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.