Industry Update Covering June 2018

Keywords:

• emerging technologies
• monoclonal antibodies
• partnering

Acquisitions, licensing deals & other commercial news

AbbVie, Calico extend collaboration focused on developing treatments for age-related disorders

AbbVie (IL, USA) and Calico (CA, USA) announced an extension of an existing collaboration formed in 2014 to develop treatments for age-related diseases, including for neurodegeneration and cancer [1]. In the new agreement, the collaboration is extended for a further three years, with Calico responsible for research and early development until 2022, and the advancement of any collaboration projects through Phase IIa up to 2027. As in the existing agreement, AbbVie will continue to support Calico in its early R&D and, following completion of Phase IIa studies, will have the option to manage late-stage development and commercial activities. The companies will each commit to contribute an additional $500 million to the collaboration and will share costs and profits equally.

In the collaboration, Calico focuses on discovery-stage research and development, whereas, AbbVie provides scientific and clinical development support and will provide commercial expertise to lead future development and commercialization activities.

Calico, backed by Alphabet (Google), was founded in 2013 and has entered into a number of other partnerships seeking new therapeutics for age-related diseases and with AncestryDNA™ (UT, USA) based on conducting research into the genetics of human lifespan.

Novartis decides to spin-off Alcon eye-care division

Novartis (Basel, Switzerland) announced that it will spin-off its eye-care division Alcon into a standalone company [2]. The decision follows a strategic review and ends considerable speculation on the future of Alcon since it was fully acquired by Novartis in 2011, and subsequently had several years of poor commercial performance.

With Alcon's prescription ophthalmic drug business already transferred to Novartis’ Innovative Medicines Divisions and Novartis’ over the counter (OTC) ophthalmic products being transferred the opposite way, Alcon will have surgical division and consumer divisions. The former provides products used in ophthalmic surgery in areas such as cataract, glaucoma and refractive errors whereas the latter, provides contact lenses, lens care products and OTC medications for conditions such as eye infections and dry eye. Having announced the sale of its OTC medicines business to GSK earlier this year, Novartis will become a prescription only medicines business, although as mentioned in previous Editorials, this may increasingly include digital medicines as well as traditional small and large molecule drugs and gene therapy.

Michael Ball, who was brought in by Novartis to help turn around the business, will become Alcon's Chairman-designate standing down from Novartis’ Executive Committee to focus on the spinout. David Endicott, Chief Operating Officer of Alcon since July 2016, will be promoted to become its CEO.

The spin-off, that should be completed in 2019, will see Alcon incorporated in Switzerland; with Fort Worth in the US (where Alcon was originally established in 1945) continuing to be a key location, and listed on SIX Swiss Exchange and New York Stock Exchange.

Oxford BioMedica & Axovant Sciences enter into a $842.5 million exclusive worldwide licence agreement for OXB-102 for the treatment of Parkinson's disease

Oxford BioMedica plc (Oxford, UK) and Axovant Sciences (Basel, Switzerland) announced a license deal in which the latter will take an exclusive license to the former's developmental gene therapy treatment for Parkinson's disease (PD), OXB-102 (now referred to as AXO-Lenti-PD) [3] Oxford BioMedica will receive a $30 million upfront payment (approximately £22 million), including $5 million as prepayment for manufacturing activities related to the drug and is also eligible to receive in excess of $800 M for the achievement of specified development, regulatory and sales milestones, as well as tiered royalties sales of AXO-Lenti-PD, once the drug is approved.

In PD, degeneration of nerve cells in the brain results in a reduction in dopamine and interruption of neuronal signaling in the brain, resulting in movement disorder and other adverse symptoms associated with the disease. The efficiency of current drugs that target dopamine deficiency, either by replacement with exogenous dopamine or use of agonists to mimic dopamine effects, tends to diminish with long-term use. AXO-Lenti-PD aims to deliver three genes that encode a critical set of enzymes required for dopamine synthesis in the brain and thus provide patient benefit for multiple years following a single administration.

Digital health

Merck & Alibaba announce a collaboration develop patient centric digital services in China

Merck (NJ, USA), announced it has signed a strategic collaboration agreement with Chinese internet healthcare company Alibaba Health (Hong Kong) to provide improved access to patient centric healthcare services for patients and carers in China [4]. The collaboration will combine Merck's expertise in diabetes, thyroid disorders and cardiovascular diseases with Alibaba Health's expertise in online healthcare, focusing initially on the latter's drug tracking platform to help ensure safety and security of drug use, as well as to add services that enhance value to patients.

Regulatory news

FDA to reject approval of Mylan's generic version of GlaxoSmithKline's Advair

Mylan (PA, USA) announced that it has been advised by the US FDA that it has found minor deficiencies in the company's application for approval of a generic version of GSK's inhaled drug, Advair, for the treatment of asthma and COPD [5]. Details of the deficiencies were not given but are due to be clarified in a Complete Response Letter that the FDA will send the company. The announcement follows previous rejections by the FDA for the generic drug to Novartis AG, Hikma Pharmaceuticals (London, UK) as well as Mylan itself, following its initial application. Assuming the deficiencies are easily addressable, and Mylan can resubmit this year, it is still likely to be ahead of the other companies in the race to enter the US market with generic Advair.

Although GSK already has competition in Europe for the drug (where is in known as Seretide) and has seen sales of the drug decline globally due to the arrival of generics as well as switching to newer drugs, it still achieved revenues of £3,130 million in 2017.

FDA clearance of GW Pharmaceuticals’ EPIDIOLEX^® to treat seizures marks first US approval of cannabinoid-derived drug

GW Pharmaceuticals (London, UK) announced that it had gained FDA approval for EPIDIOLEX^® (cannabidiol) oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in young and adult populations [6].

EPIDIOLEX is a pharmaceutical formulation of pure cannabidiol and becomes the first FDA-approved drug that contains a purified drug substance derived from marijuana. GW is also seeking approval is the Europe and is also evaluating effectiveness of the drug in other orphan seizure disorders.

Updates on clinical research

Updates in two investigational drug programs for the treatment of Alzheimer's disease

Eisai and Biogen announced results from an 18 month Phase II study looking at safety and efficacy of elenbecestat (E2609) in the treatment of Alzheimer's disease (AD) [7].

Results showed that the drug was generally safe and well tolerated by patients, with a statistically significant difference in the amyloid β (Aβ) levels in the brain measured by molecular imaging. Aβ is the main component of amyloid plaques, which are believed to disrupt healthy brain function and cause neuronal loss.

Although the study was not powered to give a statistical significant effect, there was some indication of a slowing in cognitive decline; the targeted end point in most investigational studies of disease modifying treatments for AD.

Although it is still too early to be confident of the effect of the drug, this is seen to be positive news given recent failures in a number of key AD studies, with Eli Lilly's solanezumab failing in a late-stage clinical trial for Alzheimer's; Boehringer Ingleheim's BI 409306 failing a Phase II trial; development of Merck's verubecestat being terminated when a second Phase III trial produced disappointing results and vTv Therapeutics's azeliragon missing two major goals in a Phase III trial.

Elenbecestat's mechanism of action is the inhibition of BACE, a key enzyme in the production of Aβ peptides, and this is the first study of a BACE inhibitor to show a statistically significant difference in Aβ in the brain, while also suggesting a delay of clinical symptom decline in exploratory end points.

The drug was discovered by Eisai and has been jointly developed with Biogen since March 2014. Following these encouraging results, the companies will continue to work together on a Phase III programme for the drug.

Eisai and Biogen have a wide collaboration on the joint development and commercialization of Alzheimer's disease treatments. Eisai leads the codevelopment of elenbecestat, and BAN2401, an anti-Aβ protofibril antibody, while Biogen leads the co-development of aducanumab, Biogen's investigational anti-Aβ antibody for patients with Alzheimer's disease, and the companies.

Meanwhile, AstraZeneca (Cambridge, UK) and Eli Lilly and Company (Lilly) (IN, USA) announced that they are discontinuing Phase III clinical trials of their BACE inhibitor, lanabecestat, for the treatment of AD, following recommendations by an independent data monitoring that the studies were unlikely to meet their primary end points [8]. The companies said that drug safety was not an issue and will work to wind down the programs and also consider how they can share data to support further developments of drugs for the treatment of AD.

Teva ends late-stage study of fremanezumab in chronic cluster headache as unlikely to hit main goal

Teva (Petah Tikva, Israel) announced that is terminating a Phase III study for fremanezumab in chronic cluster headache after futility analysis indicated that the primary end point is unlikely to be met [9]. The drug has already completed studies for the treatment of migraine and is under approval review at the FDA and the EMA, although approval is subject to delay due to FDA concerns about it manufacturing partner Celltrion (Incheon, South Korea). Fremanezumab is a CGRP (calcitonin-gene-related peptide) inhibitor, so in the same class as Aimovig (erenumab-aooe), developed by Amgen in collaboration with Novartis and recently cleared by the FDA for the treatment of migraine.

ASCO 2018

The American Association of Clinical Oncology (ASCO) held its annual meeting in Chicago from June 1 to 5 2018 which was attended by around 32,000 delegates from around the world. Some of the key presentations are summarized below:

Bristol-Myers Squibb & Nektar present data on the combination treatment of Opdivo & NKTR-214 in a range of cancers

Bristol-Myers Squibb (BMS) (NY, USA) and Nektar Therapeutics (CA, USA) presented preliminary data from their ongoing Phase I/II Study (PIVOT), evaluating the combination of Opdivo^® (nivolumab) with NKTR-214 [10]. Results presented at the conference were from the Phase I dose-escalation stage of the study and for the first patients consecutively enrolled into a Phase II study that will look at the safety and efficacy of the treatment in 400 patients with melanoma, renal cell cancer, urothelial cancer, non-small-cell lung cancer (NSCLC) and triple negative breast cancers. The results showed responses, including activity in programmed death-ligand 1 (PD-L1) negative patients, with many converting to be PD-L1 positive during the treatment.

PD-L1 is a molecule that inactivates T-cells by binding to the PD1 protein on the surface of activated T cells. As well as being produced by the body to downregulate the immune system, it is also produced by many cancer cells thus shielding them from the immune system. Opdivo's mode of action is to preferentially bind to PD1 receptors over PD-L1, so T-cells can remain active and able to attack the tumor cells. PD-L1 is expressed on 40–50% of melanomas which makes this type of cancer a good target and the indication for which Opdivo was first approved by the FDA and EMEA as a monotherapy in 2014 and 2015, respectively. Other tumor cells also express PD-L1, making checkpoint inhibitors effective in the treatment of some NSCLC and renal cell carcinomas, which have also been approved by the FDA. It has been argued that the use of prognostic biomarkers that measure PD-L1 expression should predict the effectiveness of PD1 inhibitors and approach employed by Merck in the use of their PD1 inhibitor KEYTRUDA^®. However, the situation appears to be more complicated than this, as PD inhibitors can still be effective even at low levels of PD-L1 expression.

As well as being used as a monotherapy, there has been interest in exploring the use of combination therapies in which Opdivo is used alongside another drug as with NKTR-214 in the PIVOT study. NKTR-214 is being developed by Nektar as an investigational drug to increase immune response by increasing the number of activated T-cells and NK cells available to attack the tumor. This can be done alone or with another complementary therapy such as Opdivo.

The results presented, support the effectiveness of Opdivo and NKTR-214 in combination. However there is some controversy in the overall response rate for the treatment appeared to fall, for more recent patients recruited into the study. But a key conclusion is that NKTR-214 appears to make Opdivo work better in PD-1 positive patients and also in PD-1 negative patients who don't normally respond to Opdivo alone, suggesting there are still considerable gaps in understanding of the mechanisms taking place. Based on the results, BMS and Nektar plan to progress to a Phase III registrational study in first-line advanced melanoma patients in Q3 2018, and also continue the design of pivotal studies in renal cell carcinoma and urothelial cancer.

Merck presents results from a Phase III study looking at the use of KEYTRUDA in combination with chemotherapy in the treatment of NSCLC

At the conference, Merck (NJ, USA), known as MSD outside the USA, also provided an update of its anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in the treatment of non-small-cell lung cancer (NSCLC) [11]. The data, from a Phase III study in which KEYTRUDA was administered alongside conventional chemotherapy drug combinations (carboplatin-paclitaxel or nab-paclitaxel) in the treatment of metastatic squamous NSCLC, showed significantly improved overall survival, with a reduction in risk of death by 36% compared with chemotherapy alone. This is the first time that a combination of an anti-PD-1 therapy and chemotherapy has significantly extended overall survival in the first-line treatment of patients with squamous NSCLC. It is also notable that results from prespecified exploratory analyses also showed the overall survival benefit was regardless of PD-L1 expression.

Based on data from the Keynote-407 trial, Merck announced back in May that it had submitted a supplemental Biologics License Application (sBLA) to the FDA for this combination treatment. KEYTRUDA was first approved by the FDA as a monotherapy for the treatment of advanced skin cancers for patients who have already taken Yervoy (ipilimumab) marketed by BMS. Since then it has gained approval in the US, EU and other markets for an increasing number of indications both as a monotherapy and in combination with other treatments.

Merck claims to have industry's largest immuno-oncology clinical research program, with more than 750 trials studying pembrolizumab across a wide variety of cancers and treatment settings both as a monotherapy and in combination with other medications, including around 15 in lung cancer, involving around 900 patients.

Eisai & Merck present data from investigational studies of LENVIMA^® (lenvatinib) & KEYTRUDA^® (pembrolizumab) combination therapy in four different tumor types

In another presentation involving KEYTRUDA, Merck, in collaboration with Eisai, presented results from studies looking at Keytruda in combination with Eisai's LENVIMA^® (lenvatinib), in four different tumor types: unresectable hepatocellular carcinoma, squamous cell carcinoma of the head and neck, advanced renal cell carcinoma and advanced endometrial carcinoma [12]. Results presented for endometrial carcinoma and renal cell carcinoma treatment support the decision to progress the program to Phase III studies which have already commenced. Early Phase Ib open-label for use of the combination in hepatocellular carcinoma with patients for whom no other appropriate therapy was available, showed evidence of response and acceptable tolerability. So the study is now progressing into an expansion study that will include additional patients with no prior systemic therapy for the disease. For squamous cell carcinoma of the head and neck, a Phase Ib/II trial demonstrated promising clinical activity, supporting further evaluation of the combination in patients with this type of cancer.

As mentioned above, KEYTRUDA is a PD-1 inhibitor, already approved for several cancer indications. Lenvatinib, a receptor tyrosine kinase inhibitor that inhibits the kinase activities of VEGF receptors, is already approved in the USA and Europe as a monotherapy for the treatment of refractory thyroid cancer and for use in combination with everolimus, a chemotherapy as a second-line treatment for drug renal cell carcinoma.

The median life expectancy of patients with metastatic renal cell carcinoma has increased with use of drugs targeting the VEGF, but the approach has limitations including drug resistance and that complete response (elimination of the cancer) is rare, resulting in short overall survival times. However, there is evidence that mechanisms of action for VEGF and PD-1 inhibition may result in an increased overall immuno response, targeting the tumor, which provides the rationale for the studies Merck and Eisai are conducting.

In March 2018, Eisai and Merck, entered into a strategic collaboration for co-development and cocommercialization of LENVIMA in global markets, both as monotherapy and in combination with Merck's anti-PD-1 therapy, KEYTRUDA.

Loxo Oncology presents interim clinical data from its study of LOXO-292 in RET-altered cancers

At the conference, Loxo Oncology (CT, USA) also presented clinical data for its drug, LOXO-292, which is being developed to treat a range of cancers including NSCLC, by inhibition of RET kinase [13].

The Phase 1 dose escalation study included 82 patients in eight dose escalation cohorts, with a range of cancers including NSCLC, thyroid and pancreatic. In the study, anti-tumor activity was observed regardless of RET fusion partner, tumor type and prior use of multikinase inhibitors. Response rates of 77% and 45% were seen in RET fusion positive NSCLC and RET-mutated medullary thyroid cancers, respectively. Significantly, 12 participants who had CNS metastases at enrolment did not show progression. Importantly, the data also suggested early evidence of durable activity for the drug, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant medullary thyroid cancer patients remaining on therapy at the cut-off for the presented data. Reduction and clearance of RET alterations in blood plasma samples was also observed and the level of adverse events was good with a relatively small number of more serious events.

The RET gene codes for a transmembrane tyrosine kinase required for development of the kidney and nervous systems. But, mutations in the RET gene and fusion with other genes can result in overactive RET signaling and uncontrolled cell growth giving rise to certain types of cancers, including lung and thyroid. In these cases, inhibition of the RET gene can be an effective treatment. Broad-spectrum tyrosine kinase inhibitors with anti-RET activity are already in use in cancer treatment but their lack of selectivity to RET can result in side effects and loss of efficiency. In contrast, LOXO-292 is highly selective to RET which suggests its will perform better for RET-mutated and RET-fusion positive cancers, as supported by the data presented at the conference.

Loxo said they are now recruiting into the expansion cohort stage of the study at one of the higher doses and they will engage with regulators to determine paths and timelines to product approvals and continue to work with Ilumina (CA, USA), a diagnostic company to develop a companion diagnostic to identify suitable patients.

Celgene & Bluebird Bio provide an update on their second-generation CAR T-cell immunotherapy in the treatment of melanoma

Celgene (NJ, USA) and Bluebird Bio (MA, USA) provided an update on a Phase I study (CRB-401) evaluating bb2121, an anti-BCMA CAR T-cell investigational immunotherapy targeting late-stage relapsed/refractory multiple myeloma [14].

A total of 43 participants were evaluated in the Phase I open-label dose escalation study. They had all had a median of 7 previous treatments for myeloma with poor outcomes. So although the median progression-free survival for patients was estimated as 11.8 months and less than the 12–15 months range anticipated by analysts based on previous work, it is still an impressive result given the study population.

Bb2121, a second-generation CAR T therapy, has received Breakthrough Therapy Designation from the FDA and PRIME eligibility from the EMA, both schemes aim to accelerate the approval of new drugs that address areas of high unmet need.

The CAR T cells used in bb2121 therapy are produced in vitro using the patient's own T cells taken from a sample of the patient's white blood cells. The T cells are then genetically modified in the laboratory to recognize specific proteins found on the surface of cancer cells and then grown to very high numbers before being reintroduced into the patient's body. The bb2121 cells recognize and bind to the B-cell maturation antigen (BCMA), a protein is present on the surface of multiple myeloma cells, killing the tumor cells.

KYMRIAH^® (tisagenlecleucel) developed by Novartis, became the first CAR T therapy (and gene therapy) to be approved by the FDA in August 2017 for the treatment of certain children and young adults with B-cell acute lymphoblastic leukaemia and several other CART T therapies have followed. First-generation CAR T treatments tend to have limited persistence and antitumor efficacy in vivo. Second-generation treatments such as bb2121 include additional cellular signaling to improve potency.

Grail presents results on early cancer detection using high-intensity sequencing

Grail Inc. (CA, USA), a life sciences company focused on the use of high-intensity sequencing approach to detect tumor signals in the blood, announced results from one of its studies in which blood and tumor tissue samples from 124 patients with various advanced cancers were sequenced to see if mutations in tumors could also be detected in blood [15]. In 89% of patients, a signal was detected, indicative of at least one of the cell mutations in the tumor. By cancer types, the results were 97% in patients with breast cancer, 85% in those with lung cancer and 84% in those with prostate cancer. They also detected some cancer related mutations in the bloodstream that were not found in the tumor tissue. Further analyses of these data are on-going to determine their source.

In a poster presentation also given at the conference, Grail presented results from a study comparing mutations in circulating cell-free DNA (cfDNA) with those from white blood cells in both people with advanced cancers and with those who were free of the disease. They concluded that a substantial number of circulating cell-free DNA mutations are attributable to mutation in white cells rather than from any cancer tumors. This work will help the company develop a model to better help distinguish signal from tumor cells.

Grail is targeting the detection of early stage cancer at which stage treatment using drugs should be easier and more effective. It has two on-going studies; CGGA, and observational study characterizing extracellular nucleic acid profiles in 7000 people with cancer and 3000 without; and the STRIVE study which is a longitudinal, prospective, observational cohort study that will evaluate a blood test for the early detection of breast cancer in a cohort of 120,000 women.

Grail, a spinout from Ilumina, has raised $1.6 billion in venture funding but is still a long way from being able to detect cancer in otherwise healthy people. Experts believe this requires the ability to achieve detection rates in early stage cancers in excess of 80% and with very few false-positives. At present, false-positives are around 1–2% which, although low, would still equate to millions of people if the tests were implemented in a large screening program. But the fact Grail can detect DNA fragments in the blood that have been secreted by cancer cells is a very significant step towards this goal.

Executive summary

• This Industry Update covers the period from 1 June through to 30 June 2018, and is based on information sourced from company press releases, scientific literature, patents and various news websites.

• The month saw the staging of American Society of Clinical Oncology Annual Meeting (ASCO) 2018 (Chicago, IL June 1–5), a leading oncology conference, at which updates on several drug trials were presented. Bristol-Myers Squibb (NY, USA) and Nektar (NY, USA) presented encouraging results from an early stage study looking at the effectiveness of a combination of Opdivo and NKTR-214 in a range of cancers. Merck (NJ, USA), made several presentations on its PD-1 inhibitor, Keytruda, including in combination with chemotherapy in the treatment of non-small-cell lung cancer in a Phase III study, and with Eisai's (NJ, USA) LENVIMA^® (lenvatinib) for several tumor types in early studies that demonstrated promising clinical activity. There were also updates from Loxo Oncology (CT, USA) and a collaboration between Celgene (NJ, USA) and Bluebird Bio (MA, USA), focusing on CAR-T therapy. Grail Inc (CA, USA), presented data for high-intensity sequencing approach to detection of tumor signals in the blood, that offer hope that it will be able to provide a diagnostic for very early detection of cancer.

• In other indications, there were encouraging results from Biogen (MA, USA) and Eisai for their BACE inhibitor being developed for the treatment of Alzheimer's, but failure of AstraZeneca and Lilly for their treatment in the same indication.

• The month also saw an approval by the US FDA of GW Pharmaceutical's (London, UK) cannabidiol drug for the treatment of epilepsy, but a further rejection for Mylan's generic version of Advair, a respiratory drug, although this time round the issues were said to be minor.

• Finally on the commercial front, Novartis (Basel, Switzerland) announced that it will spin off its ophthalmology business, Alcon as a separate company and Oxford Biomedica (Oxford, UK) and Axovant (Basel, Switzerland) announced a license deal for the former's gene therapy treatment for Parkinson's disease.

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.