Therapeutic Delivery: Industry Update Covering November 2019

Keywords:

• Alzheimer's disease
• autoinjector
• drug delivery
• Ebola
• medical device
• micro pump
• nanoparticle
• spinal muscular atrophy
• vaccine

Acquisitions, licensing deals & other commercial news

Novartis to acquire the Medicines Company

Novartis (Basel, Switzerland) announced an agreement to acquire The Medicines Company (NJ, USA) in a deal worth approximately US$9.7 billion. The main motivation for the deal is for Novartis to gain the rights to inclisiran; a drug being developed to target high levels of cholesterol that increase the risk of cardiovascular events. Inclisiran utilizes RNA interference to inhibit the PCSK9 gene encoding the PCSK9 protein. PCSK9 blocks sites in the liver that absorb low-density lipoprotein (LDL), or so-called bad cholesterol, that can promote atherosclerosis. Therefore, reducing levels of the protein enables more rapid adsorption of LDL, reduces its concentration in blood serum and hence lowers the risk of heart disease. Drugs that reduce LDL-C by inhibition of PCSK9 already exist, for example Amgen’s (CA, USA) Repatha^® and Sanofi (Paris, France)/Regeneron’s (NY, USA) Praluent^® are monoclonal antibodies that bind to proteins and inhibit their ability to bind to sites in the liver. These drugs both came to the market in 2015 but have been less successful than what was originally forecast due to their high costs compared with atorvastatin (also termed Lipitor^®), which has remained the first-line treatment for hypercholesterolemia. However, the benefit of inclisiran over Praluent and Repatha is that it only needs to be administered twice per year rather than every 2–4 weeks, which would result in better adherence as well as a lower cost. Analysts noted that only 55–60% patients are compliant on PCSK9 mAb therapy, so better dosage regimens might be beneficial [1,2].

The Medicines Company recently announced the results from three Phase III trials for inclisiran, involving over 3600 high-risk patients with atherosclerotic cardiovascular disease and familial hypercholesterolemia. In all the studies, treatment with inclisiran demonstrated a durable and potent reduction in LDL-C with good safety and tolerance. Filing for approval with the US FDA is anticipated before the end of 2020 with a filing in the EU to follow soon afterward [3].

With the deal likely to conclude in early 2020, Novartis expects inclisiran to begin to contribute to its sales for 2021, driving growth of its Cardiovascular, Renal & Metabolism franchise where it has the potential to become one of the largest products in sales in the Novartis portfolio.

Bristol-Myers Squibb completes acquisition of Celgene, creating a leading biopharma company

Bristol-Myers Squibb (NY, USA) announced completion of its acquisition of Celgene (NJ, USA), having gained all the necessary governmental regulatory approvals required for the merger process. The deal creates an enlarged pharmaceutical business with nine products each having more than $1 billion in annual sales, as well as a strong and diversified development pipeline covering franchises in oncology, hematology, immunology and cardiovascular disease [4].

One condition of the merger was the divestment of the blockbuster drug; Otezla^®, developed by Celgene and indicated for the treatment of psoriasis and psoriatic arthritis. Celgene entered into an agreement to sell the rights to this drug to Amgen, who announced this month that the deal had been concluded for a total consideration of $13.4 billion [5].

Recipharm makes a recommended offer for Consort Medical PLC

Consort Medical (Hemel Hempstead, UK) announced that it has received a takeover offer from Recipharm (Stockholm, Sweden) that is recommending shareholders to accept. The offer values Consort at £505 million ($652 million) and once closed it will make Recipharm a top five global contract manufacturing and development organization and a leading player in the inhalation devices market. In addition to its work on inhalation and nasal devise, Consort’s Bespak division has been developing its VapourSoft^® technology platform to provide a range of injection devices, which are powered by compressed gas, and has recently announced its first commercial agreements. It also offers drug fill-finish services that complement its device development and manufacturing services [6].

Update on Sensile Medical micro pump development portfolio

Gerresheimer (Düsseldorf, Germany) announced a portfolio update for its subsidiary; Sensile Medical’s novel micro pump technology [7].

It announced a new deal with SQ Innovation AG (Zug, Switzerland) for the delivery of a novel higher concentration formulation of furosemide, which is utilized to treat heart failure. They also mentioned that they have several programs with pharmaceutical companies for the use of the pump technology in various therapy areas. At the same time, they announced termination by Sanofi of a diabetes program using the same technology.

Sensile (Olten, Switzerland) is one of several companies developing wearable pump technology to deliver a range of therapies. Interest in this market has grown as there are is an increasing number of injectable drugs in development that require delivery volumes that are higher than those possible using standard injection devices, such as prefilled syringes and autoinjectors. Historically, it was considered that subcutaneous or intramuscular injections are limited to approximately 1 ml in a single dose, due to considerations of delivery time, acceptable needle size (to minimize pain) and pharmacokinetic considerations. However, more recently, evidence has been presented that suggests that this can be increased to approximately 2.25 ml. This still leaves a significant number of developmental drugs that are likely to require delivered volumes of between 3 and 10 ml. These drugs are ideally suited to wearable pump technology that is to be offered by companies such as Sensile [8].

Ypsomed demonstrates growth in the self-administration drug-delivery device market

Ypsomed (Burgdorf, Switzerland) reported a strong growth in its delivery systems business, with sales of injector pens and autoinjectors growing by 55% over the reporting period. During the first half of the 2019/2020 business year, four of its autoinjectors and six injection pen systems received marketing approval or were launched in new markets [9].

Ypsomed is a leader in the development and manufacture of disposable injection devices for self-injection and these are underpinned by a rapid growth in this market, due to new approvals of biologic drugs for chronic diseases, the arrival of biosimilars in the market and a move from administration of drugs in clinical settings to convenience of self-administration. Compared to syringes, autoinjectors provide automated drug injection, better ease of use and needle safety. Newer designs also conceal the needle at all stages of use, reducing issues around needle phobia that are estimated to be an issue for 3.5–10% of the population [10].

New collaborations

Novoheart to codevelop the first of its kind human heart-in-a-jar model for heart failure with AstraZeneca

Novoheart (BC, Canada), a biotechnology company focusing on the use of stem cell technology, announced a collaboration with AstraZeneca (Cambridge, UK) to develop a new in vitro model for heart function that has been termed ‘heart-in-a-jar’. The collaboration will utilize Novoheart’s proprietary 3D human ventricular cardiac organoid chamber technology, which is the only macroscopic cardiac tissue model that can mimic the pumping of fluid seen in actual hearts. The collaboration will initially focus on the development of a functional model for heart failure with preserved ejection fraction (HFpEF), a form of heart failure common in the elderly, especially women. A benefit of the approach over conventional animal models is that it can incorporate human-specific pluripotent stem cells and cellular structures that can mimic those observed in the hearts of HFpEF patients. Once developed, the model can then be utilized to test new drug candidates for HFpEF. The model could be valuable in bridging between in vivo animal models and clinical trials, by providing human-specific preclinical data. There are currently significant unmet needs in the treatment of HFpEF patients; RF Danielson (AstraZeneca) commented that the new model “could bridge the gap between in vivo animal models and clinical trials to help accelerate the drug discovery process by providing human-specific preclinical data” [11].

Cardiovascular, Renal and Metabolism is one of AstraZeneca’s three main therapy areas in which the company already has several approved blockbuster drugs, as well as a strong developmental pipeline. Farxiga^®, a SGLT2 inhibitor, is already approved both as a monotherapy and as part of combination therapies to improve glycemic control. In studies, it has also been evaluated for its safety and efficacy as a treatment for HFpEF [12].

As well as developing cell-based technology to support the development of heart therapeutics, Novoheart is exploring how its technology can be utilized as a transplantable graft for regenerative treatment of heart disease.

Updates on clinical research

Halozyme to focus its activities on its ENHANZE^® drug-delivery technology following failure of a cancer drug trial

Halozyme (CA, USA) announced that its investigational new drug, PEGPH20, being developed as a first-line therapy for metastatic pancreatic cancer, has failed to achieve a survival end point in a Phase III study. Despite a higher response rate in the treatment arm that involved the use of PEGPH20 in combination with existing cancer drugs gemcitabine and nab-paclitaxel, this failed to demonstrate increased survival over the control arm that utilized the other drugs without PEGPH20 [13].

As a result, Halozyme will terminate the development of PEGPH20 and focus its efforts on ENHANZE and its drug-delivery technology that supports the administration of larger subcutaneous injections, which are possible using conventional technology. This technology is already part of five approved drug products and it has development collaborations aiming to bring new therapies to the market. ENHANZE utilizes a recombinant human hyaluronidase PH20 enzyme, termed rHuPH20, to temporarily breakdown hyaluronan around the injection site, providing adsorption and dispersion of the drug co-administered in an injection [14].

Investigational drug meets primary end point in a study targeting spinal muscular atrophy

Roche (Basel, Switzerland) announced positive results from a study evaluating the use of its investigational drug, risdiplam, in the treatment of spinal muscular atrophy (SMA), a rare, progressive muscle-weakening and wasting disease. After 1 year of treatment in a study involving individuals aged between 2 and 25 years, the treatment with the drug demonstrated a significant change from baseline in the Motor Function Measure 32 scale after 1 year of treatment, compared with the placebo arm [15].

SMA arises from a deficiency of a survival motor neuron (SMN) protein, caused by a mutation in the survival motor neuron 1 (SMN1) gene. Risdiplam works by altering the spicing pattern of the SMN2 gene to increase the amount of SMN protein produced.

As part of a collaboration with the SMA Foundation and PTC Therapeutics, Roche leads the clinical development of the drug. Following these results and acceptance of a regulatory submission for Risdiplam, the FDA granted a priority review of the approval of the drug, with a decision on approval anticipated in May 2020 [16].

Biogen (MA, USA) and Novartis have already gained approval for Spinraza^® and Zolgensma^®, respectively, for the treatment of SMA, the former has to be administered intrathecally (injection into cerebrospinal fluid), whereas Risdiplam is being developed for oral administration. Zolgensma is a gene therapy that only requires a single administration. Although, ease of administration is likely to be a significant factor in establishing a competitive advantage of the three drugs in the market, long-term effectiveness and safety of the treatments may prove to be more critical.

Regulatory news

Ebola vaccines

Merck Sharp & Dohme B.V. (Amsterdam, The Netherlands) a subsidiary of Merck & Co., Inc., (NJ, USA) have been granted marketing authorization in Europe for the first vaccine against Ebola anywhere in the world. Approval was via the Centralised Procedure, which means a single application can gain authorization through the EU by a two-stage process. First, a review by the European Medicines Agency (EMA) is conducted, which was completed last month, and second, the approval of their positive recommendation by the European Commission, as announced on 11 November 2019.

Clinical development of Ervebo began 5 years ago during an outbreak of the disease in West Africa and was progressed via a public/private collaboration involving several research institutes, as well as the health ministries in several African countries. Support came from the Innovative Medicines Initiative, funded by the EU’s research and innovation program; Horizon 2020 with Merck Sharp & Dohme making a financial contribution to the programs.

Merck started manufacturing licensed doses at a plant in Germany and anticipates starting shipments in the third quarter of 2020. Meanwhile, Merck will be working closely with the WHO and other agencies to ensure the continuing supply of the investigational version of the vaccine, to help control the outbreak of Ebola in the Democratic Republic of Congo (DRC), in which 3000 individuals have already been effected and has a fatality rate as high as 67% [17].

The DRC emergency is the second deadliest Ebola outbreak in history after a 2014 crisis in West Africa and has resulted in the death of more than 11,000 individuals, sparking a surge of research in the field. The FDA is also expected to make an approval decision on the vaccine in the near future.

Meanwhile, Johnson and Johnson (NJ, USA) announced that its pharmaceutical division, Janssen, has submitted an application to the EMA for the approval of an alternative vaccine against Ebola. The vaccine regimen involves administering doses of two different vaccines approximately 8 weeks apart; the first developed by Janssen and the second by a collaborator, Bavarian Nordic (Kvistgård, Denmark). The submission follows ten Phase I–III clinical trials involving over 6500 adults and children aged between 1–7 years old.

The development originated from a collaborative research program with the US National Institute of Health and has received support from a number of initiatives including Innovative Medicines Initiative, which is funded by the European Union and through its Ebola+ Program, that has supported a number of activities for the development of a vaccine.

Janssen’s plan is to make 500,000 doses of the vaccine available for a large clinic and studies are currently being organized by DRC. It is envisaged that the vaccine will be utilized both in response to Ebola outbreaks, but also as a prophylactic to protect populations in regions where there is a high risk of the disease. This vaccine has also been in discussion with the FDA for seeking approval in the USA [18].

Celgene & Acceleron win FDA approval for a drug to treat anemia in patients with β-thalassemia

The FDA announced that it had approved a new drug, termed Reblozyl^® (luspatercept), for the treatment of anemia in adult patients with β-thalassemia, a rare inherited blood disorder that reduces the production of hemoglobin in red blood cells.

Currently, β-thalassemia must be treated by regular red cell blood transfusions, which, although are effective, can eventually cause organ failure and a reduced lifespan due to iron overload.

Approval was supported by Phase III data that demonstrated a reduction in the number of blood transfusions, with 21% of the patients who received Reblozyl achieving at least a 33% reduction, compared with 4.5% in the placebo group.

Approval is also being sought for the treatment of myelodysplastic syndrome and is currently under review with the FDA. Approval of treatments for both β-thalassemia and myelodysplastic syndrome and indication in the European Union is also under review by the EMA. Reblozyl has been developed by Celgene, in collaboration with Acceleron (MA, USA), a biopharmaceutical company focusing on therapeutics to treat serious and rare diseases [19].

Sandoz wins US approval for its Neulasta^® biosimilar

Sandoz (Hozkirchen, Germany), a Novartis division and a global leader in biosimilars, announced that the FDA has approved Ziextenzo™ (pegfilgrastim-bmez), its biosimilar version of Amgen’s Neulasta^®, a long-acting version of filgrastim. Filgrastim is used for the treatment of neutropenia, which commonly occurs after chemotherapy or radiation poisoning. The drug works by stimulating bone marrow to increase whole blood cell count. Once Ziextenzo is marketed, Sandoz will be the only company to offer both long- and short-acting filgrastim biosimilars in the USA. Sandoz’s version of the short-acting filgrastim biosimilar drug, Zarxio^®, was approved by the FDA in 2018. The FDA previously rejected approval of Ziextenzo in July 2016, whereas Mylan (PA, USA) and Coherus (CA, USA) already have FDA-approved versions of Neulasta in the USA, so there will be intense competition that is likely to lead to price cutting in order to gain a market share. Ziextenzo is already approved in Europe, as are several other biosimilar versions of Neulasta [20].

Alzheimer’s disease: therapeutic update

Biogen provides an update on aducanumab

At the Stat Summit, held in Boston this month, Al Sandrock (Biogen, USA) provided an update on aducanumab, the company’s leading investigational drug for the treatment of Alzheimer’s disease (AD). Earlier in the year, Biogen and its development partner Eisai (Tokyo, Japan) announced that they were abandoning development of the drug after an interim analysis of the data from two ongoing Phase III studies suggested that it was unlikely the studies would demonstrate efficacy. Then, in October 2019, the companies announced that analysis of a larger study dataset demonstrated that the drug had reduced clinical decline in patients with early AD and after consultation with the FDA they intended to process with a filing. At the summit, Sandrock told the audience that Biogen had shared the data with the FDA in two face-to-face meetings held in June and October and the agency had reported it was ‘reasonable’ to file for approval of aducanumab. Few details have emerged on the new data and analysis, but Biogen has indicated that the results will be presented at the ‘Clinical Trials on Alzheimer's Disease’ annual meeting held in December 2019 and it is believed that a filing for approval may be made in early 2020 [21].

Appraisal of the amyloid hypothesis in Alzheimer’s disease

Aducanumab is a monoclonal antibody that aims to slow the development of AD by removing the harmful build-up of β-amyloid plaques that are observed in the brains of those who have the disease. However, several other drugs targeting this mechanism have not been successful in studies that have led many experts to believe that the approach is futile and other approaches need to be explored. Although, in a paper published this month, Tolar et al. provided an overview of the amyloid cascade hypothesis, in which the authors noted that three criteria need to be considered in ensuring success of amyloid-targeting therapies: first, which pathogenic form of amyloid needs be inhibited or removed to slow progression of the disease, second, whether the drug candidate crosses the blood–brain barrier with sufficient efficacy to create a therapeutically effective concentration of the drug in the brain and third, what patient population should be targeted to demonstrate optimum treatment efficacy. Tolar et al. argue that previous studies targeting amyloid removal have not been successful because they have failed to address one or more of these criteria fully. For monoclonal antibodies, they note that the amount of drug crossing the blood–brain barrier has been estimated to be <1.5%, which may be too low to provide an effective dose for the removal of soluble β-amyloid oligomers. For the data reported from the aducanumab studies, the authors note that although there was a dose-dependent response for amyloid plaque reduction, this did not appear to translate into a dose response for clinical efficacy. This observation can be explained by the fact that the reduction of the plaques may not mean that the soluble oligomers have been sufficiently reduced. Finally, they comment that it is important to select the right patient group to demonstrate consistent effect. Patients with AD often have other neuropathologies that cause brain degradation which might mask the positive effect of amyloid removal. It is well known that the expression of APOE4 is the most prevalent genetic risk factor of AD and is expressed in more than half of AD patients and is associated with a high burden of β-amyloid oligomers. Thus, Tolar et al. suggest that this is the best patient group to target in clinical studies in order to observe a therapeutic effect [22,23].

Based on these arguments, Tolar’s team at Alzheon (MA, USA) have focused on the development of a drug termed ALZ-801, which is a prodrug of tramiprosate, a small molecule that can be obtained from red marine algae. Although tramiprosate failed to demonstrate a positive effect in slowing AD in studies conducted more than 10 years ago, Alzheon argue that this was not due to the ineffectiveness of the drug in reducing amyloid oligomers, but by poor study design and inappropriate patient selection for the study. The prodrug improves gastrointestinal absorption, tolerability and brain penetration, resulting in more effective dosing in the brain with good safety. The company is currently raising funds to conduct a planned Phase III study of the effects of ALZ-801 on APOE4/4 in patients with early AD.

A common safety-related problem with amyloid-lowering drugs, including aducanumab, is that it can cause inflammation and leakage of plasma and/or blood from small vessels in the brain due to the removal of the vascular amyloid. These can be seen in MRI scans and are termed amyloid-related imaging abnormalities. Therefore, if aducanumab is approved and utilized to treat AD, then regular medical imaging is likely to be required to ensure safety. Alzheon claims that amyloid-related imaging abnormalities are not observed with ALZ-801 tramiprosate, which would be another benefit of the drug if it is shown to be effective.

In summary, the amyloid hypothesis is not necessarily incorrect and drugs that target amyloid removal may be approved as treatments for AD in the coming years. However, it is also likely that, for at least some patients, other contributing factors may limit the effectiveness and will require additional therapies to be developed [22,23].

Study identifies gene variant as potential drug target for Alzheimer’s disease

Genetic data can provide insight on why some individuals may be more resistant to AD than others. For example, individuals who the carry the rare gene PSEN1 E280A mutation have a 99.9% risk of developing early-onset AD in their 40s. Research led by investigators at Massachusetts General Hospital, Boston, in collaboration with several other institutes, studied genetic data from a Colombian family with more than 6000 living members. They identified an individual from the cohort with the PSEN1 E280A mutation who had remained dementia-free until her 70s, whereas several other family members with the same mutation had suffered from early onset AD. In examining the genetic differences, the researchers demonstrated that she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant, whereas the other family members with the gene mutation, who presented with early onset AD, only had one. This led the team to conclude that carrying two copies of APOE3ch gene variant might be neuroprotective.

APOE binding to heparan sulphate proteoglycans (HSPG), a type of sugar, has been identified as a mechanism that may contribute to the buildup of amyloid and τ-protein deposits that are associated with neuronal loss in the brain. Experiments conducted as part of the study suggested that the APOE3ch gene variant reduces the ability of APOE to bind to HSPG. This research suggests that a drug or gene therapy targeting the reduction APOE and HSPG binding, might provide a new approach to treat or prevent AD [24].

T3D secures $15 million series B funding to support its metabolic drug approach to the treat AD

T3D Therapeutics (NC, USA) announced that it had closed $15 million of series B financing, meaning that it is now fully funded to initiate a Phase II study (PIONEER) to evaluate its novel treatment for AD, using T3D-959. The study is expected to commence in early 2020 and will involve up to 256 adults with mild-to-moderate AD. Participants will be recruited into one of four cohorts and given one of three doses of the investigational drug or placebo for a period of 24 weeks. In addition to the investment funds, the study has also received support from the National Institute on Aging, which is part of the US NIH [25].

T3D-959 is a dual agonist of PPAR receptors that are known to regulate blood sugar and triglyceride (fat) levels. Some scientists argue that AD arises from dysfunctional glucose and lipid metabolism in the brain. Therefore, it has been proposed that T3D-959 can reduce these processes and slow the progression of AD. In addition to its use in AD, T3D Therapeutics is also considering the drug as a potential treatment option for other neurodegenerative diseases, particularly Huntington’s disease.

Science & novel technologies

Nanoparticle drug delivery offers potential new route to pain relief

NK1 receptor antagonists are implicated in the pain pathway and more than 20 years ago were considered to be excellent candidates for analgesia. However, despite promising preclinical data in animal models, human studies failed to provide positive results, although they have been effective in other indications including the treatment of nausea and vomiting arising from chemotherapy.

However, this month, an international team of scientists from New York University’s College of Dentistry (NY, USA), Monash University, Columbia University and the University of Santiago (Santiago, Chile) published research that suggested how the application of nanotechnology might provide a route to make this class of drug effective in pain management. They argued that the problem with original studies was that the drugs failed to work because they could only block receptors at the surface of cells and activated NK1 receptors to move away from the cell surface and toward early and late endosomes located in the cell membrane. It has been well established that nanoparticles can penetrate cell membranes and can be utilized to deliver drug payloads into the cell interior. In this research, the team utilized this approach to deliver aprepitant, a drug already approved by the FDA for the treatment of nausea, into nerve cells in rodents using intrathecal injection. They demonstrated that this led to complete and persistent relief from inflammatory and neuropathic pain stimuli. Although, further work will be required before the approach will be ready for human studies, the researchers concluded that it may provide the basis for a nonopioid form of pain management [26].

Summary

This industry update covers the period from 1 November through to 30 November 2019 and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw several large acquisitions take place such as, Novartis announcing a takeover of The Medicines Company, Bristol-Myers Squibb closing its purchase of Celgene and Recipharm announcing an agreed takeover of the drug delivery device specialist Consort Medical. Growth in the parenteral drug-delivery device market was demonstrated by an announcement by Gerresheimer of a new deal involving a micro-pump being developed by its subsidiary; Sensile Medical and Ypsomed announced significant growth in its self-injection device business.

Novoheart announced a deal with AstraZeneca to develop a ‘heart-in-a-jar’ model for heart failure, intended to be utilized in drug development. Roche announced positive trial results for its investigational drug, Risdiplam, in the treatment of spinal muscular atrophy, whereas Halozyme announced that it will abandon development of a drug to treat metastatic pancreatic cancer following poor trial results and will now focus its activities on its drug-delivery platform ENHANZE. A vaccine for Ebola was approved in Europe and a second vaccine filed for approval in the same market. Celgene gained FDA approval for a drug to treat anemia in patients with β-thalassemia and Sandoz gained FDA approval for its biosimilar version of Amgen’s Neulasta.

This month also saw some significant news in the development of treatments for Alzheimer’s disease. Biogen provided an update on its drug aducanumab, for which it plans to file for approval in the coming months. A team working at the biotechnology company Alzheon presented a review of the amyloid hypothesis, arguing that this mechanism is a key factor in the development and treatment of AD and that recent failures of drugs targeting amyloid reduction can be explained by suboptimal drug and study design. An internal collaboration led by researchers at Massachusetts General Hospital identified a gene variant that appears to be neuroprotective and could support the development of new drugs against AD. T3D Therapeutics secured funding for a Phase II clinical study to examine a novel treatment for AD, based on targeting dysfunctional glucose and lipid metabolism in the brain. An international team of scientists published results that demonstrated how nanoparticle drug delivery could allow a new non-opioid approach to pain relief to be developed.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.