HIV Therapy: Safer, simpler and longer-lasting

World AIDS day on Sunday, December 1 drew attention to the 38 million people still living with the human immunodeficiency virus (HIV), and the over 777,000 deaths claimed in 2018 by the virus. But there is lots of good news, too. Well over half of those with HIV can now access effective anti-retroviral therapy – three times as many as in 2010. The rate of new infections has fallen by 40% since the 1997 peak, according to UNAIDS.

HIV therapy researchers are now focused on developing more convenient regimens with fewer side-effects, but equal or better efficacy. These include combinations that involve fewer daily pills, or implants that may remove the need for any daily therapy at all. There is also promising work developing a vaccine for the condition.

HIV is a retrovirus that infects immune system cells, weakening the body’s defences and ultimately resulting in acquired immunodeficiency syndrome (AIDS).

Gilead – with over half of the estimated $28 billion global HIV therapy market – is the player to beat. The company sells a range of combination therapies, including Atripla (a triple combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate), Truvada (a dual combo of emtricitabine/tenofovir disoproxil fumarate), or Complera (emtricitabine / rilpirivine/tenofovir disoproxil fumarate). Newer drugs like Genvoya and Biktarvy have rapidly gained share, however, thanks to improved, safer constituent chemicals.

Genvoya is Gilead’s largest drug (2018 sales: $4.62 billion). It is a single-tablet regimen which combines elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (shortened to TAF). It is the top-prescribed drug in the US in all patients, thanks in part to safety advantages of TAF over the older tenofovir disoproxil fumarate (TDF) formulation.

Those advantages relate to renal and bone mineral density side-effects. (TAF is a pro-drug formulation of tenofovir with lower serum concentrations as a result.) Given that these therapies are taken over long time periods, keeping the virus at bay for many millions, the

risk profile is particularly important. All TAF-based regimens are gradually gaining market share over older alternatives.

Yet Genvoya faces a rival in Gilead’s own Biktarvy (bictegravir/emtricitabine/TAF) in treatment-naïve patients. That’s because of an improvement to another of the constituent drugs, the integrase inhibitor. By using longer-lasting bictegravir instead of elvitegravir, drug resistance reduces, and there is no need for a metabolic booster, cobicistat, to inhibit breakdown. That means fewer chemicals, and a lower risk of GI-related side-effects. Biktarvy is also, like Genvoya, a single-pill, and “it is a relatively cheap treatment option,” according to one German KOL.

GlaxoSmithKline is going after a two-drug regimen it hopes will be as effective as Gilead’s three-way Biktarvy, in its bid to gain market share. Its majority-owned ViiV subsidiary recently announced results of a 96-week trial of Dovato, combining dolutegravir and lamivudine. The data showed that Dovato was as effective as a three-drug treatment at suppressing the virus, and no patients developed resistance, which is another problem for HIV treatments.

It will take time – and more than a single study – to convince physicians to abandon what they know works. But GSK has provided a tail-wind for Dovato by pricing it lower than Biktarvy (though actual prices paid for medicines are notoriously opaque, especially in the US).

Ultimately, however, fewer drugs are likely to mean fewer side-effects, and that should mean greater compliance and hence better outcomes. Treatments that are administered less regularly may also lead to better outcomes: that is what Merck & Co. is betting on with MK-8591, a Phase IIb compound with a novel mechanism of action that is more potent than other treatments, and which has a long-half life, meaning it stays in the cells for longer than existing therapies. That could reduce the likelihood of drug resistance, and could also allow it to be delivered as an implant. Other early stage research is looking at implant-based HIV therapies that are released slowly into the circulation and remove the need for daily pills.

Prevention is another important line of attack against HIV. Experts are optimistic that an HIV vaccine may become a reality; late-stage trials of three vaccine candidates are underway, with the first results due in early 2021. HVTN 702 completed enrolment of over 2500 women in southern Africa earlier in 2019 (women between the ages of 18-25 have a 50% infection rate). Imbokodo and Mosaico use a variety of immunogens to protect against a wide range of HIV strains; their trials are slightly further behind.

If these vaccines do prove effective, they will likely require multiple injections, and different doses. So they are unlikely to prove a panacea. But prophylaxis is already gaining traction: PrEP (pre-exposure prophylaxis) involves administering HIV therapy to patients who don’t show any signs of disease, in order to prevent infection. Gilead’s Truvada is used as PrEP, but the approach is not sufficiently widespread to prevent the virus’ spread.

Gilead continues to cover its bases. It is working on positioning Descovy (emtricitabine/TAF) as a PrEP drug of choice, given pending generic competition to Truvada, and claims of better

safety, faster onset and longer duration of action. In early November 2019, the company presented promising Phase 1 data from GS-6207, which may be effective dosed only every six-months. The candidate is an HIV-1 capsid inhibitor, which has shown potent activity and good tolerability among a broad range of patients with varying treatment histories.

As HIV therapy becomes safer, more convenient and longer-acting, Gilead hopes that its current and future candidates will remain a core component of that future treatment landscape. Competition from GSK is good news for patients and payers, since it brings in pricing as a key differentiator.

Immunotherapies battle for lead in lung cancer

Much of the buzz in lung cancer is around new immunotherapy combinations – and whether recent data from Bristol Myers Squibb will allow it to regain ground from market-leader Merck, whose Keytruda (pembrolizumab) continues to lead the pack.

 

Bristol in September 2019 released data showing that combining two of its immuno-therapy drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), improved life-expectancy, relative to chemotherapy alone, among some patients with advanced non-small cell lung cancer (NSCLC). After two years, 40% of patients on the combination were alive, versus just 33% on chemotherapy only. The data was presented at the European Society for Medical Oncology meeting.

 

Will it be enough to unseat Keytruda? Bristol’s challenge is that Keytruda is the immuno-therapy of choice in NSCLC (and many of the other almost two dozen cancer indications it is approved in), thanks to steadily accumulating – and compelling – efficacy data. Alongside chemotherapy as frontline treatment, Keytruda is shown to reduce the risk of death among metastatic NSCLC patients by over 50%. It also works in a widening group of advanced NSCLC patients. Initially approved only for patients showing at least 1% expression of the PD-L1 protein that the drug blocks, recent data shows that even patients with low or no PD-L1 expression can benefit. And Keytruda’s once-every-three-week administration fits conveniently alongside chemo, minimising the practical therapy burden.

 

Bristol claims that its checkpoint inhibitor combination provides an option for those that cannot or will not tolerate chemotherapy. The September data marked the first time a dual immunotherapy had shown superior overall survival over chemo in the first-line NSCLC setting, the company said. And, as for Keytruda, those improved survival rates held for patients with lower PD-L1 levels, too.

 

The lack of head-to-head studies comparing Keytruda efficacy head-on with Yervoy/Opdivo makes accurate comparisons difficult, though. And not everyone agrees on the rationale to skip chemo; indeed, Bristol is also testing the combo with chemotherapy. An interim analyses reported in October from another Phase III suggested that the three therapies could also improve overall survival versus chemotherapy alone, though full data has not been released.

Another issue for Bristol is that Opdivo has not stacked up as a monotherapy in first-line lung cancer: it was found in an earlier study to decrease overall survival versus chemotherapy. Opdivo is approved in various lung cancer settings as second-line therapy.

 

Yervoy, meanwhile, suffers from well-known toxicity risks. (This drug targets CTLA4, a protein expressed on T-cells.) Side-effects put an end to a 2017 trial of full-dose Yervoy with Opdivo in lung cancer. The recent combination studies used a lower dose of Yervoy, but even then, a third of patients in the trial reported in September suffered treatment-related adverse events.

 

“My treatment choice [in NSCLC] is Keytruda, since it fits nicely with the chemo dosing schedule,” said one US key opinion leader, speaking before the recent Bristol data was released. “The toxicity of combining two immuno-therapy agents puts me off, though some patients may benefit,” he continues.

 

But with “almost every patient now eligible for an immuno-therapy,” according to the physician, further combinations and options will find their place. AstraZeneca is testing a PD-L1/CTLA4 combination that looks similar to Yervoy/Opdivo, though read-out has been delayed to 2021.

 

Immuno-therapies can significantly improve the outlook for many lung cancer patients. As experience with these treatments grows, physicians are also getting better at managing associated toxicities.

 

Bristol’s combination, after twists and turns in the history of both agents, may offer some patients an important treatment option. But Keytruda’s dominance looks set to continue – including ex-US. The UK National Health Service – notoriously selective in what it funds – recently agreed to pay for Keytruda in the first-line setting for metastatic NSCLC patients, though the funding will come from the ring-fenced Cancer Drugs Fund until more mature evidence is available.

 

Analysts predict that the drug will take Humira’s place as the world’s top-selling drug in the next five years, with over $22 billion in forecast sales by 2025. Opdivo is not doing badly either: it sold $6.7 billion in 2018 across multiple cancers. But for now it is still playing second fiddle.

From Herceptin to Rozlytrek: how cancer drugs are getting more personalized

In August 2019, the US FDA approved Roche’s Rozlytrek (entrectinib) for cancer patients whose solid tumors harbor a particular genetic mutation called NTRK. The approval comes more than 20 years after the very first ‘targeted’ breast cancer therapy reached the market – Genentech (now Roche)’s Herceptin (trastuzumab).

The two drugs illustrate how cancer therapies have evolved to treat ever more narrowly-defined groups of patients. Herceptin helps the approximately 20% of breast cancer patients whose tumors over-express the HER2 protein, which can accelerate cancer cell growth. Rozlytrek is only likely to help 2% of breast cancer patients – those whose neurotrophic tyrosine receptor kinase genes have fused with other proteins to cause unwanted cell proliferation. It is the third FDA-approved “tissue agnostic” cancer therapy – one defined by tumors’ genetic signature, not by their location in the body.

Herceptin has been a huge success, and multiple copycat biosimilar versions are now available, both in Europe and the US. Rozlytrek’s success will be spread across a far wider range of cancer types – including colorectal, neuro-endocrine, non-small cell lung, pancreatic and thyroid cancers. The drug also received a tissue-specific designation, for the approximately 2% of metastatic non-small cell lung cancers that are positive for the ROS1 gene, which codes for a tyrosine kinase.

Rozlytrek will not enjoy the same first-mover advantage that Roche had with Herceptin. Bayer’s Vitrakvi (larotrectinib), approved by the FDA late 2018, also helps patients with NTRK-positive solid tumors, including breast tumors, setting up a head-long battle between the two companies. (Vitrakvi received a positive opinion from the EU’s CHMP in July 2019.)

Roche showed the strength of its intent to gain market share from its rival by pricing Rozlytrek at almost half the level of Vitrakvi – $17,000 per month, versus $33,000 for Vitrakvi. The drugs are not identical: trials showed different overall response rates, though the patient populations were different, making it tricky to draw conclusions. Yet Roche is in fact fighting two battles, in parallel with the drug’s two approved indications. One battle is

against Bayer (which acquired full rights to Vitrakvi from partner Loxo Oncology after Eli Lilly paid $8 billion to acquire Loxo in January 2019) and the other is against Pfizer, whose Xalkori is approved in the same ROS1-positive NSCLC setting as Rozlytrek.

Roche may have an advantage over both its rivals. For one thing, it has the most to lose: oncology makes up about half its total sales. As generics hit several of its blockbusters, the group has spent many billions buying oncology-focused data to improve diagnosis, trial recruitment and drug development. It also has a diagnostics business. Diagnostic testing is increasingly important to determine which patients can benefit from these increasingly narrowly-targeted medicines. Roche plans to launch a companion diagnostic test for Rozlytrek via its Foundation Medicine subsidiary; once it does, this may provide Roche with another weapon against its competitors. Finding patients with NTRK fusion genes isn’t easy, since these rare mutations are not routinely tested for. If Roche can find a way to incentivize more physicians to use its test – a big if – they are then more likely to use the associated drug.

Bayer, meanwhile, is embroiled in litigation within its agri-division (where it owns seed-maker Monsanto) accusing it of indirectly causing cancer via its Roundup weed-killer product. This may not help the company’s image as a provider of cancer therapies.

Both it and Roche may face another competitor if Turning Point Therapeutics’ repotrectinib gets through its current Phase 1/2 trial in patients with advanced TRK-positive solid tumors and ROS-1 positive NSCLC.

Breast cancer is now thought of as survivable in many cases, given a wide range of effective treatments, including Herceptin. But there are hurdles to surmount before even approved drugs like Rozyltrek are routinely available in many markets. The UK’s NICE is likely to push back on price, even before practicalities such as diagnostic testing have been sorted out.

And while battles are fought for these ever-thinner slices of the oncology market, there remains an important unmet need in the 10-20% of breast cancers that are designated ‘triple negative’ – meaning they are not fuelled by estrogen or progesterone, or by the HER2 protein that Herceptin goes after. There are medicines available for this category – including PARP inhibitors like Lynparza (olaparib) for patients with BRCA1 or BRCA2 mutations, or immune-therapy Tecentriq (atezolizumab) which targets the PD-L1 protein that helps cancer cells hide from the immune system. But they don’t help everyone.

And the first tissue-agnostic medicine to be approved, Merck’s top-selling immuno-therapy drug Keytruda (pembrolizumab), recently failed to improve overall survival compared to chemotherapy as second- or third-line monotherapy treatment in patients with metastatic triple negative breast cancer.

Breast cancer is one of the few cancer-types for which Keytruda is not approved

Tackling hypertension

Nearly one half of American adults suffer from hypertension, or high blood pressure. Globally, there are over 1 billion people with the disease – a figure that has doubled over the last 40 years. The World Health Organization estimates that hypertension causes 7.5 million deaths each year.

 

The issue is not a lack of medication. There are dozens of treatments for hypertension, which work variously to reduce vascular tension and slow down the heart; many are generic. The first problem is that high blood pressure may build up slowly and with few symptoms, silently increasing people’s risk of heart failure, stroke and kidney disease without their awareness. The second problem is that even when hypertension is diagnosed, managing it can be a challenge. Patients have to remember to take multiple pills on a daily or weekly basis. And since you can’t reliably ‘feel’ blood pressure, monitoring is required to ensure it is within a safe range.

 

Sending all hypertensive patients for regular doctor’s checks is not feasible or sustainable, either for the individuals or the health system. Technology may be able to help: patients can now use Bluetooth-enabled blood pressure devices at home; apps can help remind them to take their medication; treatment algorithms can help direct clinicians toward the most effective and convenient drug regimens for a given individual. Drug categories associated with certain side-effects can be avoided: angiotensin-converting enzyme (ACE) inhibitors, for example, cause a cough that can lead to discontinuation. Angiotensin receptor blockers work similarly well, without the side-effect.

 

These are some of the features of a new home-based, care delivery program developed at Brigham and Women’s Hospital in Boston, MA. A pilot study among 130 participants, published in Clinical Cardiology in January 2019, helped over 80% of them bring their blood pressure under control in an average of seven weeks. The participants received devices that automatically transmitted readings to their medical records. They were able to talk regularly to specialists trained to use a treatment algorithm designed, in accordance with NICE and ACC/AHA guidelines, to optimally adjust medication dose and mix according to patients’ outcomes and needs. For example, combination drugs may be prescribed to reduce pill burden and encourage maintenance treatment among those who have achieved control.

 

Most cases of hypertension can be adequately controlled by current medication, if taken appropriately. A minority of patients may have resistant hypertension, however – when blood pressure remains stubbornly high despite treatment with at least three standard drug classes. Several drug development programs focus on resistant hypertension, aiming to widen the choice of fourth medications available to patients with this condition.

 

One of them is Idorsia’s Phase III candidate, aprocitentan, in development with Janssen – part of the same Johnson & Johnson that bought Idorsia’s parent company, Actelion, in 2018. The drug works by blocking the action of endothelin, which causes vessels to constrict. Aprocitentan is in the same class as Actelion’s Tracleer (bosentan), which helped build Actelion into Europe’s leading biotech, and follow-on Opsumit (macitentan). Tracleer and Opsumit are used for a rare vascular disease called pulmonary arterial hypertension, characterized by abnormally high pressure in the blood vessels of the lung.

 

Novartis’ neprilysin inhibitor, LHW090, is in Phase II development for resistant hypertension and chronic renal insufficiency; it works to widen blood vessels and encourages salt excretion in the urine.  France’s Quantum Genomics thinks that its brain aminopeptidase A inhibitor candidate, firibastat, may offer a solution by combining multiple mechanisms in one – diuretic (eliminating water and salt to reduce blood volume), vasodilation (reducing vessel wall pressure) and lowering heart rate via the baroreflex. Firibastat has completed a Phase IIb trial.

 

Resistant hypertension is a challenging area for smaller companies, given the need to perform combination studies with other widely-used anti-hypertensives. The size of the studies required and the pricing achievable for such treatments may also provide a less compelling commercial proposition than rare diseases or other niche, underserved segments.

Big Pharma’s Psoriasis Battleground

Psoriasis is a key battleground for several Big Pharma, seeking to gain or maintain market share for their biologic drugs in the face of growing competition – including cheaper copies of AbbVie’s Humira (adalimumab), whose multiple licensed indications include psoriasis.

It is all good news for the estimated 125 million patients suffering with this chronic, inflammatory skin disease, who now enjoy a much wider range of treatment options. Psoriasis is characterised by scaly, crusty lesions on the skin, scalp or nails, which can be sore and itchy, and are caused by abnormally rapid skin-cell growth cycles. Symptoms may come and go; stress and diet just two of the possible triggers. Although scientists understand a lot more about psoriasis than they did 20 years ago, the exact cellular mechanisms of this auto-immune disorder remain elusive.

 

Hence there is no cure for psoriasis. Treatment may begin with vitamin D analogs or topical corticosteroids, progressing to photo-therapy, systemic oral drugs such as ciclosporin or methotrexate and, in the most severe cases, injectable biologics such as Humira, Remicade and a growing cohort of monoclonal antibodies that target pro-inflammatory molecules called cytokines.

 

It is here – among the injectable therapies for psoriasis – that the clinical and commercial battle is being fought most vigorously. AbbVie’s IL-23 inhibitor Skyrizi (risankizumab) is the most recent entrant, gaining approval earlier in 2019 in the US and Europe for patients with mid- to severe plaque psoriasis. It is hoping the drug will contribute $5 billion (across several indications) to revenues by 2023, helping plug at least a bit of the gaping hole left by the $20 billion Humira juggernaut. Meanwhile, the company continues to defend Humira against the biosimilar onslaught, already underway in Europe, and due to hit the US in 2023.

 

Indeed, AbbVie licensed Skyrizi, in 2016, from the very same Boehringer Ingelheim that is now snapping at its heels with a biosimilar adalimumab. The companies settled some patent litigation in May 2019, delaying BI’s biosimilar launch in the US until July 2023 and putting the German company on the hook for IP-related royalty payments. But royalties may flow the other way, too, if Skyrizi sells as well as the partners hope.

 

One tailwind may come from Johnson & Johnson’s Phase III ECLIPSE study, which pitted its own Tremfya (guselkumab) head-to-head against Novartis’ top-selling Cosentyx (secukinumab). Tremfya, like Skyrizi, inhibits an inflammation-linked cytokine called IL-23, while Cosentyx targets IL-17A. Data from ECLIPSE, published in December 2018, showed that Tremfya improved patients’ psoriasis severity scores more than Cosentyx did. That could pull Skyrizi along too –plus the AbbVie drug is dosed quarterly, rather than once every two months as for Tremfya, potentially adding points for convenience.

 

Novartis is not sitting still, however. With 2018 sales of $2.8 billion, Cosentyx is the Swiss group’s largest drug, and it is growing strongly across psoriasis and related conditions such as psoriatic arthritis (swelling and pain in the joints) and ankylosing spondylitis (inflammation of the spinal joints). Cosentyx has over five years’ worth of efficacy and safety data from the over 200,000 patients treated so far. The Swiss group is aggressively defending its territory with further clinical studies.

 

These include ARROW, designed to prove that targeting IL-17A is more effective, mechanistically, than hitting IL-23. Novartis believes that IL-17 is a more pivotal cytokine, common to more disease-causing pathways than IL-23.

 

ARROW is expected to read out at the end of 2019. Meanwhile, other players like Eli Lilly with IL-17A inhibitor Taltz (ixekizumab) are themselves trying to find a competitive edge: Lilly is pushing the drug’s effectiveness in the long-term (five-year) maintenance of clear skin.

NASH: The silent killer

NASH – non-alcoholic steatohepatitis – is an increasingly prevalent liver disease. It is characterized by a build-up of fat in the liver, plus cellular damage, often including inflammation and fibrosis. NASH typically has few noticeable symptoms until it becomes very serious. That can mean liver cancer, and/or liver failure. NASH is the fastest growing cause of liver transplant in the US.

The condition is tightly associated with metabolic disease and obesity, and already affects about one in eight of the adult population. No treatment for NASH exists – yet. But with this ‘disease of affluence’ expected to spread across more than five times as many people by 2030, representing a $20-30 billion market, drug developers are scrambling to find an answer.

It has not been an easy quest. Like its co-morbidities, obesity and diabetes, this is a complex, multi-factorial disease that likely requires an equally multi-pronged treatment approach – and behavioral change. UK guidelines recommend life-style adjustments (e.g. healthier eating and more physical activity) in the first-line setting, though in the US early pharmacological intervention is preferred. Currently, diabetes drugs such as metformin are often used to treat NASH.

Gilead – which made billions from its treatments for another kind of liver disease, Hepatitis C – saw its Phase III trial of NASH hopeful selonsertib fail earlier in 2019. But it is not giving up. In April, it joined forces with diabetes leader Novo Nordisk to take into trials a three-way combination, using two of Gilead’s other NASH development candidates plus Novo’s oral GLP-1 agonist, semaglutide. Semaglutide (branded Ozempic) has already expanded its reach from diabetes into obesity, and is in the clinic as a NASH monotherapy. The two Gilead compounds have also already, as a duo, shown promise in improving steatosis and markers of liver fibrosis.

There are many other NASH players. Madrigal Pharmaceuticals in March 2019 began a Phase 3 trial of its once daily, oral thyroid hormone receptor agonist, resmetirom. Israel’s Galmed Pharmaceuticals is planning Phase 3 trials of its fatty acid bile acid conjugate, Aramchol. This compound works by altering how fats – lipids – are metabolized in the liver. Aramchol showed beneficial effects on NASH markers, including fibrosis, in a Phase 2b study. The compound has Fast Track designation from FDA.

M&A activity in NASH has been plentiful in recent years. In 2016, Allergan acquired Tobira Therapeutics for $1.7 billion, and Gilead paid $400 million up-front (and may pay twice that in milestones) for Nimbus Apollo. (The year before, it bought a $470 million NASH program from Phenex).

Johnson & Johnson, Novartis (which bought emricasan from Conatus in December 2016) and Pfizer are among the Big Pharmas who are active in NASH. Some big players are teaming up to crack this challenge: Pfizer and Novartis joined forces in October 2018 to perform a combination study involving tropifexor (a Novartis asset) with one or more Pfizer compounds. AbbVie and Takeda are also in the mix, having acquired Allergan and Shire, respectively – each with NASH interests.

Now it is all about clinical results, as sponsors determine whether they are any closer to addressing what Galmed calls an “emerging world crisis”. With several Phase 3 NASH trials starting or reading out, developers will soon have more clues as to the most promising treatment strategies, if not a treatment itself.

Ultimately, though, the solution to NASH – like its sister conditions, obesity and diabetes – is healthier, more active lifestyles.

Hepatitis drugs are effective and ever-cheaper. Yet the disease still kills.

There are plenty of good news stories around hepatitis. Effective, and ever-cheaper treatments are available for both hepatitis B (HBV) and C (HCV), two common strains of this viral condition. HCV can be cured almost completely, thanks to the therapy revolution brought about by Gilead’s Sovaldi (sofosbuvir) starting in 2014. The A and B strains of the disease can be prevented with vaccination.  

Sovaldi’s success – the drug sold $10 billion in its first full year on the market – was also a good news story for Gilead’s shareholders. The company pulled in more than $50 billion from its hepatitis franchise between 2014 and 2017. Sovaldi famously cost $1000 per pill, or $84,000 per typical treatment course in the US.

That particular party did not last long: competition forced down prices, while market demand started to reduce as patients were effectively treated. Competition provided much-needed good news for payers, however, clobbered with astronomical bills during 2014 and 2015 but in a strong position to negotiate thereafter. That, in turn, meant more good news for patients, not all of whom had been able to access the cure at its starting price. Competition also brought more convenient, shorter treatment regimens, covering a wider range of virus genotypes. Latecomer AbbVie scooped in a not-unreasonable $3.44 billion in 2018 from HCV drug Mavyret, whose list price is 60% lower than Sovaldi’s was. Those Mavyret sales were worth more than Gilead’s entire HCV franchise that year.

Large price cuts for HCV medicines in the Western world have come alongside lower HBV treatment costs, including through generic versions of the antivirals entecavir and tenofovir, according to the World Health Organization.

Yet, despite this, 300 million people across the world are still living with hepatitis, many of them in low and middle income countries, says the World Hepatitis Alliance. Hepatitis can trigger acute and chronic infections and, in some cases, liver cirrhosis and even a need for transplant. But symptoms do not always appear, especially in the early stages. About half of people suffering with HCV don’t know they have it.

The remaining challenges are awareness and diagnosis. Don’t rely too heavily on pharmaceutical companies for that – most are losing interest in what is, for most, a declining franchise. Gilead, struggling to fill the gap left by its once-booming HCV franchise, is moving into a very crowded, and challenging hematology space, and seeking to address other kinds of liver conditions such as non-alcoholic steatohepatitis (NASH – another crowding space). Johnson & Johnson and Merck are among those to have dis-continued HCV pipeline regimens. And Mavyret won’t plug the $20 billion hole that AbbVie will face when Humira goes generic in 2023, either – hence AbbVie’s $63 billion offer to buy Allergan.

Access to adequate testing facilities and affordable diagnostic tools is the main barrier to eliminating viral hepatitis by 2030 – a goal which all countries signed up to, but which only a dozen countries are currently on track to achieve, according to the World Hepatitis Alliance.  Sovaldi brought about a treatment revolution in HCV. Another revolution is required to ensure all those who need that treatment actually receive it.

Could the gut microbiome help manage diabetes?

Diabetes remains one of the most prevalent and costliest disorders, despite a wide palette of available treatments.

Leading diabetes players continue to churn out more convenient versions of their drugs, grappling for share in a highly competitive, price-pressured market.  Novo Nordisk recently invested in a short-cut route-to-market for its oral GLP-1 agonist, semaglutide, buying a priority review voucher from another company that may allow it to launch three months earlier.

GLP-1 agonists, like Novo’s own once-daily injectable, Victoza, have proven effective among many thousands of patients. They can help delay patients’ move onto insulin, and are much easier to use.

But the growth in diabetes prevalence means that new approaches are needed. Drugs are effective when they’re taken properly, but most often, they aren’t. Technology is helping – “intelligent” insulin pens, connected glucose monitors and apps to encourage healthy behavior and medication adherence are proliferating. The diabetes challenge has also drawn in behavioural psychologists and urban planners.

The gut microbiome may be the next frontier in battling diabetes. Research is uncovering a key role for the gut flora in many diseases, not just gastro-intestinal conditions but also cancers, auto-immune, endocrine and even central nervous system disorders. Gut bacteria are now understood to communicate with the brain and influence behavior – including, in some cases, by generating neurotransmitters like serotonin, gamma-aminobutyric acid (GABA) or dopamine.

An imbalance in the gut microbiome has already been associated with the development of insulin resistance in Type 2 (acquired) diabetes. Shifts in the gut microbiota can alter host metabolism – shifting it toward greater energy-harvesting and fat-deposition, for instance, or, potentially, driving appetite even when energy stores are replete.

The precise mechanisms and molecules involved, along with causal links, remain to be figured out. But it seems intuitive that gut health will impact diabetes, not least as this is a disease exacerbated by a high-fat diet. If, as is now believed, the gut influences behavior too, then a gut-microbiome-targeted approach could provide an effective solution for the many diabetics who cannot control their condition using existing therapies and tools.

Novo has been working since mid-2018 with Kallyope to uncover novel peptides to treat diabetes and obesity. New York City-based Kallyope is one of a handful of biotech companies seeking new therapeutic approaches through harnessing the “gut-brain axis” – the multiple two-way communication channels (neuronal, endocrine and humoral) between head and stomach.

The effort is still in discovery. But if drugs or nutritional supplements could be found that modulate both physiology (blood sugar regulation, energy homeostasis, insulin resistance) and psychology (appetite, willpower), this could prove a very useful addition to the diabetes toolbox.  

TargEDys in France already markets an appetite-regulating probiotic, ProbioSatys. Available over-the-counter, it allegedly promotes a feeling of fullness by providing a protein, ClpB, which mimics a satiety hormone called alpha-MSH. ClpB is produced naturally by certain types of gut bacteria. Its action is two-pronged – it enters the blood stream to act directly on the central nervous system, but also stimulates intestinal endocrine cells to produce more alpha-MSH. ProbioSatys is designed to enhance those natural regulatory pathways.

A trial is underway among 236 overweight people, to assess the supplement’s impact on weight, as well as its tolerability and safety, over a 12-week period versus placebo. The estimated completion date is August 2019, according to clinicaltrials.gov.

Cervical cancer screening comes to your mobile phone

Effective screening programs have helped reduce cervical cancer-linked mortality by over 50% in the last forty years. But thousands of women still die each year from the disease, including many in developing countries with little or no access to screening and early diagnosis.

New technologies and artificial intelligence-based software are now making cervical cancer screening and detection easier and cheaper, and opening it up to non-specialists – including, potentially, the patients themselves.

Scientists at Duke University in Durham, North Carolina, have developed a pocket-sized colposcope – a small camera – which can be used to generate clear images of the cervix without the use of a speculum. The device, which is far smaller and cheaper than a conventional colposcope, can be inserted as easily as a tampon, by the woman herself or a non-specialist health provider. It has FDA clearance and has been tested in eight countries and over 1000 women, across the US, Peru and some African nations.

If it gains traction, the device would enable community clinics and relatively unskilled providers to detect and potentially treat cervical cancer much earlier – at the screening stage, when the traditional pap smear happens. (Colposcopy is the more involved procedure that follows a positive smear test.)

The Duke researchers are also working on algorithms that could help non-specialists detect abnormalities in the images generated by the device, and even on ways to treat early stage, pre-invasive cancer. These include an ethanol-based gel that could target and destroy cancerous lesions, scalpel-free.

Israel-based Mobile ODT is pursuing a similar goal. Its ‘smart’ colposcope, which generates advanced images of the cervix on a mobile phone, is already used in 29 countries including the US. And it has recently been enhanced with an artificial-intelligence based algorithm trained to detect abnormalities in the images. A study among 212 patients in South Korea suggests that the algorithm may be better at detecting pre-cancerous or cancerous lesions than trained humans using pap cytology. And it can do so much faster – in one minute, while the patient is still present, rather than in days.

That study was only a pilot. But the potential of artificial intelligence in medical imaging more generally is already proven, making it likely that cervical screening and early detection will continue to become more widely available.

More treatments are on the way for metastatic or recurrent cervical cancer, which remains the biggest unmet need. But there are bumps in the road: FDA in January 2019 placed a partial hold on Advaxis’ Phase III study of therapeutic cancer vaccine Axal, following a trial re-design. Two earlier trials, including combination studies, were forcibly halted due to patient deaths. Axal is a strain of listeria bacteria programmed to generate cancer-targeting T cells.

Regeneron/Sanofi’s checkpoint inhibitor Libtayo (cemiplimab), meanwhile, has shown early promise both as monotherapy and in combination with radiotherapy in early clinical trials of patients with advanced or recurrent cancer; a larger Phase III is underway. Checkpoint inhibitors like Libtayo have thus far not proven very effective in first-line cervical cancer, where platinum-based therapies and Avastin dominate.

A Big R&D Challenge

Lupus is a very challenging disease to treat effectively. This chronic, auto-immune disorder can affect multiple organs and systems, including joints, skin, the kidneys, brain, heart or lungs. It manifests very differently across the estimated 150 –per- 100,000 people worldwide with the condition – most of whom are women.

Only one drug, GlaxoSmithKline’s belimumab (Benlysta), is approved specifically for systemic lupus erythematosus (SLE), the most common form of the condition. The drug is a monoclonal antibody that dampens the activity of B cells within the immune system.  But Benlysta does not work for everyone. And it’s indicated as an add-on therapy for those whose disease has not responded to standard, more generic treatments currently used to alleviate symptoms. These include glucocorticosteroids, non-steroidal anti-inflammatory drugs and other immune-suppressive treatments.

The good news is that Benlysta was approved in April 2019 for use in children suffering from lupus. The condition is often more aggressive in children, and damage can accrue very fast. Despite this, lupus remains a high unmet need.  All current treatments come with significant side-effects, and cannot be tolerated by all patients. None provides anything near a cure. The upshot: poor quality of life for many, and high co-morbidity rates.

The disease’s heterogeneity makes it very tricky to define and accurately measure appropriate end-points during clinical trials. Multiple, sometimes organ-specific instruments may be required; each must be reliable and responsive to changes in symptoms. Many clinical trials have failed primary and secondary endpoints, in part due to this measurement challenge.

Bristol Myers-Squibb’s Orencia (abatacept) inhibits the activation of T-cells, another kind of immune system cell. It joined the ranks of disappointing Phase III results in lupus during 2018, after failing to meet a primary endpoint of complete renal response at one year. BMS promised more analysis, after noticing some positive signs among sub-groups.

AstraZeneca’s anifrolumab also flunked a Phase III trial in 2018. Anifrolumab is an antibody that neutralizes the receptors of interferon type 1, one of the proteins that regulate the immune system. It failed to reduce disease activity at 12 months, as measured by an index of 12 symptoms.

Anifrolumab and abatacept remain in their respective sponsors’ pipeline charts. So does Merck Serono’s Phase II fusion protein, atacicept, and ImmuPharma’s Lupuzor, a T-cell modulator. Lupuzor’s Phase III results did not quite make the mark, either – as measured by the SLE Responder Index, a composite outcome designed specifically for SLE.  But ImmuPharma has announced an extension to the trial, and still hopes that its candidate may make it to market, potentially as a disease –modifying agent, rather than just a symptom-treater. (A partner has proven hard to come by, however.)

Although lupus remains un-tamed, hope remains for patients. Growth in disease prevalence should encourage drug developers to persist in seeking the most appropriate, sensitive and meaningful measures of the condition, and in designing their trials accordingly. Most of the mechanisms and molecules in development are more targeted than existing immuno-suppressants, so may one day provide relief, with fewer side-effects, even for just a sub-set of patients.