tracker research, conducting extensive primary research across healthcare markets. He has more than 20 years’ experience in equities. Previously, he was a senior healthcare analyst and therapeutic sector head at Ridgemark Capital and Broadfin Capital, and a healthcare analyst at Mehta Partners.

Summary

Despite the fact that cannabis has been used for medical purposes for thousands of years, there are only a handful of therapeutics containing cannabis that have been approved by regulatory authorities, with worldwide sales of just $53m in 2018 according to Evaluate Pharma. GW Pharma’s Epidiolex (cannabidiol, CBD) is a potential game changer and is likely to be the largest FDA-approved cannabinoid drug in history. However, the pipeline of cannabinoids for regulatory approval after Epidiolex is relatively sparse and generally consists of reformulations rather than anything truly novel or innovative, with a heavy focus on pain indications as that is one of the areas in which data on the efficacy of cannabis are the strongest.

Few approvals historically

Prior to 2018, the FDA had only approved three cannabinoid products (two of them based on the same active ingredient, dronabinol) with all of them being synthetic compounds. Marinol and Cesamet were both approved by the FDA in 1985 and were the first cannabinoids to gain approval, though Cesamet was withdrawn in 1989 for commercial reasons (it was resuscitated by Valeant, which regained approval for the drug in 2006). There were no additional US approvals until 2016 when Syndros, a reformulation of dronabinol into a liquid, was approved. The approvals have typically been in relatively niche areas, such as chemotherapy-related nausea as well as to improve the appetite of those with HIV.

Epidiolex leading the way

In June 2018, the FDA approved Epidiolex from GW Pharma for the treatment of certain rare epilepsies. Consensus estimates expect sales of $1.7bn in 2024, which would make it the largest cannabis-related FDA approved drug in history (it is also the first plant-based cannabinoid to gain approval). Epidiolex is a natural pharmaceutical-grade version of CBD and was able to demonstrate efficacy in a heavily pre-treated refractory population suffering from a debilitating disease. The US pediatric epilepsy population alone is over 466,000 patients, with the uncontrolled pediatric population is between 93,000 to 140,000 in total.

Likely Winners

  • Biotech/Pharma: GW, Arena, Corbus
  • Consumers: Patients with a variety of ailments including epilepsy and pain

Likely Losers

  • Opioid-focused specialty pharma: Purdue, Insys, Endo, Teva
  • Alcohol companies: AB InBev, Heineken, Molson Coors,

Winners and losers/The companies shown above do not translate into buys and sells as other themes (and valuation parameters) may conflict with this one.

A timeline of medical cannabis:

Cannabinoids as therapeutics

Cannabis is thought to be one of the oldest plants cultivated by humans with multiple medicinal uses (including problems with the eyes, gynecological disorders as well as to fight inflammation) documented in ancient Egyptian texts. In all, cannabis was used to treat a wide variety of different indications, including pain, spasticity, cancer, epilepsy, nausea, anorexia and infectious disease.

But despite the fact that cannabis has been used for various medical purposes for thousands of years (and has a safety profile that is superior to alcohol in many respects), there are surprisingly few therapeutics containing cannabis that have been approved by major regulatory authorities, with worldwide sales totaling only around $53m in 2018 according to Evaluate Pharma. However, Epidiolex was only launched at the end of 2018 and is expected to have $1.7bn in sales in 2024 based on consensus forecasts. Also the World Health Organization, in January of 2019, called on a rescheduling of cannabis to facilitate trade for medicinal and scientific purposes.

Exhibit 1: Cannabis therapeutics currently authorized by regulator
Brand name Originator Description Indications Form Location of approvals
Sativex (nabiximols) GW Extract of cannabis: mix of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), 1:1 ratio Multiple sclerosis-related spasticity Sublingual spray 25 countries in Europe, Latin America, North America and Australasia. Not approved in the US
Marinol (dronabinol) Unimed Synthetic delta-9-THC Loss of appetite in people with AIDS and nausea and vomiting caused by chemotherapy Capsules US, Canada, Germany, Australia and New Zealand
Syndros (dronabinol) Insys Synthetic delta-9-THC Loss of appetite in people with AIDS and nausea and vomiting caused by chemotherapy Liquid US
Cesamet (nabilone) Lilly Synthetic cannabinoid similar to THC Nausea and vomiting caused by chemotherapy Capsules US, Canada, Europe, Australia
Bedrocan (dried cannabis flower tips) Bedrocan Medical grade cannabis Various Cannabis flower tips Certain countries within Europe where medical cannabis is legal
Epidiolex GW Cannabidiol (CBD) Dravet and Lennox-Gastaut syndromes (pediatric epilepsies) Liquid US

Source: European Monitoring Centre for Drugs and Addiction, FDA, drug labels, company reports

Marinol and Cesamet were both approved by the FDA in 1985 and were the first cannabinoids to gain approval though Cesamet was withdrawn in 1989 for commercial reasons (it was resuscitated by Valeant, which regained approval for the drug in 2006). There were no additional US approvals until 2016 when Syndros, a reformulation of dronabinol into a liquid, was approved and then Epidiolex (CBD) was approved for Dravet and Lennox-Gastaut (LGS) syndromes in 2018. Sativex, an extract of the cannabis plant, was first approved in the UK in 2010 but never approved in the US.

The pipeline of cannabinoids for regulatory approval is relatively sparse and generally consists of reformulations of phytocannabinoids (defined as cannabinoids derived from plants), CBD and/or THC rather than anything truly novel or innovative (see Exhibit 2), with a heavy focus on pain indications as that is one of the areas in which data on the efficacy of cannabis are the strongest.

Exhibit 2: Select clinical-stage cannabinoid programs
Company Product Generic name Phase Indication
Insys Therapeutics Cannabidiol Cannabidiol III Epilepsy, Prader-Willi syndrome
Tilray Cannabidiol oil capsule Cannabidiol; III Anxiety
Corbus Lenabasum Ajulemic acid III Systemic sclerosis, dermatomyositis, lupus, cystic fibrosis
Tetra Bio-Pharma PPP005 Cannabidiol; tetrahydrocannabinol II/III Cancer pain
Zynerba ZYN002 Cannabidiol II/III Fragile X
Arena APD371 Olorinab II Gastrointestinal pain
Therapix Biosciences THX-110 Dronabinol; palmitoylethanolamide II Tourette syndrome, obstructive sleep apnea and pain
CMXTwenty CMX-020 CMX-020 II Pain
Tilray Cannabis (vaporized) Cannabidiol; tetrahydrocannabinol II PTSD
Tilray TN-TC19LM Cannabidiol; tetrahydrocannabinol II HIV
Tetra Bio-Pharma PPP001 Cannabidiol; tetrahydrocannabinol II Cancer pain
GW Pharmaceuticals GWP42006 Cannabidivarin II Epilepsy, autism, Rett syndrome
GW Pharmaceuticals GWP42002 Cannabidiol; tetrahydrocannabinol II Glioblastoma
GW Pharmaceuticals GWP42003 Cannabidiol II schizophrenia, neonatal hypoxic-ischemic encephalopathy
Kalytera Therapeutics CBD Cannabidiol II GvHD
Botanix BTX 1503 Cannabidiol II Acne
Botanix BTX 1204 Cannabidiol II Atopic dermatitis
MGC Pharma CannEpil Cannabidiol II Epilepsy
MGC Pharma CogniCann Cannabidiol; tetrahydrocannabinol II Mild dementia and Alzheimer’s disease
Tilray TN-TC11G Cannabidiol; tetrahydrocannabinol I/II Glioblastoma
Intec Pharma AP-CBD Cannabidiol I Pain
Intec Pharma AP-THC Tetrahydrocannabinol I Pain
Artelo Biosciences ART27.13 ART27.13 I Anorexia
Bird Rock Bio Nimacimab Nimacimab I NASH, diabetic kidney disease
Veritas Pharma CTL-X Undisclosed I Acute pain

Source: EvaluatePharma, company reports, clinicaltrials.gov

One big issue with developing an FDA-approved cannabinoid product is that while the clinical trial process is no shorter, the period of exclusivity is especially short if the product is simply a reformulation of THC or CBD. First, Hatch-Waxman exclusivity is only three years for a product that is not a new chemical entity. Second, any patents in this area will likely be particularly narrow due to the high level of prior art affecting patentability of THC and CBD formulations. And any granted patents will likely be challenged once the Hatch-Waxman exclusivity expires. This challenging intellectual property landscape is likely a major reason that larger biotechnology and pharmaceutical companies have not involved themselves in this space.

One strategy that could get around this intellectual property issue would be to develop one of the 100+ minor cannabinoids that exist in cannabis plants into a drug as the level of actual invention would be far higher than with THC and CBD. Besides the possibility of cleaner and broader intellectual property, these cannabinoids may also have a differentiated efficacy and toxicity profile (see Exhibit 3). Research into these minor cannabinoids is still in relatively early days due to the expense of harvesting them, but new synthetic processes promise to make them available at a lower cost, which would encourage additional research.

Targeting the endocannabinoid system (a group of molecules and receptors in the brain that mediates the effects of cannabis) with novel synthetic compounds, such as Lenabasum from Corbus or APD371 from Arena, would be another strategy as they would be associated with new composition of matter patents, a key selling point for any large pharmaceutical partner. Both of these compounds are agonists of the cannabinoid receptor type 2 (CB2), which is mainly expressed in the periphery in immune cells and has a role in inflammation. The cannabinoid receptor type 1 (CB1), which is highly expressed in the brain, is the one associated with the psychoactive effects and has been a troublesome target for pharmaceutical development while either activating it (agonism), due to those psychoactive effects, or blocking its activation (antagonism), as this can lead to increased risk of suicidality as seen with Sanofi’s Acomplia (rimonabant).

Exhibit 3: Select cannabinoids and what they do
Name Abbreviation Comments
Tetrahydrocannabinol THC Most abundant cannabinoid in cannabis. Responsible for the euphoric feeling. A synthetic version is FDA approved for treating anorexia in AIDS patients and to treat nausea in cancer patients. Believed to potentially have efficacy with regards to pain, anxiety, depression, nausea, spasms and certain cancers. CB1 agonist (central nervous system disorders).
Cannabidiol CBD Second most abundant cannabinoid. Not psychoactive. A natural version has been approved by the FDA for refractory epilepsy. Also thought to work against pain, anxiety, depression, nausea, insomnia, spasms, psychosis and certain cancers. Antagonist of CB1/CB2 agonists, CB2 inverse agonist (anti-inflammatory), positive allosteric modulator (pain), TRPA1 agonist (pain), TRPM8 antagonist (prostate cancer), TRPV1 agonist (psychosis, pain).
Cannabichromene CBC Third most abundant cannabinoid. Not psychoactive. Preliminary studies indicate a potential to treat acne, diarrhea, pain, inflammation, depression, anxiety, multiple sclerosis and increase bone growth. Anandamide reuptake inhibitor (various neurological conditions).
Cannabigerol CBG Cannabis plants usually contain less than 1% CBG. Not psychoactive. Potential to treat pain, bacterial and fungal infections, cancers and depression. CB1 and CB2 partial agonist (neurological conditions), anandamide reuptake inhibitor (neurological conditions), TRPA1 agonist (pain), TRPV1 agonist (pain), TRPM8 antagonist (prostate cancer).
Cannabigerolic acid CBGA Precursor to all other cannabinoids. Not psychoactive. May have applications in pain and inflammation.
Cannabinol CBN Produced through the degradation of THC and typically plants contain less than 1% CBN. Minor psychoactive effects. Potential against bacteria, epilepsy, inflammation, anorexia, cancer, insomnia, glaucoma, bone healing and pain.l (CBD)
Delta-9-Tetrahydrocannabinolic acid THCA Precursor to THC, which turns into THC when burned or vaporized. Not-psychoactive. Potential to treat inflammation, nausea, cancers and act as a neuroprotective. TRPA1 partial agonist (pain), TRPM8 antagonist (prostate cancer).
Cannabidiolic acid CBDA Precursor to CBD, suggested to have efficacy in cancer, pain, nausea and inflammation. TRPA1 partial agonist (pain), TRPV1 agonist (pain), TRPM8 (prostate cancer), COX-2 inhibitor (pain/inflammation).
Tetrahydrocannabivarin THCV Works very differently from THC. Potential to treat obesity, diabetes, anxiety, Alzheimer’s disease, epilepsy and stimulate bone growth. CB1 antagonism (epilepsy).

Source: Izzo et al., Non-psychotropic plant cannabinoids, Trends in Pharmacological Sciences. 2009 Oct;30(10):515–27. 2018 Cannabis Investment Report by Ackrell Capital

Cannabinoids for epilepsy

Earlier last year, the most monumental approval of a cannabinoid occurred in the neurologic realm, specifically for the treatment of epilepsy. In June of 2018, the FDA approved Epidiolex for the treatment of a pair of pediatric epilepsies, namely Dravet and LGS. Epidiolex is a natural pharmaceutical-grade version of CBD and was able to demonstrate efficacy in a heavily pre-treated refractory population suffering from a debilitating disease (see Exhibit 4).

Exhibit 4: Epidiolex trial data in Dravet and LGS
Indication Doses tested Median baseline seizure frequency Epidiolex seizure reduction Placebo seizure reduction p value
Dravet 20mg/kg 13 convulsive seizures -39% (20mg/kg) -13% 0.0123
LGS Trial 1 20mg/kg 74 drop seizures -44% (20mg/kg) -22% 0.0135
LGS Trial 2 20mg/kg and 10mg/kg 85 drop seizures -42% (20mg/kg), -37% (10mg/kg) -17% 0.0047 (20mg/kg), 0.0016 (10mg/kg)

Source: GW Pharmaceuticals
 

Indication Number of patients Average age Average number of AEDs currently prescribed Number of previously tried AEDs Dropouts due to AEs
Dravet 120 10 3 4 13%
LGS Trial 1 171 15 3 6 14%
LGS Trial 2 225 16 3 7 8% (20mg/kg), 1% (10mg/kg)

Source: GW Pharmaceuticals

Dravet syndrome is an extremely malignant form of childhood epilepsy that typically presents itself within the first year of life with prolonged febrile and afebrile, generalized clonic or hemiclonic epileptic seizures in otherwise normally developing children. Around 10–14% of Dravet patients end up dying, typically around the age of six or seven. Besides the risk of death, by the time the children are teenagers they exhibit either severe or profound learning disabilities. In one study of 31 typical and borderline Dravet patients (14 were typical Dravet, 17 were borderline) who were followed until adulthood, 22.6% could speak no words at all, 29% could speak several words, 29% could make primitive conversation and 16.1% could make simple conversation and read to some extent. Only one (3.2%) with borderline Dravet could lead an independent life, although he developed psychosis. The incidence of Dravet ranges from 1:20,000 to 1:40,000 births, which suggests an overall disease prevalence of 5,500 patients in the US and 6,700 European patients.

LGS, like Dravet, is a rare form of epilepsy, although it typically starts later in life, at between two and eight years of age vs six months for Dravet. As with Dravet, outcomes are extremely poor for these patients, with 90% becoming mentally handicapped with a progressive reduction in IQ. The mortality rate is high, although the exact percentage varies based on the study and ranges between 3% and 25%. Incidence estimates for LGS vary, but it accounts for approximately 2–5% of all childhood epilepsies. This suggests 16,000 pediatric patients with LGS in the US and 24,000 in Europe with prevalence potentially doubling if including adult LGS patients according to the LGS Foundation.

With regards to the total pediatric epilepsy market, it is estimated that 20–30% of those treated for epilepsy are considered to be uncontrolled, with seizure free rates plummeting dramatically after failing the first drug. As the US pediatric epilepsy population alone is over 466,000 patients, the uncontrolled pediatric population is between 93,000 to 140,000 in total. With an average annual price for Epidiolex at $32,500, this suggests a $3bn to $4.5bn addressable market in the US alone (note that in Europe the submission is under review, with approval for Epidiolex expected around the middle of 2019), assuming expansion beyond Dravet and LGS to other uncontrolled pediatric epilepsy patients.

As caregivers discuss the possibility of substituting cheaper, non-standardized grade CBD products for Epidiolex, it is important to remember the fate of ZYN002, a synthetic transdermal cannabidiol that was being developed for adult epilepsy patients with focal seizures by Zynerba. In its Phase II trial, the drug failed to show significance in any of the primary or secondary endpoints. While Epidiolex was able to show a ~40% reduction in seizure frequency in its three Phase III trials (in a pediatric population), ZYN002 was only able to show an 18.4% reduction in the low dose and a 14.0% reduction in the high dose (both in adults). Simply put, not all CBD products are the same and the high-quality data from GW has set a very high bar.

Cannabinoids in other approved indications

Marinol and Cesamet have been approved for chemotherapy-related nausea and a review of data from 23 trials indicates that cannabinoids are superior to placebo and approximately in line with other anti-emetic therapies, though the cannabinoids were associated with dizziness, dysphoria, euphoria and sedation.
Both Marinol and Cesamet have also been approved to improve the appetite of those with HIV, which makes sense as smoking cannabis has been associated with 40% greater caloric intake. In a review of four studies with 255 participants, one review concluded that “there was some evidence that dronabinol is associated with an increase in weight when compared to placebo. More limited evidence suggested that it may also be associated with increased appetite, greater percentage of body fat, reduced nausea and improved functional status.”

Cannabinoids for pain

After epilepsy, pain is probably the area with the highest quantity of evidence associated with the efficacy of cannabinoids and is simply an enormous market. According to the Centers for Disease Control, 20.4% of adults in the US (around 50 million people) have chronic pain, with around 40% of those (around 19.6 million people) experiencing high-impact chronic pain. In Europe, the prevalence of moderate to severe pain in the adult population is estimated to be similarly high at 19% (around 80 million people). However, while pain is a very promising and large market for cannabinoids, the clinical data have been a little inconsistent.

In a review of 28 studies covering 2,454 patients, the authors concluded “studies generally suggested improvements in pain measured associated with cannabinoids but these did not reach statistical significant in most individual studies”. In one of the few high-grade clinical trials in the space, which was sponsored by GW Pharmaceuticals, Sativex was tested versus placebo in 298 patients with pain due to diabetic neuropathy, but only showed a minor benefit that did not reach significance with a p value of 0.63. However, usage data from states that have legalized medical cannabis indicates that patients are using it for pain and this has led to less opioid use. In one survey of 244 medical cannabis patients in Michigan, cannabis use was associated with a 64% decline in opioid use, a tremendous decrease that would speak to at least some efficacy for the drug. Also, in an analysis of Medicare Part D data, medical cannabis legalization was associated with a statistically significant 11.4% reduction in the use of prescription pain medication statewide.

One of the most advanced therapeutic programs in pain belongs to Arena Pharmaceuticals, which is developing a full CB2 agonist (due to CB2’s effect on microglial activation and inflammation) for the treatment of pain associated with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), two highly prevalent indications. According to the International Foundation for Gastrointestinal Disorders, between 25 and 45 million people in the US suffer from IBS, while the Centers for Disease Control estimates that 1.0–1.3 million Americans have IBD. Around 30% of IBD patients and 35% of IBS patients receive opiates for their pain. The company conducted a 14-patient Phase IIa trial in adults with Crohn’s disease where patients received either 25mg or 100mg three times daily. At peak effect, 85% of those with evaluable data at week four (13 of the 14 patients) and 100% of those with evaluable data at week eight demonstrated a greater than 30% change from baseline in their average abdominal pain scores (AAPS) with the data being consistent at both doses. Importantly, there were no psychotropic effects and no discontinuations due to adverse events. The company is currently preparing for a Phase IIb study.

Cannabinoids in other neurological disorders

Cannabinoids have been tested in a variety of problems including Tourette’s, anxiety and post-traumatic stress syndrome (PTSD), though the evidence of efficacy so far is rather limited as there have been few large trials.

Two small-scale randomized, controlled clinical studies have been performed examining dronabinol for the treatment of Tourette’s. In the US, the CDC estimates that 138,000 children are diagnosed with the disease, while the National Institute of Neurological Disorders and Stroke estimates that there are 200,000 children and adults with Tourette’s.

Exhibit 5: Cannabinoid pipeline in pain
Company Product Generic name Phase Comments
Tetra Bio-Pharma PPP001 Cannabidiol;
tetrahydrocannabinol
II/III Smokable cannabis
pellets for cancer pain. Only data so far have been
Phase I study in healthy volunteers. Phase III program
ongoing.
Arena APD371 Olorinab II CB2 agonist for the treatment of GI-based
visceral pain. In a Phase IIa in 14 patients, 79%
had clinically relevant reductions in pain at weeks
four and eight. Preparing for Phase IIb.
Therapix Biosciences THX-110 Dronabinol; palmitoylethanolamide II Dronabinol and PEA for chronic low back pain. No data yet. Phase IIa ongoing.
CMXTwenty CMX-020 CMX-020 II Oral and intravenous cannabinoid. Current status
uncertain.
Tetra Bio-Pharma PPP005 Cannabidiol; tetrahydrocannabinol II Cannabis oil for cancer pain. No data so far.
Intec Pharma AP-CBD Cannabidiol I Sustained release CBD for
low back pain, neuropathic pain and fibromyalgia. In
Phase
I.
Intec Pharma AP-THC Tetrahydrocannabinol I Sustained release THC for low back pain,
neuropathic pain and fibromyalgia. In Phase I.
Veritas Pharma CTL-X Undisclosed I Undisclosed cannabinoid
product for acute pain

Source: EvaluatePharma, company reports, clinicaltrials.gov

The first study was a randomized crossover trial of 12 individuals, and it showed a 22% improvement in the Yale Global Tic Severity Scale (YGTSS), although it did not reach statistical significance. However, a statistical improvement was seen for complex motor tics (p=0.015) and for patient reported symptoms (p=0.015). The second study examined 24 patients in placebo and dose escalation cohorts (ranging from 2.5mg to 10mg of dronabinol per day).

It reached similar results, showing improvement in symptom ratings of motor tics (p=0.04) and patient reported symptoms (p<0.05), but failed to reach statistical significance in the overall YGTSS. Also, in 2018, Therapix, which is combining dronabinol with palmitoylethanolamide (PEA), saw a 21% reduction in tic severity (p=0.002) in a trial of 16 Tourette’s patients.

In anxiety, in a 24-patient trial in which patients either received 600mg of CBD or placebo and then had to conduct simulated public speaking, the CBD arm saw a greater improvement in anxiety compared to placebo. This data is likely the basis of a 50-patient, eight-week trial being sponsored by Tilray studying CBD oil capsules in patients with anxiety. Data is expected in Q420. As a reminder, anxiety disorders are highly prevalent, with 19.1% of adults suffering from them on an annual basis according to the National Comorbidity Survey conducted by Harvard Medical School.

With regards to PTSD, in a trial in 10 Canadian military personnel in which the participants alternated between receiving Cesamet and placebo, patients on Cesamet saw a statistically significant reduction in nightmares (p=0.03) as well as a general improvement in Clinical Global Impression of Change (p=0.05) in seven of 10 patients compared to only two of 10 on placebo. While small, this is an interesting signal as military-related PTSD is notoriously difficult to treat.

Only 20% of military-related PTSD patients were effectively treated in previous SSRI studies (the current standard of care). And if you count both civilian and military PTSD, it is a rather large indication. Based on the results of a national comorbidity survey, 3.5% of the adult population have PTSD. Tilray is conducting a 42-patient trial of vaporized dried cannabis in patients with PTSD with data expected in Q220.

There is also some data related to using cannabinoids in the treatment of recurrent glioblastoma. In a 21-patient trial in recurrent glioblastoma sponsored by GW Pharmaceuticals, patients who received a combination of CBD and THC had an 83% one-year survival rate, compared to 44% for patients on placebo (p=0.042). Median survival was also 662 days in the CBD/THC combination group compared to 369 days for patients in the control arm.

According to the Central Brain Tumor Registry of the United States, glioblastoma represents 15% of all brain and central nervous system tumors, amounting to approximately 11,000 new cases per year. GW is continuing the program and Tilray is involved with a 30-patient glioblastoma trial for another CBD and THC combination product, TN-TC11G, with data expected around the middle of 2020.

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Companies
Market cap ($m)
Share price ($)
Eli Lilly and Co
112,247
115.6
GW Pharmaceuticals
5,498
14.7
Tilray
4,733
48.9
Arena Pharmaceuticals
2,774
56.0
Corbus Pharmaceuticals
476
7.4
Pynerba Pharmaceuticals
293
13.9
Insys Therapeutics
89
1.2
MGC Pharmaceuticals
53
0.0
Therapix Biosciences
3.3
Intec Pharma
5.3

Source: Refinitiv at 16 May 2019


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